Handbook of Office-based Buprenorphine Treatment of Opioid Dependence

HANDBOOK OF

Office-Based Buprenorphine Treatment OF OPIOID DEPENDENCE

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HANDBOOK OF

Office-Based Buprenorphine Treatment OF OPIOID DEPENDENCE Edited by

John A. Renner Jr., M.D. Petros Levounis, M.D., M.A.

Washington, DC London, England

Note: The authors have worked to ensure that all information in this book is accurate at the time of publication and consistent with general psychiatric and medical standards, and that information concerning drug dosages, schedules, and routes of administration is accurate at the time of publication and consistent with standards set by the U.S. Food and Drug Administration and the general medical community. As medical research and practice continue to advance, however, therapeutic standards may change. Moreover, specific situations may require a specific therapeutic response not included in this book. For these reasons and because human and mechanical errors sometimes occur, we recommend that readers follow the advice of physicians directly involved in their care or the care of a member of their family. Books published by American Psychiatric Publishing, Inc., represent the views and opinions of the individual authors and do not necessarily represent the policies and opinions of APPI or the American Psychiatric Association. Copyright © 2011 American Psychiatric Publishing, Inc. ALL RIGHTS RESERVED Manufactured in the United States of America on acid-free paper 14 13 12 11 10 5 4 3 2 1 First Edition Typeset in Adobe’s ACaslon and Eurostile American Psychiatric Publishing, Inc. 1000 Wilson Boulevard Arlington, VA 22209-3901 www.appi.org Library of Congress Cataloging-in-Publication Data Handbook of office-based buprenorphine treatment of opioid dependence / edited by John A. Renner Jr., Petros Levounis. — 1st ed. p. ; cm. Includes bibliographical references and index. ISBN 978-1-58562-369-3 (pbk. : alk. paper) 1. Opioid abuse—Chemotherapy. 2. Buprenorphine—Therapeutic use. I. Renner, John A., 1938– II. Levounis, Petros. [DNLM: 1. Opioid-Related Disorders—drug therapy. 2. Buprenorphine— therapeutic use. WM 284] RC568.O45H36 2010 615'.7822—dc22 2010026314 British Library Cataloguing in Publication Data A CIP record is available from the British Library.

Contents Contributors . . . . . . . . . . . . . . . . . . ix Dedication . . . . . . . . . . . . . . . . . . . . xiii Foreword . . . . . . . . . . . . . . . . . . . . xv Frank J. Vocci, Ph.D.

Introduction. . . . . . . . . . . . . . . . . . xvii

1

Opioid Dependence in America HISTORY AND OVERVIEW . . . . . . . . . . . . . 1 John A. Renner Jr., M.D.

2

Experience With Buprenorphine in the United States, 2002–2008 . . 27 David A. Fiellin, M.D.

3

General Opioid Pharmacology . . . . . . 45 John T. Pichot, M.D.

4

Efficacy and Safety of Buprenorphine . . . . . . . . . 59 Eric C. Strain, M.D.

5

Patient Assessment . . . . . . . . . . . . 79 Petros Levounis, M.D., M.A.

6

Clinical Use of Buprenorphine . . . . . . 95 Ricardo Restrepo, M.D., M.P.H. Petros Levounis, M.D., M.A. CASE 1 ............................................116

7

Clinical Management I BUPRENORPHINE TREATMENT IN OFFICE-BASED SETTINGS . . . . . . . . . . . . 119 Jeffrey D. Baxter, M.D. CASE 2 ............................................145

8

Clinical Management II PSYCHOSOCIAL AND SUPPORTIVE TREATMENT . . . . . . . . . . . . 147 Peter D. Friedmann, M.D., M.P.H. Patricia A. Cioe, M.S., R.N.P. CASE 3 ............................................161 CASE 4 (CONTINED IN CHAPTER 11) ............161 CASE 5 (CONTINUED IN CHAPTER 9) ............162

9

Psychiatric Comorbidity. . . . . . . . . 165 Elinore F. McCance-Katz, M.D., Ph.D. CASE CASE CASE CASE

10

5 (CONTINUED FROM CHAPTER 8) ........ 187 6 ........................................... 187 7 ........................................... 188 8 ........................................... 188

Medical Management . . . . . . . . . . 191 Jeanette M. Tetrault, M.D. Lynn E. Sullivan, M.D. David A. Fiellin, M.D. CASE 9 ........................................... 207

11

Management of Acute and Chronic Pain . . . . . . . . . 213 Daniel P. Alford, M.D., M.P.H., F.A.C.P. CASE 4 (CONTINUED FROM CHAPTER 8) ........ 223 CASE 10 ......................................... 223

12

Opioid Use by Adolescents . . . . . . . 227 Ximena Sanchez-Samper, M.D. Sharon Levy, M.D., M.P.H. CASE 11 ......................................... 249

13

Logistics of Office-Based Buprenorphine Treatment . . . . . . . 253 Joji Suzuki, M.D.

14

Comments on the Case Vignettes . . 275 John A. Renner Jr., M.D. Gregory Acampora, M.D.

Appendix 1 USEFUL WEB SITES AND RECOMMENDED READINGS . . . . . . . . 285 Appendix 2 STUDY QUESTIONS

AND

ANSWER GUIDE . . . 291

Index . . . . . . . . . . . . . . . . . . . . . . 323

Contributors Gregory Acampora, M.D. Teaching Fellow/Resident, Department of Psychiatry, Boston University School of Medicine, Boston, Massachusetts Daniel P. Alford, M.D., M.P.H., F.A.C.P. Associate Professor of Medicine, Clinical Addiction Research and Education (CARE) Unit, Section of General Internal Medicine, Department of Medicine, Boston Medical Center, Boston University School of Medicine, Boston, Massachusetts Jeffrey D. Baxter, M.D. Assistant Professor, Department of Family Medicine and Community Health, University of Massachusetts Medical School, Worcester, Massachusetts Patricia A. Cioe, M.S., R.N.P. Staff Nurse Practitioner, Division of General Internal Medicine, Rhode Island Hospital, Providence, Rhode Island David A. Fiellin, M.D. Associate Professor, Departments of Internal Medicine and Investigative Medicine, Yale University School of Medicine, New Haven, Connecticut Peter D. Friedmann, M.D., M.P.H. Professor of Medicine and Community Health, Alpert Medical School of Brown University; Director, Center on Systems, Outcomes and Quality in Chronic Disease and Rehabilitation, Providence Veterans Affairs Medical Center; Director, Research Section, Division of General Internal Medicine, Rhode Island Hospital, Providence, Rhode Island Petros Levounis, M.D., M.A. Director, The Addiction Institute of New York; Chief, Division of Addiction Psychiatry, The St. Luke’s and Roosevelt Hospitals; Associate Clinical Professor of Psychiatry, Columbia University College of Physicians and Surgeons, New York, New York

ix

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Handbook of Office-Based Buprenorphine Treatment of Opioid Dependence

Sharon Levy, M.D., M.P.H. Assistant Professor of Pediatrics, Harvard Medical School; Medical Director of the Adolescent Substance Abuse Program, Children’s Hospital, Boston, Massachusetts Elinore F. McCance-Katz, M.D., Ph.D. Professor of Psychiatry, University of California, San Francisco, School of Medicine, San Francisco, California John T. Pichot, M.D. Private Practice, General Psychiatry and Addiction Psychiatry; South Texas Veterans Healthcare System, San Antonio, Texas John A. Renner Jr., M.D. Associate Professor of Psychiatry, Boston University School of Medicine, VA Boston Healthcare System, Boston, Massachusetts Ricardo Restrepo, M.D., M.P.H. Assistant Clinical Professor of Psychiatry, Columbia University College of Physicians and Surgeons; Director, Addiction Psychopharmacology Clinic, The Addiction Institute of New York at St. Luke’s and Roosevelt Hospitals; Attending Psychiatrist, Adult Outpatient Clinic, St. Luke’s and Roosevelt Hospitals, New York, New York Ximena Sanchez-Samper, M.D. Instructor, Harvard Medical School; Addiction Psychiatrist, Adolescent Substance Abuse Program, Children’s Hospital, Boston, Massachusetts Eric C. Strain, M.D. Professor, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland Lynn E. Sullivan, M.D. Assistant Professor of Medicine, Yale University School of Medicine, New Haven, Connecticut Joji Suzuki, M.D. Medical Director of Addictions, Department of Psychiatry, Brigham and Women’s Hospital; Instructor in Psychiatry, Harvard Medical School, Boston, Massachusetts Jeanette M. Tetrault, M.D. Assistant Professor of Medicine, Yale University School of Medicine, New Haven, Connecticut

Disclosures of Interest

xi

Disclosures of Interest The following contributors to this book have indicated a financial interest in or other affiliation with a commercial supporter, a manufacturer of a commercial product, a provider of a commercial service, a nongovernmental organization, and/or a government agency, as listed below: Peter D. Friedmann, M.D., M.P.H. Speakers’ Bureau: Reckitt Benckiser Petros Levounis, M.D., M.A. Speakers’ Bureau: AstraZeneca, Cephalon, Forest Pharmaceuticals, Pfizer, Takeda John A. Renner Jr., M.D. Speakers’ Bureau: Forest Labs (acamprosate); Stock Ownership: Johnson & Johnson Eric C. Strain, M.D. In the past 12 months, I have provided consulting services or received other forms of support (e.g., travel, research) from the following companies: Abbott Laboratories, Reckitt Benckiser Pharmaceuticals, Shire Pharmaceuticals*, The Oak Group*, Titan Pharmaceuticals. *No direct connection with the contents of the chapter. In the past 12 months, I have also received forms of support (e.g., honoraria, research grants) from the following federal agencies or from contract agencies used by these agencies: The Center for Substance Abuse Treatment (CSAT); The National Institute on Drug Abuse (NIDA). The following contributors to this book have indicated no competing interests to disclose during the year preceding manuscript submission: Gregory Acampora, M.D.; Daniel P. Alford, M.D., M.P.H., F.A.C.P.; Jeffrey D. Baxter, M.D.; Patricia A. Cioe, M.S., R.N.P.; Sharon Levy, M.D., M.P.H.; Elinore F. McCance-Katz, M.D., Ph.D.; John T. Pichot, M.D.; Ricardo Restrepo, M.D., M.P.H.; Lynn E. Sullivan, M.D.; Joji Suzuki, M.D.; Jeanette M. Tetrault, M.D.

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Dedication PEOPLE SOMETIMES ASK US, “Why do you do this work?” The assumption is that caring for addicts is frustrating and depressing; these patients don’t get better and are manipulative, ungrateful, or worse. These ideas have always seemed strange and more than a little sad to us—and very foreign to our actual experience as clinicians. The introduction of buprenorphine in the United States coincided with the crystal methamphetamine epidemic in the gay community and the first wave of young veterans returning from conflicts in the Middle East. Our work with buprenorphine has been affected profoundly by these events. Early in the crystal methamphetamine epidemic, I started treating gay men who were addicted not only to crystal meth but also to opioids, alcohol, and nicotine; sometimes sexual compulsions further complicated the clinical picture. As director of the Addiction Institute of New York, I enlisted the support of the city of New York in creating a multifaceted treatment program specifically designed for gay men who struggle with addictive substances and behaviors. The work and collaboration of great colleagues, the use of sublingual buprenorphine, and the techniques of motivational interviewing have been the key ingredients in the project’s enormous success. Gay men from all walks of life—from the famous executive who helplessly saw his empire crumble under his meth use, to the 19-year-old musician who just arrived in New York only to find himself in the midst of prostitution and heroin addiction— now come to a “safe space” to discuss addiction, sexuality, and living as gay men in a primarily homophobic world. Every day I’m inspired by the courage of these men who fight addiction, battle discrimination, and pursue their individual paths to healing and happiness—quite often in the face of nothing less but ostracism by family and society. I am profoundly grateful to my patients who have trusted me to be a partner in their recovery and would like to dedicate this book to them. Petros Levounis, M.D., M.A. xiii

xiv Handbook of Office-Based Buprenorphine Treatment of Opioid Dependence

As part of my work in the addiction program at the VA Boston Healthcare System, I decided to start a buprenorphine therapy group for returning veterans. They easily bonded as combat veterans and as recovering addicts, and buprenorphine very quickly enabled most of them to gain control over their opioid use problem. The core issue for the “BUP Group” became their struggle to regain self-respect and confidence for a meaningful future. How do you square your image as a tough combat veteran—responsible for the survival of your squad— with the conning, lies, and degradation of addicted behavior? What do you do with the terror and guilt that haunts your dreams when you know that opioids will provide instant relief? The BUP Group taught me the meaning of true courage—honestly facing the worse in your past and finding the strength both to forgive yourself and to move forward. For some of these men, recovery has come with little or no support or trust from family, friends, and even other members of 12-step groups. The unique bond within this remarkable group of combat veterans has been a powerful source of understanding, respect, and caring. It has been my good fortune to be a part of the buprenorphine story, to see recovery become possible where before there was little hope and much despair. I have learned that we don’t cure addiction, but we can manage it successfully and that recovery is real. This book is dedicated to all the patients who have used buprenorphine to reclaim their hope and their lives, but most especially to the veterans in my BUP Group. With my love, respect, and admiration, it has been my privilege to share this road with you. John A. Renner Jr., M.D.

Foreword THE NATIONAL INSTITUTE on Drug Abuse (NIDA) had an interest in the development of buprenorphine as a treatment for opioid dependence in the late 1970s. Although a previous licensing agreement with Norwich Eaton Pharmaceuticals prevented Reckitt & Colman (now Reckitt Benckiser) from codeveloping buprenorphine for opioid dependence with NIDA, they provided NIDA with buprenorphine to perform clinical studies in the 1980s. Following clinical pharmacology studies that pointed to the sublingual route as the preferred route of drug delivery, Drs. Ed Johnson, Jerry Jaffe, and Paul Fudala of the NIDA Intramural Research Program performed a clinical trial of buprenorphine that provided the first evidence of its effectiveness for the treatment of opioid dependence (Johnson et al. 1992). I believe this compelling evidence was crucial in Reckitt & Colman’s decision to develop buprenorphine for the treatment of opioid dependence. NIDA negotiated a Cooperative Research and Development Agreement (CRADA) with Charles O’Keeffe, Reckitt & Colman’s U.S. president in 1993–1994. NIDA collaborated with Reckitt & Colman on a liquid dosage form and, subsequently, on the solid dosage forms that are today known as Subutex (buprenorphine) and Suboxone (buprenorphine and naloxone). NIDA’s grantees and contractors performed the pharmacokinetics studies, clinical pharmacology studies (to determine the ratio of buprenorphine to naloxone for the Suboxone formulation), and multicenter clinical trials (with the Department of Veterans Affairs Cooperative Studies Program) that were necessary for the U.S. Food and Drug Administration approval of Subutex and Suboxone, which occurred in October 2002. Successful partnerships require groups of competent, effective people working toward a common goal. Improving the treatment of opioid dependence was the common goal that propelled the CRADA between NIDA and Reckitt Benckiser. Subutex and Suboxone were launched in January 2003. Since that time, thousands of physicians have become registered to prescribe buprenorphine and hundreds of thousands of patients are receiving this medication, alone or in combination with naloxone. By July 2009, the 16,700 physicians who were xv

xvi Handbook of Office-Based Buprenorphine Treatment of Opioid Dependence

registered to prescribe Subutex or Suboxone treated over 1 million people with these medications. This is a testament to the successful partnership between NIDA and Reckitt Benckiser and the adoption by the treatment community of Subutex and Suboxone as first-line products for managing opioid dependence. This book is a continuation of the collaborative spirit that sustained the NIDA–Reckitt Benckiser CRADA. May you use the information contained herein to improve the lives of the patients you treat with Subutex and Suboxone. Frank J. Vocci, Ph.D. President, Friends Research Institute Baltimore, Maryland July 2009

References Johnson RE, Jaffe JH, Fudala P: A controlled trial of buprenorphine treatment for opioid dependence. JAMA 267:2750–2755, 1992

Introduction Background Between 2002 and 2010, a group of American Psychiatric Association (APA) members and staff devoted considerable time and effort to the presentation of more than 100 buprenorphine training courses across the United States. Under the supervision of the former APA Council on Addiction Psychiatry, this was part of a larger training effort that also included the American Academy of Addiction Psychiatry, the American Society of Addiction Medicine, and the American Osteopathic Association of Addiction Medicine. To date, more than 23,000 physicians have completed the training required to quality for the Drug Enforcement Administration (DEA) waiver to prescribe buprenorphine in an office-based setting, and the Council on Addiction Psychiatry (hereafter, “the Council”) made significant progress toward its goal of expanding the number of psychiatrists trained to treat opioid-dependent patients. The bulk of the funding for the buprenorphine training courses was provided by Reckitt Benckiser, the manufacturer of Suboxone (the sublingual buprenorphine-naloxone tablet), in the form of unrestricted educational grants to the various professional societies. In anticipation of the end of its exclusivity rights to the drug, Reckitt Benckiser eliminated the majority of these training grants in 2008. The leadership of the Council recognized that the end of commercial funding presented a major challenge for the APA to develop new options for training physicians. The inspiration for this manual came primarily from Beatrice Eld, Associate Director, APA’s Department of Quality Improvement and Psychiatric Services. She is the APA’s primary staff support for the Council and the individual most responsible for organizing all of the APA buprenorphine courses. Ms. Eld opened discussions about this book with American Psychiatric Publishing and encouraged us to take on this project as a compliment to other APA buprenorphine training activities. We are sincerely grateful for her support and enthusiasm—none of the APA’s success with buprenorphine training would have been possible without her dedication and hard work. xvii

xviii Handbook of Office-Based Buprenorphine Treatment of Opioid Dependence

How to Use This Manual Although it is our intention that this manual will serve as a general resource for anyone interested in the problem of opioid dependence—and in particular the role of buprenorphine in office-based treatment—the core of the manual is designed to mirror the content of the face-to-face buprenorphine training courses. It is intended to cover all of the basic information needed to care for buprenorphine patients. The print format permitted us to provide a depth of information not possible in the face-to-face courses, and particularly to expand on topics such as counseling approaches and the treatment of adolescents, which were rarely included in the original courses. One of the most successful elements of the courses was the small group case discussions. We have therefore included a number of brief case vignettes throughout the manual (in Chapters 6–12). The cases were chosen to illustrate important clinical or administrative issues, and each is followed by a series of questions that will focus the reader’s attention on specific aspects of the cases. We recommend that readers review the cases after reading the relevant chapters and that they then check the case discussions at the end of the manual (Chapter 14, “Comments on the Case Vignettes”) to be sure that they correctly understand the material that has been presented. The chapter authors are all expert clinicians and most of them regularly participated as faculty in buprenorphine training programs. This volume, therefore, draws on a wealth of clinical and educational expertise. We have endeavored to present the information in a manner that is both practical and accessible. Two useful appendixes also are provided for readers: Appendix 1, “Useful Web Sites and Recommended Readings,” provides a listing of resources that clinicians will find valuable in the practice of office-based buprenorphine treatment. In addition, questions are included in Appendix 2, “Study Questions and Answer Guide,” to help readers assess their knowledge of the material presented and to ensure their understanding of the major points in the text.

1 Opioid Dependence in America HISTORY

AND

OVERVIEW

John A. Renner Jr., M.D.

OPIOID ABUSE and dependence have been a serious problem in the United States since before the Civil War. This chapter traces the evolution of this problem from the era of opium-laced patent medicines, through the problems with injectable morphine after the Civil War, to the heroin epidemics of the twentieth century, and finally to the current epidemic of opioid pharmaceutical abuse that began in the 1990s. I emphasize the history of medical efforts to manage opioid dependence and recurrent conflicts with a public policy approach that has emphasized criminal justice solutions to the problem. The introduction of office-based buprenorphine treatment is best understood as an effort to restore a medical treatment model and a more coherent public health approach to what has become an intractable medical, legal, and social problem.

Opioid Dependence 1830–1995 OPIATE ABUSE

IN THE

NINETEENTH CENTURY

In eighteenth-century America, opium extracts such as laudanum, which contained alcohol, and black drop opium, which contained no alcohol, were common 1

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Handbook of Office-Based Buprenorphine Treatment of Opioid Dependence

ingredients in a wide range of prescriptions and patent medicines. These medications were used to treat food poisoning and other gastrointestinal problems, and were valued for their sedating and calming effects. The first apparent opioid problem in the United States occurred in the early nineteenth century when patent medicines laced with tincture of opium were readily available from apothecaries or door-to-door peddlers. Because the drugs were cheap, individuals with mild states of dependence had no problem maintaining medication supplies and had relatively little functional disability. The typical abuser at that time was a white, middle-class farm housewife who became addicted while self-medicating a wide range of physical and psychological ailments. Although some individuals were more impaired by their dependency, there was no association with criminal behavior. At worse, the addict was perceived as “sickly” or neurasthenic (Musto 1999). Physicians and the public associated the risks for dependence with the lower social classes. The risks for dependence were noted, but they were thought to be minimal and to be balanced by the medicinal benefits of opium. Some physicians even claimed that opiates could improve the functioning of strong-willed individuals (Wood 1868). Advances in technology in the early nineteenth century permitted the isolation of specific alkaloids from crude opium and led to the identification of morphine as a potent agent with significant physiological and psychological effects. Commercial morphine production began in the United States in 1832. The invention of the hypodermic syringe permitted the direct injection of this powerful and habit-forming substance and opened the door to both more effective pain treatment and increased risks for opioid dependence. A second and more visible group of nineteenth-century addicts were Civil War veterans who became addicted to intramuscular morphine after being treated for combat injuries. By 1870, some physicians began to recognize the habit-forming risk of morphine injections, though they were thought to present less of a dependence risk than oral opium preparations (Allbutt 1870). In the decades following the Civil War, it became common medical practice for physicians to give patients morphine as long-term therapy to manage chronic pain. This morphine dependence syndrome was called soldier’s disease, a reflection of both the origin of the disorder, the relatively acceptable social status of the patient, and the medical paradigm that guided society’s understanding of the condition. During the late nineteenth century, rates of morphine dependence in the United States far exceeded those of other Western industrialized nations. Although this was commonly attributed to the aftermath of Civil War injuries, other major European nations also experienced wars and extensive use of morphine without having comparable rates of dependence (Musto 1999). The reasons for the high levels of U.S. opium consumption and the unique vulnerability to opioid dependence in this country have never been adequately explained. In the United States, social attitudes regarding the long-term use of opiates began to shift with the increased immigration of Chinese laborers and growing

Opioid Dependence in America

3

public concern about the devastating effect that opium abuse had on China. This, along with the growth of the Temperance Movement, led to a fear of opium addiction as a dangerous, foreign, “un-American” problem that needed to be eradicated. These attitudes led to a decline in the per capita consumption of crude opium, as was first noted in 1887. (The misperception of opioid abuse as un-American remains a common attitude, despite data that suggest that compared with other advanced European nations, U.S. citizens have an unusual propensity to abuse opioids.) By the end of the nineteenth century, the conceptual paradigm for opioid dependence had shifted from a medical model to a moral and criminal justice model—a conceptual ambiguity that continued throughout the twentieth century. Although the medical value of the drug was not questioned, physicians gradually came to recognize the dangers associated with the overprescription of morphine. There was a perception that the risks of addiction were most prevalent in immigrant groups such as the Chinese and in the lower social classes. Unlike with alcohol, there was no evidence that opiates destroyed body tissues. Therefore, it was presumed that the social deterioration associated with chronic opiate use was a reflection of the user’s weak character and lack of morals. Very gradual dose reduction, or detoxification, was thought to be the cure, though it was recognized that successful treatment requires a high level of motivation. In Germany, there were reports of high relapse rates following attempts to wean patients from morphine, and it was hypothesized that regular use of morphine would induce predictable physiological changes that would make anyone an addict (Levinstein 1878). These observations contrasted with the dominant opinion in England and in the United States, and supported the notion that the moral deterioration associated with addiction was a consequence of the disorder and not the cause. By 1900, there were an estimated 250,000 opiate addicts in the United States. In many cities, efforts to manage the problem shifted from the individual physician’s office to a system of morphine clinics, where groups of addicts were given daily morphine injections. In some cities these clinics were administered by law enforcement authorities, a further reflection of the confusion between the medical and criminal justice paradigms. Opiate dependence, along with alcoholism and syphilis, were lumped together as vices, social afflictions that were difficult to cure, that predominantly impacted the lower classes, and that led to eventual physical, moral, and social deterioration. With the gradual development of modern treatments for many common medical conditions, the value of opiates as all-purpose medications for a wide range of physical and psychological conditions became identified with a form of backward and unscientific medical practice. This shift in practice made it much easier to support the need to closely regulate this aspect of medicine. Beyond modest tariffs, no restrictions on the importation of opium and opium products existed during the nineteenth century. The unregulated use of

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inexpensive patent medicines, often with opiates or cocaine as their primary active ingredient, reached a peak in the late nineteenth century. Attempts by individual states to regulate the sale of opiate products were largely ineffective, although some states and cities began to require that morphine could only be ordered with a physician’s prescription. There was no requirement for accurate labels on patent medicines involved in interstate commerce until the passage of the Pure Food and Drug Act in 1906. In 1909, the importation of smoking opium was prohibited. None of these measures was successful in eliminating the opiate abuse problem.

THE HARRISON ACT AND THE PROHIBITION OF ADDICTION TREATMENT The control of opioid medications changed dramatically in 1914 with the passage of the Harrison Narcotics Tax Act, which established the U.S. Food and Drug Administration (FDA) and a federal system for the regulation of drug manufacturers, pharmacies, and physician prescribing. The Harrison Act made it illegal to prescribe opioids for the maintenance or treatment of addiction. This led to the closing of the existing 44 morphine maintenance clinics, and ultimately the jailing of more than 3,000 physicians who refused to stop prescribing opioids for their patients. After the Supreme Court upheld the Harrison Act in 1919, organized medicine abandoned all support for the treatment of addicts, and management of the opioid addiction problem was conclusively shifted to the criminal justice system. Ultimately, the criminal justice model proved ineffective as a strategy for handling the opioid addiction problem. In the late nineteenth century, a process had been discovered for converting morphine into heroin (diacetylmorphine). The commercial availability of heroin in 1898 introduced a new, potent, and highly reinforcing opioid that insured the perpetuation of the opioid dependence problem. Regulation of patent medicine production and the elimination of any legitimate medical treatment for opioid addiction ushered in the era of the heroin black market. Despite efforts to eliminate the problem, there were major heroin epidemics in the United States following World War I, World War II, and the Vietnam War. Chronic heroin users were stigmatized as a deviant and criminal minority. For most of the twentieth century, the lifetime risk for heroin dependence was assumed to be relatively low and to range from 0.4% to 0.7% (Compton et al. 2007; Grant 1996; Kessler et al. 1994; Regier et al. 1990). At any one time, there were an estimated 1,000,000 active heroin addicts in the United States. The typical addict in this era was a white, urban, working class male; the largest and most visible segment of the addicted population was localized in New York City.

Opioid Dependence in America

5

In the 1960s Vincent Dole, an internist at The Rockefeller Institute (now The Rockefeller University), was approached by New York law enforcement authorities and was asked to explore a medical approach for managing opioid addiction. In 1965, Dole and his wife Marie Nyswander published their landmark paper on the efficacy of methadone maintenance (Dole and Nyswander 1965). The legalization of methadone maintenance treatment occurred in 1972 when the FDA issued the initial federal methadone regulations (37 Federal Register 26790–26807, Vol. 37, No. 242, December 15, 1972), which reversed elements of the Harrison Act. While this change reflected the failure of the prohibitionist criminal justice model, the FDA regulations established a heavily regulated methadone clinic system that typically operated outside of mainstream medical practice. Dole and Nyswander stressed the importance of adequate methadone doses to block the euphoria caused by heroin; the need for long-term, if not indefinite, maintenance treatment; and the importance of counseling and other ancillary psychosocial services. Over the next 30 years, there were rarely more than 100,000 addicts in methadone maintenance treatment at any one time, generally less than 10% of the population in need of treatment. Despite evidence of its efficacy (Ball and Ross 1991), methadone maintenance treatment was never welcomed by the majority of addicts or by most communities. There is little evidence of efficacy for most of the other treatments available for opioid dependence. Short-term detoxification, even when followed by outpatient counseling, is generally associated with a 95% relapse rate. Although the therapeutic community movement attracted some measure of public support, therapeutic community programs have never been particularly effective in retaining participants. Rarely do more than 10% of voluntarily admitted patients complete treatment. However, among those individuals who complete a 9- to 18-month therapeutic community program, about 80% achieve longterm recovery (Hubbard et al. 1997). Today most of these programs primarily work with court-referred individuals, though retention in treatment still remains a problem. The most comprehensive review of the long-term course of opioid dependence is the work of Hser et al. (2001), who conducted a 33-year follow-up of 581 male heroin addicts treated in the California Civil Addict Program from 1962 to 1964 (Figure 1–1). By 1996–1997, at the time of the 33-year followup, 284 individuals (48% of the original sample) had died. Among the 242 surviving subjects who were interviewed, 40.5% had used heroin within the past year, 20.7% tested positive for heroin, 9.5% refused to be tested, and 4% were incarcerated. Also, 22.1% were daily alcohol drinkers and many others reported other illicit drug use (35.5%, marijuana; 19.4%, cocaine; 10.3%, crack; and 11.6%, amphetamines). Only 22% were abstinent and another 6% were in methadone maintenance treatment. Overall this study demonstrates the lethal-

6

Handbook of Office-Based Buprenorphine Treatment of Opioid Dependence

ity of heroin addiction; the relatively low rate of recovery, even with enforced treatment; and the long-term stable pattern of heroin use for the majority of addicts. Heroin addiction was demonstrated to be a chronic lifetime disorder with severe health and social consequences (Hser et al. 2001).

HEROIN ABUSE IN THE POST–WORLD WAR II/VIETNAM ERA From World War II to the early 1990s, heroin abuse was the predominant opioid problem in the United States. Annual estimates of drug use have been available from the Monitoring the Future survey since 1975 and the National Survey on Drug Use and Health (NSDUH; formerly called the National Household Survey on Drug Abuse) since the early 1990s, but information on drug use disorders has rarely been collected. Data from the 2006 NSDUH indicate that the annual number of new users of heroin ranged from 28,000 to 80,000 between 1984 and 1994. This increased to an average of 100,000 from 1995 to 2001, but then declined slightly to 91,000 in 2006 (Substance Abuse and Mental Health Services Administration 2007). As a percentage of the total U.S. population, the annual number of new heroin users was relatively unchanged from 1965. NSDUH 2006 data estimated that 3.79 million Americans had used heroin at least once in their lifetime; 323,000, or less than 10% of that group, were classified with either heroin abuse or dependence (Substance Abuse and Mental Health Services Administration 2007).

Prevalence of Substance Use Disorders The 2006 NSDUH data are consistent with earlier studies that estimated that 10%–15% of individuals who use licit or illicit opioids are at risk for developing dependence or abuse. The risk is presumed to be significantly higher in individuals with co-occurring psychiatric disorders, particularly depressive disorder). The most recent major national survey on substance use disorders, the 2001–2002 National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), collected specific data on the use and abuse of both illicit drugs and prescribed medications. This was the first national survey that separated data on opioids from data on other drugs of abuse, and the first to separate data on heroin from data on the abuse of prescription pain relievers. NESARC data indicated that prevalence rates of 12-month and lifetime drug dependence were 0.6% and 2.6%, respectively; the corresponding rates for drug abuse were 1.4% and 7.7%. Higher rates of abuse and dependence were re-

Abstinence

90

Methadone maintenance

80

Sample, %

70

Occasional use

22% 2% 6% 7% 4%

60 Daily narcotic use

50

Opioid Dependence in America

100

40 30

48%

Incarcerated Deceased

20 10 Unknown

12%

0 ‘56 ‘58 ‘60 ‘62 ‘64 ‘66 ‘68 ‘70 ‘72 ‘74 ‘76 ‘78 ‘80 ‘82 ‘84 ‘86 ‘88 ‘90 ‘92 ‘94 ‘96

1956 through 1996

FIGURE 1–1. The natural history of narcotics addiction among a male sample (N=581) [follow-up of the California Civil

7

Addict Program]. Source. Reprinted from Hser YI, Hoffman V, Grella CE, et al: “A 33-year follow-up of narcotic addicts.” Archives of General Psychiatry 58:503–508, 2001. Copyright © 2001 American Medical Association. All rights reserved.

8

Handbook of Office-Based Buprenorphine Treatment of Opioid Dependence

ported in men versus women, and in American Indians versus whites. The mean age of onset for opioid dependence or abuse was 22.8 years. Data for the nonmedical use of prescription opioids indicated a 4.7% lifetime prevalence of use, compared with a lifetime prevalence of 1.4% for nonmedical opioid drug use disorders. These findings suggest that there is at least a 30% risk for developing a drug use disorder among users of prescription pain relievers, which is between two and three times the risk reported for the development of drug use disorders among users of heroin. The most recent national survey, NSDUH 2008, reported that 1.7 million individuals age 12 or older met criteria for dependence or abuse of pain relievers in the past year; this number has been stable for the last 4 years (Substance Abuse and Mental Health Services Administration 2009b). Despite the growing number of individuals with opioid use disorders, fewer than one-third of individuals in this group have ever received treatment. NESARC data showed a lag of 3.4 years between the mean age of onset of an opioid use disorder (22.8 years) and the mean age of first treatment (26.2 years) (Compton et al. 2007).

The New Epidemic of Abuse of Pain Relievers For most of the twentieth century, the illicit use of pain relievers was assumed to be a relatively small part of the U.S. drug problem. Physicians thought that there was minimal risk for dependence among individuals treated for acute or chronic pain. The introduction of pentazocine (Talwin) in the 1960s was associated with a brief period of abuse after addicts discovered that they could induce a potent sense of euphoria by injecting a combination of Talwin and amphetamines (“Ts and blues”). This problem was resolved after the FDA ordered a reformulation of the drug as a combination tablet of Talwin and naloxone (Talwin Nx). The abuse of opioid pharmaceuticals remained at a low level until more potent pain medications were introduced to the U.S. market in the 1990s. From 1970 to 1995, the annual number of new nonmedical users of pain relievers was reported to range from 700,000 to 1,000,000 (Substance Abuse and Mental Health Services Administration 2005a). As the medical community became comfortable with the use of these new opioid pharmaceuticals for the treatment of severe pain, there was interest in the development of more potent medications with low abuse potential and with a longer duration of action that would permit pain patients to sleep through the night. Although oxycodone showed promise because of its potency, the sustained-release technology that had been successful in the development of a long-acting formulation of morphine, morphine sulfate (MS Contin), could

Opioid Dependence in America

9

not be successfully adapted for oxycodone. In 1996, Purdue Pharma resolved this problem with the introduction of OxyContin, an acrylic-coated formulation of oxycodone that dissolves slowly and provides 12 hours of pain relief. Doses ranging from 10 mg to 160 mg can be delivered with this formulation, far exceeding the 30-mg maximum dose of oxycodone tablets. Neither the FDA nor Purdue anticipated a significant abuse problem with such a slowrelease formulation, and Purdue was permitted to market OxyContin as a firstline medication for the treatment of nonmalignant pain with less abuse potential than other comparable pain relievers. The drug proved highly successful and rapidly gained a significant share of the U.S. market for pain medications (Meier 2003). Within 2–3 years of the introduction of OxyContin, physicians in rural Maine and Virginia reported that young adults were crushing the tablets and injecting or snorting the drug. With these methods of ingestion, users were exposed to very high doses of oxycodone. The experience was extremely euphoric and reinforcing, and many of the users rapidly became addicted. Correspondingly, the number of opioid overdose deaths reported nationally began to increase dramatically. It gradually became apparent that the reports of addictive behavior and the growing number of overdose deaths did not just involve individuals using the drug illicitly. Physicians began to report that patients being treated for legitimate pain problems were becoming addicted to OxyContin and that some of them were finding it impossible to stop using the drug (Meier 2003). Over the next few years, NSDUH data showed a dramatic increase in the number of nonmedical abusers of opioid pharmaceuticals. Physicians eventually realized that very little data existed to support the notion that there is a minimal risk for iatrogenic addiction when opioids are used to treat chronic pain. Most of the published reports describing a low risk for iatrogenic addiction dealt only with the treatment of acute pain. There was no credible published research on the risks for addiction with newer, long-acting, and high-potency drugs such as OxyContin, when prescribed for either acute or chronic pain. By 2000, the number of new abusers of pain relievers tripled to 2,500,000 (Figure 1–2) (Substance Abuse and Mental Health Services Administration 2003). While this change corresponded with the introduction of OxyContin to the U.S. market, it also reflected the widespread illicit use of drugs such as Vicodin (hydrocodone-acetaminophen) and Percocet (oxycodone-acetaminophen). Since that time there has been a significant shift from the abuse of heroin to the abuse of opioid pharmaceuticals as the dominant opioid abuse problem in the United States. In 2007, 5.2 million Americans—2.1% of individuals age 12 or older—reported using prescription pain relievers nonmedically in the past month. This rate did not differ significantly from the rate in 2002. However, the rate among males in this group increased from 2.0% to 2.6% during the same period. In 2007, there were 2,147,000 new initiates to

10

Pain relievers

New users (thousands)

2,500 2,000 1,500

Tranquilizers 1,000 Stimulants 500 Sedatives 0 1965

FIGURE 1–2. Source.

1970

1975

1980

1985

1990

1995

2000

Annual numbers of new nonmedical users of psychotherapeutics: 1965–2001. Substance Abuse and Mental Health Services Administration 2003.

Handbook of Office-Based Buprenorphine Treatment of Opioid Dependence

3,000

Opioid Dependence in America

11

the abuse of pain relievers, surpassing even marijuana as the most common drug of abuse; in comparison, there were only 106,000 new users of heroin in 2007 (Figure 1–3) (Substance Abuse and Mental Health Services Administration 2008, 2009a). These numbers were comparable in 2008, when the NSDUH reported 2.176 million new initiates to the abuse of pain relievers compared with 2.2 million new initiates to marijuana use (Substance Abuse and Mental Health Services Administration 2009b). Of note is the decline in new initiates of OxyContin abuse from 615,000 in 2004 to 478,000 in 2008 (Substance Abuse and Mental Health Services Administration 2009b). The mean age for first use among new initiates to the abuse of pain relievers in 2007 was 21.2 years (Substance Abuse and Mental Health Services Administration 2008). This new group of drug abusers tends to be younger, better educated, and less antisocial than the typical heroin addict (Table 1–1). They initially use the drug orally or snort it, and are much less likely to use drugs intravenously. They are also more likely to have psychiatric problems such as depression or anxiety.

Buprenorphine and the Return to Office-Based Treatment More than 55.7% of people age 12 or older who abuse pain relievers are given their drugs for free by friends or relatives and another 14.8% buy or take the drugs from friends or relatives, whereas fewer than 4% purchase their drugs from a dealer or stranger (Figure 1–4) (Substance Abuse and Mental Health Services Administration 2007). Another 19.1% report they got the drug from just one physician. Although many in this group are able to control their use and remain occasional social users, a significant number become dependent. It has been estimated that 10%–30% of individuals exposed to licit and illicit opioids may develop symptoms of dependence or abuse. Rates may be significantly higher in individuals with a family history of drug or alcohol dependence, or in individuals with co-occurring psychiatric disorders, particularly individuals with attention-deficit/hyperactivity disorder or those exposed to combat trauma or sexual abuse. As users’ habits progress, they start purchasing drugs from illicit sources and often switch to heroin once they recognize that it is less expensive than pain relievers. At this point, some users, though not all, also switch from snorting to injecting heroin or other opioids. This transition is often associated with a rapid deterioration in social functioning and an increase in antisocial behavior. Although the total number of Americans with substance dependence or abuse has remained stable, ranging from 22.0 million in 2002 to 22.2 million

12

Past-year initiates (thousands)

2,147

2,090

2,000

1,500 1,232

1,000

906 781

775 642

500 270

198 106

58

0 Marijuana Cocaine Inhalants LSD Heroin Pain relievers Tranquilizers Ecstasy Stimulants Sedatives

FIGURE 1–3.

Past-year initiates for specific illicit drugs among persons age 12 or older: 2007. LSD=lysergic acid diethylamide; PCP=phencyclidine. Source. Substance Abuse and Mental Health Services Administration 2008.

PCP

Handbook of Office-Based Buprenorphine Treatment of Opioid Dependence

2,500

Opioid Dependence in America

TABLE 1–1.

13

Comparison of heroin users with abusers of pain relievers

Characteristics

Pre-1995

Post-1995

Drug of choice

Heroin

Prescription pain relievers

Age

Older

Younger

Drug source

Dealer

Free from friends

Use pattern

Intravenous

Oral/snorting

Medical problems

Hepatitis C; HIV infection

None or pain issues

Legal problems

Common

Rare

Education

High school dropouts

Some college

in 2008, there has been an increase in the number of individuals abusing pain relievers, which now rank second to marijuana among significant illicit drugs of abuse in the United States. The current prevalence of nonmedical opioid use disorders is almost three times the level of prior estimates of heroin use disorders. Among young adults ages 18–25, the rate for current illicit use of prescription pain relievers increased from 4.1% in 2002 to 4.6% in 2007; among adults age 26 and older, the rate increased from 1.3% in 2002 to 1.6% in 2007 (Substance Abuse and Mental Health Services Administration 2009a). The incidence of past-year abuse of or dependence on pain relievers among persons 12 years old or older was stable at 1.7 million in both 2007 and 2008 (Substance Abuse and Mental Health Services Administration 2009b), although this is more than eight times the incidence of abuse or dependence involving heroin (Substance Abuse and Mental Health Services Administration 2008). NSDUH data estimated that 23.2 million persons age 12 or older needed treatment for an illicit drug or alcohol problem in 2007, of whom only 2.4 million received treatment at a specialty substance abuse treatment facility. Among the individuals in this group, 558,000 sought treatment for problems related to the abuse of pain relievers compared with 335,000 who sought treatment for heroin-related problems. More than 20.8 million individuals needed, but did not receive, substance abuse treatment. Among those who sought treatment, more than 30% were unable to access care because of lack of health insurance coverage or financial resources and another 15% either could not find treatment or lacked transportation (Substance Abuse and Mental Health Services Administration 2008). The increase in addiction to pain relievers has also fueled a secondary increase in heroin dependence. From 1984 to 1994 the number of new heroin us-

14

Drug dealer/ stranger More than 3.9% one doctor 1.6% One doctor 19.1%

Bought on Internet 0.1%

Other a 4.9%

Source where friend/relative obtained

Free from friend/relative 55.7% One doctor 80.7%

Bought/took from friend/relative 14.8% Just one doctor 80.7%

FIGURE 1–4.

More than one doctor 3.3% Free from friend/relative 7.3% Bought/took from friend/relative 4.9%

Othera 2.2%

Drug dealer/ stranger 1.6%

Where pain relievers were obtained for most recent nonmedical use among past-year users age 12 or older: 2006. Totals may not sum to 100% because of rounding or because suppressed estimates are not shown. aThe Other category includes these sources: “Wrote fake prescription,” “Stole from doctor’s office/clinic/hospital/pharmacy,” and “Some other way.” Source. Substance Abuse and Mental Health Services Administration 2007.

Handbook of Office-Based Buprenorphine Treatment of Opioid Dependence

Source where respondent obtained

Opioid Dependence in America

15

ers each year ranged from 28,000 to 80,000. The number averaged over 100,000 per year from 1995 to 2001, but dropped to 94,000 in 2007. In 2006, NSDUH data estimated that 3.79 million Americans had used heroin at least once in their lifetime; of that group 323,000 were classified with either heroin dependence or abuse, and 250,000 were estimated to be in methadone maintenance treatment (Substance Abuse and Mental Health Services Administration 2007). Concerns about the legal and clinical constraints mandated for methadone maintenance treatment and its relatively low level of appeal to most heroin addicts led to a search for a safer yet clinically effective alternative treatment. This problem became even more acute in the mid-1990s when the rapid increase in the number of individuals abusing opioid pharmaceuticals far outstripped the capacity of the addiction treatment system. Buprenorphine was identified as a target medication to develop for treating opioid dependence after early studies suggested clinical efficacy, a strong safety profile, and less abuse potential than methadone (see Chapter 4, “Efficacy and Safety of Buprenorphine”). Its very favorable safety profile suggested that buprenorphine could be prescribed safely in office-based clinical settings, thus avoiding the legal constraints of the methadone clinic system that were felt to discourage addicts from participating in treatment. Indeed, heroin addicts typically delay participation in methadone maintenance treatment for 4–5 years beyond the point when treatment is warranted. This delay typically translates into more severe social, behavioral, and medical deterioration, thus guaranteeing a more treatment-resistant and complicated condition. Before 2002, only methadone and LAAM (L-α-acetylmethadol) were approved as opioid agonist treatments and both medications could only be dispensed in heavily regulated opioid treatment programs (OTPs). When buprenorphine was approved by the FDA in 2002 for the treatment of opioid dependence in office-based settings, it was estimated that fewer than 1 in 10 heroin addicts were receiving any type of effective treatment. Detoxification treatment was still the most common form of treatment provided, despite little evidence of efficacy. Because of buprenorphine’s wider availability in less stigmatized, office-based settings, it was hoped that this new treatment option would both fill the gap in treatment resources and lead to earlier participation in treatment. The primary goal was to expand treatment options by returning opioid addiction treatment to mainstream medical practice and to train a much larger group of physicians to effectively care for these patients. It was hoped that better-educated physicians would encourage patients to shift to more effective long-term treatment models and to avoid repeated episodes of shortterm detoxification.

16

Handbook of Office-Based Buprenorphine Treatment of Opioid Dependence

Drug Addiction Treatment Act of 2000 Implementing this change required an amendment to the federal Controlled Substances Act, the Drug Addiction Treatment Act of 2000 (P.L. 106-310; DATA 2000). This law authorized practitioners to prescribe FDA-approved narcotic drugs in Schedules III, IV, and V, or combinations of such drugs, for maintenance or detoxification treatment of opioid dependence. The law placed no limit on the quantities of drugs that could be prescribed for unsupervised use, unless the drugs have been subject to an adverse determination. In essence, this meant that physicians could prescribe up to a month’s supply of medication, with refills, as deemed appropriate. DATA 2000 specified that the drugs utilized and the prescribing physicians (practitioners) must meet certain requirements. Practitioners had to be deemed qualifying physicians, which was defined as having the capacity to refer patients for appropriate counseling and ancillary services. There was no legal requirement that the physician personally provide drug counseling or other ancillary services. The intent of the law was to require that the physician provide the more traditional and relatively limited medical role of monitoring medication use. It was hoped that this would encourage physicians who were not specialists in addiction psychiatry or addiction medicine to expand their practice to include the management of opioid agonist treatment.

QUALIFYING PHYSICIANS Qualifying physicians were initially limited to no more than 30 patients at one time for an individual practice or a group practice. The 30-patient limit was intended to avoid the development of large buprenorphine practices, similar to the “methadone mills” seen in the 1970s, and to thus ensure more individualized and appropriate care for all buprenorphine patients. It was quickly realized that limiting group practices (which in many cases meant very large health care systems) to 30 patients was unrealistic and defeated the purpose of expanding access to addiction treatment. In 2006, DATA 2000 was amended to eliminate the 30-patient limit for group practices and to permit individual physicians to request approval to expand their practice to 100 patients after 1 year’s experience using buprenorphine. DATA 2000 defined seven possible routes through which a licensed physician could be recognized as qualifying under the requirements of the legislation: 1. Being board-certified in addiction psychiatry by the American Board of Psychiatry and Neurology

Opioid Dependence in America

17

2. Being certified in addiction medicine by the American Society of Addiction Medicine (ASAM) 3. Being certified in addiction medicine by the American Osteopathic Association (AOA) 4. Experience as an investigator in buprenorphine clinical trials 5. Having completed 8 hours of training provided by the American Psychiatric Association, the American Academy of Addiction Psychiatry, ASAM, the American Medical Association, AOA, or other organizations that may be designated by the secretary of the U.S. Department of Health and Human Services (DHHS) 6. Training or experience as determined by a state medical licensing board 7. Other criteria as established by the secretary of DHHS. To date, DHHS has not designated any other organization to provide training, and the American Medical Association has chosen not to offer buprenorphine addiction treatment training courses. No state medical licensing board has designated other specific training or experience as required for prescribing buprenorphine, nor has the secretary of DHHS established any other criteria. To obtain the waiver necessary to prescribe buprenorphine, a physician must notify the secretary of DHHS in writing by mail, by fax, or online at www.buprenorphine.samhsa.gov, giving his or her name and U.S. Drug Enforcement Administration (DEA) registration number, identifying the category under which he or she meets the criteria to become a qualifying physician (of the seven listed above), and certifying that that he or she will comply with the requirements of the law. The Substance Abuse and Mental Health Services Administration (SAMHSA) has developed a Waiver Notification Form (SMA-167), which is available online (www.buprenorphine.samhsa.gov/ howto.html) and which can be used to submit the required information. DHHS has 45 days to review the physician’s application to determine whether the physician meets the requirements of DATA 2000. Once a positive determination is made, DHHS notifies DEA, which then assigns a new DEA identification number to the practitioner. This number comprises the physician’s original DEA number, but the first letter is substituted with an X. DEA is also required to issue this X number if DHHS has not completed its review within the 45-day period. Once the practitioner has received his or her X number, the practitioner may begin to prescribe buprenorphine for the treatment of opioid dependence. Whenever physicians write a prescription under the requirements of DATA 2000, they must list both their primary DEA number and their X number on the prescription. Should a physician decide to prescribe sublingual buprenorphine for an unapproved indication—for a condition other than opioid dependence, such as for pain—he or she should not use the X number. Despite the fact that the X number is to be used only when prescribing bu-

18

Handbook of Office-Based Buprenorphine Treatment of Opioid Dependence

prenorphine for the treatment of opioid dependence, it is important that practitioners recognize that any violation of federal or state prescribing regulations or narcotics laws puts both their X number and their primary DEA number at risk. The most common circumstance that has led to revocation of DEA registration is violation of the 30-patient or 100-patient limit.

PHYSICIAN LOCATOR The Waiver Notification Form also asks whether the applicant wants to be listed as a provider of buprenorphine treatment on the physician locator page of SAMHSA’s Web site (http://buprenorphine.samhsa.gov/bwns_locator). If the physician indicates his or her willingness to be listed, the physician’s name, address, and telephone number are posted on the Web site. Because prospective patients use this information to contact the physician, it is important that office contact information and not home numbers be provided. Physicians can choose to be listed on the physician locator page at any time and can also request that their information be removed at any time.

FDA APPROVAL

OF

BUPRENORPHINE

The second principal element of DATA 2000 is the specification that the authorization to treat opioid dependence in an office-based setting only applies to narcotic drugs that have been approved by the FDA for the maintenance or detoxification treatment of opioid dependence. The law applies to drugs, or combinations of drugs, in Schedules III, IV, or V. Sublingual buprenorphine and the combination sublingual formulation of buprenorphine-naloxone are the only drugs currently approved by the FDA for this purpose under DATA 2000. When the FDA approved these two sublingual formulations of buprenorphine, all of the available formulations of buprenorphine were rescheduled to Schedule III. Previously, the only FDA-approved formulations of buprenorphine were the intramuscular and intravenous formulations, marketed as Buprenex. Those formulations are only approved for the treatment of pain and were previously in Schedule V. Before the approval of sublingual buprenorphine, many hospitals had been using Buprenex outside of its approved labeling, for the inpatient detoxification of opioid dependence. It is important to understand that DEA considers such off-label use of Buprenex to be illegal and that practitioners risk sanctions if they continue this practice. There are no restrictions or special authorizations required for the use of sublingual buprenorphine in an inpatient setting for opioid detoxification, because in that setting the drug is dispensed and not prescribed. The buprenorphine waiver and X number are only required for the prescription of buprenorphine in the outpatient setting.

Opioid Dependence in America

19

DATA 2000 also permits the dispensing of sublingual buprenorphine in OTPs with a methadone program registration. There is no limit on the number of buprenorphine patients that can be treated in the OTP setting. However, the same regulations that apply to the dispensing of methadone also apply to the dispensing of buprenorphine in this setting. For the first 90 days, patients must be seen 6 days a week and are permitted only one take-home dose per week. After 90 days, if they have demonstrated good treatment compliance and there is no evidence of continued illicit drug use as demonstrated by urine toxicology, take-home medication may be increased to 2 days per week. Following standard OTP regulations, it would take a minimum of 2 years of proven treatment success before a patient would achieve monthly take-home medication privileges. These limitations on take-home privileges have significantly limited the use of buprenorphine in OTPs. In June 2009, the secretary of DHHS proposed a modification of OTP regulations to remove the restrictions on take-home use for buprenorphine dispensed in the OTP setting (74 Federal Register 29153– 29158, 42 CFR Part 8.12[i]). If implemented, this change will likely expand the use of buprenorphine in OTPs. In addition to providing closer supervision and monitoring than office-based treatment, the OTP setting also has the advantage of providing a higher level of on-site ancillary services. OTPs are a more appropriate setting for the treatment of complicated patients who require close monitoring and high levels of counseling and other services. OTPs are particularly appropriate for patients at high risk for diversion or for unstable individuals who are not at the stage where they can successfully comply with the requirements of office-based treatment. SAMHSA was mandated by DATA 2000 to publish a Treatment Improvement Protocol (TIP) that provides clinical guidance for the use of buprenorphine. This is TIP 40, “Clinical Guidelines for the Use of Buprenorphine in the Treatment of Opioid Addiction,” which was published in 2004. The TIP Series has been an invaluable resource for clinicians treating patients with alcohol- and drug-related problems. Of particular interest are TIP 42, “Substance Abuse Treatment for Persons With Co-Occurring Disorders,” and TIP 43, “Medication-Assisted Treatment for Opioid Addiction in Opioid Treatment Programs.” All of the TIPs are available free of charge from SAMHSA and can be ordered from their Web site, www.kap.samhsa.gov/products/manuals/tips/ index.htm. Other useful sources of information and support are the Federation of State Medical Boards Web site, www.fsmb.org/pdf/2002_grpol_opioid_ addiction_treatment.pdf, and the National Alliance of Advocates for Buprenorphine Treatment, www.naabt.org. A particularly useful free mentoring system is the Physician Clinical Support System (PCSS), www.pcssmentor.org (see also Chapter 2, “Experience With Buprenorphine in the United States, 2002–2008”). PCSS is administered by ASAM under a contract from SAMHSA’s Center for Substance

20

Handbook of Office-Based Buprenorphine Treatment of Opioid Dependence

Abuse Treatment and in cooperation with the other DATA-approved training organizations (the American Psychiatric Association, the American Academy of Addiction Psychiatry, and AOA). Any physician with the buprenorphine waiver is eligible to join PCSS. He or she is then assigned to a buprenorphine expert clinician in the physician’s area, who acts as an ongoing mentor and supervisor. Mentors are readily available by telephone and e-mail and are also willing to have their mentees visit their offices for direct observation of patient care. PCSS has proved to be a particularly valuable resource for clinicians with little prior experience treating opioid- and heroin-dependent patients.

Evaluation of DATA 2000 DATA 2000 required that there be an evaluation of the results of this legislation during the first 3 years following FDA approval of buprenorphine. DHHS was mandated to assess the clinical efficacy of the drug, including whether the treatment has been effective in the office setting, whether access to treatment has improved, and whether there have been any adverse consequences for the public health. DEA was mandated to evaluate safety issues, including the extent of violations of the 30-patient limit, physician recordkeeping and security measures related to on-site drug storage, data related to emergency room drug mentions, and the risks of overdose (Substance Abuse and Mental Health Services Administration 2006b). In compliance with this mandate, DEA inspected two buprenorphine practitioners in each DEA district every 18 months. On the basis of these evaluation results, DHHS and DEA could decide whether the provisions of DATA 2000 should remain in effect. The law would cease to be in effect 60 days after an adverse evaluation was published; thus, additional legislative action was not required to repeal the law. Should difficulties such as significant misuse or drug diversion become a major problem, it would be relatively easy for these government agencies to terminate office-based treatment for opioid dependence with buprenorphine. In 2010, DEA began systematic inspections of all DATA-waivered practitioners, primarily to monitor compliance with the 30- to 100-patient limit. In March 2006, the secretary of DHHS issued a formal Determinations Report on the evaluation of DATA 2000 that indicated that the buprenorphine waiver program had expanded access to treatment and had produced effective treatment outcomes without producing negative public health issues (Substance Abuse and Mental Health Services Administration 2006a). As of May 2010, it was estimated that 1–2 million patients in the United States have been treated with buprenorphine. Regarding accessibility to treatment, DHHS determined that 31% of patients taking buprenorphine were new to any type of substance abuse treatment and 60% were new to medication-assisted treatment

Opioid Dependence in America

21

(Figure 1–5). Only 9% were transferred from methadone to buprenorphine treatment. Of equal importance was the finding that 60% of buprenorphine patients had been addicted to nonheroin opioids, a population that has historically avoided participation in methadone treatment. Indeed, patients treated under the buprenorphine waiver have much more accurately reflected the population of illicit drug users in the community, as compared with patients in methadone treatment. In community samples of individuals abusing opioids, only 4% of the population were using heroin, whereas 96% were using nonheroin opioids (Figure 1–6). Patients entering methadone treatment have primarily been addicted to heroin (83%, vs. 17% addicted to nonheroin opioids or the combination of heroin and nonheroin opioids) compared with the 40% addicted to nonheroin opioids who have entered buprenorphine treatment. There have also been significant demographic differences between methadone and buprenorphine patients. Buprenorphine treatment populations have had higher percentages of women than methadone treatment populations as well as higher percentages of whites and employed individuals, and more than three times as many individuals with some postsecondary education (Figure 1–7) (Stanton et al. 2006; Substance Abuse and Mental Health Services Administration 2005b).

Conclusion Opioid dependence has been a long-standing problem in the United States. Although medical management of chronic opioid dependence was common practice in the nineteenth century, it was made illegal under the Harrison Narcotics Tax Act in 1914 and most contemporary physicians have no experience treating the opioid use disorders. Heroin abuse remained endemic throughout the twentieth century despite ongoing efforts to eliminate supplies and incarcerate users. A new epidemic of the abuse of pain relievers began in the mid-1990s and opioid pharmaceuticals quickly replaced heroin as the dominant opioid problem among young adults, almost surpassing the prevalence of marijuana abuse in this population. As compared with heroin abuse, the use of these more potent opioid pharmaceuticals is associated with a higher risk of opioid dependence disorder, even among legitimate pain treatment patients, and a more rapid progression of the addiction syndrome. This new addict population is younger, better educated, and less antisocial than typical heroin addicts, though there is a high incidence of co-occurring depression and anxiety disorders. The legalization of methadone maintenance treatment in 1972 represented a return to a medical management model, but few addicts were willing to attend heavily regulated methadone clinics and this approach had minimal impact on the incidence of heroin abuse. The limitations of the methadone clinic

80% 60%

60% 40%

31%

20%

9%

0% New to substance abuse treatment

FIGURE 1–5.

60%

New to medicationassisted treatment

Transitioned from methadone

Characteristics of respondents in buprenorphine patient study. patient study, drug of abuse. Source. Substance Abuse and Mental Health Services Administration 2005b. aIn

Addicted to nonheroin opioidsa

Handbook of Office-Based Buprenorphine Treatment of Opioid Dependence

Percentage of patients treated

22

100%

Methadone treatment

Treatment under the BUP waiver

NSDUH past month use 2002

TEDS 2002 admissions involving methadone treatment

Patient study BUP evaluation 2005

96% Nonheroin only

4,549,570 reported opioid abuse

Heroin only

40% Nonheroin only

83% Heroin only

111,885 admissions involved methadone treatment

Nonheroin opioids only

Opioid Dependence in America

Opioid abuse

434 patients recruited from 132 sites

Heroin and nonheroin opioids

FIGURE 1–6. Discrepancy between populations abusing opioids and populations treated. BUP=buprenorphine; NSDUH=National Survey on Drug Use and Health; TEDS =Treatment Episode Data Set. Source. Substance Abuse and Mental Health Services Administration 2005b. 23

Handbook of Office-Based Buprenorphine Treatment of Opioid Dependence

Percentage of patients treated

24

100% 80% 60% 40% 20% 0%

Female

White

Methadone admissions to TEDS sites Buprenorphine patient study

Employed

Some postsecondary education

FIGURE 1–7. Methadone patients and buprenorphine patient study sample: demographic differences. The Treatment Episode Data Set (TEDS) reports primarily on admissions to facilities receiving public funding. Admissions to private facilities are underrepresented. Source. Substance Abuse and Mental Health Services Administration 2005b. system led authorities to consider other medications that might be safely utilized in more general medical practice settings. Buprenorphine, a partial opioid agonist, was identified as both an effective and a safe medication for use in office-based settings. With the approval of sublingual buprenorphine in 2002, there has been a significant increase in available treatment options. In early 2010, it was estimated that there were 300,000 individuals currently in buprenorphine treatment, compared with an estimated 275,000 individuals in methadone treatment. Although the abuse of both heroin and opioid pharmaceuticals continues to be a significant problem, office-based buprenorphine treatment has been proved to be an effective public health approach to containing the epidemic (Sullivan et al. 2005). And although the recent leveling off of nonmedical use of prescription pain relievers among young people ages 12 and older is promising, it is premature to assume that buprenorphine treatment has effectively curbed the problem of opioid dependence in the United States. It is clear, however, that large numbers of addicts have found life-saving treatment and have been able to become functioning and contributing members of society. For the first time, an effective medical treatment has had a significant impact on this chronic public health problem.

Opioid Dependence in America

25

References 74 Federal Register 29153–29158/Vol 74, No 117/Friday, June 19, 2009/Proposed Rules: Opioid drugs in maintenance and detoxification treatment of opiate addiction; buprenorphine and buprenorphine combination; approved opioid treatment medications use. Department of Health and Human Services, 42 CFR Part 8, RIN 0930-AA14. Available at: http://buprenorphine.samhsa.gov/NPRM-06-192009.pdf. Accessed May 5, 2010. Allbutt TC: On the abuse of hypodermic injections of morphia. Practitioner 5:327–331, 1870 Ball JC, Ross A: The Effectiveness of Methadone Maintenance Treatment: Patients, Programs, Services, and Outcome. New York, Springer-Verlag, 1991 Compton WM, Thomas YF, Stinson FS, et al: Prevalence, correlates, disability, and comorbidity of DSM-IV drug abuse and dependence in the United States: results from the national epidemiologic survey on alcohol and related conditions. Arch Gen Psychiatry 64:566–576, 2007 Dole VP, Nyswander M: A medical treatment for diacetylmorphine (heroin) addiction: a clinical trial with methadone hydrochloride. JAMA 193:646–650, 1965 Drug Addiction Treatment Act of 2000, Pub. L. No. 106-310. Available at: http:// buprenorphine.samhsa.gov/fulllaw.html. Accessed April 22, 2010. Grant BF: Prevalence and correlates of drug use and DSM-IV drug dependence in the United States: results of the National Longitudinal Alcohol Epidemiologic Survey. J Subst Abus 8:195–210, 1996 Hser YI, Hoffman V, Grella CE, et al: A 33-year follow-up of narcotics addicts. Arch Gen Psychiatry 58:503–508, 2001 Hubbard RL, Craddock SG, Flynn PM, et al: Overview of 1-year follow-up outcomes in the Drug Abuse Treatment Outcome Study (DATOS). Psychology of Addictive Behaviors 11:261–278, 1997 Kessler RC, McGonagle KA, Zhao S, et al: Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States: results from the National Comorbidity Survey. Arch Gen Psychiatry 51:8–19, 1994 Levinstein E: Morbid Craving for Morphia. Translated by Harrer C. London, Smith, Elder, 1878 Meier B: Pain Killer: A “Wonder” Drug’s Trail of Addiction and Death. Emmaus, PA, Rodale, 2003 Musto DF: The American Disease: Origins of Narcotic Control, 3rd Edition. New York, Oxford University Press, 1999 Regier DA, Farmer ME, Rae DS, et al: Comorbidity of mental disorders with alcohol and other drug abuse: results from the Epidemiologic Catchment Area (ECA) Study. JAMA 264:2511–2518, 1990 Stanton A, McLeod C, Luckey B, et al: SAMHSA/CSAT evaluation of the buprenorphine waiver program. Paper presented at the annual meeting of the American Society of Addiction Medicine, San Diego, CA, May 2006 Substance Abuse and Mental Health Services Administration: Results From the 2002 National Survey on Drug Use and Health: National Findings (Office of Applied Studies, NHSDA Series H-22, DHHS Publ No SMA 03–3836). Rockville, MD, Substance Abuse and Mental Health Services Administration, 2003. Available at: http://www.oas.samhsa.gov/nhsda/2k2nsduh/results/2k2Results.htm. Accessed April 29, 2010.

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Substance Abuse and Mental Health Services Administration: Results From the 2004 National Survey on Drug Use and Health: National Findings. (Office of Applied Studies, NSDUH Series H-28, DHHS Publ No SMA 05-4062). Rockville, MD, Substance Abuse and Mental Health Services Administration, 2005a. Available at: http://www.oas.samhsa.gov/NSDUH/2k4NSDUH/2k4results/2k4results.htm. Accessed April 29, 2010. Substance Abuse and Mental Health Services Administration: Evaluation of the Buprenorphine Waiver Program: Results From SAMHSA/CSAT’s Evaluation of the Buprenorphine Waiver Program, June 20, 2005b. Available at: http:// www.buprenorphine.samhsa.gov/findings.pdf. Accessed May 31, 2010. Substance Abuse and Mental Health Services Administration: The Determinations Report: A Report on the Physician Waiver Program Established by the Drug Addiction Treatment Act of 2000 (“DATA”), March 30, 2006a. Available at: http:// www.buprenorphine.samhsa.gov/SAMHSA_Determinations_Report.pdf. Accessed April 29, 2010. Substance Abuse and Mental Health Services Administration: The SAMHSA Evaluation of the Impact of the DATA Waiver Program: Summary Report, Task Order 277-00-6111, March 30, 2006b. Available at: http://www.buprenorphine.samhsa. gov/FOR_FINAL_summaryreport_colorized.pdf. Accessed April 29, 2010. Substance Abuse and Mental Health Services Administration: Results From the 2006 National Survey on Drug Use and Health: National Findings (Office of Applied Studies, NSDUH Series H-32, DHHS Publ No SMA 07-4293). Rockville, MD, Substance Abuse and Mental Health Services Administration, 2007. Available at: http://www.oas.samhsa.gov/NSDUH/2k6NSDUH/2k6results.cfm. Accessed June 29, 2008. Substance Abuse and Mental Health Services Administration: Results From the 2007 National Survey on Drug Use and Health: National Findings (Office of Applied Studies, NSDUH Series H-34, DHHS Publ No SMA 087-4343). Rockville, MD, Substance Abuse and Mental Health Services Administration, 2008. Available at: http://www.oas.samhsa.gov/NSDUH/2k7NSDUH/2k7results.cfm. Accessed November 14, 2008. Substance Abuse and Mental Health Services Administration: The NSDUH Report: Trends in Nonmedical Use of Prescription Pain Relievers: 2002 to 2007 (Office of Applied Studies), February 5, 2009a. Rockville, MD, Substance Abuse and Mental Health Services Administration, 2009a. Available at: http://www.oas.samhsa.gov/ 2k9/painRelievers/nonmedicalTrends.cfm. Accessed April 29, 2010. Substance Abuse and Mental Health Services Administration: Results From the 2008 National Survey on Drug Use and Health: National Findings (Office of Applied Studies, NSDUH Series H-36, DHHS Publ No SMA 09-4434). Rockville, MD, Substance Abuse and Mental Health Services Administration, 2009b. Available at: http://www.oas.samhsa.gov/nsduh/2k8nsduh/2k8Results.cfm. Accessed April 29, 2010. Sullivan LE, Chawarski M, O’Connor PG, et al: The practice of office-based buprenorphine treatment of opioid dependence: is it associated with new patients entering treatment? Drug Alcohol Depend 79:113–116, 2005 Wood GB: A Treatise on Therapeutics, and Pharmacology, or Materia Medica, 3rd Edition (two volumes). Philadelphia, PA, JB Lippincott, 1856

2 Experience With Buprenorphine in the United States, 2002–2008 David A. Fiellin, M.D.

Creating a New Treatment Paradigm The implementation of buprenorphine treatment in the United States represented a new treatment paradigm and a collaborative effort between researchers, government, industry, medical societies, and physicians. In this chapter, I review the legislative and regulatory changes that permitted the use of buprenorphine for the treatment of opioid dependence, and present an overview of the experience in the United States since the initiation of this new treatment paradigm. Research in the 1970s through the 1990s funded by the National Institute on Drug Abuse (NIDA) led to the development of buprenorphine and the U.S. Food and Drug Administration’s (FDA’s) approval in 2002 as a treatment for opioid dependence. The approval of buprenorphine in the United

This chapter is adapted with permission from Fiellin DA: “The First Three Years of Buprenorphine in the United States: Experience to Date and Future Directions.” Journal of Addiction Medicine 1:62–67, 2007. 27

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States followed licensing, research, and its use as a treatment for opioid dependence in the 1990s, most notably in France and Australia. Since the Harrison Narcotics Tax Act of 1914, U.S. physicians were not allowed to provide opioid agonist medication to patients for the sole purpose of treating opioid dependence. As the prevalence of opioid dependence increased (see Chapter 1, “Opioid Dependence in America”) and a new treatment was emerging, U.S. government agencies considered mechanisms to broaden treatment access. The policy argument put forth in support of an amendment to the Controlled Substances Act—to allow for an expansion of access to agonist medications for the treatment of opioid dependence—included specific reference to the efficacy of these treatments and their limited availability vis-à-vis the treatment need. Regulatory changes were put in place to expand methadone treatment services to standard medical settings (Clark 2006) and to loosen the restrictions on take-home doses for those receiving this treatment (Fiellin and O’Connor 2002), but these changes did not amount to widespread expansion of methadone treatment. Greater effort was directed toward the use of physician prescription of medications with less abuse and diversion potential (i.e., Schedule III vs. Schedule II medications), such as buprenorphine, because this was seen as a more plausible paradigm for widespread treatment of opioid dependence. Congress passed modifications to the Controlled Substances Act, termed the Drug Addiction Treatment Act of 2000 (P.L. 106-310; DATA 2000), and in October of 2002 the FDA approved buprenorphine and the buprenorphine-naloxone combination for the treatment of opioid dependence in office-based settings. At almost the same time as FDA approval, the U.S. Drug Enforcement Administration (DEA) changed the schedule of all buprenorphine products from Schedule V to Schedule III, a move that preserved DEA’s role according to DATA 2000. The implementation of this new paradigm required efforts to train and support physicians (Gordon et al. 2008).

Implementing the New Paradigm PHYSICIAN TRAINING Between November 1, 2001, and January 1, 2009, approximately 20,000 physicians (Table 2–1) received training in the treatment of opioid dependence from one of the five medical societies that are named in DATA 2000 as capable of providing this type of training. These trainings were provided in a face-to-face format, via the Internet, or on CD-ROM. Of note, DATA 2000 provides for the future approval of other medications in Schedules III through V and does not mandate that the trainings focus specifically on the use of buprenorphine, but rather requires that they be generically applicable to treatment and management

Experience With Buprenorphine in the United States, 2002–2008

TABLE 2–1.

29

Physician training and certification according to the stipulations in DATA 2000, as of January 2009 Total trainees

In-person training

Web-based training

Physicians who have received training

20,235

14,504

5,731

Waiver notification forms received by CSAT

17,623

NA

NA

Waiver notifications certified by CSAT

16,183

NA

NA

115

NA

NA

Waiver notifications denied by CSAT

Note. CSAT=Center for Substance Abuse Treatment; DATA 2000=Drug Addiction Treatment Act of 2000; NA=data not available. Source. N. Reuter, Center for Substance Abuse Treatment, personal communication.

of opioid-dependent patients. The initial training materials were developed in 2000 as a standard curriculum through funding to medical societies from the federal Center for Substance Abuse Treatment (CSAT) of the Substance Abuse and Mental Health Services Administration (SAMHSA). This curriculum consists of a large set of standard slides and has been updated once, in 2003. In late 2008, discussions were under way at CSAT regarding the need to produce another update to the curriculum to incorporate new evidence and clinical experience. Before the approval of buprenorphine and buprenorphine-naloxone for the treatment of opioid dependence in 2002, CSAT provided funds for the majority of physician training. From 2002 through 2008, the burden of training physicians fell primarily on the medication’s manufacturer, provided through unrestricted educational grants to medical societies. As of early 2010, the funding for future face-to-face trainings is unclear, although the Web-based and CD-ROM–based options still exist. A number of training paradigms have been developed for the face-to-face courses; most rely on a mixture of didactics and case discussions. One model provides for 4 hours of training (half of the 8-hour training requirement) to be conducted online before the face-to-face course (Gunderson et al. 2006). The quality and outcomes of training have never been fully investigated, although most anecdotal reports and evaluations are positive regarding the organization and content. In addition, organizations have performed faculty development to help improve quality (Wong et al. 2005). One concern has been that approxi-

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Handbook of Office-Based Buprenorphine Treatment of Opioid Dependence

mately 10% of trainees apparently do not go on to notify CSAT and DEA of their intent to prescribe under DATA 2000 (Table 2–1). In one published instance, despite high satisfaction with the training, only 6 of 29 trainees went on to seek certification and only 2 indicated that they were prescribing buprenorphine or buprenorphine-naloxone (Gordon et al. 2008). It is known that some of the perceived barriers to utilization of the medication (e.g., induction logistics, access to mental health services) become less important over time and with experience prescribing buprenorphine (Netherland et al. 2009).

PHYSICIAN SUPPORT The uniqueness of this new practice in U.S. medicine may deter some physicians from seeking training or the appropriate registration to provide buprenorphine. In one survey of 235 Massachusetts physicians with the ability to prescribe buprenorphine, 66% indicated that they were in fact prescribing (Walley et al. 2008). Being a primary care physician compared with a psychiatrist (adjusted odds ratio [AOR], 3.02; 95% confidence interval [CI], 1.48– 6.18) and having a solo practice only compared with having a group practice (AOR, 3.01; 95% CI, 1.23–7.35) were associated with prescribing, whereas reporting low patient demand (AOR, 0.043; 95% CI, 0.009–0.21) and insufficient institutional support (AOR, 0.37; 95% CI, 0.15–0.89) were associated with not prescribing (Walley et al. 2008). In response to concerns that physicians might need additional assistance beyond initial training in implementing buprenorphine treatment in officebased practice, SAMHSA in 2004 provided financial support to create a Physician Clinical Support System (PCSS) that is designed to support physicians who are considering or currently treating opioid-dependent patients with buprenorphine. PCSS (www.pcssmentor.org) is a collaborative effort between the American Society of Addiction Medicine (ASAM), the American Psychiatric Association, the American Osteopathic Association (AOA), the American Academy of Addiction Psychiatry, and 25 other primary care, addiction, pain, and HIV specialty societies. In late 2008, PCSS had 87 physicians who served as mentors and provided support to over 3,600 participants in all 50 states and Puerto Rico. Services are provided via e-mail, telephone, and visits to the mentor’s place of care. The most common services provided by PCSS include information on induction timing and procedures, medication management, patient scheduling, payment for services, and paperwork. Also in 2004, the HIV/AIDS Bureau of the Health Resources and Services Administration funded an initiative through its Special Projects of National Significance branch to develop and evaluate programs that integrate HIV infection primary care and buprenorphine treatment for opioid dependence. This program was designed to address the specific issues that relate to the integra-

Experience With Buprenorphine in the United States, 2002–2008

31

tion of buprenorphine into HIV infection clinical care (Sullivan et al. 2006a, 2006b). The 10 sites involved in this project received training and support from a centralized Evaluation and Support Center (www.bhives.org) and began enrolling patients in mid-2005. As of late 2008, the sites had enrolled more than 321 HIV-positive opioid-dependent patients into care with buprenorphine. A pilot study from one site demonstrated promising results (Sullivan et al. 2006c). The U.S. Department of Veterans Affairs (VA) has created efforts to support physician prescription of buprenorphine. This process helps areas of the country in which VA facilities do not have methadone services for veterans with opioid dependence. The VA Substance Use Disorders Quality Enhancement Research Initiative has developed a service that provides consultation to VAbased physicians to improve their capacity to provide buprenorphine. The service consists of clinical experts, a resource guide regarding implementing buprenorphine treatment, and a monthly newsletter. As of late 2007, all 14 registered VA sites have used the service (Gordon et al. 2007). Other programs have developed around the country to assist with the implementation of buprenorphine therapy. Various state and local entities have engaged in efforts to help support the implementation of office-based treatment with buprenorphine (Baltimore City Health Department 2007). These efforts have ranged from organized team trainings to formalized state-based support systems (McCarty et al. 2004). One such effort is based on a nurse or nurse practitioner model and exemplifies the potential role of nonphysician staff in the care of opioid-dependent patients (Labelle 2008).

Evaluating the Impact of the New Paradigm PHYSICIAN REGISTRATION As of early 2009, over 16,000 physicians had notified the federal government of their intention to prescribe under the auspices of DATA 2000 (Table 2–1). California and New York led the nation with approximately 1,800 such physicians each. Included in these numbers are those who meet the legislation’s requirements based on either completing the 8-hour training or another criterion such as being certified in addiction psychiatry by the American Board of Psychiatry and Neurology, in addiction medicine by AOA, or in addiction medicine by ASAM. It is perhaps important to note that among the physicians who have received a DEA registration number to prescribe buprenorphine (noted by the first alphanumeric of the applicant’s existing registration number replaced with an X), the majority are eligible due to completion of the training outlined in the legislation, whereas a minority meet criteria based on their specialty certification.

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PHYSICIAN PRESCRIBING There is no central registry of physician prescribing of buprenorphine in the United States. Prescribing behavior can be extrapolated from information maintained on controlled substances by the DEA, Office of Diversion Control. This information, assembled in the Automation of Reports and Consolidated Orders System, shows that in 2006 the distribution of buprenorphine increased from 58,291 grams in the first quarter to 85,418 grams in the fourth quarter. Overall 287,101 grams of buprenorphine were distributed during 2006, with 93% distributed to 28,430 pharmacies nationwide. This represented an increase over the 98 grams in 2002. States receiving the largest supplies include California, Florida, Massachusetts, New York, and Pennsylvania. States receiving the smallest supplies include Arkansas, Nebraska, North Dakota, South Dakota, and Wyoming. The states with the largest number of grams distributed on a per capita basis were Vermont, Maine, Massachusetts, Rhode Island, and Connecticut. Those with the fewest grams distributed per capita were South Dakota, Iowa, Arkansas, Nebraska, and Kansas. Additional information regarding physician prescribing can be deduced from the congressionally mandated 3-year evaluation (see the following section, “Congressionally Mandated Evaluation”). An early survey indicated that approximately 105,000 patients in the United States had received treatment with buprenorphine (Substance Abuse and Mental Health Services Administration 2005). Of these, only 10%–15% transitioned from methadone treatment. Information from a national prescription database demonstrates an increase in the number of prescriptions of buprenorphine-naloxone from 39,000 in 2003 to 1,719,000 in 2007, an average annual growth rate of 113% (Mark et al. 2009). Twenty-eight percent of prescriptions were written by psychiatrists. In a separate study of psychiatrists (Thomas et al. 2008), nearly 90% of addiction specialists surveyed had the appropriate DEA registration to prescribe buprenorphine and two-thirds had treated patients with the medication. However, fewer than 10% of non–addiction specialist psychiatrists had prescribed buprenorphine. Information from the medication’s manufacturer estimates that 15,603,273 daily doses or 42,749 patient-years of buprenorphine and/or buprenorphine-naloxone were provided in 2006, assuming an average daily dose of 16 mg. For the 3-year period between January 2003 and December 2006, an estimated 300,000 patients were treated with buprenorphine and/or buprenorphine-naloxone. In the last quarter of 2006, prescriptions were written for buprenorphine and/or buprenorphine-naloxone by 4,641 physicians with special DEA registration. The most recent information, from the third quarter of 2008, indicates that approximately 326,000 individuals had received treatment over a 90-day period and that 225,600 were receiving treatment at a single point in time. Of those

Experience With Buprenorphine in the United States, 2002–2008

33

225,600 patients, an estimated 95% were receiving the buprenorphine-naloxone combination product instead of the buprenorphine-alone formulation and 76% were engaged in ongoing maintenance therapy in contrast to a planned short-term medication taper (E. Johnson, personal communications, September 2007 and December 2008).

CONGRESSIONALLY MANDATED EVALUATION DATA 2000 includes a stipulation that allows the secretary of the U.S. Department of Health and Human Services “to make a determination of whether treatments provided under waivers...have been effective forms of maintenance treatment and detoxification treatment in clinical settings...[;] whether such waivers have significantly increased (relative to the beginning of such period) the availability of maintenance treatment and detoxification treatment; and...whether such waivers have adverse consequences for the public health.” To this end, SAMHSA’s CSAT commissioned a series of surveys designed to assess the impact of the introduction of buprenorphine on the treatment system. The Addiction Physician Survey (Quarter 4, 2003) was sent to a sample of approximately 1,000 physician addiction specialists. The Waivered Physician Survey (Quarter 1, 2005) was sent to a sample of approximately 1,800 physicians, all of whom had waivers to prescribe buprenorphine, to learn more about physicians’ experience treating with buprenorphine once it had been available for at least 1 year. Finally, the patient survey (Kissin et al. 2006) collected data by telephone interview from a cohort of about 400 buprenorphine patients to assess their response to and satisfaction with buprenorphine therapy. Although the complete final findings have not yet been published, presentations by federal officials provide insight into the initial findings (Table 2–2).

BUPRENORPHINE DIVERSION There is evidence of buprenorphine diversion, although few reports indicate that this diversion is for abuse or euphoria. The primary use of diverted doses appears to be for “paraprescribing” or “unobserved treatment” in which an opioid-dependent person takes a dose of the medication that was not prescribed for him or her for the purpose of avoiding opioid withdrawal or using illicit opioids. A U.S. survey of 1,000 patients seeking treatment for prescription opioid abuse at 100 drug treatment programs around the country showed that 20%– 35% had misused buprenorphine “to get high” in the past 30 days, but that fewer than 3% were primarily addicted to buprenorphine (Cicero et al. 2007b). A November 2006 report from CSAT concluded that buprenorphine diversion and abuse were concentrated in specific geographic areas (JBS International 2006). A report based on a network of drug abuse experts noted that there was

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TABLE 2–2.

Major findings from SAMHSA CSAT surveys on DATA 2000

Physician survey The number of states, and number of sites within states, providing medication-assisted treatment for opioid dependence increased in the year following the introduction of buprenorphine. 53% of waivered physicians had no prior experience providing medicationassisted treatment. 56% of waivered physicians were not addiction specialists. The largest proportion of waivered physicians reported that they practiced in individual practices. The smallest proportion of waivered physicians practiced in opioid treatment programs and/or specialty substance abuse treatment clinics. The majority of physicians reported providing induction for ≤100 patients. 21% of physicians reported providing detoxification only, whereas 79% reported providing detoxification and maintenance treatment. The proportion of physicians who described buprenorphine treatment as “very effective” was 32% for those who provided the medication to patients for <7 days at a time, 40% for those who provided it for 8–40 days, and 74% for those who provided it for >1 month. 217 of 47,664 patients (0.5%) experienced severe adverse reactions, nearly half of which were described as “withdrawal.” The top five challenges to physician prescribing were cost, patient’s resistance to counseling, patient’s use of other drugs, patient compliance/retention, and the 30-patient limit. The most common patient census counts per physician were 1–5 (27%) and 30 (20%). Patient survey 60% of patients were dependent on nonheroin opioids. 60% of patients were new to medication-assisted treatment. 63% of patients reported one or two visits to the physician during the first 30 days of treatment. 41% of patients reported no counseling sessions in the first 30 days of treatment. 65% of patients reported nonopioid illicit drug use or binge alcohol use in the past 30 days.

Experience With Buprenorphine in the United States, 2002–2008

TABLE 2–2.

35

Major findings from SAMHSA CSAT surveys on DATA 2000 (continued)

32% of patients reported a lifetime diagnosis of chronic pain. 95% of patients indicated that buprenorphine was very or extremely helpful. 60% of patients reported retention in treatment at 6 months. 64% and 65% of patients indicated that it is harder to buy buprenorphine on the street than methadone or OxyContin (oxycodone), respectively. Note. CSAT=Center for Substance Abuse Treatment; DATA 2000=Drug Addiction Treatment Act of 2000; SAMHSA=Substance Abuse and Mental Health Services Administration. Source. Kissin et al. 2006.

no difference in the frequency of reports of buprenorphine abuse versus tramadol abuse and that each was much lower than the frequency of abuse reported for oxycodone or methadone (Cicero and Inciardi 2005). In this study, more than 33% of those who had abused buprenorphine reported that they took the medication as an attempt at self-medication. A further study conducted with 501 heroin-using subjects in New York City determined that only one subject had abused buprenorphine or buprenorphine-naloxone (Davis and Johnson 2008). The Drug Abuse Warning Network presents national estimates of drugrelated visits to hospital emergency departments (Substance Abuse and Mental Health Services Administration 2008). In 2006, there were an estimated 247,669 (95% CI, 214,160–281,177) emergency department visits for nonmedical use of prescription medications, of which 4,440 (95% CI, 823–8,057) were reports of nonmedical use of buprenorphine and or buprenorphine-naloxone. During the same time, there were no reports of buprenorphine associated with suicide attempts (Substance Abuse and Mental Health Services Administration 2008, Table 16). Another study looked at reports to 18 regional poison control centers around the United States and noted that the average quarterly ratio of abuse cases per 1,000 prescriptions dispensed was 0.08 (SD ±0.09) for buprenorphine, and 0.16 (SD±0.08) for buprenorphine-naloxone (Smith et al. 2007). Research using reports from a key informant network at 233 substance abuse treatment centers in the United States demonstrated that buprenorphine, compared with other prescription opioids, had the lowest number of unique recipients of dispensed drug (individuals for whom prescriptions were written) and was among the drugs with the lowest numbers of cases of abuse per 100,000 population (approximately 0.2), but was among those with the highest numbers of reports of abuse per unique recipient of dispensed drug (Cicero et al. 2007a). One interpretation of these data is that buprenorphine has

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little value as a drug that produces euphoria, yet is more likely to be shared by those to whom it is prescribed.

DRUG ENFORCEMENT ADMINISTRATION ACTION DATA 2000 indicates that “the Attorney General may make a determination of the extent to which there have been violations of the numerical limitations” of patients who are treated by physicians. Initially the legislation set the limit at 30 patients per individual physician and/or group practice as defined by the Social Security Act. This was subsequently changed to 30 patients per individual physician, irrespective of their affiliation with a group practice. DEA has been responsible for monitoring physician practice involving buprenorphine since FDA approval of the medication in late 2002. This monitoring has included 425 individual physician investigations that were conducted by field agents during the period between October 2003 and January 2008. Of these investigations, 253 (59.5%) cited no problems or revealed that the physicians had yet to begin a practice using buprenorphine. Of the 74 investigations that cited problems or actions taken by investigators (involving 0.006% of all registered physicians), 35 manifested as verbal warnings (e.g., record-keeping or dispensing violations), 23 manifested as letters of admonition (e.g., recordkeeping, dispensing, and security violations), 8 manifested as surrender of DEA registrations for cause, 2 manifested as show cause proceedings, 1 led to a civil action, and 5 were still undergoing active investigation (Curry 2008).

LEGISLATIVE CHANGES AND REGULATORY CONCERNS Congress has acted twice to modify DATA 2000 since the original legislation. The first modification occurred in January 2005 and changed the 30-patient limit such that it applied to an individual physician and not a group practice. This allowed individual physicians to care for up to 30 patients with medications such as buprenorphine even if they were practicing within a group practice in which other physicians were providing the same type of treatment. In December 2006, Congress again modified the legislation, to allow physicians who had possessed a registration for at least 1 year and who had applied to the secretary of the Department of Health and Human Services for a waiver to treat up to 100 patients with medications such as buprenorphine. As of early 2009, 2,729 physicians had notified CSAT of their intent to treat up to 100 patients. In summary, the modifications by Congress were designed to expand the number of patients that physicians could care for under the provisions of DATA 2000 and the Controlled Substances Act.

Experience With Buprenorphine in the United States, 2002–2008

37

In addition to funding the congressionally mandated waiver evaluation and PCSS, CSAT has effected regulatory action and provided guidance. CSAT moved in May 2003 to add buprenorphine to the list of medications that could be provided by federally regulated opioid treatment programs (68 Federal Register 27937–27939). Opioid treatment programs were not subject to the same numerical limits that apply when individual physicians prescribe buprenorphine but rather were subject to the regulations (e.g., patient-counselor ratios, frequency of take-home medications) that cover the provision of all opioid agonist treatments in these facilities. In April 2006, CSAT issued a “Dear Colleague” letter expressing concerns over pharmacies that were compounding buprenorphine and buprenorphinenaloxone in “various strengths, colors and flavors,” indicating that this practice presented potentially serious public health and safety issues (Clark 2006). Specific concerns were expressed regarding the possibility of degradation of compounded buprenorphine and naloxone into toxic substances via moisture and oxidation. In addition, concern was expressed regarding the unknown pharmacokinetics of compounded products.

FUNDING In the spring of 2003, the National Association of State Alcohol and Drug Abuse Directors conducted a survey of the directors of all state agencies on alcohol and other drugs (AOD agencies), and the AOD agency directors of the District of Columbia and five U.S. territories (National Association of State Alcohol and Drug Abuse Directors 2004). The survey included responses from 94% (n=47) of the state AOD agency directors and 33% (n=2) of the U.S. territorial AOD agencies. Forty-nine percent of the respondents indicated that their state did not plan to expend Substance Abuse Prevention and Treatment (SAPT) Block Grant monies or other monies controlled by the state AOD agency in support of appropriate services for patients receiving buprenorphine. Fifty-nine percent of states did not plan to expend SAPT Block Grant monies or other monies controlled by the state AOD agency to cover the cost of buprenorphine for patients in the public AOD system. Forty-nine percent of state respondents indicated that they did not anticipate their state would include buprenorphine on their state’s Medicaid formulary. Finally, only 47% of state respondents indicated that their state’s Medicaid benefits would cover physician and medication costs associated with office-based buprenorphine treatment for eligible clients. A 2004 working paper prepared for CSAT outlined the complex environment in which reimbursement for buprenorphine and related services must occur. The report highlighted that given the complicated processes, restricted coverage for substance abuse care, and multiple funding streams, treatment with

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buprenorphine would not occur to any great degree unless the payment systems, organized care systems, and public funders were willing to reimburse physicians, therapists, pharmacists, and the medication’s manufacturer and distributor for their services and product (Avisa Group 2005). Over time, it appears that coverage from public and private insurers has increased, although this is not universal. Legislative changes, including legislation that addresses parity between mental health and medical disorders, may provide further expansion. Finally, the potential introduction of generic versions of the medication following the manufacturer’s period of exclusivity could portend reduced medication-related fees.

Improving the New Paradigm ONGOING RESEARCH Federal databases reveal approximately 60 research projects involving buprenorphine funded by the National Institutes of Health. The research covers a wide range of topics including counseling, pregnancy, HIV infection, incarceration, and adoption by health maintenance organizations. In addition, the NIDA Clinical Trials Network has recently completed studies on the use of buprenorphine for detoxification and in the treatment of adolescent patients (Woody et al. 2008) and has ongoing trials investigating the use of buprenorphine in patients addicted to prescription opioids and comparing its effects on hepatic transaminases with those of methadone.

UNDERINVESTIGATED AREAS Despite the importance of this ongoing work, the U.S. experience thus far indicates some important areas for further investigation for clinical and policy guidance (Table 2–3). The clinical areas reflect issues that are frequently identified in physician discussions of buprenorphine and/or those that are highlighted in the existing evaluations. To date there has been a dearth of research, observational or experimental, on the use of the buprenorphine-naloxone combination in the doses available in the United States for the treatment of patients with isolated pain disorders or pain syndromes that are comorbid with opioid dependence. Likewise, the current investigations provide a snapshot into what clinical practice is like; however, there is no current mechanism for collecting detailed information regarding the quality of care that is provided by physicians. Some of the clinical issues are not unique to the U.S. implementation of buprenorphine use (Auriacombe et al. 2004; Carrieri et al. 2006). Many of the barriers articulated by U.S. physicians mirror those cited regarding programs in other countries (Lintzeris et al. 2004). Other barriers are unique to the implementation

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TABLE 2–3.

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Clinical and policy areas for further investigation

Clinical 1. The appropriate use of buprenorphine-naloxone for pain 2. The need for and appropriate use of alternate formulations of buprenorphine-naloxone 3. The integration of buprenorphine into programs that traditionally do not provide medication 4. The quality of care received by patients in office-based practices (e.g., number of physician and counseling visits, medication dosage and duration) 5. The appropriate level, type, and delivery strategy for counseling for patient subgroups 6. Strategies to assist physicians in addressing the barriers of medication cost, patient’s use of counseling, patient retention, patient’s use of other drugs, induction, medication management, patient scheduling, and payment 7. The need for additional physician training regarding record keeping Policy 1. How best to engage larger numbers of non–addiction physicians in the provision of buprenorphine treatment 2. How best to train and support physicians and practices for the provision of buprenorphine treatment 3. The appropriate role of governmental and pharmaceutical entities in providing physician education and support 4. How best to address the geographic variation in access to buprenorphine treatment 5. The role of prescribing by nonphysicians with DEA registrations 6. Strategies to encourage the use of buprenorphine in specialty and opioid treatment programs 7. Strategies to ensure payment for medication, physician services, and ancillary services 8. The need for ongoing evaluation of the impact of DATA 2000 on access, care, and public health given the potential expansion of practices enabled by legislative changes 9. Surveillance of physicians’ charging practices for services 10. Surveillance for diversion, especially findings that indicate injection misuse of buprenorphine and buprenorphine-naloxone Note. DATA 2000=Drug Addiction Treatment Act of 2000; DEA=U.S. Drug Enforcement Administration.

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in the United States. For instance, issues regarding medication cost and physician payment are not as pertinent in countries with a single payer system. The policy issues center on training and support, expansion of access, and ongoing monitoring of the impact of buprenorphine therapy implementation. The available data suggest that more than half of the physicians who have received a DEA registration number that allows them to prescribe under DATA 2000 have limited to no experience providing this type of medication or practicing in the field of addiction treatment. This is to be expected given the restrictions on this type of practice in the United States before 2003. In addition, greater physician involvement in the care of opioid-dependent patients and an effort to expand access to treatment were the intent of those who drafted DATA 2000. Training and supporting physicians in this new practice of medicine have been a challenge for the specialty medical societies, CSAT, and the medication’s manufacturer. The rapid growth in the use of the medication, the apparent benefits realized by patients, and the lack of evidence of adverse effects on the public health provide reassurance that the training and support efforts to date have been successful, or at least not detrimental. The scope and nature of, and payment for, future training and support services will likely have a profound effect on the ability of this treatment to reach larger groups of patients. Payment for buprenorphine-related treatment services is likely to have an even greater effect on their expansion. In 2003 commercial and public funding systems were not in place to provide reimbursement for the provision of opioid agonist therapy by physicians. Although formal cost-effectiveness studies of buprenorphine therapy have been conducted (Schackman et al. 2006), there is evidence that large health care providers may see the provision of methadone, instead of buprenorphine, as a viable alternative for their patients (Avisa Group 2005).

Conclusion Office-based buprenorphine treatment has introduced a significant new paradigm for the treatment of opioid dependence in the United States. Effective strategies to improve the geographic distribution of treatment services and to engage a larger number of providers in the use of buprenorphine have been elusive. The treatment of addictive disorders by mainstream medical providers will likely continue to expand, with medications available for the treatment of nicotine, alcohol, and opioid addiction. It is likely that time combined with growing experience by physicians who adopt the practice early on will serve to establish buprenorphine as a mainstream medication. Efforts to increase education at the resident physician level should help in this regard. Many practices have incorporated the use of nurses, nurse practitioners, and physician assistants into the provision of buprenorphine treatment. In some states, nurse practitioners and

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physician assistants have DEA registrations that allow them to prescribe controlled substances (e.g., opioid pain medications) and consideration should be given to expanding DATA 2000 to include these health professionals. Finally, given the importance of the problem of untreated opioid dependence and recent legislative changes that will allow practices to expand dramatically, the findings from the federal evaluation of DATA 2000 and ongoing evaluation beyond the 3-year congressional mandate will be essential to help guide further policies and programs. Future iterations of the surveys will be needed to help address some of the areas outlined above and in Table 2–3. This information will provide evidence to gauge both the negative and positive effects of this new practice of medicine in the United States and allow for improved care of patients addicted to opioids.

References 68 Federal Register 27937–27939/Vol 68, No 99/Thursday, May 22, 2003/Rules and Regulations: Opioid drugs in maintenance and detoxification treatment of opiate addiction; addition of buprenorphine and buprenorphine combination to list of approved opioid treatment medications. Department of Health and Human Services, 42 CFR Part 8, RIN 0910-AA52. Available at: http://www.buprenorphine.samhsa. gov/bwns/InterimFinalRule-05-22-2003.pdf. Accessed August 20, 2009. Auriacombe M, Fatséas M, Dubernet J, et al: French field experience with buprenorphine. Am J Addict 13 (suppl 1):S17–S28, 2004 Avisa Group: Evaluation of the Buprenorphine Waiver Program: Buprenorphine Reimbursement and Availability Tracking Study. September 2005. Available at: http:// www.avisagroup.com/images/Final_Report_of_Tracking_Study.pdf. Accessed August 21, 2009. Baltimore City Health Department: Baltimore Buprenorphine Initiative: Interim Progress Report, July 2007. Available at: http://www.baltimorehealth.org/ buprenorphine.html. Accessed August 11, 2009. Carrieri MP, Amass L, Lucas GM, et al: Buprenorphine use: the international experience. Clin Infect Dis 43 (suppl 4):S197–S215, 2006 Cicero TJ, Inciardi JA: Potential for abuse of buprenorphine in office-based treatment of opioid dependence. N Engl J Med 353:1863–1865, 2005 Cicero TJ, Surratt H, Inciardi JA, et al: Relationship between therapeutic use and abuse of opioid analgesics in rural, suburban, and urban locations in the United States (see comment). Pharmacoepidemiol Drug Saf 16:827–840, 2007a Cicero TJ, Surratt HL, Inciardi J: Use and misuse of buprenorphine in the management of opioid addiction. J Opioid Manag 3:302–308, 2007b Clark HW: Dear Colleague letter. Rockville, MD, Center for Substance Abuse Treatment, April 3, 2006. Available at: www.buprenorphine.samhsa.gov/ CompoundingandSellingBuprenorphine.pdf. Accessed August 10, 2009. Curry D: Drug Enforcement Administration Report. Buprenorphine Summit, Center for Substance Abuse Treatment, Washington, DC, February 21–22, 2008. Available at: http://buprenorphine.samhsa.gov/presentations/Buprenorphine_Summit.02. 21.08.v2.ppt. Accessed August 12, 2009.

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Davis WR, Johnson BD: Prescription opioid use, misuse, and diversion among street drug users in New York City. Drug Alcohol Depend 92:267–276, 2008 Drug Addiction Treatment Act of 2000, Pub. L. No. 106-310. Available at: http:// buprenorphine.samhsa.gov/fulllaw.html. Accessed April 22, 2010. Fiellin DA, O’Connor PG: New federal initiatives to enhance the medical treatment of opioid dependence. Ann Intern Med 137:688–692, 2002 Gordon AJ, Trafton JA, Saxon AJ, et al: Implementation of buprenorphine in the Department of Veterans Affairs: results of the first three years. Drug Alcohol Depend 90:292–296, 2007 Gordon AJ, Liberto J, Granda S, et al: Outcomes of DATA 2000 certification trainings for the provision of buprenorphine treatment in the Veterans Health Administration. Am J Addict 17:459–462, 2008 Gunderson EW, Fiellin DA, Levin FR, et al: Evaluation of a combined online and in person training in the use of buprenorphine. Subst Abuse 27:39–45, 2006 JBS International: Diversion and Abuse of Buprenorphine: A Brief Assessment of Emerging Indicators. Final report, November 30, 2006. Available at: http:// buprenorphine.samhsa.gov/Buprenorphine_FinalReport_12.6.06.pdf. Accessed August 11, 2009. Kissin W, McLeod C, Sonnefeld J, et al: Experiences of a national sample of qualified addiction specialists who have and have not prescribed buprenorphine for opioid dependence. J Addict Dis 25:91–103, 2006 Labelle C: Nurse Care Manager Model. Buprenorphine Summit, Center for Substance Abuse Treatment, February 21–22, 2008, Washington, DC. Available at: http:// www.buprenorphine.samhsa.gov/presentations/LaBelle.pdf. Accessed January 26, 2009. Lintzeris N, Ritter A, Panjari M, et al: Implementing buprenorphine treatment in community settings in Australia: experiences from the Buprenorphine Implementation Trial. Am J Addict 13 (suppl 1):S29–S41, 2004 Mark TL, Kassed CA, Vandivort-Warren R, et al: Alcohol and opioid dependence medications: prescription trends, overall and by physician specialty. Drug Alcohol Depend 99:345–349, 2009 McCarty D, Rieckmann T, Green C, et al: Training rural practitioners to use buprenorphine; using The Change Book to facilitate technology transfer. J Subst Abuse Treat 26:203–208, 2004 National Association of State Alcohol and Drug Abuse Directors: States’ Perspectives on Buprenorphine and Office Based Medication Assisted Dependency Treatment. June 14, 2004. Available at: http://www.nasadad.org/resource.php?base_id=83. Accessed August 10, 2009. Netherland J, Botsko M, Egan JE, et al; BHIVES Collaborative: Factors affecting willingness to provide buprenorphine treatment. J Subst Abuse Treat 36:244–251, 2009 Schackman BR, Merrill JO, McCarty D, et al: Overcoming policy and financial barriers to integrated buprenorphine and HIV primary care. Clin Infect Dis 43 (suppl 4):S247–S253, 2006 Smith MY, Bailey JE, Woody GE, et al: Abuse of buprenorphine in the United States: 2003–2005 (see comment). J Addict Dis 26:107–111, 2007 Substance Abuse and Mental Health Services Administration: Evaluation of the Buprenorphine Waiver Program: Results From SAMHSA/CSAT’s Evaluation of the Buprenorphine Waiver Program, June 20, 2005. Available at: http:// www.buprenorphine.samhsa.gov/findings.pdf. Accessed May 31, 2010.

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Substance Abuse and Mental Health Services Administration: Drug Abuse Warning Network, 2006: National Estimates of Drug-Related Emergency Department Visits (Office of Applied Studies, DAWN Series D-30, DHHS Publ No SMA 08-4339). Rockville, MD, 2008. Available at: http://dawninfo.samhsa.gov/files/ ED2006/DAWN2k6ED.htm. Accessed January 26, 2009. Sullivan LE, Barry D, Moore BA, et al: A trial of integrated buprenorphine-naloxone and HIV clinical care. Clin Infect Dis 43 (suppl 4):S184–S190, 2006a Sullivan LE, Bruce RD, Haltiwanger D, et al: Initial strategies for integrating buprenorphine into HIV care settings in the United States. Clin Infect Dis 43 (suppl 4):S191–S96, 2006b Sullivan LE, Tetrault J, Bangalore D, et al: Training HIV physicians to prescribe buprenorphine for opioid dependence. Subst Abuse 27:13–18, 2006c Thomas CP, Reif S, Haq S, et al: Use of buprenorphine for addiction treatment: perspectives of addiction specialists and general psychiatrists. Psychiatr Serv 59:909– 916, 2008 Walley AY, Alperen JK, Cheng DM, et al: Office-based management of opioid dependence with buprenorphine: clinical practices and barriers. J Gen Intern Med 23:1393–1398, 2008 Wong JG, Holmboe ES, Jara GB, et al: Faculty development in small-group teaching skills associated with a training course on office-based treatment of opioid dependence. Subst Abuse 25:35–40, 2005 Woody GE, Poole SA, Subramaniam G, et al: Extended vs short-term buprenorphinenaloxone for treatment of opioid-addicted youths: a randomized trial. JAMA 300:2003–2011, 2008

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3 General Opioid Pharmacology John T. Pichot, M.D.

OPIOIDS HAVE PLAYED a significant role in the human experience for more than five millennia. Evidence found at Neolithic Period dig sites located in present-day Switzerland indicates cultivation of Papaver somniferum seeds and pods and suggests that the first organized human farming included the intentional growing of the opium poppy (Booth 1999). The earliest historical record began with the Sumerian civilization located along the banks of the Tigris-Euphrates river system of lower Mesopotamia in what is now southern Iraq. Clay tablets from around 3,400 B.C. include the oldest-known medical writings and represent the opium poppy by the ideograms Hul and Gil, which translate to the “joy plant” (Booth 1999). For thousands of years, opioids have been used to control coughing, diarrhea, and pain, and to induce euphoria, primarily by oral ingestion of opium. In the 1600s, opium smoking also became prevalent and spread around the world from Asia to Europe and the American colonies, primarily through British-controlled trade routes (Booth 1999). In the nineteenth century, a number of scientific and technical developments set the stage for the modern era of opioid use and abuse. In 1806, a German publication described the first isolation of a component of opium, named morphium after Morpheus, the Greek god of dreams and sleep. By the 1820s, morphine was commercially available around the world. The develop45

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ment of the syringe in the mid-1800s, perfected by Dr. Alexander Wood of Edinburgh in 1853, allowed efficient parenteral delivery of morphine. The first semisynthetic opioid, heroin, was discovered in 1874 by pharmacist C.R. Wright in London’s St. Mary’s Hospital. The first completely synthetic opioid was designed as a replacement for morphine by German scientists during World War II when the Allied blockade prevented access to opium (Booth 1999). In this chapter, I will review key features of the opioids and their interactions with opioid receptors. I will then focus on buprenorphine interactions with opioid receptors. Finally, I will turn our attention to pharmacological issues with clinical relevance for using buprenorphine in the treatment of opioid addiction, including the treatment of withdrawal and its use as a maintenance medication for opioid dependence disorder.

Opioid Key Features Opioid is the broad term for the entire group of compounds that have agonist effect on the µ opioid receptors. This term opioid includes three basic subgroups (Booth 1999): 1. Opiates—the naturally occurring substances present within raw opium. Examples of these naturally occurring compounds isolated from raw opium include morphine, codeine, and thebaine. 2. Semisynthetic opioids—these do not occur in nature but are derived by modification of a naturally occurring opiate. Examples of semisynthetic opioids include heroin, developed from the opiate morphine, and oxycodone and buprenorphine, each developed from the opiate thebaine. 3. Synthetic opioids—these neither occur in nature nor are developed from opiates, but are fully synthetic compounds designed to act as opioid receptor agonists. Methadone and fentanyl are examples of synthetic opioids, as are many of the other opioid prescription medications in common clinical use. There are several pharmacological characteristics of drugs that increase abuse potential as demonstrated in animal experimental models and in human behavior. Three primary factors that all result in a more rapid onset of opioid pharmacological effects are relevant to this increase in abuse potential: 1) drugs with a faster route of administration have greater abuse potential—that is, injecting and smoking a drug give it greater abuse potential than oral ingestion; 2) drugs with a shorter half-life have greater abuse potential, such as short-acting heroin versus long-acting methadone; and 3) drugs with greater lipophilic properties, which allow for more rapid transport across the blood-brain barrier, are associated with greater abuse potential. For example, heroin (diacetylmor-

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TABLE 3–1.

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Opioid agonist effects

Acute use effects

Chronic use effects

Overdose effects

Euphoria Emesis Constricted pupils Slowed respirations Drowsiness Analgesia Decreased awareness Altered consciousness

Physical dependence Psychological dependence Variable energy changes Constipation

Nonresponsive Pinpoint pupils or “blown” pupils Bradycardia Hypotension Skin cyanotic Muscles flaccid Pulmonary edema Slowed respirations

Source. American Psychiatric Association 2000; Booth 1999; Center for Substance Abuse Treatment 2004.

phine) rapidly crosses the blood-brain barrier, even faster than morphine, due to the presence of two extra acetyl groups. These factors help explain why heroin is so euphorigenic, is so addictive, and is at the center of a multibillion dollar, worldwide illegal market—and has been for many decades (Booth 1999; Center for Substance Abuse Treatment 2004).

Opioid Receptors There are three main types of opioid receptors: µ, κ, and δ receptors. The µ opioid receptor is the primary receptor relevant to the use of buprenorphine in the treatment of opioid-dependent patients, and is therefore the focus of the rest of this clinically oriented chapter. For those interested in a more through discussion of buprenorphine’s potential interactions with other receptors, Cowan and Lewis (1995) published a textbook reviewing several decades of research on buprenorphine. Cowan recently published a paper updating some of these topics (Cowan 2007). The µ opioid receptor was named mu specifically because it was found to be the binding site for morphine. Mu receptors are widely distributed throughout the human nervous system. Agonist binding and activation of these receptors results in the actions listed in Table 3–1 (Center for Substance Abuse Treatment 2004; Reckitt Benckiser Healthcare 2006). A substance’s action, once it binds to the µ opioid receptor, can be very different depending on some key pharmacological properties. These differences are demonstrated in Figure 3–1 (Center for Substance Abuse Treatment 2004). In this figure, moving up the vertical axis represents an increasing opioid effect and moving to the right on the horizontal axis represents an increasing dose of the medication.

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Opioid effect

Full agonist (methadone)

Partial agonist (buprenorphine)

Antagonist (naloxone) Log dose

FIGURE 3–1. Conceptual representation of opioid effect versus log dose. Conceptual representation only; not to be used for dosing purposes. Source. Center for Substance Abuse Treatment 2004. Full agonists of the µ receptor include morphine, heroin, and methadone, as well as most of the prescription opioids. Full agonist binding is highly reinforcing in animal models of addiction and in human beings; full agonists are clearly the most widely abused type of opioid. This is demonstrated in Figure 3–1 by the squares labeled “Full agonist (methadone).” The illustration demonstrates how the level of opioid effect steadily increases (vertical axis) as the dose of the full agonist increases (horizontal axis). If the full agonist dose is too high then the opioid effect may become too great, and the individual is at risk of dying from respiratory depression. Partial agonists of the µ receptor bind the receptors but have a ceiling to the level of agonist activity that results from the receptor binding. Buprenorphine is an example of a partial agonist of the µ receptor. When it binds to the µ receptor, opioid agonist effects as listed in Table 3–1 may be experienced, or if the person is in opioid withdrawal, withdrawal symptoms may be relieved, but these effects are limited in degree. It is clear that buprenorphine’s ability to induce euphoria and respiratory depression has a ceiling effect even at high doses.

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This is demonstrated in Figure 3–1 by the circles labeled “Partial agonist (buprenorphine).” As the dose of the partial agonist increases (horizontal axis), the level of opioid effect steadily increases (vertical axis) until a ceiling is reached and no additional opioid effect is added even if the dose continues to increase. Even if the dose is very high, the opioid effect is limited and the risk of opioid overdose is minimal. Antagonists of the µ receptor are also shown in Figure 3–1, represented by the triangles labeled “Antagonist (naloxone)” demonstrating that they, too, bind the receptor but they provide no opioid effect at all regardless of the dose. Two examples of opioid antagonists are naltrexone and naloxone. Naltrexone is an oral medication with a half-life of sufficient duration to allow for once-daily dosing, or even alternate-day dosing, and is also approved by the U.S. Food and Drug Administration as a treatment for opioid dependence disorder. It works primarily by blocking agonists from binding to the µ receptor. It has not proven to be as effective a treatment for opioid dependence disorder as medications with agonist action, primarily because of the lack of any agonist effects and the absence of significant reduction in craving to use opioids (Center for Substance Abuse Treatment 2004). Naloxone is also an antagonist medication, but one that has to be given parenterally. Its primary clinical role has been to treat acute opioid overdose emergently by reversing the opioid effects including respiratory depression, by displacing opioid agonists off the µ receptors. Naloxone triggers a full opioid withdrawal disorder in individuals who are physically tolerant and dependent. Naloxone also has a clinical role in preventing diversion of buprenorphine as an integrated component of one sublingual product that combines buprenorphine and naloxone in a single tablet. This product is discussed in greater detail later in this chapter (see “Buprenorphine: Clinical Use Issues”). In summary, buprenorphine functions as a partial agonist with a ceiling effect for both opioid-induced euphoria and opioid-induced respiratory depression, and therefore clearly has an improved safety margin over all full opioid agonists. This is the primary reason that buprenorphine has been proven to be a clinically effective and safe treatment for opioid dependence disorder and has FDA approval for use in office-based settings (Center for Substance Abuse Treatment 2004). What is less clear is whether buprenorphine acts as a partial agonist regarding its analgesic effects. Cowan suggests in his recent paper (2007) that buprenorphine’s analgesic effect has not been clearly demonstrated to have a ceiling. He also reports that buprenorphine’s agonist actions at the opioid receptor-like-1 (ORL-1) receptor may have a role in explaining some of the analgesic effect of buprenorphine (Cowan 2007). The ORL-1 receptor was identified as a G protein-coupled receptor that is structurally very similar to opioid receptors. Subsequently the ORL-1 receptor’s endogenous ligand nociceptin (orphanin FQ) was discovered. This ligand-receptor system is the focus of

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ongoing research regarding its role in pain and analgesia. Fioravanti and Vanderah’s article (2008) provides a review that is beyond the scope of this chapter.

Opioid Withdrawal Issues When opioids are repeatedly dosed within a relatively short period of time, physical tolerance develops. Tolerance manifests as either a need for increased amounts of opioids to obtain the desired effect or a markedly diminished effect with continued use of the same amount of opioid (American Psychiatric Association 2000). Once physical tolerance and physical dependence on opioids have been established, opioid withdrawal is often experienced. Opioid withdrawal disorder is a specific mental disorder defined in the current version of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR; American Psychiatric Association 2000) and criteria include key signs and symptoms: 1) dysphoric mood, 2) nausea or vomiting, 3) muscle aches, 4) lacrimation or rhinorrhea, 5) pupillary dilation, piloerection, or sweating, 6) diarrhea, 7) yawning, 8) fever, and 9) insomnia. This DSM-IV-TR definition also accounts for the two main types of opioid withdrawal that are important to understand in the clinical use of buprenorphine, spontaneous withdrawal and precipitated withdrawal: •

•

Spontaneous withdrawal occurs when the usual opioid dosage is significantly reduced or when opioids are suddenly discontinued. For patients who are tolerant to short-acting opioids, such as hydrocodone or heroin, the onset of spontaneous withdrawal is within 24 hours of stopping opioid use and often begins within 8 hours after last use. In the case of long-acting opioids, such as methadone, spontaneous withdrawal does not develop for 24 hours or more after opioid use has ended. Precipitated withdrawal can occur when full agonists are displaced from the µ opioid receptor by substances that have greater affinity for receptor binding and have less agonist action; therefore, displacement by either an antagonist or a partial agonist rapidly reduces the level of agonist effect. If the person is opioid tolerant this will likely trigger the opioid withdrawal disorder, often suddenly and with a strong intensity.

Affinity and dissociation are two characteristics of µ opioid receptor binding that are important to understanding buprenorphine’s pharmacological actions. The affinity for a receptor refers to the strength to which the substance binds the receptor regardless of its action once bound. Buprenorphine has very strong affinity for the µ receptor, so much so that it displaces any full agonist that may be occupying the µ receptor. That is why the patient must wait until

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Opioid effect

Full agonist (methadone)

Partial agonist (buprenorphine)

Antagonist (naloxone) Log dose

FIGURE 3–2. Precipitated withdrawal if buprenorphine displaces full opioid agonist. Conceptual representation only; not to be used for dosing purposes. Source. Center for Substance Abuse Treatment 2004. all full opioid agonists are off the receptors before taking buprenorphine, so that buprenorphine will not displace the full agonists and precipitate opioid withdrawal. Naloxone and naltrexone also have strong µ receptor affinity, and displace full agonists and trigger full opioid withdrawal disorder (Center for Substance Abuse Treatment 2004). Figure 3–2 demonstrates this concept by the downward arrow representing the clinically significant sudden displacement of full agonists from the µ receptor by buprenorphine and the resultant decrease in the full agonist opioid effect in the central nervous system to a much reduced level, represented by the ceiling effect of the partial agonist. This rapid relative reduction to the partial agonist ceiling level results in opioid withdrawal symptoms even though some opioid agonist effect is still present from buprenorphine’s binding. If an antagonist is given and displaces the full agonist from the µ receptors, the point of the arrow will drop all the way to the horizontal axis, where no opioid agonist effect is present and full opioid withdrawal disorder will be experienced.

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Dissociation from a receptor refers to how easily the drug uncouples from the receptor when it is already bound. Buprenorphine dissociates very slowly from the µ receptor and, once bound, stays tightly attached—so tightly that full opioid agonists given after buprenorphine has attached to the µ receptors cannot displace it. This has two important clinical implications: 1. If the physician accidentally precipitates withdrawal in a person by displacing full agonists with buprenorphine, do not then give full agonists to treat the precipitated opioid withdrawal disorder because they will not displace the buprenorphine. 2. Once buprenorphine has successfully been inducted and the person continues to take it, taking another opioid will not produce any additional opioid effects and most likely the person will feel no effect. Even the injection of heroin will not displace buprenorphine off the µ receptors; thus the drug’s slow dissociation from the receptors has an added therapeutic advantage. This also has potential implications for giving opioids for analgesia if a buprenorphine patient needs acute pain management, but there are several options to address pain management in these circumstances (see Chapter 11, “Management of Acute and Chronic Pain”). The specifics of spontaneous and precipitated withdrawal are relevant for buprenorphine induction and in explaining to patients the importance of having stopped taking all opioids prior to induction, how long they must wait for initial buprenorphine dosing, and that they must be experiencing the opioid withdrawal disorder before the first dose of buprenorphine may be given. The details of induction are covered in Chapter 6 (“Clinical Use of Buprenorphine”).

Buprenorphine PHARMACOKINETICS Buprenorphine is approximately 96% protein bound in the plasma and undergoes N-dealkylation via the cytochrome P450 (CYP450) 3A4 enzyme system to produce an active metabolite, norbuprenorphine. Both buprenorphine and norbuprenorphine also undergo glucuronidation in the liver. Thirty percent of the drug is eliminated in urine and 70% in feces. Buprenorphine has a mean elimination half-life from plasma of 37 hours (Center for Substance Abuse Treatment 2004; Reckitt Benckiser Healthcare 2006). Buprenorphine’s metabolism by the CYP450 3A4 enzyme means that inhibitors of 3A4 or other substrates metabolized by the 3A4 enzyme could raise buprenorphine levels

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and that 3A4 inducers could lower buprenorphine levels. Table 3–2 shows a partial list of medications interacting with the CYP450 3A4 enzyme system. With the exception of interactions with some antiretroviral medications, it appears that most of these interactions are not clinically significant (see also Chapter 6, section “Drug-Drug Interactions,” and Chapter 9, “Psychiatric Comorbidity,” section “Drug Interactions With Buprenorphine”). Deaths have been associated with injecting buprenorphine with benzodiazepines and/or other central nervous system depressants (Reynaud et al. 1998a, 1998b). Therefore the use of sedative-hypnotics (benzodiazepines, barbiturates, and others) is a relative contraindication to treatment with buprenorphine, because the combination of buprenorphine and sedative-hypnotics may increase depression of the central nervous system. If treatment with buprenorphine and sedative hypnotics is necessary, the doses of both medications may need to be lowered (Center for Substance Abuse Treatment 2004). Side effects of buprenorphine can include constipation, nausea, and emesis but the frequency and intensity of these side effects are much lower than with full opioid agonists (Center for Substance Abuse Treatment 2004). Patients maintained with buprenorphine show no clinically significant disruption in cognitive and psychomotor performance on formal testing (Walsh et al. 1994). Elevated levels of the liver enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST) have been reported in patients taking buprenorphine (Lange et al. 1990; Petry et al. 2000). Petry et al. (2000) reported mild elevations in liver enzyme levels in patients who received sublingual buprenorphine for more than 40 days and who were treated with various dosages (2, 4, or 8 mg/70 kg/day). They found that patients with a history of viral hepatitis were significantly more likely to have enzyme level increases shown on their liver function tests compared with those without a history of hepatitis. This study had 72 patients with a history of hepatitis who had a median increase in ALT of 8.5 (range, −12 to 54) and a median increase in AST of 9.5 (range, −8 to 32); and 48 patients without a history of hepatitis who had a median ALT increase of 0 (range, −7 to 8) and a median AST increase of 1 (range, −6 to 4.5). The likelihood of seeing an increase in AST level varied as a function of buprenorphine dosage. It is important to note that these increases, while statistically significant, were quite small and of questionable clinical significance (Petry et al. 2000). There are reports of very high transaminase elevations (13–50 times normal levels) associated with intravenous buprenorphine use in patients infected with the hepatitis C virus. The proposed mechanism is inhibition of hepatic mitochondrial function by very high buprenorphine concentrations associated with injection, but not with sublingual dosing (Berson et al. 2001; Johnson et al. 2003).

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TABLE 3–2. Inhibitorsb Amiodarone Clarithromycin Delavirdine Erythromycin Fluconazole Fluoxetine Fluvoxamine Grapefruit juice Indinavir Itraconazole Ketoconazole Metronidazole Miconazole Nefazodone Nelfinavir Nicardipine Norfloxacin Omeprazole Paroxetine Ritonavir Saquinavir Sertraline Verapamil Zafirlukast Zileuton

aFor

Medications metabolized by cytochrome P450 3A4 (partial list)a Substrates Alprazolam Amlodipine Astemizole Atorvastatin Carbamazepine Cisapride Clindamycin Clonazepam Cyclobenzaprine Cyclosporine Dapsone Delavirdine Dexamethasone Diazepam Diltiazem Disopyramide Doxorubicin Erythromycin Estrogens Etoposide Felodipine Fentanyl Fexofenadine Glyburide Ifosfamide Indinavir Ketoconazole Lansoprazole Lidocaine

Loratadine Losartan Lovastatin Miconazole Midazolam Nefazodone Nelfinavir Nicardipine Nifedipine Nimodipine Ondansetron Oral contraceptives Paclitaxel Prednisone Progestins Quinidine Rifampin Ritonavir R-warfarin Saquinavir Sertraline Simvastatin Tacrolimus Tamoxifen Verapamil Vinblastine Vinorelbine Zileuton

Inducers c Carbamazepine Dexamethasone Efavirenz Ethosuximide Nevirapine Phenobarbital Phenytoin Primidone Rifampin

a continuously updated list of cytochrome P450 3A4 drug interactions, visit http://medicine.iupui.edu/clinpharm/ddis. bPotentially increasing blood levels of buprenorphine. cPotentially decreasing blood levels of buprenorphine. Source. Center for Substance Abuse Treatment 2004.

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CLINICAL USE ISSUES Three different clinical formulations of buprenorphine are available in U.S. pharmacies as of this writing in 2010. One is FDA approved for use as a parenteral analgesic and two sublingual forms are FDA approved for use in the treatment of opioid withdrawal disorder and opioid dependence disorder.

Parenteral Analgesic Parenteral buprenorphine hydrochloride (HCl) is a formulation that is available as a solution for intramuscular or intravenous use and has been approved by the FDA as an analgesic. Parenteral buprenorphine HCl is available in a solution with a concentration of 0.3 mg/mL, and recommended dosing for moderate to severe pain is 0.3 mg intramuscularly or intravenously. This initial dose may be repeated once after 30–60 minutes, then every 6–8 hours as needed for pain control (Ben Venue Laboratories 2004). It is important to understand that it is against U.S. federal laws for any prescriptions to be written for parenteral buprenorphine for the treatment of either opioid withdrawal disorder or opioid dependence disorder. It is not just beyond the FDA-approved uses to prescribe parenteral buprenorphine HCl for these opioid disorders, it is against the law and puts the physician at risk for federal prosecution and punishment.

Sublingual Forms Sublingual buprenorphine is available in the United States in two forms. One is Suboxone, referred to as the combo product, which combines buprenorphine and naloxone in a homogenous compressed tablet; the other is Subutex, referred to as the mono product, a tablet that contains only buprenorphine. Both are FDA approved for the treatment of opioid dependence, which applies to DSM-IV-TR diagnoses of opioid withdrawal disorder and opioid dependence disorder. The combo product combines buprenorphine and naloxone in a 4-to-1 ratio in two dose sizes, either 8 mg buprenorphine with 2 mg naloxone or 2 mg buprenorphine with 0.5 mg naloxone. The mono product contains only buprenorphine in two dose sizes, either 8 mg buprenorphine or 2 mg buprenorphine. The target clinical dosage range for both the combo and mono product is 8–16 mg of buprenorphine per day, with a maximum recommend dosage of 32 mg/day. As Table 3–3 shows, sublingual buprenorphine has poor oral availability. Swallowing these tablets results in no clinically significant effects. Buprenorphine tablets dissolved sublingually, as designed, allow the buprenorphine to be absorbed and to be clinically effective. In the case of the combo product, the buprenorphine is absorbed when dissolved sublingually but the naloxone is not significantly absorbed and has no clinical effect. However, if the combo prod-

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TABLE 3–3.

Bioavailability of buprenorphine Buprenorphine bioavailability relative to route of administration

Route of administration

Intravenous

Intramuscular

Sublingual solution

100%

—

—

Intramuscular

70%

100%

—

Sublingual solution

49%

70%

Sublingual tablet

29%

Intravenous

42%

100% 50%–70%

Source. Brewster et al. 1981; Kuhlman et al. 1996; Lloyd-Jones et al. 1980; Nath et al. 1999; Schuh and Johanson 1999; Strain and Stitzer 1999; Weinberg et al. 1988. Adapted from Center for Substance Abuse Treatment 2004.

uct is dissolved into solution and injected, then naloxone is clinically active and binds to the µ receptors and its antagonist effect predominates, blocking much of the opioid effect. Naloxone also triggers opioid withdrawal disorder if the individual who injects it is opioid dependent. When the mono product is injected, buprenorphine can produce significant levels of euphoria, clearly can be abused for its euphoric effect, and is subject to diversion for misuse. The only reason naloxone is an added component of the combo tablet is to prevent dissolving and injecting the tablet for euphoric effect, thus minimizing the risk of diversion (Center for Substance Abuse Treatment 2004; Stoller et al. 2001).

Conclusion Humans have used opiates for medicinal and euphorigenic purposes for thousands of years. The recent development of opioid antagonists and partial agonists has expanded our therapeutic options and, with buprenorphine, has added a unique agent for the treatment of opioid dependence. Because of its high affinity for opioid receptors, its long duration of action, and the ceiling effect on respiratory depression, it has proved to be an unusually safe and effective medication for managing opioid addiction. Dosing is relatively straightforward, though clinicians must be careful to avoid precipitating opioid withdrawal when initiating buprenorphine treatment in individuals who have recently used other opioids. The presence of naloxone in the buprenorphine combo tablet is an added safety feature that reduces the potential for abuse and diversion and further enhances the drug’s clinical utility.

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Clinical Pearls • Opioids are more likely to be abused if they 1. Have a faster route of administration, 2. Have a shorter half-life, and 3. Are more lipophilic, which allows them to pass through the blood-brain barrier more easily. • Buprenorphine, a µ opioid receptor partial agonist, binds tightly to opioid receptors but only partially activates them. Thus, buprenorphine's ability to produce euphoria and respiratory depression is limited, even at high doses. • Patients who are physically dependent on opioids can develop a precipitated withdrawal with buprenorphine; therefore, patients need to be in opioid withdrawal before receiving the initial dose of buprenorphine. • Buprenorphine is metabolized by the CYP450 3A4 system, but most drug-drug interactions do not appear to be clinically significant. • The buprenorphine-naloxone combination is the preferred form of the medication in order to diminish the likelihood of diversion to injected use.

References American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision. Washington, DC, American Psychiatric Association, 2000 Ben Venue Laboratories: Buprenorphine hydrochloride injection: prescribing information. Bedford, OH, Ben Venue Laboratories, August 2004. Available at: http:// www.bedfordlabs.com/BedfordLabsWeb/products/inserts/Div-BUP-P00.pdf. Accessed June 15, 2010. Berson A, Gervais A, Cazals D, et al: Hepatitis after intravenous buprenorphine misuse in heroin addicts. J Hepatol 34:346–350, 2001 Booth M: Opium: A History. New York, St Martin’s Griffin, 1999 Brewster D, Humphrey MJ, Mcleavy MA: The systemic bioavailability of buprenorphine by various routes of administration. J Pharm Pharmacol 33:500–506, 1981 Center for Substance Abuse Treatment: Clinical Guidelines for the Use of Buprenorphine in the Treatment of Opioid Addiction. Treatment Improvement Protocol (TIP) Series 40. DHHS Publ No (SMA) 04-3939. Rockville, MD, Substance Abuse and Mental Health Services Administration, 2004. Available at: http:// www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=hssamhsatip& part=A72248. Accessed April 29, 2010.

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Cowan A: Buprenorphine: the basic pharmacology revisited. J Addict Med 1:68–72, 2007 Cowan A, Lewis JW (eds): Buprenorphine: Combatting Drug Abuse with a Unique Opioid. New York, Wiley-Liss, 1995 Fioravanti B, Vanderah TW: The ORL-1 receptor system: are there opportunities for antagonists in pain therapy? Curr Top Med Chem 8:1442–1451, 2008 Johnson RE, Strain EC, Amass L: Buprenorphine: how to use it right. Drug Alcohol Depend 79:S59–S77, 2003 Kuhlman JJ, Lalani S, Magluilo J, et al: Human pharmacokinetics of intravenous, sublingual, and buccal buprenorphine. J Anal Toxicol 20:369–378, 1996 Lange WR, Fudala PJ, Dax EM, et al: Safety and side-effects of buprenorphine in the clinical management of heroin addiction. Drug Alcohol Depend 26:19–28, 1990 Lloyd-Jones JG, Robinson P, Henson R, et al: Plasma concentration and disposition of buprenorphine after intravenous and intramuscular doses to baboons. Eur J Drug Metab Pharmacokinet 5:233–239, 1980 Nath RP, Upton RA, Everhart ET, et al: Buprenorphine pharmacokinetics: relative bioavailability of sublingual tablet and liquid formulations. J Clin Pharmacol 39:619– 623, 1999 Petry NM, Bickel WK, Piasecki D, et al: Elevated liver enzyme levels in opioid-dependent patients with hepatitis treated with buprenorphine. Am J Addict 9:265–269, 2000 Reckitt Benckiser Healthcare: Buprenorphine hydrochloride and naloxone hydrochloride dihydrate sublingual tablets (Suboxone) and buprenorphine hydrochloride sublingual tablets (Subutex): prescribing information. Hull, United Kingdom, Reckitt Benckiser Healthcare, September 2006 Reynaud M, Petit G, Potard D, et al: Six deaths linked to concomitant use of buprenorphine and benzodiazepines. Addiction 93:1385–1392, 1998a Reynaud M, Tracqui A, Petit G, et al: Six deaths linked to misuse of buprenorphinebenzodiazepine combinations. Am J Psychiatry 155:448–449, 1998b Schuh KJ, Johanson CE: Pharmacokinetic comparison of the buprenorphine sublingual liquid and tablet. Drug Alcohol Depend 56:55–60, 1999 Stoller KB, Bigelow GE, Walsh SL, et al: Effects of buprenorphine/naloxone in opioiddependent humans. Psychopharmacology (Berl) 154:230–242, 2001 Strain EC, Stitzer ML (eds): Methadone Treatment for Opioid Dependence. Baltimore, MD, Johns Hopkins University Press, 1999 Walsh SL, Preston KL, Stitzer ML, et al: Clinical pharmacology of buprenorphine: ceiling effects at high doses. Clin Pharmacol Ther 55:569–580, 1994 Weinberg DS, Inturrisi CE, Reidenberg B, et al: Sublingual absorption of selected opioid analgesics. Clin Pharmacol Ther 44:335–342, 1988

4 Efficacy and Safety of Buprenorphine Eric C. Strain, M.D.

History and Rationale for the Development of Buprenorphine for Treatment of Opioid Dependence This chapter provides a review of the history of buprenorphine from its initial development as an analgesic to its current use as a treatment for opioid dependence. The discussion includes an overview of the safety and efficacy trials that established its value as a medication for maintenance treatment and for the management of opioid withdrawal. Buprenorphine was first synthesized in the late 1960s and was initially developed and marketed throughout the world as an analgesic. In the United States it was sold under the brand name Buprenex and outside the United States as Temgesic. In the United States, it was only available in a parenteral form for the treatment of pain. However, a sublingual analgesic form was marketed in other countries (e.g., New Zealand). Although buprenorphine was initially marketed for the treatment of pain, it was quickly recognized that buprenorphine might have value as a medication that could be used for the treatment of opioid dependence. A paper published by Jasinski and coworkers (1978) described the pharmacological profile of buprenorphine in humans under a variety of experimental conditions and concluded that the medication had characteristics that might make it particularly useful and effective for the treatment of opioid dependence. 59

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PHARMACOLOGICAL FEATURES Of its pharmacological characteristics, three primary features of buprenorphine are particularly relevant to its use as an opioid dependence treatment medication. Two of these may be seen as advantageous, whereas the third is a relatively minor detriment to its use. Although it is beyond the scope of this chapter to address each in detail, these three characteristics are reviewed here because they have direct clinical implications. 1. Buprenorphine acts as an agonist at the µ opioid receptor. It has been long recognized that it is a partial agonist at the µ receptor. Partial agonist medications produce effects that are very similar to full agonist medications at the lower end of a dose-response curve, but as the dose of a partial agonist increases, the effect of the medication plateaus, such that there is less of a maximal effect compared with a full agonist medication. The common medications that are contrasted with buprenorphine are full µ opioid receptor agonists such as methadone and morphine, which generally have the capacity to produce greater effects than buprenorphine at higher doses. Notably, the relative degree of maximal effect of a partial agonist relative to a full agonist can vary as a function of the outcome measure being considered (e.g., in the case of opioids, respiratory depression vs. gastrointestinal motility vs. analgesia). The fact that buprenorphine acts at the µ opioid receptor is important for several reasons. Agonism at the µ receptor means that buprenorphine can suppress spontaneous opioid withdrawal, ensuring that patients who are in opioid withdrawal at the time they take their first dose of buprenorphine will have suppression of those withdrawal symptoms. In addition, occupancy at the µ receptor provides blockade, so a subsequently administered dose of another µ opioid receptor agonist (such as heroin) is not experienced to the same degree as would occur if no buprenorphine were present. Finally, opioids that act at the µ receptor generally decrease craving for illicit opioids in persons who are physically dependent on opioids and who receive maintenance therapy with a µ agonist. 2. Buprenorphine has a bell-shaped dose-response curve. That is, as the dose of buprenorphine increases, there is an increase in a measured effect (e.g., analgesia, respiratory depression) until a maximal effect is achieved, then the measured effect decreases at even higher doses. Notably, this bell-shaped dose-response curve has only been shown in animal models (i.e., no human studies to date have shown it). However, in animals buprenorphine’s bellshaped curve has been shown for several measures, including analgesia, gastrointestinal motility (i.e., constipation), and respiratory depression.

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The reason for the decrease in effects at higher doses was originally thought to be related to a second opioid receptor effect of buprenorphine— antagonism at the κ receptor. (This combination of partial agonism at the µ receptor and antagonism at the κ receptor is the reason buprenorphine is sometimes called an opioid mixed agonist-antagonist. There are several other marketed opioid mixed agonist-antagonist analgesics, such as pentazocine and butorphanol.) However, more recent preclinical data suggest that the descending limb of buprenorphine’s dose-response curve can be attributed to an alternative pharmacological action of this medication—a nonopioid action at the opioid receptor-like-1 (ORL-1) receptor. That is, buprenorphine acts as an agonist at the ORL-1 receptor. Animal studies suggest that when ORL-1 receptors are not present, buprenorphine produces effects that look like those of a full agonist opioid (i.e., no descending limb to the dose-response curve). These two pharmacological effects translate to clinical advantages. Mu receptor agonism means that buprenorphine suppresses withdrawal, blocks the effects of other opioids, and decreases craving. The bell-shaped doseresponse curve, combined with the lower maximal effect as a partial µ agonist, means that there is a lower risk of respiratory depression associated with an overdose of the drug. However, the third feature of the drug is not a particularly advantageous characteristic (although it is not a marked disadvantage, either). 3. Buprenorphine has poor oral bioavailability. The most common delivery route for medications taken on an outpatient basis is swallowing, and although other routes can be used (e.g., the injection of insulin, topical administration of nicotine with a patch), they are less common routes of administration. Buprenorphine has fair sublingual bioavailability and a sublingual form was developed for the treatment of opioid dependence. Although this route of administration is relatively uncommon for medications that are self-administered, it has been accepted by patients. Because a sublingual tablet needs to be water soluble, a concern with this formulation was that it could be relatively easy to dissolve in water and inject. Given that the sublingual bioavailability is only fair compared with parenteral bioavailability, sublingual doses are relatively high compared with typical parenteral analgesic doses (8–16 mg vs. 0.2–0.3 mg, respectively). Thus, a water-soluble sublingual tablet has the potential to be relatively easy to dissolve and inject with the subsequent delivery of a relatively high dose of the drug. These aspects of administration route and relative bioavailability could impact the risk of diversion and parenteral misuse of a sublingual buprenorphine tablet. To address this potential, tablets that contain naloxone

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were developed. Although a full description of the scientific basis for a buprenorphine-naloxone tablet is not provided here, the logic of this combination is based on three observations. First, naloxone has very poor sublingual bioavailability. Second, injected naloxone precipitates an opioid withdrawal syndrome in persons with opioid dependence. And third, opioid withdrawal is distressing but rarely life threatening. Thus, when a combined buprenorphine-naloxone tablet is taken via the intended therapeutic route (sublingually), the desired therapeutic effect is achieved. However, if the tablet is dissolved and injected (by an opioid-dependent person), then the naloxone effect occurs and the person experiences the opioid withdrawal syndrome. (However, note that this would only be the case for a person who is opioid dependent.) Although the withdrawal syndrome is distressing, it is generally tolerable and not a medical emergency. These pharmacological features of buprenorphine suggested that it could be a useful agent for the treatment of opioid dependence, and furthermore that it would be pharmacologically different from traditional full µ opioid receptor agonist medications (i.e., methadone and L-α-acetylmethadol [LAAM]). As these features came to be appreciated, there was recognition that it might be possible for buprenorphine to be used outside the traditional methadone clinic delivery system. In order to appreciate this aspect of buprenorphine’s development, the context of medications development needs to be appreciated, in particular the approval and use of LAAM in the United States.

U.S. APPROVAL AND USE OF LAAM AND ITS IMPACT ON BUPRENORPHINE DEVELOPMENT During the 1990s, when buprenorphine was being intensively studied as a potential treatment for opioid dependence, another opioid treatment medication was also being studied and eventually approved for use in the United States— LAAM. Although LAAM had been identified as a possible treatment for opioid dependence in the 1970s, it had languished for years until the National Institute on Drug Abuse (NIDA) took the initiative to obtain U.S. Food and Drug Administration (FDA) approval for this medication, which then occurred in 1993. However, LAAM needed to be dispensed through the opioid treatment program (OTP) system—that is, methadone clinics. Despite the availability of this new alternative medication that had good efficacy, there was very limited use of LAAM and essentially no expansion of the treatment system was associated with the availability of LAAM. Although subsequent concerns arose regarding potential cardiac effects of LAAM, its eventual withdrawal from the U.S. market was due to low sales rather than its cardiac effects.

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The experience with LAAM impacted planning for the eventual approval and use of buprenorphine. LAAM could only be provided through the OTP system, and had not expanded treatment capacity. In order to avoid a similar experience with buprenorphine in the United States, federal legislative changes were enacted that permitted the use of certain types of medications in officebased practices for the treatment of opioid dependence. This law, the Drug Addiction Treatment Act of 2000, identified potential medications for officebased treatment as being on Schedule III, IV, or V (i.e., having less abuse potential than Schedule II medications, such as methadone). Although this legislation did not specify buprenorphine, it was clearly designed with buprenorphine in mind. Because buprenorphine was approved as a Schedule III medication (based on its pharmacological characteristics suggesting it has lower abuse potential), it could then be used in office-based practices. This increased the likelihood that buprenorphine would not be another LAAM.

SUMMARY Although buprenorphine was initially developed for use as an analgesic, it is interesting that buprenorphine’s major clinical impact has occurred as a treatment for opioid dependence. As has been noted repeatedly over the years, the pharmacological effects of buprenorphine are unique, and these unique features— such as its partial agonist effects and the bell-shaped dose-response curve— make it particularly suited for the treatment of opioid addiction. Because of these features, buprenorphine was well positioned to be used outside of the traditional OTP system, which in turn made it a medication that has helped to expand the treatment of opioid dependence.

Controlled Trials Assessing Buprenorphine’s Efficacy for Maintenance Treatment of Opioid Dependence Clinical studies testing the efficacy of buprenorphine have included both inpatient (or residential) human laboratory studies and outpatient clinical trials. The former have tended to be smaller studies with a within-subject design (i.e., in which volunteers serve as their own control subject over the course of the study). There have been an extensive number of these studies, and reviewing all of them is beyond the scope of this chapter. The results from these studies provided critical information about buprenorphine, although direct translation to clinical use

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of the medication was not always the purpose of the studies. Outpatient clinical trials, on the other hand, provide important data that are more representative of and relevant to clinical use. These generally have been group comparison studies, and two primary comparisons have been used to test buprenorphine’s efficacy in outpatient clinical trials—studies that compared it with placebo, and those that compared it with methadone. Although most of these studies were conducted in the 1990s, before buprenorphine’s approval in the United States, there continue to be outpatient clinical trials testing its efficacy.

HUMAN LABORATORY STUDIES Multiple human laboratory studies have tested the blockade efficacy of buprenorphine under different experimental conditions. In general, these studies enroll opioid-dependent volunteers, maintain the subjects with buprenorphine or buprenorphine-naloxone (either buprenorphine solution or, in later studies, the tablet formulation), and then test whether opioid agonist–like effects are produced when subjects receive a prototypic µ opioid receptor agonist such as morphine, heroin, or hydromorphone. The subject might be challenged directly with the drug (Bickel et al. 1988; Strain et al. 1997, 2002) and assessed for the drug’s effects, or be allowed to self-administer the drug to determine whether the drug’s relative reinforcing effects are diminished by buprenorphine treatment (Comer et al. 2001, 2005; Mello and Mendelson 1980). One difficulty with these human laboratory studies is that the ideal control condition—a period of time when the subject is maintained with placebo and challenged with an opioid or allowed to self-administer an opioid—is not included in the studies. A placebo maintenance period would permit the efficacy of buprenorphine to be more accurately characterized. However, it is not practical to conduct such a study, even if conducted under the controlled conditions of an inpatient ward as is typical for these projects. Participants would need to be fully withdrawn from opioids, making blinding of buprenorphine versus placebo maintenance conditions problematic. Alternatively, a separate group of subjects who do not have active opioid dependence could be used as a comparison group, although groups need to be matched to ensure that other factors do not account for differences that might be noted. Given these qualifications, studies have typically compared the relative efficacy of different doses of buprenorphine, with the idea that greater attenuation of opioid effect or less selfadministration for a higher dose of buprenorphine (vs. a lower dose) provides evidence of efficacy. When buprenorphine is studied in the human laboratory, dose-related blockade is generally demonstrated. That is, volunteers maintained on buprenorphine (or buprenorphine-naloxone) report lower ratings of opioid agonist–like effects with higher doses of buprenorphine, and self-administer less

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of a µ opioid receptor agonist at the higher doses. Dosages of either 2 or 4 mg of buprenorphine per day (or the equivalent of buprenorphine-naloxone) produce significantly less blockade of opioid effects and less self-administration of an opioid, compared with dosages of 8–32 mg of buprenorphine per day (or the equivalent of buprenorphine-naloxone). These effects have been shown both with direct challenge sessions and in self-administration studies. Some evidence suggests that 16 mg may be more effective than 8 mg of buprenorphine daily, although not all studies have shown a distinction. However, this should not be interpreted to mean that daily doses of greater than 8 mg of buprenorphine are not more effective than 8 mg/day, and clearly there are some subjects in studies (and some patients in clinical practice) who have better outcomes with daily doses greater than 8 mg. There can be considerable variability in the responses of individual subjects in a human laboratory study. Results from these studies also show that there is often incomplete blockade or suppression of self-administration of a µ opioid receptor agonist when a person is maintained with buprenorphine—especially if a sufficiently high dosage of the µ agonist is employed in the study. Although these studies provide critical data relevant to the demonstration of buprenorphine’s efficacy, they also highlight that the medication alone is not a magic bullet that fully addresses all of the factors that can lead to use of illicit opioids by a person with opioid addiction. Although maintenance with buprenorphine—probably at a dosage of at least 8 mg/day for most patients—can be very effective at decreasing the subjective effects of opioids and the likelihood of taking these drugs, optimal outcomes are achieved when buprenorphine is taken by a motivated patient who is engaged in other treatment services that concurrently address drug use (see Chapter 8, “Clinical Management II,” and Chapter 9, “Psychiatric Comorbidity”).

OUTPATIENT GROUP COMPARISON CLINICAL TRIALS Human laboratory studies provide data from highly controlled experimental conditions that allow characterization of buprenorphine’s efficacy when confounding factors (e.g., other drug use, presence of a comorbid condition) are controlled for or excluded from study participants. Outpatient clinical trials, on the other hand, provide data that can be viewed as more reflective of “real life.” Such studies, although closer to clinical practice than residential studies, often employ design features that distinguish these trials as significantly different from routine care (e.g., double-blind dosing, random assignment to treatment conditions, intensive collection of standard outcome measures). It is worth noting that the goal of a controlled clinical trial is not to model exactly how a medication will be used by clinicians, but to provide a scientific basis for answering

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specific questions about the efficacy and/or safety of the medication under the particular experimental conditions utilized. There are advantages to both outpatient clinical trials and inpatient/residential laboratory study approaches, and they should be seen as complementary with each being relevant to the drug development process. The next two sections describe findings from outpatient clinical trials of buprenorphine’s efficacy compared with placebo and compared with methadone.

Buprenorphine Compared With Placebo Relatively few studies have tested the efficacy of buprenorphine compared with a true placebo condition. In part, this is related to the inherent difficulty in blinding placebo medication use for a person who is opioid dependent. It is very likely that the blind would be immediately broken if an opioid-dependent person were to directly start taking placebo, because the person would readily detect the lack of withdrawal suppression and subjective opioid agonist effects, and the resulting classic opioid withdrawal symptoms. However, strategies have been employed to provide true placebo control conditions; probably the most common such approach has been to have participants who have been assigned to a placebo condition undergo a period of active treatment medication that includes gradual withdrawal and transfer onto placebo doses of buprenorphine. In alternative methods to this approach, one study used a low-dose buprenorphine condition as a placebo-like control condition (Ling et al. 1998), and another used a novel choice procedure that allowed volunteers to switch from placebo to active medication (Johnson et al. 1995). Controlled outpatient clinical trials that have tested the efficacy of buprenorphine compared with placebo have consistently shown that buprenorphine is more effective than placebo for primary outcome measures of treatment retention and illicit opioid use (Fudala et al. 2003; Johnson et al. 1995; Kakko et al. 2003; Krook et al. 2002; Ling et al. 1998). Cross-study comparisons are somewhat difficult, given the use of different dosages of buprenorphine, different durations of treatment, and different outcome assessments. In general, however, dosages of 8–16 mg of sublingual buprenorphine per day (or the equivalent of buprenorphine-naloxone) have typically been compared with 0 mg (or in one case, a 1-mg placebo-like control condition) and shown to be superior. Although dosages greater than 16 mg/day have been tested, the relative efficacy of higher dosages compared with 8–16 mg/day has not been a primary outcome assessed. Such higher dosages (up to 32 mg/day) may be clinically indicated for some patients, and there is clearly variability in the optimal dosage needed for some patients. Although it is difficult to compare outcomes from these studies, it is worth noting that retention of buprenorphine-treated patients is consistently superior

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to retention of patients treated with placebo. Indeed, placebo-treated participants in these studies generally drop out. For example, after 16 weeks of treatment in one study, the retention rate for patients treated with 16 mg of buprenorphine per day was 61% versus 40% for the 1-mg (placebo-like) condition (Ling et al. 1998). In a study of 1 year’s duration, 75% of participants treated with 16 mg of sublingual buprenorphine per day remained in treatment at 1 year, compared with none of the participants who underwent double-blind buprenorphine withdrawal followed by placebo treatment (Kakko et al. 2003). In summary, these rigorously conducted, controlled clinical trials show that daily sublingual buprenorphine is superior to placebo in the outpatient treatment of opioid dependence. A final point regarding these studies, and the clinical trials comparing buprenorphine versus methadone that are summarized in the next section, is worth noting. The goal of these studies was to test the efficacy of buprenorphine. However, optimal clinical outcomes for the treatment of opioid dependence (and other addictions) occur when pharmacotherapies are combined with nonpharmacological treatments (Amato et al. 2004). Thus, if the interested clinician reader reviews these papers and studies, it is important to keep in mind that it is likely the reported outcomes can be considerably improved when buprenorphine is used outside the constraints of a clinical trial, and with the concurrent care of committed clinicians.

Buprenorphine Compared With Methadone Although the number of studies that have tested buprenorphine’s efficacy compared with placebo is relatively small, many more outpatient studies have compared buprenorphine with methadone treatment (Mattick et al. 2008). The general conclusions drawn here are based on well-conducted clinical trials. Studies that were not double-blind, did not randomize participants to dose conditions, or had other methodological features that make interpretation of findings problematic are generally not factored in when considering buprenorphine’s efficacy relative to methadone’s efficacy in this section. (Such studies can provide supportive evidence, but confounds in design or execution make interpretation of findings problematic.) Despite the use of good clinical trial methods, features of these studies can differ considerably—for example, in the dosages of buprenorphine and methadone used, the frequency of buprenorphine dosing, whether the doses of each medication are fixed or flexible, and the primary outcome assessments and the frequency of collection for these primary outcome assessments. Despite these differences, several general conclusions regarding buprenorphine’s efficacy compared with methadone’s can be made. Outcomes with buprenorphine treatment are generally similar to those achieved with methadone, with methadone dosages of up to about 60 mg/day. When methadone dosages

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of greater than 60 mg/day are used, it appears that methadone provides better outcomes (treatment retention and some measure of illicit opioid use—selfreported use and/or urine testing results—are typically used as primary outcome measures in most studies). However, it is worth noting that most clinical trials have been conservative with buprenorphine dosing (despite the apparent safety of this medication at high doses), that no studies have tested the efficacy of dosages greater than 32 mg of sublingual buprenorphine per day, and that few have tested doses even that high. It is useful to elaborate on this point. Recall that buprenorphine has a bell-shaped dose-response curve. Theoretically, it is possible that at higher doses a decrease in some effects might occur, but that greater degrees of opioid blockade might still be achieved. Thus it is interesting that despite the apparent safety of high doses of buprenorphine, no controlled clinical trials have tested dosages greater than 32 mg/day. Indeed, there has been little research in humans that has examined the effects of daily doses greater than 32 mg under any experimental conditions, such as human laboratory studies. It appears that dosages of about 8–24 mg of buprenorphine per day produce outcomes similar to those seen with moderate dosages of methadone (i.e., up to 60 mg/day). Most of the studies that have compared buprenorphine versus methadone were conducted in methadone treatment clinics (OTPs), and it is important to note that the circumstances under which buprenorphine is used in the United States—in an office-based setting that is physician based—are very different from the treatment provided at an OTP. Although there has been research looking at the efficacy of buprenorphine in office-based settings (Fiellin et al. 2006), this work is more limited and generally has not compared office-based buprenorphine to traditional OTP-delivered methadone treatment. Although findings from controlled clinical trials comparing daily sublingual buprenorphine with methadone suggest that outcomes achieved with methadone may be better at higher methadone doses, this should not be interpreted to suggest that buprenorphine is not a treatment option for patients with higher levels of opioid physical dependence. There can be considerable variability in the response that different patients have to a medication. Indeed, it has been shown that the bioavailability of buprenorphine can vary twofold between different subjects treated with the same dose, suggesting that conclusions based on the dose delivered may obscure differences related to blood levels (Strain et al. 2004). And, the impact of nonpharmacological aspects of treatment (e.g., intensity of counseling services), the particular circumstances of the patient (e.g., his or her level of motivation), and the features of the setting of treatment (e.g., ready access to office-based treatment) can impact the efficacy of buprenorphine. Perhaps the most important conclusion that can be drawn from the controlled clinical trials that have compared buprenorphine and methadone is that both medications are efficacious, and that a patient who

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is not responding well to one—when all aspects of the treatment have been optimized (e.g., dosage, level of counseling, involvement of significant others)— should be considered for treatment with the other. Both are excellent options for the treatment of opioid dependence.

Controlled Trials Assessing Buprenorphine’s Efficacy for Opioid Withdrawal Treatment When buprenorphine first became available for the treatment of opioid dependence in the United States, a considerable proportion of its use was for the treatment of opioid withdrawal. Indeed, before the approval of the sublingual tablet it was very common for clinicians to report that they used the parenteral form of buprenorphine to treat opioid withdrawal. Although the current relative proportion of buprenorphine use for withdrawal versus maintenance treatment is not known, it appears that the growth of buprenorphine use in the United States in recent years has been greater for maintenance than for withdrawal treatment. Before the use of buprenorphine for the treatment of opioid withdrawal, a common pharmacological treatment used to alleviate opioid withdrawal, especially in inpatient settings, was clonidine. An early study that directly compared buprenorphine with clonidine found that buprenorphine had an overall better profile of efficacy and safety than clonidine (Cheskin et al. 1994), and subsequent studies have had similar findings (Gowing et al. 2004; Ling et al. 2005; Ziedonis et al. 2009). Although situations in which clonidine would be preferred for the treatment of opioid withdrawal in a particular patient can be imagined, in general clonidine is no longer a first-line agent for this indication—especially on an inpatient basis, where dosing can be supervised and risk of diversion or misuse of buprenorphine is quite low. On an outpatient basis, methadone or buprenorphine may be used to treat opioid withdrawal. Studies that have directly compared buprenorphine with methadone for the outpatient treatment of withdrawal have been uncommon, and those that have done so have tended to involve either small samples, special groups such as adolescents, or subjects who were treated concurrently with other medications, making interpretation of findings more difficult (Ebner et al. 2004; Gowing et al. 2004; Seifert et al. 2002). Studying the efficacy of buprenorphine versus methadone in the outpatient treatment of opioid withdrawal in the United States is further confounded by the two very different mechanisms under which each medication can be provided. Virtually all methadone treatment in the United States for opioid dependence treatment is pro-

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vided through OTPs, a centralized and regulated system of care that has limited availability and often strict rules that emphasize treatment adherence in a very standardized form for patients at a particular clinic. This is a markedly different system of care compared with buprenorphine’s availability via officebased practices, where treatment is decentralized, can be more individualized, has a higher degree of medical involvement, and may involve fewer counseling services and behavioral interventions than an OTP. Some general conclusions regarding the use of buprenorphine for the treatment of opioid withdrawal can be made: • •

•

Longer periods of withdrawal (at least 30 days) are probably more effective than shorter withdrawal periods (Amass et al. 1994; Katz et al. 2009). Buprenorphine is superior to clonidine (and is approved for the treatment of opioid dependence in the United States, whereas clonidine is not), and should be the medication of choice when considering which of these two medications to use. Lofexidine, an α2-adrenergic agonist like clonidine, is available for treating opioid withdrawal in the United Kingdom, but is not available in the United States. A few studies have compared buprenorphine with lofexidine for the treatment of opioid withdrawal, but firm conclusions about the relative efficacy of the two medications are probably premature at this time. The efficacy of buprenorphine compared with that of methadone has not been well characterized, and this is a topic that needs to be addressed—both with respect to office-based methadone (vs. buprenorphine) treatment and with respect to OTP-delivered buprenorphine (vs. methadone) treatment.

Buprenorphine’s Safety and Side Effects Buprenorphine is a safe medication with a relatively unremarkable side-effect profile. Several areas of potential concern have been identified in recent years regarding medications used to treat opioid dependence. Each of these topics is addressed in this section as it relates to buprenorphine, followed by a section that summarizes the side effects associated with buprenorphine treatment. It is important to stress that in general, buprenorphine is a medication that is safe and effective for the overwhelming majority of patients who take it.

LIVER FUNCTION A few case reports have shown that very high doses of buprenorphine delivered by intravenous injection can produce an acute change in liver function test re-

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sults. Before buprenorphine’s approval in the United States, a retrospective evaluation of patients treated with sublingual buprenorphine found that there were slight increases in liver enzyme levels (serum transaminase levels) when patients with a history of hepatitis C infection were treated with buprenorphine (Petry et al. 2000). Subsequently, the FDA-approved labeling for buprenorphine included a caution regarding liver function and buprenorphine use. However, clinical experience has generally not supported a particular concern about this potential adverse event. At present, the NIDA Clinical Trials Network is conducting a study looking at buprenorphine’s possible effects on liver function. Pending the results from that study, there are no specific recommendations regarding monitoring of buprenorphine’s effects on liver function, although it would seem prudent to monitor liver enzyme levels in a patient who may be at particularly high risk for liver problems.

CARDIAC CONDUCTION The opioid agonist medication LAAM was briefly marketed in the United States and Europe for the treatment of opioid dependence. However, it was withdrawn from the European market due to concerns about cardiac conduction effects, especially prolongation of the QTc interval and the risk of torsades de pointes (a potentially fatal arrhythmia). It was also withdrawn from the U.S. market, but at the initiative of the manufacturer, apparently due to poor sales. These experiences with LAAM led to a reappraisal of the potential cardiac effects of other µ opioid receptor agonists. Various reports have examined both methadone and buprenorphine to see whether there is evidence of QTc interval prolongation associated with either of these medications. This is currently a controversial topic with respect to methadone, with some reports suggesting there may be QTc prolongation with very high doses of methadone (although the full clinical meaning of such prolongation is debated). However, of more relevance to this chapter, assessments of buprenorphine have not found evidence that it is associated with prolongation of the QTc interval (Fanoe et al. 2007; Wedam et al. 2007).

PRECIPITATED W ITHDRAWAL A potential adverse effect of buprenorphine is precipitated opioid withdrawal associated with the first dose of sublingual buprenorphine. Buprenorphine’s partial agonist effects at the µ receptor, as reviewed earlier in this chapter (in “Pharmacological Features”), may produce less effect than a full opioid agonist. Under the right circumstances, an acute dose of buprenorphine can precipitate an opioid withdrawal syndrome. It is important to note that this is an effect produced by buprenorphine itself, and that this phenomenon differs from the

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precipitated withdrawal produced by the injection of naloxone when a buprenorphine-naloxone tablet is injected (Stoller et al. 2001). Buprenorphinerelated precipitated withdrawal can occur in opioid-dependent persons and is associated with the first sublingual dose of the medication. It generally increases in likelihood if the first dose of buprenorphine is high (e.g., ≥ 8 mg sublingual buprenorphine), if the patient has a high level of physical dependence on opioids (e.g., the equivalent of ≥60 mg of oral methadone per day), and/or if there is a short time interval between the last dose of a full opioid agonist and the first dose of buprenorphine (e.g., ≤2 hours since the last dose of the full agonist). Thus, longer time intervals since the last dose of agonist, lower first doses of buprenorphine, and lower levels of physical dependence decrease the risk of buprenorphine-related precipitated withdrawal. For patients who are thought to be at higher risk for buprenorphine-related precipitated withdrawal (e.g., a patient maintained with 100 mg of oral methadone per day), it may be useful to give small (e.g., 2-mg) repeated doses of buprenorphine (or buprenorphine-naloxone) every 2 hours rather than a single larger first dose (Rosado et al. 2007). Ideally, the patient should show some evidence of early spontaneous opioid withdrawal before the first dose of buprenorphine, to minimize the risk of precipitating withdrawal. Finally, the risk of buprenorphine-related precipitated withdrawal is associated with the first dose of the medication—once the patient is regularly taking buprenorphine, there is no risk of buprenorphine precipitating withdrawal.

OVERDOSE Although patients have overdosed with buprenorphine, there does not appear to be the same risk of respiratory depression as seen with overdoses of full opioid agonists (e.g., heroin). The exception to this is when a patient overdoses with buprenorphine along with a sedative such as a benzodiazepine. Shortly after buprenorphine became available in France, there were reports of patient deaths associated with injection of buprenorphine tablets along with a benzodiazepine such as flunitrazepam, an injectable benzodiazepine not available in the United States (Reynaud et al. 1998; Tracqui et al. 1998). However, overdose of buprenorphine alone does not seem to carry the same risk of death. The U.S. label for buprenorphine notes there should be caution when buprenorphine is used concurrently with a benzodiazepine. This should be viewed as a relative rather than an absolute contraindication, because oral benzodiazepines were used by many patients enrolled in clinical trials with buprenorphine before its approval, and there were no deaths noted in those studies. The risk for death associated with a buprenorphine-benzodiazepine combination may be greatest when higher doses of both medications are injected.

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OTHER SIDE EFFECTS In addition to the safety and side effects points noted above, five other topics should be briefly addressed when considering buprenorphine: headache, constipation, erectile dysfunction, cognitive functioning/performance, and sweating. According to the FDA-approved labeling for buprenorphine, in a 4-week study that compared buprenorphine alone or in combination with naloxone versus placebo, the most common side effect noted by patients treated with buprenorphine was headache and the rate of headaches was higher in the buprenorphinenaloxone (36.4%) and buprenorphine (29.1%) groups than in the placebo group (22.4%). Similarly, rates of reported constipation were higher in buprenorphine-naloxone recipients (12.1%) and buprenorphine recipients (7.8%) than in placebo recipients (2.8%). However, for both headache and constipation, comparisons with placebo tell only part of the story, because it would be helpful to know how buprenorphine compares with another opioid treatment medication such as methadone. There are limited data reporting on such comparisons, although it appears that in terms of these side effects buprenorphine and methadone are generally not markedly different (Lofwall et al. 2005). Some evidence suggests that there may be higher rates of erectile dysfunction in patients treated with methadone than in those treated with buprenorphine (Hallinan et al. 2008; Quaglio et al. 2008). However, it is important to note that studies to date have been based on patients in treatment who have received the medications under nonblinded conditions, and potential confounding features to such analyses make interpretation of findings somewhat difficult. Studies of buprenorphine suggest that the doses typically used in the treatment of opioid dependence do not produce impairment in cognitive functioning or performance (Mintzer et al. 2004; Soyka et al. 2001), although there is some evidence that patients with opioid dependence may do less well than normal control subjects on such measures (Soyka et al. 2008). Finally, some clinicians have noted patient reports of increased sweating while receiving buprenorphine maintenance therapy. Interestingly, this side effect has been noted with methadone maintenance therapy as well.

SUMMARY Based on the studies and reports published to date, buprenorphine appears to be a safe medication with no significant or critical side effects. Initial concerns about possible liver effects have not been well supported, although data from the NIDA Clinical Trials Network study will help to address this question. Other effects, such as constipation, headache, and sweating, are not uncommon for patients treated with opioids, and do not appear to be severe. There

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appears to be a lack of effects in notable areas, including measures of cognition and performance, erectile dysfunction, and cardiac conduction. Although other side effects may be yet identified, the extensive use of buprenorphine to date suggests that if major adverse effects or significant side effects were to occur, then they should have been noted by now. The conscientious clinician should remain aware of possible effects noted in this section, but should also be reassured that buprenorphine has an overall mild side-effect profile.

Future Directions for Buprenorphine Treatment of Opioid Dependence Buprenorphine has been a highly successful addition to the interventions clinicians can use for the treatment of opioid dependence. There are three future directions regarding buprenorphine use to briefly mention here: •

•

•

Development of alternative, novel formulations of buprenorphine: There has been considerable interest in developing an injectable or implantable, sustained-release form of buprenorphine that could be delivered monthly or even every several months. At least two such formulations have been tested, although an approved product that could be marketed is still probably a year or two away. In addition, a patch form of buprenorphine and a buccal soluble film form have been tested in humans. Use of higher doses: At present, studies have generally tested maximum daily doses of 32 mg. Given the dose-response curve for buprenorphine and its safety at higher doses, it is somewhat surprising that the efficacy (and safety) of dosages higher than 32 mg/day have not been tested. Transition off buprenorphine: Given the success of this medication, it is probable that some proportion of patients maintained with buprenorphine could transition off it (e.g., take the sustained-release form of naltrexone instead). How this can be optimally done needs to be determined—especially for the clinician in an office-based practice.

These three areas—novel formulations, the use of higher doses, and the transition off buprenorphine—should be areas of research as this medication becomes more firmly established in clinical use.

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Conclusion Buprenorphine is a novel opioid. Its unique profile of effects makes it very well suited for the treatment of opioid dependence, and research has confirmed its clinical efficacy and safety for the treatment of opioid dependence. Studies have demonstrated that it is superior to placebo treatment and that its efficacy is comparable to that of moderate doses of methadone (with the qualification noted that higher doses of buprenorphine have not been systematically tested for efficacy and safety). In addition to demonstrated efficacy, it is also a safe medication with no substantial adverse effects or significant side effects. This profile of effects makes it well suited for use in office-based treatment, where it has been able to make a substantial impact.

Clinical Pearls • Buprenorphine (and buprenorphine-naloxone) is a safe and effective medication for the treatment of opioid dependence. • Buprenorphine (and buprenorphine-naloxone) is more effective than placebo and is at least as effective as moderate doses of methadone (about 60 mg of daily methadone). High doses of buprenorphine (>32 mg/day) for the treatment of opioid dependence have not been rigorously studied in human clinical trials. • Buprenorphine (and buprenorphine-naloxone) has a good safety profile with a side-effect profile that is similar to that seen with other opioids. The most common side effects are headache, constipation, and increased sweating. • There do not appear to be increases in the QTc interval associated with buprenorphine use.

References Amass L, Bickel WK, Higgins ST, et al: A preliminary investigation of outcome following gradual or rapid buprenorphine detoxification. J Addict Dis 13:33–45, 1994 Amato L, Minozzi S, Davoli M, et al: Psychosocial combined with agonist maintenance treatments versus agonist maintenance treatments alone for treatment of opioid dependence. Cochrane Database of Systematic Reviews 2008, Issue 4. Art. No.: CD004147. DOI: 10.1002/14651858.CD004147.pub3. Bickel WK, Stitzer ML, Bigelow GE, et al: Buprenorphine: dose-related blockade of opioid challenge effects in opioid dependent humans. J Pharmacol Exp Ther 247:47–53, 1988

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Cheskin LJ, Fudala PJ, Johnson RE: A controlled comparison of buprenorphine and clonidine for acute detoxification from opioids. Drug Alcohol Depend 36:115– 121, 1994 Comer SD, Collins ED, Fischman MW: Buprenorphine sublingual tablets: effects on IV heroin self-administration by humans. Psychopharmacology (Berl) 154:28–37, 2001 Comer SD, Walker EA, Collins ED: Buprenorphine/naloxone reduces the reinforcing and subjective effects of heroin in heroin-dependent volunteers. Psychopharmacology (Berl) 181:664–675, 2005 Ebner R, Schreiber W, Zierer C: Buprenorphine or methadone for detoxification of young opioid addicts? [in German] Psychiatr Prax 31 (suppl 1):S108–S110, 2004 Fanoe S, Hvidt C, Ege P, et al: Syncope and QT prolongation among patients treated with methadone for heroin dependence in the city of Copenhagen. Heart 93:1051– 1055, 2007 Fiellin DA, Pantalon MV, Chawarski MC, et al: Counseling plus buprenorphinenaloxone maintenance therapy for opioid dependence. N Engl J Med 355:365– 374, 2006 Fudala PJ, Bridge TP, Herbert S, et al: Office-based treatment of opiate addiction with a sublingual-tablet formulation of buprenorphine and naloxone. N Engl J Med 349:949–958, 2003 Gowing L, Ali R, White J: Buprenorphine for the management of opioid withdrawal. Cochrane Database of Systematic Reviews 2009, Issue 3. Art. No.: CD002025. DOI: 10.1002/14651858.CD002025.pub4. Hallinan R, Byrne A, Agho K, et al: Erectile dysfunction in men receiving methadone and buprenorphine maintenance treatment. J Sex Med 5:684–692, 2008 Jasinski DR, Pevnick JS, Griffith JD: Human pharmacology and abuse potential of the analgesic buprenorphine: a potential agent for treating narcotic addiction. Arch Gen Psychiatry 35:501–516, 1978 Johnson RE, Eissenberg T, Stitzer ML, et al: A placebo controlled clinical trial of buprenorphine as a treatment for opioid dependence. Drug Alcohol Depend 40:17– 25, 1995 Kakko J, Svanborg KD, Kreek MJ, et al: 1-year retention and social function after buprenorphine-assisted relapse prevention treatment for heroin dependence in Sweden: a randomised, placebo-controlled trial. Lancet 361:662–668, 2003 Katz EC, Schwartz RP, King S, et al: Brief vs. extended buprenorphine detoxification in a community treatment program: engagement and short-term outcomes. Am J Drug Alcohol Abuse 35:63–67, 2009 Krook AL, Brors O, Dahlberg J, et al: A placebo-controlled study of high dose buprenorphine in opiate dependents waiting for medication-assisted rehabilitation in Oslo, Norway. Addiction 97:533–542, 2002 Ling W, Charuvastra C, Collins JF, et al: Buprenorphine maintenance treatment of opiate dependence: a multicenter, randomized clinical trial. Addiction 93:475–486, 1998 Ling W, Amass L, Shoptaw S, et al: A multicenter randomized trial of buprenorphinenaloxone versus clonidine for opioid detoxification: findings from the National Institute on Drug Abuse Clinical Trials Network. Addiction 100:1090–1100, 2005 Lofwall MR, Stitzer ML, Bigelow GE, et al: Comparative safety and side effect profiles of buprenorphine and methadone in the outpatient treatment of opioid dependence. Addiction Disorders and Their Treatment 4:49–64, 2005

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Mattick RP, Kimber J, Breen C, et al: Buprenorphine maintenance versus placebo or methadone maintenance for opioid dependence. Cochrane Database of Systematic Reviews 2008, Issue 2. Art. No.: CD002207. DOI: 10.1002/14651858.CD002207. pub3. Mello NK, Mendelson JH: Buprenorphine suppresses heroin use by heroin addicts. Science 207:657–659, 1980 Mintzer MZ, Correia CJ, Strain EC: A dose-effect study of repeated administration of buprenorphine/naloxone on performance in opioid-dependent volunteers. Drug Alcohol Depend 74:205–209, 2004 Petry NM, Bickel WK, Piasecki D, et al: Elevated liver enzyme levels in opioid-dependent patients with hepatitis treated with buprenorphine. Am J Addict 9:265–269, 2000 Quaglio G, Lugoboni F, Pattaro C, et al: Erectile dysfunction in male heroin users, receiving methadone and buprenorphine maintenance treatment. Drug Alcohol Depend 94:12–18, 2008 Reynaud M, Petit G, Potard D, et al: Six deaths linked to concomitant use of buprenorphine and benzodiazepines. Addiction 93:1385–1392, 1998 Rosado J, Walsh SL, Bigelow GE, et al: Sublingual buprenorphine/naloxone precipitated withdrawal in subjects maintained on 100mg of daily methadone. Drug Alcohol Depend 90:261–269, 2007 Seifert J, Metzner C, Paetzold W, et al: Detoxification of opiate addicts with multiple drug abuse: a comparison of buprenorphine vs. methadone. Pharmacopsychiatry 35:159–164, 2002 Soyka M, Horak M, Dittert S, et al: Less driving impairment on buprenorphine than methadone in drug-dependent patients? J Neuropsychiatry Clin Neurosci 13:527– 528, 2001 Soyka M, Lieb M, Kagerer S, et al: Cognitive functioning during methadone and buprenorphine treatment: results of a randomized clinical trial. J Clin Psychopharmacol 28:699–703, 2008 Stoller KB, Bigelow GE, Walsh SL, et al: Effects of buprenorphine/naloxone in opioiddependent humans. Psychopharmacology (Berl) 154:230–242, 2001 Strain EC, Walsh SL, Preston KL, et al: The effects of buprenorphine in buprenorphine-maintained volunteers. Psychopharmacology (Berl) 129:329–338, 1997 Strain EC, Walsh SL, Bigelow GE: Blockade of hydromorphone effects by buprenorphine/naloxone and buprenorphine. Psychopharmacology (Berl) 159:161–166, 2002 Strain EC, Moody DE, Stoller KB, et al: Relative bioavailability of different buprenorphine formulations under chronic dosing conditions. Drug Alcohol Depend 74:37–43, 2004 Tracqui A, Kintz P, Ludes B: Buprenorphine-related deaths among drug addicts in France: a report on 20 fatalities. J Anal Toxicol 22:430–434, 1998 Wedam EF, Bigelow GE, Johnson RE, et al: QT-interval effects of methadone, levomethadyl, and buprenorphine in a randomized trial. Arch Intern Med 167: 2469–2475, 2007 Ziedonis DM, Amass L, Steinberg M, et al: Predictors of outcome for short-term medically supervised opioid withdrawal during a randomized, multicenter trial of buprenorphine-naloxone and clonidine in the NIDA clinical trials network drug and alcohol dependence. Drug Alcohol Depend 99:28–36, 2009

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5 Patient Assessment Petros Levounis, M.D., M.A.

THE ASSESSMENT of a patient for buprenorphine treatment is essentially the same as the assessment of any patient who has an addiction. In this chapter, I describe the complete evaluation of a patient and cover a broad range of issues that may impact addiction treatment. Everyday clinical practice often dictates a symptom-focused evaluation, and treating patients with buprenorphine is not an exception. For example, I include a brief discussion of physical examination as part of a complete patient assessment. However, the majority of psychiatrists do not routinely conduct physical examinations; typically they collaborate with internists and other primary care physicians who cover this aspect of the patient’s medical care. Treating patients with buprenorphine should not change your way of evaluating your patients and managing your practice.

Establishing a Relationship When the clinician is interviewing a patient who is opioid dependent, a matter-of-fact, nonjudgmental, and respectful approach works best. Many patients have been discriminated against or mistreated because of their substance use disorder. Understandably, they may be mistrustful of physicians and may not be eager to talk about events and activities that are embarrassing and often illegal. Open the interview by asking about the patient’s level of comfort. For example, 79

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you may want to say, “How are you feeling?” “Are you feeling any withdrawal symptoms?” “When was the last time you used any opioids?” This approach helps to establish you as considerate and compassionate and may influence how likely the patient will be to retain information you give—as well as how likely he or she will be to open up about sensitive problems and to return to your office. Establishing a trusting and secure relationship is one of the most powerful elements of successful addiction treatment and is critical in the management of any chronic relapsing disorder (Najavits and Weiss 1994). Recognize that some information is difficult to talk about and acknowledge the patient’s discomfort. For example, at some point you may say: “You seemed to get quiet when I asked that.” Assure confidentiality and tell the patient that you are asking because you are concerned for his or her health. I have found that being genuinely interested and curious about your patient’s life provides the most powerful means of smoothing out awkward feelings and allowing your patient to open up about his or her drug history. Using curiosity as your primary approach to the patient also helps you persist in getting full answers to difficult questions and following up on qualified answers. For example, if the answer to the question “Have you ever injected heroin?” is “Not really,” you may then ask the patient to tell you all about the last time he or she injected. In some cases, it may be easier to lead with assumptive questions, such as “When was the last time you injected heroin?”

Taking a History of Drug Use THE BASICS Patients who use heroin and/or prescription opioids often use other substances as well. When taking a drug history, inquire about both legal and illegal substances. Asking specifically about each class of drugs, as well as about each possible source such as dealers, friends and family, prescriptions, the Internet, herbal stores, and over-the-counter medications can give surprising and valuable results. For each drug, you should gather information about 1) frequency of use, 2) amount used, 3) route of administration, 4) acute response to the effects of the drug, and 5) changes in use over time. Typically, start with questions about legal drugs (nicotine, alcohol, prescription pills) and then progress to illegal drugs (e.g., cannabis, heroin, hallucinogens, cocaine, and crystal methamphetamine). Patients are less likely to be defensive when describing their use of legal drugs, and the discussion may then progress more easily into areas associated with illegal drugs and illegal activities. Another way of obtaining the drug history is to start with the first psychoactive agent used and work chronologically through the patient’s experience with substances of abuse. Either way, information about the most recent use, including use in the weeks and

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TABLE 5–1.

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Commonly abused opioids

Diacetylmorphine (heroin) Codeine Oxycodone (OxyContin, Percodan, Percocet, Tylox) Hydrocodone (Vicodin, Lortab) Morphine (MS Contin, Oramorph) Hydromorphone (Dilaudid) Meperidine (Demerol) Fentanyl (Sublimaze, Actiq) Propoxyphene (Darvon) Methadone (Dolophine) Opium days just before the assessment, is likely to be the most helpful in evaluating the patient for buprenorphine treatment. In general, assumptive, open-ended questions generate more detailed and productive information. For example, you may ask, “How are things at home since you started drinking regularly?” or “What has been going on in your life since you lost your job?” Opioids are abused by all routes of administration including intravenous, oral, inhalation (snorting), smoking, subcutaneous (skin “popping”), and intramuscular. Heroin is often used intravenously, but in recent years more and more people inhale heroin. This shift in the pattern of use may be due to the AIDS epidemic and the associated danger of infection from contaminated needles. It may also be due to the increase in the purity of heroin, which is now potent enough to give the user an adequate “high” even if it is inhaled and not injected. Prescription opioids are typically taken orally but may also be snorted, chewed, or crushed and injected. Pills are crushed to circumvent the mechanism that delays the release of the active ingredients in long-acting formulations such as OxyContin (an acryliccoated formulation of oxycodone). Please see Table 5–1 for a list of the most commonly abused opioids and Table 5–2 for other commonly abused substances. Family participation in the evaluation is ideal but often not an option. Patients have often been cut off from contact with their loved ones because of the illness of addiction. However, when family members come to the office, they tend to offer very useful information and insights into the patient’s illness. They can also become great allies in carrying out the patient’s treatment plan, helping him or her both logistically and emotionally, and can act as your liaison in the patient’s home.

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TABLE 5–2.

Other commonly abused substances

Nicotine Alcohol Benzodiazepines Cocaine Methamphetamine (crystal meth) Cannabis Phencyclidine (PCP) “Club drugs” (ecstasy, ketamine, γ-hydroxybutyrate) Noncontrolled substances (e.g., clonidine, dextromethorphan)

THE CONSEQUENCES Almost all patients who abuse opioids have experienced opioid withdrawal at some point in their lives. Although they are very familiar with the actual symptoms and consequences of intoxication and withdrawal, they may not be familiar with the medical terms, and these should be explained. It may also be necessary to explain to the patient what is meant by tolerance; that is, that with time greater amounts of the drug are needed to achieve the same effect, or there is a diminished effect from the same amount of the drug. Asking the patient about the different consequences of his or her use is useful in two ways. First, it helps paint a multidimensional picture of the patient’s life and thus establish past and current levels of psychosocial functioning. Second and perhaps more important, it helps the patient identify losses in his or her life, which may increase motivation for change. I often review five areas of consequences of drug use: 1. Medical consequences may include hepatitis C, HIV infection, and other infections (e.g., endocarditis, abscesses), as well as injuries from falls and burns secondary to intoxication. Medical comorbidities are discussed further in Chapter 10 (“Medical Management”). 2. Psychiatric consequences may include opioid-induced depression, sexual dysfunction, and sleep disorders. Although opioids are less likely to result in symptoms of mental illness than are most other drugs of abuse, differentiating between substance-induced and independent psychiatric disorders can be challenging. This topic is discussed further in Chapter 9, “Psychiatric Comorbidity.” 3. Interpersonal and family consequences may include separation or divorce and estrangement from parents, siblings, and children.

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4. Financial and employment consequences can include bankruptcy, loss of job, and loss of a professional license. 5. Legal consequences may include arrests for driving under the influence (DUI) or driving while intoxicated (DWI), incarceration, parole or probation, and loss of custody of children.

PREVIOUS TREATMENTS

AND

RECOVERY EFFORTS

Before getting into the patient’s previous medical treatments, the clinician needs to know whether the patient has tried to stop using by himself or herself. Frequently people who are addicted to opioids have tried to quit on their own, either with the help of home products and over-the-counter medications such as antidiarrheal agents and sleeping aids, or with no pharmacological help at all, that is, going “cold turkey.” (The expression cold turkey comes from the piloerection and characteristic clammy appearance of the skin during opioid withdrawal.) If this is the case, ask what happened. Ask about the severity and duration of any withdrawal symptoms, and how the patient expects to feel differently with medical treatment. Some patients may also have a history of involvement with mutual help groups, which are sometimes called self-help groups or 12-step groups, like Alcoholics Anonymous and Narcotics Anonymous. Finding out how long the patient has been attending meetings and how many meetings he or she attends each week can give you an indication of the patient’s motivation for treatment. If the patient has been attending mutual help meetings consistently, has formally joined a group, and has a sponsor, then he or she is more likely to be committed to the recovery process. Reviewing with the patient previous medical treatments typically involves the following four areas: 1. Detoxification, which includes inpatient hospital admissions and outpatient community-based programs 2. Rehabilitation in 28-day or other residential treatment facilities 3. Outpatient counseling or psychotherapy 4. Long-term pharmacotherapy, which includes maintenance with methadone (a µ opioid receptor agonist), maintenance with buprenorphine (a µ opioid receptor partial agonist), or treatment with naltrexone (a µ opioid receptor antagonist). You may also ask the patient about his or her longest period of abstinence, how it was attained, and what worked to sustain it. Inquiring about drug cravings and triggers to relapse (including emotions, people, places, and things) helps the patient remember the major obstacles to sobriety. The review of trig-

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gers signals to the patient that serious effort will be required to identify, avoid, and cope with these powerful culprits of drug relapse. It also alerts the clinician to the patient’s specific vulnerabilities that will need to be addressed in a comprehensive treatment plan (see Chapter 7, “Clinical Management I”).

SUMMARY MNEMONIC One way to keep in mind the different elements of taking a history of drug use is by remembering the acronym TRAPPED (Welsh 2003), which stands for the following: 1. Treatment history (inpatient, outpatient; methadone, buprenorphine, naltrexone) 2. Route of administration (intravenous, intranasal, intramuscular) 3. Amount (in dollars, “bags,” or milligrams) 4. Pattern of use (changes over time) 5. Prior abstinence (with or without medical help) 6. Effects (medical, psychiatric, psychosocial) 7. Duration of use (including most recent use).

MEDICAL, PSYCHIATRIC, FAMILY, PSYCHOSOCIAL HISTORY

AND

Apart from the direct medical consequences of drug use discussed earlier in this chapter, the medical history also includes significant acute and chronic medical illnesses as well as operations, allergies, and current medications. The inventory of current medications should list not only medications prescribed to the patient but also medications prescribed to others (often family members or friends) that the patient may be taking from others’ medicine cabinets, and prescription medications that the patient may be buying on the street. This list should also include over-the-counter preparations, dietary supplements, and herbal pills. The psychiatric history consists of the review of psychiatric hospitalizations, outpatient treatments, and psychiatric medications. Be sure to inquire about treatment delivered by nonpsychiatrists, such as a primary care physician who prescribes an antidepressant or a psychologist who provides psychotherapy. Chapter 9 discusses psychiatric assessment in detail. It is well established that both addiction and other psychiatric conditions, like depression, schizophrenia, and bipolar disorder, have significant genetic components. A detailed family history therefore contributes valuable information to aid in our understanding of the patient’s vulnerabilities and helps us dis-

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TABLE 5–3.

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Stages of change

1.

Precontemplation—“I don’t want to ever quit.”

2.

Contemplation—“Someday, I may want to think about quitting.”

3.

Preparation (determination)—“I’m seriously planning to quit in the next few weeks.”

4.

Action—“I have just stopped using and work hard to stay clean.”

5.

Maintenance—“I have been sober for several months.”

tinguish between a primary psychiatric disorder and a substance-induced psychiatric condition (Pickens and Svikis 1988). The psychosocial history, sometimes also referred to as personal history, completes the comprehensive history portion of the patient assessment. It consists of gathering information about the patient’s childhood development; education; employment; military service; physical or sexual abuse; run-ins with the law; spouse or partner; children; housing and living situation; and religion and spirituality. Several elements of the psychosocial history have already been covered in this chapter, given that addiction tends to interfere with—and often destroy—many aspects of a person’s life.

MOTIVATION

FOR

CHANGE

Based on the Transtheoretical Model of Change developed by Prochaska and DiClemente (1982), patients have different levels of motivation for changing their substance use. The five stages of change are listed in Table 5–3. Although many patients seem to progress sequentially through the stages of change from precontemplation to maintenance, clinicians often treat patients who skip stages or sometimes go back to an earlier stage despite considerable early gains toward motivation for sobriety. For example, a patient may be working hard on the action stage of change, during which he or she may be attending meetings and taking medication; however, a slip with heroin use may severely disappoint and discourage the patient, who may then experience a setback and return to the contemplation stage: “Do I really want to stop using? Maybe I’m meant to be a heroin addict and I should just accept it.” Most patients are ambivalent about change, but exploring this ambivalence is a critical element in enhancing their motivation. An additional stage of change is relapse. With addiction being a chronic relapsing illness, it is reasonable to expect that some patients will relapse. Relapse is part of the natural history of the illness and of the recovery process, and as such plays a significant role in the progression of a person through the change

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cycle. Patients who relapse typically reenter the stages of change at the contemplation level and may progress more rapidly during subsequent treatment (Levounis and Arnaout 2010).

Physical Examination The physical examination is particularly helpful in identifying and caring for the intravenous drug user. Needle marks and sclerosed veins (track marks) on the upper extremities, secondary to chronic heroin injecting, can be easily concealed by long-sleeved shirts but become apparent on physical examination. Skin infections can lead to cellulitis and abscesses that, unless they are discovered and treated in a timely fashion, may progress to even more serious conditions. Furthermore, the physical examination is essential in the medical treatment of the patient who also has hepatitis C and/or HIV infection. Physical examination is also helpful in identifying the presence and severity of opioid intoxication (e.g., constricted pupils) and opioid withdrawal (e.g., dilated pupils). Sinusitis and chronic cough are also consistent with chronic opioid use. Chapter 10 discusses the basic assessment and management of the patient with opioid dependence and co-occurring medical illnesses.

Laboratory Examination Certain laboratory test results can raise our level of suspicion for alcohol and drug abuse. Abnormal liver function test results (especially an elevated aspartate aminotransferase to alanine aminotransferase ratio and an elevated γglutamyltransferase level), elevated red blood cell mean corpuscular volume, and carbohydrate-deficient transferrin are all associated with alcohol abuse and dependence. Antibodies to HIV, hepatitis B virus, and hepatitis C virus may indicate intravenous drug use. Urine toxicology examinations (UTs) are helpful in the evaluation (and often the treatment) of the substance-abusing patient. Heroin and codeine metabolize into morphine, which is the substance detected in urine. Codeine metabolizes into morphine slowly, so it can be present either as codeine or morphine (or both) in urine. However, heroin (diacetylmorphine) is never found in urine because it hydrolyzes very quickly to morphine. Occasionally, the intermediate product in this hydrolysis, 6-monoacetylmorphine (6-MAM), is transiently detected in urine and the test for this is sometimes used in forensic settings. If urine is positive for 6-MAM, the patient certainly used heroin; however, if 6-MAM detection is negative, then the test gives no information about heroin use. Routine UTs for opioids typically test only for morphine and codeine, so tests for semisynthetic opioids like oxycodone, hydrocodone, and

Patient Assessment

TABLE 5–4.

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DSM-IV-TR criteria for substance abuse

A. A maladaptive pattern of substance use leading to clinically significant impairment or distress, as manifested by one (or more) of the following, occurring within a 12-month period: (1) recurrent substance use resulting in a failure to fulfill major role obligations at work, school, or home (e.g., repeated absences or poor work performance related to substance use; substance-related absences, suspensions, or expulsions from school; neglect of children or household) (2) recurrent substance use in situations in which it is physically hazardous (e.g., driving an automobile or operating a machine when impaired by substance use) (3) recurrent substance-related legal problems (e.g., arrests for substance-related disorderly conduct) (4) continued substance use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of the substance (e.g., arguments with spouse about consequences of intoxication, physical fights) B. The symptoms have never met the criteria for substance dependence for this class of substance. Source. Reprinted from American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision. Washington, DC, American Psychiatric Association, 2000. Copyright © 2000 American Psychiatric Association. Used with permission.

hydromorphone often have to be ordered separately. UTs also test for cocaine, benzodiazepines, and cannabis, but, if the patient uses such substances sporadically, he or she may not have used near the time of sample collection and the result may be negative (see Chapter 7). Detecting drugs in hair, saliva, and sweat samples has attracted great attention as alternatives to UTs. However, the current clinical usefulness of these methods is limited, and they are used primarily in experimental settings.

Diagnosis The Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR; American Psychiatric Association 2000) provides detailed criteria for establishing the diagnosis of substance abuse (Table 5–4) and substance dependence (Table 5–5). Please note that substance dependence and substance addiction are identical terms. Although American psychiatrists are still

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TABLE 5–5.

DSM-IV-TR criteria for substance dependence

A maladaptive pattern of substance use, leading to clinically significant impairment or distress, as manifested by three (or more) of the following, occurring at any time in the same 12-month period: (1) tolerance, as defined by either of the following: (a) a need for markedly increased amounts of the substance to achieve intoxication or desired effect (b) markedly diminished effect with continued use of the same amount of the substance (2) withdrawal, as manifested by either of the following: (a) the characteristic withdrawal syndrome for the substance (refer to Criteria A and B of the criteria sets for withdrawal from the specific substances) (b) the same (or a closely related) substance is taken to relieve or avoid withdrawal symptoms (3) the substance is often taken in larger amounts or over a longer period than was intended (4) there is a persistent desire or unsuccessful efforts to cut down or control substance use (5) a great deal of time is spent in activities necessary to obtain the substance (e.g., visiting multiple doctors or driving long distances), use the substance (e.g., chain-smoking), or recover from its effects (6) important social, occupational, or recreational activities are given up or reduced because of substance use (7) the substance use is continued despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by the substance (e.g., current cocaine use despite recognition of cocaine-induced depression, or continued drinking despite recognition that an ulcer was made worse by alcohol consumption) Specify if: With Physiological Dependence: evidence of tolerance or withdrawal (i.e., either Item 1 or 2 is present) Without Physiological Dependence: no evidence of tolerance or withdrawal (i.e., neither Item 1 nor 2 is present)

Patient Assessment

TABLE 5–5.

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DSM-IV-TR criteria for substance dependence (continued)

Course specifiers: Early Full Remission Early Partial Remission Sustained Full Remission Sustained Partial Remission On Agonist Therapy In a Controlled Environment Source. Reprinted from American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision. Washington, DC, American Psychiatric Association, 2000. Copyright © 2000 American Psychiatric Association. Used with permission.

struggling to reach consensus about which is the better name for the disorder, there is little disagreement about the illness itself; the two terms, dependence and addiction, are used interchangeably throughout the scientific and clinical literature, including the present volume. Given that the U.S. Food and Drug Administration has approved sublingual buprenorphine specifically for the treatment of opioid dependence, it is necessary that patient assessment clearly document that the patient meets DSM-IV-TR criteria for this disorder. It is also helpful to specify whether the diagnosis is “with physiological dependence” (if there is evidence of tolerance or withdrawal) or “without physiological dependence.”

Buprenorphine Versus Methadone: Regulatory Criteria and Limitations The regulatory criteria for the use of buprenorphine differ from the criteria for methadone use in the treatment of opioid dependence. Although buprenorphine can be prescribed to anyone age 16 years and older who currently meets DSM-IVTR criteria for opioid dependence, methadone treatment requires that patients be at least 18 years old; currently meet DSM-IV-TR criteria for opioid dependence; and have been addicted for at least 1 year before admission to treatment. Buprenorphine for the treatment of opioid dependence can be prescribed at the office or clinic of any physician who has a valid waiver from the U.S. Drug Enforcement Administration. In comparison, methadone for the treat-

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ment of opioid dependence can only be administered at a federally approved and regulated clinic, an opioid treatment program (OTP) facility. This difference gives buprenorphine a tremendous practical and social advantage. Physicians can now provide mainstream treatment for opioid addiction as part of their everyday practice, and patients can address their substance use problems within the privacy and comfort of the patient-physician relationship. On the other hand, methadone treatment in an OTP facility, which requires daily attendance at least for the first several months of treatment, may be best for patients who require a highly structured environment. For example, patients who have polysubstance dependence and/or other psychiatric conditions that require more comprehensive care usually benefit from the daily encounters, monitoring, services, and routines of an OTP (Schottenfeld et al. 2005). In general, patients who are less stable and less motivated, with a lower level of functioning and a higher need for psychosocial supports, may be more appropriate for methadone treatment in an OTP than for buprenorphine in an office-based treatment practice. Table 5–6 summarizes the selection considerations for selecting office-based buprenorphine treatment versus OTP-based methadone treatment. Another option that has recently become more widely available is buprenorphine treatment provided in an OTP. This may be the best choice for a patient who prefers buprenorphine to methadone, yet may not have the stability required for office-based buprenorphine treatment. Some patients are most successful when they begin buprenorphine treatment in the highly structured environment of an OTP, and then move to an office-based clinic or private office when they are psychiatrically, socially, and medically ready for the transition.

Appropriateness for Office-Based Buprenorphine Treatment The majority of patients who are opioid dependent should be considered for treatment with buprenorphine. Specifically, the risks and benefits of buprenorphine therapy should be balanced against the alternatives of nontreatment or other forms of treatment (Fishman et al. 2010). Although several pharmacological and nonpharmacological interventions have been shown to be useful (methadone and naltrexone, cognitive-behavioral therapy, and 12-step facilitation; see Chapter 8, “Clinical Management II”), the efficacy, safety, and tolerability profile of buprenorphine recommends this medication as a first-line treatment of opioid dependence (see Chapter 4, “Efficacy and Safety of Buprenorphine”). As summarized by Gordon et al. (2007), a patient should be considered an appropriate candidate for treatment with buprenorphine if he or she:

Patient Assessment

TABLE 5–6.

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Selection considerations: buprenorphine versus methadone

Selection considerations

Buprenorphinea

Methadoneb

Criteria

Current DSM-IV-TR diagnosis of opioid dependence

Current DSM-IV-TR diagnosis of opioid dependence 1-year history of addiction

Age

≥ 16 years

≥18 years

Reliability

Higher

Lower

Motivation

Higher

Lower

Social needs

Lower

Higher

Level of function

Higher

Lower

aOffice-based bOpioid

• • • •

treatment. treatment program.

Meets DSM-IV-TR criteria for the diagnosis of opioid dependence Is interested in office-based treatment of his or her illness Understands the risks and benefits (as well as the induction requirements) of the medication Demonstrates motivation for change.

This being said, treatment outcomes are considerably better when patients also engage in nonpharmacological therapies and receive psychosocial support. Multiple studies have shown that buprenorphine treatment is successful in a wide variety of office practices and clinics (Barry et al. 2009; Fiellin et al. 2008). The decision to initiate buprenorphine treatment for a patient at your setting also depends on how well your resources match the patient’s needs. For example, a patient who has multiple and significant medical problems may be better served in a medical office that offers buprenorphine treatment than in a private psychiatric office. Conversely, a patient who has borderline personality disorder may not be treated as successfully by a physician who is not trained in psychiatry. If the patient has a significant chronic pain syndrome as well as opioid dependence, then medication management may be best addressed in a pain management specialist’s office. And if the patient’s severity of addiction requires a higher level of care, such as an intensive outpatient program or partial hospitalization, then referral to an addiction treatment center or an OTP (as discussed in the previous section, “Buprenorphine Versus Methadone: Regulatory Criteria and Limitations”) may be indicated.

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Conclusion Several factors improve the chances for successful office-based treatment. The ideal buprenorphine candidate adheres to the treatment plans; is medically and psychiatrically healthy; lives in a stable and supportive psychosocial environment; attends mutual help meetings regularly; does not use alcohol or other drugs; and does not have a history of multiple previous treatments and relapses. However, the question the physician should be asking is not whether one patient is a better buprenorphine candidate than another patient, but whether a particular individual will be better off with buprenorphine or without buprenorphine treatment. If your practice is suitable for the patient and you have access to additional resources (e.g., a medical specialist or an intensive outpatient program), then office-based buprenorphine treatment is one of the very best options you can offer to your opioid-dependent patient.

Clinical Pearls • Assess your patients for buprenorphine therapy the same way you assess all your patients. • Explore the patient’s motivation and identify his or her stage of change. • Establish the diagnosis of opioid dependence using the DSM-IVTR criteria. Specify whether the diagnosis is with or without physiological dependence. • Regard buprenorphine as your first-line treatment of opioid dependence, but also consider other pharmacological and nonpharmacological options.

References American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision. Washington, DC, American Psychiatric Association, 2000 Barry DT, Irwin KS, Jones ES, et al: Integrating buprenorphine treatment into officebased practice: a qualitative study. J Gen Intern Med 24:218–225, 2009 Fiellin DA, Moore BA, Sullivan LE, et al: Long-term treatment with buprenorphine/ naloxone in primary care: results at 2–5 years. Am J Addict 17:116–120, 2008 Fishman MJ, Shulman GR, Mee-Lee D, et al: ASAM Patient Placement Criteria: Supplement on Pharmacotherapies for Alcohol Use Disorders. Baltimore, MD, Lippincott Williams & Wilkins, 2010

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Gordon AJ, Trafton JA, Saxon AJ, et al; for the Buprenorphine Work Group of the Substance Use Disorders Quality Enhancement Research Initiative: Implementation of buprenorphine in the Veterans Health Administration: results of the first 3 years. Drug Alcohol Depend 90:292–296, 2007 Levounis P, Arnaout B (eds): Handbook of Motivation and Change: A Practical Guide for Clinicians. Washington, DC, American Psychiatric Publishing, 2010 Najavits LM, Weiss RD: Variations in therapist effectiveness in the treatment of patients with substance abuse disorders: an empirical review. Addiction 89:679–688, 1994 Pickens RW, Svikis DS (eds): Biological Vulnerability to Drug Abuse. National Institute on Drug Abuse Research Monograph 89 (DHHS Publ No ADM 90-1590). Rockville, MD, National Institute on Drug Abuse, 1988. Available at: http:// archives.drugabuse.gov/pdf/monographs/89.pdf. Accessed July 1, 2010. Prochaska JO, DiClemente CC: Transtheoretical therapy: towards a more integrative model of change. Psychotherapy: Theory, Research and Practice 19:276–288, 1982 Schottenfeld RS, Chawarski MC, Pakes JR, et al: Methadone versus buprenorphine with contingency management or performance feedback for cocaine and opioid dependence. Am J Psychiatry 162:340–349, 2005 Welsh CJ: “Trapped": a mnemonic for taking a substance use history (letter). Acad Psychiatry 27:289, 2003

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6 Clinical Use of Buprenorphine Ricardo Restrepo, M.D., M.P.H. Petros Levounis, M.D., M.A.

IN THIS CHAPTER, we review the clinical use of buprenorphine in the treatment of opioid dependence. This is a “how to” chapter. We first present a brief overview of the pharmacology of buprenorphine and some general considerations in setting up the treatment, then describe in detail the practical aspects of buprenorphine induction, stabilization, and maintenance therapy. We also briefly describe the option of using buprenorphine for opioid detoxification, although this approach has considerable limitations and drawbacks as discussed in Chapter 4 (“Efficacy and Safety of Buprenorphine”). We hope that this chapter will be used as a quick reference to the nuts and bolts of treating the opioiddependent patient with buprenorphine. A case is presented at the end of this chapter, including related questions for additional consideration. For discussion of this case, please see Chapter 14, “Comments on the Case Vignettes.”

Buprenorphine Formulations The formulations approved for the treatment of opioid dependence by the U.S. Food and Drug Administration (FDA) are 1) buprenorphine (Subutex), often 95

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FIGURE 6–1.

The 2-mg buprenorphine tablet (the 2-mg mono product, 2-mg Subutex). Photography by Henry B. Lee.

FIGURE 6–2.

The 8-mg buprenorphine tablet (the 8-mg mono product, 8-mg Subutex). Photography by Henry B. Lee.

referred to as the mono product; and 2) a buprenorphine-naloxone combination tablet in a 4:1 ratio (Suboxone), the combo product. The mono product is available in doses of 2 mg (Figure 6–1) and 8 mg (Figure 6–2) of buprenorphine; the combo product is available in doses of 2 mg buprenorphine/0.5 mg naloxone (Figure 6–3) or 8 mg buprenorphine/2 mg naloxone (Figure 6–4). For practical purposes, when physicians refer to the combo product as “8 mg of bup” or “2 mg of bup,” it is understood that what they mean is 8 mg of buprenorphine with 2 mg of naloxone or 2 mg of buprenorphine with 0.5 mg of naloxone, respectively. Another buprenorphine formulation that is available for pain management—but is not approved for the treatment of opioid dependence in the United States—is injectable buprenorphine (Buprenex).

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FIGURE 6–3.

The 2-mg buprenorphine/0.5-mg naloxone tablet (the 2-mg combo product, 2-mg Suboxone). Photography by Henry B. Lee.

FIGURE 6–4.

The 8-mg buprenorphine/2-mg naloxone tablet (the 8-mg combo product, 8-mg Suboxone). Photography by Henry B. Lee.

Pharmacology Overview Buprenorphine is a long-acting partial agonist at the µ opioid receptor. The medication has high affinity, slow dissociation, and low intrinsic activity at the µ receptor. The partial agonist effects of buprenorphine on the µ receptor increase linearly with increasing doses of the drug, until moderate doses result in a plateau of pharmacological effects and further increases in doses result in no additional

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effect. The advantage of this ceiling effect is that buprenorphine carries a lower risk of abuse, addiction, and serious side effects (e.g., respiratory depression) compared with full opioid agonists. On the other hand, buprenorphine can precipitate opioid withdrawal in a person who is physiologically dependent on a full opioid agonist (see Chapter 3, “General Opioid Pharmacology”), so patients need to be monitored during induction therapy in order to avoid such precipitated withdrawal. Buprenorphine has poor oral bioavailability, which is the main reason the sublingual tablet was developed. In addition, the buprenorphine-naloxone combination formulation was developed to discourage diversion for intravenous use. The sublingual buprenorphine-naloxone tablet, taken as indicated, has an almost exclusively buprenorphine effect—naloxone absorbed by the sublingual route does not precipitate withdrawal because it has minimal sublingual bioavailability. However, if a patient attempts to get “high” by crushing and injecting the combination tablet, naloxone will precipitate opioid withdrawal because it has excellent intravenous bioavailability (Chapter 3). An expert panel convened by the Center for Substance Abuse Treatment (part of the federal Substance Abuse and Mental Health Services Administration) recommended that the buprenorphine-naloxone combination tablets be used for all treatment purposes—including induction, stabilization, and maintenance—with the exception of use in pregnant patients. For pregnant women, even the minute amounts of naloxone that become bioavailable through the sublingual route can be detrimental to the fetus and the mono product is therefore preferred (see Chapter 10, “Medical Management”). For the rest of this chapter, we use the term buprenorphine to refer to the buprenorphine-naloxone combination tablet unless otherwise specified.

Buprenorphine Induction The goal of buprenorphine induction and stabilization is to find the lowest dosage of buprenorphine at which the patient 1) discontinues or markedly reduces use of other opioids; 2) experiences no cravings for opioids of abuse; 3) has no opioid withdrawal symptoms; 4) has minimal or no side effects from the medication; and 5) starts feeling that his or her life is no longer out of control. Buprenorphine induction must be managed carefully because withdrawal symptoms can arise from either too little or too much medication, resulting in spontaneous or precipitated withdrawal, respectively. Undermedication will not treat the patient’s opioid withdrawal symptoms adequately, and overmedication may bring on the very symptoms from which the patient is seeking relief (Center for Substance Abuse Treatment 2004). Furthermore, underdosing buprenorphine may lead the patient to try to self-medicate withdrawal symptoms

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with other opioids, alcohol, or benzodiazepines. Overdosing buprenorphine during the induction phase may result in potentially significant respiratory depression in individuals who are also using other central nervous system (CNS) depressants. After buprenorphine induction and the patient has been stabilized with an appropriate dosage of the medication, buprenorphine maintenance is usually the preferred treatment, but some patients may elect to undergo detoxification. One of the most significant advantages of buprenorphine is that the patient does not have to make this decision at the start of therapy, a time when typically he or she is in the midst of a crisis. Instead, the decision can be made several weeks later, when the patient’s condition has stabilized. Whether the patient ultimately decides to continue taking the medication or discontinue taking it, the initial steps are the same: induction and stabilization.

PHYSICIAN CHOICES Getting the Pills Physicians have the option of either a) keeping a supply of medication in the office for the induction, or b) instructing the patient to fill a prescription for the first doses in a pharmacy and then to bring the medication to the office, where it will be administered. Either way, secure access to the medication by establishing a list of pharmacies in your area that are familiar with the medication. If the first option is followed and a supply of buprenorphine tablets is kept in the office, the physician and the institution must keep detailed records as required by federal and state laws. These laws mandate specific conditions for maintaining supplies of controlled substances for administration or dispensing (see Chapter 13, “Logistics of Office-Based Buprenorphine Treatment”). Unless you work in a hospital or other institution with adequate on-site pharmacy resources, the option whereby the physician gives the patient a prescription for the first day’s dosage may be preferable. However, asking the patient to fill the prescription and bring the medication back to the office implies a delay with the first day’s dosing and a risk that the patient may not return with the filled prescription. Another option is to fax the prescription to the pharmacy and then have it delivered to your office.

Deciding Between Mono and Combo Tablets In most circumstances, induction can begin with the buprenorphine-naloxone combination tablet. As previously mentioned (in “Pharmacology Overview”), there is essentially no naloxone bioavailability by the sublingual route, so the patient will not experience precipitated withdrawal from the naloxone con-

100 Handbook of Office-Based Buprenorphine Treatment of Opioid Dependence

tained in a first dose of buprenorphine-naloxone. Induction with buprenorphine mono tablets should generally be avoided. It can be done in very limited circumstances, such as in a hospital-based detoxification or in pregnant patients who are not candidates for methadone use. If the buprenorphine mono formulation is used for induction in nonpregnant patients, we recommend switching to buprenorphine-naloxone as soon as possible to reduce the risk of diversion of the medication.

Choosing the Day of the Week Monday through Wednesday, in the morning, is the ideal time to start the induction. An early morning appointment decreases the risk of opioid use before the office visit and starting early in the week allows more opportunities for follow-up assessment visits. Avoid induction during the weekend, unless your work setting has the personnel and infrastructure needed to treat patients at that time.

Selecting the Setting National clinical guidelines recommend observing the initial buprenorphine induction directly in the physician’s office and monitoring the patient’s progress by regular office visits during the stabilization and maintenance phases of the patient’s treatment. A new treatment setting for the induction has recently been suggested. It is defined as a home buprenorphine induction, in which the patient initiates the medication off-site after the initial assessment is completed and instructions are given by the clinician (Lee et al. 2009). However, more clinical data are needed before recommending this alternative as a routine procedure. Whatever approach you choose, it is helpful to partner with a colleague who is also certified to prescribe buprenorphine and can cover your practice when necessary.

PATIENT INSTRUCTIONS Preparing for the Induction Following assessment of the patient and the decision to initiate buprenorphine treatment (see Chapter 5, “Patient Assessment”), you need to give your patient instructions in preparation for induction to buprenorphine treatment. The most important direction is that the patient needs to arrive at the office in the state of withdrawal. Explain that withdrawal depends on many factors, such as

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101

level of tolerance, amount of use, and the type of opioid(s) abused. Ask your patient not to take any opioids for symptomatic relief while preparing for the induction; list opioids for the patient using both common and street names of the drugs to avoid confusion.

Taking the Pills Explain to the patient that buprenorphine is a sublingual tablet, which takes about 5–10 minutes to dissolve. While dissolving the tablet under the tongue, the patient should 1) not talk, 2) not drink, and 3) not chew the tablet or swallow the medication until the entire tablet has dissolved. Absorption improves with a moist mouth. Taking more than one tablet at the same time can be uncomfortable and may result in a paste-like mass with poor absorption. Advise the patient to take one pill at a time until he or she completes the full dosage for the day.

LEVEL

OF

WITHDRAWAL

The patient should experience mild to moderate withdrawal before taking the first buprenorphine sublingual dose. As a general rule, the longer the physician can delay the first dose of buprenorphine, the easier and less complicated the induction will be (Casadonte 2009). In order to reliably assess withdrawal symptoms, we recommend that the clinician use the Clinical Opiate Withdrawal Scale (COWS; Figure 6–5). COWS items include both signs (objective items such as resting pulse, pupil size, tremor, runny nose or tearing, yawning, sweating, and gooseflesh skin) and symptoms (subjective items such as anxiety or irritability, restlessness, bone or joint aches, and gastrointestinal upset). Each item is scored from 0–4 or 0– 5, and the total score is interpreted as follows (Wesson and Ling 2003): 5–12

Mild withdrawal

13–24

Moderate withdrawal

25–36

Moderately severe withdrawal

>36

Severe withdrawal

In addition to COWS, the clinician can provide the patient with a subjective scale, the Subjective Opiate Withdrawal Scale (SOWS; Figure 6–6). The symptoms are rated by the patient on a scale score of 0 (not at all present) to 4 (an extreme feeling) (Handelsman et al. 1987). The patient may complete this form in the waiting room and thus easily provide the clinician with a quick first estimate of the level of opioid withdrawal.

102 Handbook of Office-Based Buprenorphine Treatment of Opioid Dependence

Patient’s name:___________________________ Date: ______________ Buprenorphine induction: Enter scores at time zero, 30 minutes after first dose, 2 hours after first dose, etc. Times: ____ ____ ____ ____ Resting pulse rate: (record beats per minute) Measured after patient has been sitting or lying for 1 minute. 0 pulse rate 80 or below 1 pulse rate 81–100 2 pulse rate 101–120 4 pulse rate >120 Sweating: over past half-hour not accounted for by room temperature or patient activity. 0 no report of chills or flushing 1 subjective report of chills or flushing 2 flushed or observable moistness on face 3 beads of sweat on brow or face 4 sweat streaming off face Restlessness: observation during assessment. 0 able to sit still 1 reports difficulty sitting still, but is able to do so 3 frequent shifting or extraneous movements of legs/arms 5 unable to sit still for more than a few seconds Pupil size: 0 pupils pinned or normal size for room light 1 pupils possibly larger than normal for room light 2 pupils moderately dilated 5 pupils so dilated that only the rim of the iris is visible FIGURE 6–5.

Clinical Opiate Withdrawal Scale.

Clinical Use of Buprenorphine

Bone or joint aches: if patient was having pain previously, only the additional component attributed to opiate withdrawal is scored. 0 not present 1 mild diffuse discomfort 2 patient reports severe diffuse aching of joints/ muscles 4 patient is rubbing joints or muscles and is unable to sit still because of discomfort Runny nose or tearing: not accounted for by cold symptoms or allergies. 0 not present 1 nasal stuffiness or unusually moist eyes 2 nose running or tearing 4 nose constantly running or tears streaming down cheeks Gastrointestinal (GI) upset: over last half-hour. 0 no GI symptoms 1 stomach cramps 2 nausea or loose stool 3 vomiting or diarrhea 5 multiple episodes of diarrhea or vomiting Tremor: observation of outstretched hands. 0 No tremor 1 tremor can be felt, but not observed 2 slight tremor observable 4 gross tremor or muscle twitching Yawning: observation during assessment. 0 no yawning 1 yawning once or twice during assessment 2 yawning three or more times during assessment 4 yawning several times/minute FIGURE 6–5.

Clinical Opiate Withdrawal Scale. (continued)

103

104 Handbook of Office-Based Buprenorphine Treatment of Opioid Dependence

Anxiety or irritability: 0 none 1 patient reports increasing irritability or anxiousness 2 patient obviously irritable anxious 4 patient so irritable or anxious that participation in the assessment is difficult Gooseflesh skin: 0 skin is smooth 3 piloerection of skin can be felt or hairs standing up on arms 5 prominent piloerection Total scores with observer’s initials: Score: 5–12=mild 13–24 =moderate 25–36 =moderately severe >36= severe withdrawal FIGURE 6–5.

Clinical Opiate Withdrawal Scale. (continued)

Flow sheet for measuring symptoms over a period of time during buprenorphine induction. For each item, write in the number that best describes the patient’s sign or symptom. Rate it on just its apparent relationship to opiate withdrawal. For example, if heart rate is increased because the patients was jogging just before assessment, the increased pulse rate would not be added to the score. Source. Template from the American Society of Addiction Medicine.

INDUCTION W ITH PATIENTS DEPENDENT ON SHORT-ACTING OPIOIDS In general, the patient can begin buprenorphine therapy 12–16 hours after the last use of a short-acting opioid (e.g., heroin, hydrocodone, immediate-release oxycodone). Before receiving the first dose of buprenorphine, the patient needs to exhibit objective opioid withdrawal symptoms (a COWS score of > 12). If there is no or little clinical evidence of mild to moderate opioid withdrawal, reassess the last use of opioids and consider asking the patient to either 1) return another day, or 2) wait in the office until evidence of withdrawal is clear. A third option, allowing the patient to leave the office and return later that day, with clear instructions to not take any opioids while he or she is away from the office, is not recommended because there is the possibility that the patient will use more opioids and/or not return.

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105

Please score each of the 16 items below according to how you feel now (circle one number). Scale:

0=not at all 1=a little 2=moderately 3=quite a bit 4=extremely

Date: Time:

Symptom

Score

1 I feel anxious

0

1

2

3

4

2 I feel like yawning

0

1

2

3

4

3 I am perspiring

0

1

2

3

4

4 My eyes are teary

0

1

2

3

4

5 My nose is running

0

1

2

3

4

6 I have goose bumps

0

1

2

3

4

7 I am shaking

0

1

2

3

4

8 I have hot flushes

0

1

2

3

4

9 I have cold flushes

0

1

2

3

4

10 My bones and muscles ache

0

1

2

3

4

11 I feel restless

0

1

2

3

4

12 I feel nauseous

0

1

2

3

4

13 I feel like vomiting

0

1

2

3

4

14 My muscles twitch

0

1

2

3

4

15 I have stomach cramps

0

1

2

3

4

16 I feel like using now

0

1

2

3

4

TOTAL (range 0–64):

FIGURE 6–6. Source.

Subjective Opiate Withdrawal Scale. Handelsman et al. 1987.

106 Handbook of Office-Based Buprenorphine Treatment of Opioid Dependence

Once mild to moderate withdrawal is established, the patient is given 2–4 mg of buprenorphine. After the initial dose, it is recommended that the clinician monitor the patient in the office for 2 hours to confirm that opioid withdrawal symptoms subside and do not reemerge. The length of time the patient is monitored in the office varies depending on the clinician’s familiarity with the patient and experience with the medication. Relief of opioid withdrawal symptoms should begin within 30–45 minutes after the first dose. If symptoms start to subside, a second dose of 2–4 mg is typically administered, and frequently, the patient is instructed to take additional buprenorphine at home as needed for symptom relief. The maximum amount of buprenorphine at the end of the first day of induction ranges from 8 to 16 mg (Sullivan and Fiellin 2008). If symptoms of opioid withdrawal worsen or reemerge after the first dose of buprenorphine, precipitated withdrawal is a likely explanation (see “Managing Precipitated Withdrawal” below). Advise your patient to avoid driving or operating other machinery until he or she is familiar with the effects of the medication.

INDUCTION W ITH PATIENTS DEPENDENT ON INTERMEDIATE- AND LONG-ACTING OPIOIDS In general, patients who are using intermediate-acting opioids (e.g., sustainedrelease oxycodone) should first be given buprenorphine 18–24 hours after their last use of the intermediate-acting opioid; for patients using long-acting opioids (e.g., methadone) we recommend waiting 36–48 hours after last use of the full agonist. If the patient attends a methadone program, confirm his or her dosage, management, and the rationale for switching from methadone to buprenorphine with both the patient and the patient’s counselor. Methadone has a very long duration of action and accumulates in tissue stores, resulting in an increased risk of precipitated withdrawal during buprenorphine induction. Current clinical practice recommends that patients first taper—slowly—their methadone use to no more than 30 mg/day (or its equivalent, if taking another long-acting opioid or an intermediate-acting opioid). We then recommend holding the dosage of methadone to 30 mg/day for a minimum of 1 week in order to establish a steady state. Then discontinue methadone use and evaluate the patient frequently, possibly daily for 2–3 days, until mild to moderate signs and symptoms of opioid withdrawal develop (a COWS score of >12). At that point, you can safely administer the first buprenorphine dose of 2–4 mg and proceed with the induction as described above under “Induction With Patients Dependent on Short-Acting Opioids.” If the patient does not tolerate a methadone taper to 30 mg/day, it is still possible to start buprenorphine use; however, in this case the judgment of the clinician will guide the induction process. As described above, the first dose of

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buprenorphine should not be given until there is clear evidence of opioid withdrawal, and the patient may require very close monitoring to avoid or manage any precipitated withdrawal (see the next section, “Managing Precipitated Withdrawal”). The scientific literature on this topic is limited, with few guidelines on how to safely switch patients from methadone dosages higher than 30 mg/day to buprenorphine treatment (Glasper et al. 2005).

MANAGING PRECIPITATED WITHDRAWAL If opioid withdrawal worsens or reemerges shortly after the first dose of buprenorphine, the medication has most likely precipitated a withdrawal syndrome due to its high affinity for the µ receptor and resultant displacement of the full opioid agonist from the receptor. Precipitated withdrawal is not a medical emergency but can be very uncomfortable. The preferred strategy in the management of precipitated withdrawal is to administer additional doses of buprenorphine, 2 mg every 1–2 hours, attempting to provide enough agonist effect to suppress the withdrawal. Increasing the dosage of the medication responsible for the adverse effect may seem counterintuitive, especially to the affected patient, but it makes both pharmacological and clinical sense. Once buprenorphine has precipitated withdrawal, the medication cannot be taken back—therefore, pushing the dosage to achieve an agonist response is the best alternative. In rare circumstances when the induction needs to be stopped, as in the case of a patient who refuses to take any more buprenorphine, supportive treatments for the patient’s withdrawal symptoms are necessary. The following medications can be used: clonidine, 0.1 mg every 8 hours (or lofexidine outside the United States) to reduce autonomic withdrawal symptoms while monitoring the patient’s blood pressure; antiemetics for nausea; dicyclomine for abdominal cramps; hydroxyzine for agitation; loperamide for diarrhea; trazodone for insomnia; and nonsteroidal anti-inflammatory agents such as ibuprofen for myalgias and arthralgias. Ask the patient to return to the office the next day for a follow-up visit and possibly a new buprenorphine induction attempt.

SECOND DAY

OF INDUCTION

After the first day of buprenorphine induction, the procedures for patients dependent on short-, intermediate-, or long-acting opioids are the same. A review of the patient’s subjective experience on the first day of buprenorphine induction, a COWS score check, and a clinical evaluation may be used to determine the need for dosage adjustment, depending on the withdrawal or overmedication symptoms experienced by the patient. If the patient continues to experience withdrawal symptoms, he or she should receive the total dose used on the first day and additional 2- to 4-mg increments of buprenorphine until a total dose of 12–16 mg is achieved

108 Handbook of Office-Based Buprenorphine Treatment of Opioid Dependence

on the second day of induction. If the patient feels sedated and overmedicated at the end of the first day, lower the daily dose by 2–4 mg. If neither withdrawal nor overmedication symptoms are observed on the second day, repeat the total dose from the first day. A good night’s sleep is a good measure of adequate coverage. Sometimes the induction takes more than 2 days. You may ask the patient to come back to the office for further dose adjustments, or you may review the clinical status over the telephone or by e-mail and adjust as needed. Dose adjustments follow the same principles as above: raise the dosage if withdrawal symptoms continue and/or cravings for opioids occur, and lower the dosage if adverse effects occur. Whereas the maximum daily dose is 32 mg of buprenorphine by the end of the first week, the majority of patients stabilize with 8–16 mg/day. Do not assume that the patient has not used any other opioids since the first day of induction—ask your patient if he or she has used any opioids since leaving the office. Suspect active opioid use if the patient continues experiencing opioid withdrawal symptoms and/or difficulties with medication adherence. A urine toxicology examination for drugs of abuse may be indicated to guide clinical interventions.

SPECIAL CASES Pregnancy At the present time, methadone (a pregnancy category C medication) is the only FDA-approved medication for opioid-dependent pregnant women. Pregnant patients should be offered methadone maintenance therapy when available. If buprenorphine (also a pregnancy category C medication) is indicated (e.g., a pregnant patient refuses to take methadone and buprenorphine’s benefits outweigh its risks, or there is no methadone treatment available in your community), use the mono formulation of buprenorphine only. Mono buprenorphine does not contain naloxone, which can cause fetal and maternal hormonal changes. It also reduces the potential that the medication could result in maternal and fetal withdrawal symptoms if the patient tries to use the drug intravenously (see also Chapter 10).

Opioid Dependence Without Physiological Dependence People who have opioid dependence but are not currently physically dependent can also benefit from treatment with buprenorphine. For example, someone who has been addicted to heroin for many years but has not used for the past 6 months while incarcerated is at high risk for relapse on release from prison. Also, patients who binge on opioids but do not meet criteria for physiological dependence (tol-

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109

erance or withdrawal) may still meet criteria for opioid dependence according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR; American Psychiatric Association 2000) due to severe psychosocial deterioration. Reinduction with buprenorphine may also be appropriate for a patient who recently completed detoxification treatment but has begun to use opioids occasionally. In this case, there would be no reason to delay treatment until the patient has resumed daily use and is again physically dependent. Buprenorphine treatment can address such patients’ cravings and keep them safe. Buprenorphine induction for patients who are not physiologically dependent on opioids starts with 2–4 mg of buprenorphine. Raise the dose by 2-mg increments during the following days until the patient is comfortable and cravings abate. You may repeat a target dose of buprenorphine that was successful during past stabilization and maintenance phases.

Buprenorphine Stabilization The stabilization phase lasts 1–2 months. During this period, patients are seen regularly, every 1–3 weeks, in order to find a homeostatic state in the opioid system. Adjust the dosage of buprenorphine, if needed, to determine the minimum dosage necessary to eliminate withdrawal symptoms, markedly decrease cravings, and minimize side effects. Once you achieve initial control of withdrawal symptoms and craving, further dose increases should be approached in a very conservative manner. Because of the drug’s long half-life (24–60 hours, mean elimination half-life of 37 hours) it may take 10–14 days to achieve the full benefit of an increased dosage. More frequent increases may therefore result in unnecessary and excessive doses. The average daily dose is 8–16 mg of buprenorphine but some patients require as much as 32 mg/day. If a patient continues to have significant cravings and/or withdrawal symptoms at 32 mg/day, consider discontinuing buprenorphine and treating the patient with methadone. During the stabilization phase, discuss with the patient the possibility of engaging in psychosocial treatments and 12-step programs (see Chapter 8, “Clinical Management II”). This is an appropriate point at which to reinforce the message that the patient should not expect buprenorphine to eliminate all of his or her problems, and that the most successful outcomes are seen in patients who combine medication with psychosocial treatment and other recovery efforts.

Buprenorphine Maintenance Buprenorphine maintenance lasts several months or years depending on the patient’s individual needs. Many opioid-dependent patients require treatment

110 Handbook of Office-Based Buprenorphine Treatment of Opioid Dependence

with buprenorphine indefinitely, not unlike patients with diabetes requiring insulin treatment or bipolar patients needing lithium maintenance. During this time, continue to review the benefits and adverse effects of buprenorphine; periodically run liver function tests; and counsel the patient on relapse prevention, physical well-being, and mental health (see also Chapter 8). After completion of the stabilization phase, most patients continue with the same dosage, typically 8–16 mg/day. However, several medical and psychosocial factors may dictate a change in dosage. Medical factors include significant weight increase or decrease, progression of liver disease, changes in other prescription medications, and pregnancy or menopause. As patients stabilize further and feel healthy, their life circumstances get better, finances recover, relationships blossom, and coping skills improve. As a result, patients may have fewer opioid cravings, have a lower risk of relapse, and need less medication. Even if complete detoxification is not the goal of treatment, discuss with your patient the possibility of working toward a lower dosage of buprenorphine as long as he or she still feels comfortable and safe from relapse. Reassure the patient that he or she can always return to the maintenance dosage if needed (see also Chapter 7, “Clinical Management I”).

DOSING STRATEGIES Once the patient is stable and the buprenorphine maintenance daily dose is established, he or she may switch to a less-than-daily dosing schedule (Johnson et al. 2003). Buprenorphine can be taken sublingually safely and effectively on an alternate-day dosing schedule (every 48 hours) by doubling the maintenance dose (e.g., if the patient is taking 8 mg/day, switch to 16–16–24 mg/day on Monday, Wednesday, Friday, respectively) (Amass et al. 1994). Alternative schedules include dosing every 72 hours by tripling the maintenance dose (Bickel et al. 1999); or dosing every 96 hours by quadrupling the maintenance dose (Petry et al. 2000). The efficacy of thrice-weekly dosing has been well documented; however, more data are needed before these other dosing schedules can be recommended. Although daily dosing is generally recommended to improve medication adherence, less-than-daily dosing regimens are also clinically useful for several reasons: 1. Alternate-day dosing schedules have been shown to be preferred by some patients to daily dosing. 2. Thrice-weekly dosing has been shown to be safe and effective. 3. In an opioid treatment program (OTP), these dosing schedules decrease the risk of diversion, because they reduce the need for take-home medication. In addition, monitoring and ensuring compliance with medication can be done at the clinic if diversion is suspected.

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111

4. Less-than-daily dosing schedules may be an incentive to patients contingent on abstinence from illicit drugs and compliance with treatment, as with methadone. It is likely that the benefits of less-than-daily dosing schedules with buprenorphine will be more advantageous when prescribed in an OTP facility, but these schedules may also be considered for buprenorphine treatment in an officebased setting (Marsch et al. 2005). On the other hand, although once-daily dosing is an effective treatment to block opioid craving and relapse, in some cases more frequent dosing may be advised. Some patients report that buprenorphine works well through the morning but experience a recurrence of thoughts and urges to use late in the afternoon or early in the evening. One effective strategy is to keep the same daily dose but to have the patient divide the tablet and the dosing—that is, change from one 8-mg tablet every morning to a half-tablet (4 mg) every morning and another half-tablet (4 mg) in the mid- or late afternoon. It has been suggested that the recurrence of thoughts and urges to use is a psychological effect in individuals who have been using short-acting opioids with multiple doses every day for many years. In other words, twice-daily dosing is a way for patients to feel better psychologically about buprenorphine’s effectiveness by mirroring their long-term drug use pattern. However, it is possible that there is also a pharmacological explanation for this complaint—as in the case of pain management, when it is usually necessary to recommend divided daily doses.

DRUG-DRUG INTERACTIONS Buprenorphine is metabolized to norbuprenorphine by the cytochrome P450 3A4 (CYP3A4) isoenzyme. Buprenorphine is primarily a substrate of CYP3A4. Medications that can inhibit or induce the CYP3A4 isoenzyme may increase or decrease, respectively, the plasma concentrations of buprenorphine. Inhibitors of the CYP3A4 isoenzyme include macrolide antibiotics (e.g., erythromycin), azole antifungals (e.g., ketoconazole), antidepressants (e.g., fluoxetine, fluvoxamine, sertraline), and HIV protease inhibitors (e.g., ritonavir, saquinavir, indinavir). CYP3A4 isoenzyme substrates can also raise buprenorphine levels, including alprazolam, diazepam, buspirone, trazodone, zolpidem, caffeine, haloperidol, pimozide, erythromycin, and oral contraceptives. Based on buprenorphine’s ceiling effect (see “Pharmacology Overview” earlier in this chapter), the increase in plasma concentrations of buprenorphine do not result in clinical complications unless buprenorphine is used with other CNS depressants (see below). Inducers of the CYP3A4 isoenzyme include carbamazepine, phenytoin, phenobarbital, reverse transcriptase inhibitors (e.g., zidovudine), nonnucleoside

112 Handbook of Office-Based Buprenorphine Treatment of Opioid Dependence

reverse transcriptase inhibitors (e.g., efavirenz), and rifampin. Reduction in plasma concentrations of buprenorphine might induce withdrawal if the buprenorphine does not provide sufficient µ receptor coverage. However, buprenorphine has an active metabolite, norbuprenorphine, which is also a µ opioid agonist and thus helps reduce the risk of a buprenorphine–CYP3A4 inducer interaction resulting in withdrawal. With the exception of interactions with the retroviral drugs atazanavir and ritonavir, it is not clear that any of these theoretical interactions has any practical clinical implications. For further discussion of the interaction between buprenorphine and the CYP3A4 system, please see “Drug Interactions With Buprenorphine” in Chapter 9, “Psychiatric Comorbidity.” In Chapter 3, Table 3–2 provides a partial list of medications metabolized by CYP3A4 and may be a helpful reference. Buprenorphine has such high affinity for the µ opioid receptor that it will displace most full opioid agonists and may thus precipitate withdrawal. Although this concept has been reviewed multiple times in buprenorphine training curricula (including this book), the likelihood of buprenorphine-precipitated withdrawal is low, and even when it does occur it is mild in intensity and short in duration. For a detailed discussion of the interaction of buprenorphine with full opioid agonists, please see Chapter 3 and Chapter 11 (“Management of Acute and Chronic Pain”). The opioid antagonist naltrexone is approved by the FDA for the treatment of opioid dependence and alcohol dependence but should not be combined with buprenorphine. Naltrexone has adequate oral bioavailability and could potentially precipitate withdrawal in a patient who is taking buprenorphine. There is a potential synergistic effect in combining CNS depressants with buprenorphine, especially when taken intravenously. In a study conducted with rats (Nielsen and Taylor 2005), the ceiling effect of buprenorphine disappeared when buprenorphine was combined with high doses of benzodiazepines. The combination of buprenorphine and diazepam resulted in respiratory depression similar to the effect of full agonists. Although the combination of buprenorphine and benzodiazepines or other CNS depressants is not contraindicated, patients taking buprenorphine who also take sedatives (either prescribed by a physician or purchased illegally) are at increased risk of respiratory depression. A medical advisory published by Reckitt Benckiser (2009), the manufacturer of Suboxone and Subutex, advises the following: • • • •

Consider reducing the dosage of either buprenorphine or the benzodiazepine or both. Educate the patient about the potential danger. Treat co-occurring psychiatric disorders, such as depression and/or anxiety. Avoid prescribing benzodiazepines whenever possible.

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For a detailed discussion of the interaction of buprenorphine with benzodiazepines and other sedating agents, please see also the section “Overdose” in Chapter 4.

Detoxification With Buprenorphine The treatment of opioid withdrawal by administering a medication taper and eventually discontinuing it is sometimes called medical withdrawal and sometimes detoxification. Strictly speaking, the term detoxification is a misnomer because opioids are not in themselves neurotoxic (as compared with alcohol, for example, which is directly toxic to the nervous system), but the term detoxification has prevailed both in the medical literature and the community. Buprenorphine can be used for detoxification from opioids safely and effectively in both inpatient and outpatient settings. Studies support that buprenorphine is more effective and is better tolerated than clonidine for the treatment of opioid withdrawal (Ziedonis et al. 2009). Before the FDA approval of sublingual buprenorphine in the United States, the analgesic formulation was administered by injection and used for opioid withdrawal. At the present time, the injectable formulation is not recommended, based on the clinical advantages of the sublingual preparation (American Psychiatric Association 2007). Since the approval of sublingual buprenorphine for the treatment of opioid dependence, the FDA has specifically stated that the parenteral formulation should no longer be used for this purpose. Both buprenorphine and methadone have long action and proven effectiveness in detoxification. Buprenorphine has the additional advantage of being very safe because of its ceiling effect. However, well-designed studies comparing buprenorphine and methadone for opioid withdrawal are limited (Polydorou and Kleber 2008). The management of opioid withdrawal can be divided into three scenarios: 1) rapid detoxification in 3 or fewer days, 2) detoxification in 4–30 days, and 3) detoxification in more than 30 days. All approaches require that patients experience mild to moderate opioid withdrawal (a COWS score of >12) before the first dose of 2–4 mg of buprenorphine is administered. Equally important is that all approaches recommend that patients engage in some form of psychosocial treatment and support after completion of detoxification. The average daily dose of buprenorphine on the first and second days of rapid detoxification ranges between 8 and 12 mg; on the third day the patient is given 6 mg of buprenorphine; then the medication is discontinued (Cheskin et al. 1994). Alternatively, the buprenorphine dosage can be decreased in decrements of 2 mg/day over the following days if necessary (Horspool et al.

114 Handbook of Office-Based Buprenorphine Treatment of Opioid Dependence

2008). Two 5-day protocols have been shown to be safe and efficacious in treating acute withdrawal, with the higher-dosage buprenorphine schedule (8–8–8– 4–2 mg/day on days 1–5) demonstrating moderate superiority over the lowerdosage protocol (2–4–8–4–2 mg/day on days 1–5) (Oreskovich et al. 2005). Information on the long-term efficacy of these interventions is limited. The moderate-length detoxification approach allows patients to undergo induction and stabilization before medication tapering begins. Patients first stabilize with an adequate buprenorphine dosage according to their withdrawal severity, cravings, adverse effects, and other drug use. The average daily dose of buprenorphine on a moderate detoxification schedule is 8 mg. The Clinical Trials Network (CTN), a project sponsored by the National Institute on Drug Abuse, has used a 13-day detoxification dosing schedule that is suitable for inpatient and outpatient settings (Table 6–1). On the first day, 4 mg of buprenorphine and an additional 4 mg, if needed, are administered; on the second day 8 mg and on the third day 16 mg are given. For the next 4 days (day 4 through day 7), buprenorphine dosages are decreased in decrements of 2 mg/day, reaching 8 mg on the seventh day of detoxification. Then the daily dose is decreased gradually by 2 mg every 2 days. During the last 2 days (days 12 and 13 ) of the CTN protocol, the patient takes 2 mg of the medication per day (Ling et al. 2005). However, this CTN protocol is only one of the detoxification schedules using buprenorphine sublingual tablets that are suggested in the literature, and the comparative effectiveness of the approaches is largely unknown. A study of 364 patients with opioid dependence (Katz et al. 2009) compared a brief, 5-day buprenorphine detoxification protocol with an extended, 30-day protocol. The results suggest that longer detoxification schedules improve treatment engagement, increase the chances for successful completion of detoxification, and facilitate transition to long-term addiction treatment. Withdrawal symptoms associated with a more gradual reduction in buprenorphine dosage, over a period longer than 30 days, are less severe than they are with shorter detoxification protocols. The medical literature reports less illicit opioid use and greater treatment retention with longer detoxification schedules (Horspool et al. 2008; Sullivan and Fiellin 2008). As previously mentioned, the clinician can also use additional, nonopioid medications for symptomatic relief of opioid withdrawal during the detoxification with buprenorphine, if clinically indicated (see “Managing Precipitated Withdrawal”). Clinical evidence of insomnia, anxiety, restlessness, nausea, vomiting, diarrhea, and muscle cramps has justified the use of ancillary medications.

Clinical Use of Buprenorphine

TABLE 6–1.

115

National Institute on Drug Abuse Clinical Trials Network buprenorphine withdrawal protocol

Study day

1

2

3

4

5

6

7

8

9 10 11 12 13

Combinationa daily dose (mg)

4b

8 16 14 12 10

8

6

6

4

4

2

2

aBuprenorphine-naloxone. bPlus

additional 4 mg, as needed. Source. Ling et al. 2005.

Buprenorphine Taper Sometimes both patients and physicians plan to discontinue buprenorphine after a period of stabilization. It is unclear whether tapering a stable buprenorphine dosage is best accomplished with a short- or long-term discontinuation schedule. A study of 516 patients taking buprenorphine found a modest advantage of a 7-day taper versus a 28-day taper, with 44% versus 30% of patients having opioid-free urine specimens, respectively, at the end of the taper (Ling et al. 2009). It is important to underscore that discontinuation of buprenorphine is frequently an ineffective treatment of opioid dependence; in a study by Ling et al. (2009), only 12% (with a 7-day taper) to 13% (with a 28-day taper) of the subjects remained opioid free at the 3-month follow-up.

Conclusion Treating opioid dependence with buprenorphine is technically simple and straightforward. The treatment has three phases: induction, stabilization, and maintenance. During induction, the patient works closely with the physician to avoid withdrawal symptoms (spontaneous or precipitated) and ensure a smooth transition. Maximizing symptom relief and minimizing adverse effects is the balancing act of the stabilization phase. During the maintenance phase, the focus shifts from dose adjustments to promotion of a healthy lifestyle, investment in various psychosocial treatments, and fulfillment of the patient’s personal goals. The majority of patients feel mild to moderate discomfort for a few hours during the first day of induction, but this is quickly followed by profound relief and gratitude once they experience the beneficial effects of the medication. For physicians, effecting this dramatic transformation can be one of the most rewarding and gratifying aspects of medical practice.

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Clinical Pearls • Always use the buprenorphine-naloxone formulation except in pregnant patients (who may receive the mono buprenorphine formulation if necessary). • If the patient is physiologically dependent on opioids, make sure that he or she is in mild to moderate withdrawal before starting the induction. The longer you can delay the first dose of buprenorphine, the easier and less complicated the induction will be. • Start the induction with 2–4 mg of buprenorphine and raise the dosage over the first couple of days of induction to a target daily dose of 8–16 mg; the maximum dosage is 32 mg/day. • Stabilize the patient over 1–3 weeks. If further dose adjustments are needed, a) increase the dosage to manage cravings or withdrawal symptoms, or b) lower the dosage, as tolerated, to reduce side effects or for patient preference. Because of buprenorphine’s long half-life, dose increases should occur no more frequently than once a week. • Avoid using other opioid agonists or opioid antagonists while the patient is taking buprenorphine. Drug-drug interactions with most other classes of drugs can be managed with dose adjustments. • If you decide to use buprenorphine for detoxification, keep in mind that the longer the taper, the greater the chance of success.

CASE 1 Sally is a 21-year-old sophomore at a local college. She makes an appointment after seeing your name on the Internet buprenorphine physician locator list. In the office, she is taciturn and makes little eye contact. You learn that she started occasional use of pain pills in high school when “everyone was doing it on the weekends.” Three months ago, a friend gave her “Oxys.” She is worried now because she uses them almost daily. She says: “I feel lousy if I don’t get them.” She recently failed two exams and has stopped her daily jogging routine. She admits to occasional marijuana use and has a few drinks on weekends but denies use of other drugs. “I tried to stop, but I can’t. My parents are going to kill me....”

1. Does Sally demonstrate DSM-IV-TR criteria for opioid dependence? 2. Does Sally demonstrate DSM-IV-TR criteria for opioid abuse? 3. Does she meet legal criteria for opioid agonist therapy? Is her age an issue?

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4. Is she a candidate for office-based buprenorphine treatment, or should she be referred to an OTP?

♦ ♦

♦

♦

♦ ♦

♦

You conduct a thorough evaluation and decide that Sally would benefit from office-based buprenorphine therapy. She reports that she has been recently using “two 80s a day” (i.e., two 80-mg tablets of OxyContin daily). She makes it clear that she doesn’t want to stay on buprenorphine “forever.”

1. What would you consider “adequate education” before starting treatment? 2. Would you feel comfortable writing a prescription for her to bring buprenorphine back to the office? 3. Is a urine toxicology examination indicated? 4. What initial buprenorphine dosage would you prescribe? 5. How would you determine your initial target dosage for this patient? 6. If she experiences precipitated withdrawal in your office what would you do next? 7. When would you give the next dose if she is able to tolerate the initial dose? 8. What are your treatment goals? (Brief taper with drug-free counseling? Gradual taper? Long-term maintenance?) How necessary is counseling in this case?

References Amass L, Bickel WK, Higgins ST, et al: Alternate-day dosing during buprenorphine treatment of opioid dependence. Life Sci 54:1215–1228, 1994 American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision. Washington, DC, American Psychiatric Association, 2000 American Psychiatric Association: Practice guideline for the treatment of patients with substance use disorders, 2nd edition. Am J Psychiatry 164(4 Suppl):5–123, 2007. Available at: http://www.psychiatryonline.com/pracGuide/pracGuideTopic_5. aspx. Accessed April 23, 2010. Bickel WK, Amass L, Crean JP, et al: Buprenorphine dosing every 1–3 days in opioiddependent patients. Psychopharmacology 146:111–118, 1999 Casadonte PP: Buprenorphine induction, in Physicians Clinical Support System–Buprenorphine (PCSS-B), Clinical Guidance. October 27, 2009. Available at: http:// www.pcssbuprenorphine.org/pcss/documents2/PCSS_BuprenorphineInduction_ 050308.pdf. Accessed May 7, 2010. Center for Substance Abuse Treatment: Clinical Guidelines for the Use of Buprenorphine in the Treatment of Opioid Addiction. Treatment Improvement Protocol (TIP) Series 40. DHHS Publ No (SMA) 04-3939. Rockville, MD, Substance Abuse and Mental Health Services Administration, 2004. Available at: http:// www.kap.samhsa.gov/products/manuals/index.htm. Accessed April 29, 2010.

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Cheskin LJ, Fudala PJ, Johnson RE, et al: A controlled comparison of buprenorphine and clonidine for acute detoxification from opioids. Drug Alcohol Depend 36:115–121, 1994 Glasper A, Reed LJ, de Wet CJ, et al: Induction of patients with moderately severe methadone dependence onto buprenorphine. Addict Biol 10:149–155, 2005 Handelsman L, Cochrane KJ, Aronson MJ, et al: Two new rating scales for opiate withdrawal. Am J Drug Alcohol Abuse 13:293–308, 1987 Horspool MJ, Seivewright N, Armitage CJ, et al: Post-treatment outcomes of buprenorphine detoxification in community settings: a systematic review. Eur Addict Res 14:179–185, 2008 Johnson RE, Strain EC, Amass L: Buprenorphine: how to use it right. Drug Alcohol Depend 70 (suppl 1): 59–77, 2003 Katz EC, Schwartz RP, King S, et al: Brief vs. extended buprenorphine detoxification in a community treatment program: engagement and short-term outcomes. Am J Drug Alcohol Abuse 35:63–67, 2009 Lee JD, Grossman E, DiRocco D, et al: Home buprenorphine/naloxone induction in primary care. J Gen Intern Med 24:226–232, 2009 Ling W, Amass L, Shoptaw S, et al: Buprenorphine Study Protocol Group: A multicenter randomized trial of buprenorphine-naloxone versus clonidine for opioid detoxification: findings from the National Institute on Drug Abuse Clinical Trials Network. Addiction 100:1090–1100, 2005 Ling W, Hillhouse M, Domier C, et al: Buprenorphine tapering schedule and illicit opioid use. Addiction 104:256–265, 2009 Marsch LA, Bickel WK, Badger GJ, et al: Buprenorphine treatment for opioid dependence: the relative efficacy of daily, twice and thrice weekly dosing. Drug Alcohol Depend 77:195–204, 2005 Nielsen S, Taylor DA: The effect of buprenorphine and benzodiazepines on respiration in the rat. Drug Alcohol Depend 79:95–101, 2005. Epub 2005 Feb 17 Oreskovich MR, Saxon AJ, Ellis ML, et al: A double-blind, double-dummy, randomized, prospective pilot study of the partial mu opiate agonist, buprenorphine, for acute detoxification from heroin. Drug Alcohol Depend 77:71–79, 2005 Petry NM, Bickel WK, Badger GJ: A comparison of four buprenorphine dosing regimens using open-dosing procedures: is twice-weekly dosing possible? Addiction 95:1069–1077, 2000 Polydorou S, Kleber HD: Detoxification of opioids, in The American Psychiatric Publishing Textbook of Substance Abuse Treatment, 4th Edition. Edited by Galanter M, Kleber HD. Washington, DC, American Psychiatric Publishing, 2008, pp 265–287 Reckitt Benckiser: Medical Advisory & Best-Practices Update. Richmond, VA, Reckitt Benckiser Pharmaceuticals, May 2008. Available at: http://www.suboxone.com/ pdfs/MedicalAdvisory.pdf. Accessed June 8, 2010. Sullivan LE, Fiellin DA: Narrative review: buprenorphine for opioid-dependent patients in office practice. Ann Intern Med 148:662–670, 2008 Wesson DR, Ling W: The Clinical Opiate Withdrawal Scale (COWS). J Psychoactive Drugs 35:253–259, 2003 Ziedonis DM, Amass L, Steinberg M, et al: Predictors of outcome for short-term medically supervised opioid withdrawal during a randomized, multicenter trial of buprenorphine-naloxone and clonidine in the NIDA clinical trials network drug and alcohol dependence. Drug Alcohol Depend 99:28–36, 2009

7 Clinical Management I BUPRENORPHINE TREATMENT IN OFFICE-BASED SETTINGS Jeffrey D. Baxter, M.D.

ADOPTING A NEW treatment modality can be challenging, especially in outpatient office settings where providers and staff may feel their resources are stretched to meet the needs of the patient population they already are serving. But, as has been described in earlier chapters of this book, the need to expand treatment services is urgent, and the potential to improve the lives of patients hurt by the disease of opioid addiction is great. Most providers have found that buprenorphine treatment integrates easily into their outpatient office practices, and that patients greatly appreciate the opportunity to receive treatment. The purpose of this chapter is to offer some suggestions for managing patients in office-based buprenorphine treatment. It is my hope that the procedures outlined below will provide a foundation for organizing treatment in a way that will be rewarding both for providers and for the patients seeking treatment. 119

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A case is presented at the end of this chapter, including related questions for additional consideration. For discussion of this case, please see Chapter 14, “Comments on the Case Vignettes.”

Organizing Your Office to Support Buprenorphine Treatment A number of steps can be taken to help prepare an office for providing buprenorphine treatment. Begin by establishing administrative and clinical procedures for each stage of the treatment, including screening, induction, and ongoing treatment. Important elements include managing referrals and inquiries, staff education and training, and communication and coordination with other treatment providers. Also, because drug addiction shares many of the features of chronic medical illness (McLellan et al. 2000), providers should consider adapting office systems already in place for managing other chronic diseases for office-based buprenorphine treatment (Saitz et al. 2008). The care management models described below are effective ways to implement this treatment approach.

MANAGING REFERRALS

AND INQUIRIES

How will referrals for treatment, either self-referral from patients or referrals from outside providers, be managed? If you are participating in one of the available online treatment referral resources, such as the treatment finder supported by the Substance Abuse and Mental Health Services Administration, your office will receive calls from patients and providers, from both within and outside your local area (see Chapter 13, “Logistics of Office-Based Buprenorphine Treatment”). It is important to identify the phone number these callers will use and how their calls will be managed. Will office staff answer those calls, or will patients and providers be asked to leave a message? Who will return those calls? Some offices have designated nonphysician providers to manage the initial communication and screening with patients, to ensure that patients are appropriate and eligible for care in the office before any physician time is invested. It may be useful to develop an initial screening tool that outlines any inclusion or exclusion criteria that may be specific to your office.

STAFF EDUCATION

AND

TRAINING

Because the treatment of addiction has been managed outside of medical and psychiatric office settings for most of the last century, it is important to provide

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education and informational resources for support staff. Nurses, office staff, and even many medical providers may hold deep-seated beliefs about the causes or treatment of addiction, many of which are not at all evidence based. Common misconceptions include beliefs that addiction is a sign of character flaws or moral weakness and that medical treatment doesn’t work for such conditions. Some staff may object to the idea of opioid agonist treatment, believing that buprenorphine treatment involves substituting one addiction for another. Finally, some individuals may have personal experience with addiction, either themselves or with close family members, and these experiences may influence their feelings or behaviors toward others with an addictive illness. Any investment made in educating staff about the natural history and treatment of opioid dependence will provide immediate value in the clinical setting. The National Institute on Drug Abuse–sponsored Web site Buprenorphine (Suboxone) Training and Practice Tools (www.buppractice.com) contains links to training guides and courses specifically designed for clinical and administrative staff.

CARE MANAGEMENT MODEL Any office providing buprenorphine treatment should be able to provide either well-coordinated or fully integrated medical, psychiatric, and behavioral treatment. To facilitate this comprehensive care, some medical offices utilize care management models for buprenorphine treatment similar to those used for diabetes and other chronic medical illnesses. In these models, a nurse, a clinical social worker, or another nonphysician provider takes a leadership role in monitoring patients under the direction of the physician. Although nonphysician providers may not prescribe buprenorphine under the current authorizing legislation, they may provide many of the components of care, including the initial screening, management of the induction and early stabilization periods, ongoing adherence and recovery monitoring, communication with outside providers, and other coordination of care (Bodenheimer et al. 2002a, 2002b; Saitz et al. 2008). Similarly, psychiatrists often work in close collaboration with behavioral treatment providers who provide screening, assessment, and ongoing clinical services. Collaboration with a behavioral treatment provider offers the additional benefit of integrating evidence-based individual and/or group counseling services into the care process. The ability to establish care management or other more advanced collaborative models varies, depending on what resources are available locally, the quality of communication among members of the treatment team, and what nonphysician services are reimbursable under patients’ insurance plans. In any shared model, physicians need to ensure that the amount of physician supervision and contact is safe, appropriate, and consistent with clinical guidelines. For a discussion of other models of care, see Chapter 13.

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COMMUNICATION AND COORDINATION WITH OTHER TREATMENT PROVIDERS Communication with other providers involved in each patient’s care is essential for safe and effective office-based buprenorphine treatment. Most buprenorphine providers require that patients identify all treatment providers involved in their care, and that patients sign information release forms compliant with the Health Insurance Portability and Accountability Act of 1996 (HIPAA) to allow communication with the other providers, before starting treatment. Buprenorphine providers may choose to mandate that other providers or consultants be active participants in a patient’s care, or that patients engage in certain types of treatment. The most common situation is for buprenorphine providers to require participation in some form of group or individual counseling and/or 12-step recovery program. Other examples include psychiatrists who may require that a patient have a primary care physician, or medical care providers who may require ongoing treatment with a psychiatrist. Establishing collaboration and referral agreements among providers of different types of services will assist patients in accessing these treatments and will facilitate communication and documentation. Making connections with specialty substance abuse treatment providers such as those who work at detoxification centers and in methadone maintenance programs is particularly important in case patients do not do well with office-based treatment and ultimately need more intensive or more highly structured care. For buprenorphine providers who do not have formal collaborative relationships, monitoring adherence to other treatment and coordinating care with other providers may pose a significant challenge. For busy providers, taking time to communicate with other providers may not seem to be a priority compared with other issues that have to be managed during a visit. Completing the required release forms to allow a more formal exchange of protected information is also time consuming. Finally, patients may resist treatment providers’ efforts to communicate with each other, because of either embarrassment, fear that disclosure of an addiction diagnosis may affect the quality of the care provided, or a desire to obtain medications from other providers that may not be safe or appropriate in combination with buprenorphine. Some techniques to facilitate communication include the following: 1. Create a letter that identifies the patient as a participant in buprenorphine treatment and provides basic information about the medication and contact information for you and your office. Have every patient sign releases so that this letter may be sent to each provider involved in a patient’s care. Consider requesting that a copy of the documentation from patients’ visits with other treatment providers be copied formally to you following each appointment.

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2. Create a communication form for patients to give to consultants and other providers that requests a quick summary of their office visit along with information about how that provider can be contacted in case you have questions. Keep it short, because no provider appreciates additional paperwork. This form could also include a request for the consultant to acknowledge that he or she is aware that the patient is currently enrolled in a buprenorphine treatment program. 3. If possible, include HIPAA-compliant release of information statements on these forms for patients to sign, so that all necessary documentation is included as part of a single-page document. See Chapter 13 for a sample release of information form. 4. Have the patient be responsible for transporting these forms or other types of documentation between providers, and include this responsibility in the list of activities required for buprenorphine treatment. You need to consider what responses you will take if providers refuse communication, if patients report that outside appointments are canceled or changed, or if, for some other reason, patients do not return paperwork to your office.

Establishing a Therapeutic Environment After a patient has been screened, assessed, and found to be appropriate for treatment with buprenorphine within your clinical setting, a number of additional steps are recommended before induction to help establish a safe and effective therapeutic environment, as summarized below.

INFORMED CONSENT Patients must be able to provide informed consent for participation in buprenorphine treatment. As for any treatment, obtaining informed consent involves reviewing the nature of the proposed treatment and making sure that the patient understands the potential benefits and risks of treatment, not only for themselves but also for the people around them. Informed consent procedures for buprenorphine treatment usually include reviewing the following: • • •

That buprenorphine is an opioid that causes physical dependence The goals of opioid substitution therapy, such as relieving withdrawal symptoms and eliminating drug abuse Alternative treatment options, such as inpatient detoxification or methadone maintenance

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•

Potential medication interactions and side effects, including opioid withdrawal symptoms.

Obtaining informed consent is different from reviewing a treatment agreement or contract, which focuses more on office procedures and expected behaviors (see the next section, “Treatment Agreements”). Informed consent should be obtained before starting treatment, and renewed on a periodic basis during treatment. Obtaining informed consent is challenging in many ways. Providers must be able to communicate the risks and benefits of treatment to patients who usually have no medical training and may have low literacy levels or limited English proficiency. Patients with an opioid addiction may be desperate for treatment and may rush through a review of the risks and alternative treatment options in order to obtain treatment. Some providers may request that a patient’s spouse or other family member participate in the informed consent process, both to help ensure that the patient understands the information presented, and to educate family members so they can better support patients entering treatment. Figure 7–1 shows a model informed consent form adapted from the tools used in my office. This document includes information that pertains specifically to one office setting and is in no way perfect or exhaustive; it is meant only to model the process and provide a foundation for other providers initiating buprenorphine treatment.

TREATMENT AGREEMENTS Traditional treatment agreements, known as contracts, have focused mostly on what is expected of the patient during treatment, such as behavioral codes, office procedures, and treatment components with which patients are expected to comply. Patients have often perceived these contracts as a set of rules being imposed by one party (the provider) onto another (the patient). Providers have often considered any deviation from these contracts as a violation or breach that could result in the discontinuation of treatment. More recently, treatment contracts have been replaced by the concept of the treatment agreement. The goal of a treatment agreement is to establish a mutually agreed-on understanding of what is expected of the patient, the provider, and the provider’s office staff during treatment. As in agreements or contracts in business settings, these documents are designed to outline the expectations and responsibilities of all of the parties signing the agreement. The hope is that clear, written parameters established up front will help avoid conflict and confusion during the course of treatment. Each provider needs to develop an agreement that reflects the unique needs within the clinical setting in which he or she works. A sample treatment agreement is included in Figure 7–2. Please note again that this is only an example, and that the components listed may or may not apply to your treatment setting.

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I, __________________________, have read and understand the following (initial each line as it is reviewed): _____Buprenorphine is a medication used to treat people with addiction to opioids, such as heroin, oxycodone, or hydrocodone. Buprenorphine is an opioid that can be used to replace the drugs you are abusing, to prevent the withdrawal sickness and help you stop abusing drugs. Like other opioids, after taking buprenorphine for a while, you will feel withdrawal sickness if you stop taking it suddenly. _____Buprenorphine is used to treat opioid addiction, and does not directly help with abuse of alcohol or other drugs such as cocaine or amphetamines. _____Buprenorphine treatment is flexible and can last as long as is needed to help prevent relapse to drug use. Each patient will plan how long to be in treatment with the doctor. When a patient and doctor agree that it is time to decrease the medication, the dose will be decreased slowly to help prevent withdrawal sickness. _____Buprenorphine lasts a long time in the body and should be taken only once per day, unless otherwise instructed by the physician or member of the treatment team. _____Buprenorphine treatment is a tool to help patients recover from opioid addiction, but taking this medication alone is not considered enough treatment to help patients get better, and patients will be required to participate in other forms of treatment such as counseling or 12-step programs. _____Buprenorphine is available in a tablet called Suboxone, which is buprenorphine mixed with a medicine called naloxone. This tablet will work only if you leave it under your tongue and let it completely dissolve. Even though it may have a bad taste, you cannot eat or drink while taking the medicine, because if you swallow it, it will not work. _____Buprenorphine may make you constipated, or feel tired or sleepy. You may not be able to drive a car or operate machinery while taking this medicine. If you are having any side effects from the medicine, you must notify the doctor immediately. _____ This medicine may hurt the liver. Blood tests will be done to make sure you do not have liver problems from the medicine.

FIGURE 7–1. ment.

Sample informed consent form for buprenorphine treat-

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_____ If you take this medicine with alcohol or any medicine or drug that causes sleepiness, you could become very sick or die. Taking sedatives such as Klonopin, Valium, or Xanax (or any benzodiazepine) can be dangerous for people taking buprenorphine and should never be done without the permission of your doctor. _____ If other people take buprenorphine when it is not prescribed for them, they could become very sick or even die, especially children. To participate in buprenorphine treatment, patients must be able to keep this medication locked up, in a cabinet or a lock box, so children cannot get to it. If a child or other person takes your medication, you must call 911 immediately. _____ Taking lower doses of the medication will decrease the chances of having side effects or other problems with buprenorphine. Patients should always work with the doctor to find the lowest dose of the medicine that helps. _____If you take buprenorphine while you have other opioid medications such as oxycodone, hydrocodone, or methadone in your body, you may suffer severe withdrawal sickness. All patients must tell the doctor if they are taking any other opioid drugs or medications. _____ This medicine will block the effect of opioid pain medications, including medicines given in emergencies and after surgery. Notify all physicians that you are taking this medication. Notify your physician immediately if you need to have surgery or any medical or dental procedure so you can plan ahead for pain medication. Other doctors may not know about this medicine, so carry the buprenorphine treatment information card† at all times. _____ This medicine is not currently approved for use in women who are pregnant. Women who are pregnant require different medications and special treatment services to protect the woman and the baby. If you are pregnant, or considering getting pregnant, please notify the doctor immediately. _____ Buprenorphine treatment is not right for everyone. Some patients may have problems with their physical or mental health that make them ineligible for treatment. Other patients may need more intensive treatment to get better. If the doctor decides that buprenorphine treatment is not safe or appropriate for you, he or she will help you get into another type of treatment program.

FIGURE 7–1. Sample informed consent form for buprenorphine treatment. (continued) †Available

from the drug manufacturer.

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Some patients feel that buprenorphine treatment is too risky for them, or that they do not want to do some of the things being asked of them in order to participate in treatment. If you do not qualify for or do not want buprenorphine treatment, we can help refer you to other forms of treatment, including: • Methadone maintenance, where patients go to a program and get methadone every day to help prevent withdrawal sickness and drug abuse • Inpatient detoxification, where patients are admitted to a hospital or treatment program and receive treatment for the withdrawal sickness for a few days • Outpatient treatment, where patients go for counseling but do not typically receive medications to treat withdrawal sickness • Residential treatment, where patients work on recovery skills while living away from home with other patients recovering from addiction.

I have read this form and discussed it with a medical care provider. I have had the opportunity to ask questions and would like to: _____ start buprenorphine treatment. _____ be referred to another treatment instead of buprenorphine. ____________________________________ Patient signature

_______________ Date

Provider statement: I have reviewed the above information with this patient and believe they understand what buprenorphine treatment involves, including potential risks and benefits. _____________________ Provider signature

_____________________ Provider name

________________ Date

FIGURE 7–1. Sample informed consent form for buprenorphine treatment. (continued)

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I, ___________________________as a participant in buprenorphine treatment at____________________________ understand and voluntarily agree that (initial each statement after reviewing): _____ I will keep (and be on time for) all my scheduled appointments with the doctor and other members of the treatment team. _____ I will participate in group or individual counseling, 12-step recovery programs, or other types of treatment that I am asked to participate in. _____ I will keep the medicine safe, secure, and out of the reach of children. If the medicine is lost or stolen, I understand it will not be replaced until my next appointment. _____ I will take my medication as instructed and not change the way I take it without first talking to the doctor or another member of the treatment team. _____ I will tell the doctor or another member of the treatment team if I stop my treatment for any reason. I understand that I will need to plan ahead for any surgery or other medical procedures for which I may need medicines for pain. _____ I will not call between appointments, or at night or on the weekends looking for refills. I understand that prescriptions will be filled only during scheduled office visits with the treatment team. _____ I will make sure I have an appointment for refills. If I am having trouble making an appointment, I will tell a member of the treatment team immediately. _____ I will treat the staff at the office respectfully at all times. I understand that if I am disrespectful to staff or disrupt the care of other patients my treatment will be stopped. _____ I will not sell this medicine or share it with others. I understand that if I do, my treatment will be stopped. _____ I will sign a release form to let the doctor speak to all other doctors and counselors that I see. _____ I will tell the doctor about all other medicines that I take, and let him or her know right away if I have a prescription for a new medicine. _____ I will use only one pharmacy to get all of my medicines: Pharmacy name/phone # _____ I will not get any opioid pain medicines or other medicines that can be addictive such as benzodiazepines (Klonopin, Xanax, Valium) or stimlulants (Ritalin, amphetamines) without telling a member of the treatment team before I fill that prescription. I understand that the only exception to this is if I need pain medicine for an emergency at night or on the weekends. _____ I will not use illegal drugs such as cocaine, marijuana, or amphetamines while taking buprenorphine. I understand that if I do, my treatment may be stopped. _____I will not take any prescribed medication that can be addictive, such as benzodiazepines, stimulants, or opioid pain medicines, without the approval of the physician prescribing buprenorphine.

FIGURE 7–2.

Sample buprenorphine treatment agreement with program statement.

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_____ I will come in for drug testing and counting of my pills within 24 hours of being called. I understand that I must make sure the office has current contact information in order to reach me, and that any missed tests will be considered positive for drug use. _____ I will keep up to date with any bills from the office and tell the doctor or a member of the treatment team immediately if I lose my insurance or can’t pay for the treatment anymore. _____ I understand that I may lose my right to treatment in this office if I break any part of this agreement. Buprenorphine Treatment Program Statement We here at _____________________ are making a commitment to work with you in your efforts get better. To help you in this work, we agree that: • We will help you schedule regular appointments for medicine refills. If we have to cancel or change your appointment for any reason, we will make sure you have enough medication to last until your next appointment. • We will make sure that this treatment is as safe as possible. We will check regularly to make sure you are not having bad side effects. • We will keep track of your prescriptions and test for drug use regularly to help you feel like you are being monitored well. • We will help connect you with counseling, 12-step programs, and other forms of treatment to help you with your recovery work. • We will help you set treatment goals and monitor your progress in achieving those goals. • We will work with any other doctors you are seeing and provide education and information to them about buprenorphine so that they can treat you safely and effectively. • We will include anyone from your family in your treatment if you want them to participate and feel that it would be helpful to have them be a part of it. • We will work with you to make sure you get safe and appropriate pain treatment when needed. • We will work with you to help you stop using other drugs, such as cigarettes, alcohol, and cocaine. • We will work with your medical insurance providers to make sure you do not go without medicine because of paperwork or other things they may ask for. • When it is time to decrease the dose of the medicine, we will work with you to decrease it slowly so that you do not feel a lot of withdrawal symptoms and to help make sure you do not start to use drugs again. If for some reason you can’t stay on buprenorphine treatment, we will help you find other treatment and, as best we can, work to make sure you do not get sick from stopping the medicine. __________________________ Patient signature __________________________ Provider signature

FIGURE 7–2.

_________________________ Patient name _________________________ Provider name

__________ Date __________ Date

Sample buprenorphine treatment agreement with program statement. (continued)

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ESTABLISHING TREATMENT GOALS/ TREATMENT PLANNING Formal, structured treatment planning is a central component of most behavioral and substance abuse treatment modalities. For medical providers, treatment planning occurs more informally in the context of the office visit, and is incorporated into the plan section of a progress note. Regardless of the approach, there are a few general principles of treatment planning that, when utilized, help both patients and providers monitor treatment progress. Providers should begin by helping patients identify the goals of treatment. Most patients quickly identify cessation of drug use and improvements in their financial or legal situations as immediate goals. Be sure to explore areas that patients may not have considered, such as the potential for improvement in medical and psychiatric conditions, employment, family and interpersonal relationships, education, and housing. It is important to work with patients to identify specific goals and actions to be taken, and help set a timeline for achieving those goals. The provider must be sure to set reasonable expectations about what can be achieved in a set amount of time, and to monitor and measure progress. Establishing unrealistic goals or timelines risks reinforcing feelings of failure and a patient’s belief that he or she is unable to make lasting positive change. Goals (and the types of actions needed to meet those goals) will change across time as patients progress in treatment, making it important to review and update treatment goals with every visit. Discussing the length of opioid agonist treatment is particularly important. Contrary to popular belief, very few patients enter medication-assisted treatment hoping to continue treatment indefinitely. Most patients, through their own wishes or under pressure from their families or others in our society, only want short-term treatment. Patients must recognize that although treatment is voluntary and they may leave at any time, studies have shown that ongoing maintenance treatment with an opioid agonist results in the best outcomes (National Consensus Development Panel 1998; Sees et al. 2000) and that patients with opioid dependence who leave opioid agonist treatment return to drug use more than 80% of the time (Magura and Rosenblum 2001) and have a high rate of death by overdose (Zanis and Woody 1998). Overall, the longer the treatment the better the outcome, and for many patients indefinite treatment may be needed to sustain abstinence and continue to make progress on other treatment goals. One of the most critical aspects of treatment planning is to link patients’ goals to the duration of treatment. What do patients want to achieve, and how long will it take to accomplish their goals? After months or years of enduring the consequences of opioid addiction, why rush through treatment? Encourage patients to have patience—to give themselves enough

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time to meet their treatment goals and enjoy the benefits of the investment they have made by engaging in treatment.

Clinical Philosophy: The Chronic Disease Paradigm McLellan et al. (2000) offered a clinical paradigm for drug addiction that is very helpful in approaching patients with addictive diseases. These authors suggested that drug addiction shares many characteristics with other common chronic medical illnesses, such as diabetes, asthma, and hypertension: 1. 2. 3. 4. 5.

Genetic heritability A role for personal responsibility Well-defined pathophysiology Good response to treatment Similar rates of noncompliance with treatment.

Like those medical conditions, and similar to many chronic psychiatric conditions, drug addiction involves a complex interplay of genetic, environmental, and behavioral factors that must all be addressed in order to maintain good health and support recovery.

SHORT-TERM VERSUS LONG-TERM TREATMENT It is helpful to conceptualize opioid addiction as a brain disease, in which repeated exposure to drugs leads to alterations of neurotransmitter levels and receptor function in the brain (Dole 1988). When these neurochemical changes are coupled with the subjective “high” provided by the drug and the behaviors associated with drug use, the brain’s internal reward system is functionally hijacked. The experience of the drug becomes the brain’s primary reward, resulting in compulsive drug use, the inability to cut down or discontinue use, and the ongoing use of drugs despite suffering negative consequences—the core manifestations of the disease of addiction. More important, these neurochemical and behavioral changes are not easily reversible. The purpose of opioid agonist treatment with buprenorphine (or methadone) is to stabilize these neurochemical changes in order to allow patients to engage in the longer-term work of recovery. These medications are not sufficient in themselves for patients to sustain recovery, but they are often essential for helping patients regain control of their lives and begin the recovery process. To many people, considering drug addiction as a medical disease needing medical treatment may seem misguided. Each individual has the choice

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whether or not to take a drug, and if he or she stops taking the drug, most of the problems associated with addiction will be resolved. Many people have used drugs in their lifetime but have not developed addiction. Others have developed problems but resolved them on their own or with minimal intervention. We do not usually consider it to be the person’s fault if a person develops a chronic disease. So, if it’s not the person’s fault that he or she developed a chronic addiction, how can we hold the individual responsible for working to improve the condition? As suggested by McLellan et al. (2000), addiction results from a complex interaction between an individual’s genetics, social and family contexts, and personal choices. I believe it is important to acknowledge up front for patients, their families, and other members of society that patients’ personal choices are instrumental not only in the development of drug addiction, but in achieving recovery as well. In my office, the take-home message for patients is: “It may not be 100% your fault that you became addicted, but it will be 100% your responsibility to achieve recovery. And we are here to help.” It is helpful to remember that personal choices similarly affect the development and course of medical diseases such as diabetes, hypertension, and asthma. Yet the responses from our society and the medical profession to people with addiction have been very different than the responses to patients with these other chronic medical illnesses. For example, who would suggest that patients with diabetes who go through a 5-day sugar detoxification program would be cured of their diabetes? Or that a patient with diabetes or hypertension should be discharged from care for noncompliance when they stop taking a medication or “relapse” to eating fast food or dessert again? In addition, a common characteristic of individuals with more severe and persistent forms of addiction is the presence of a co-occurring psychiatric disorder. These individuals are the least likely to achieve sobriety on their own, and typically require long-term comprehensive treatment for both their substance use disorder and their other psychiatric problems (see Chapter 9, “Psychiatric Comorbidity”). But, would a 30-day residential treatment program effectively prevent a patient from ever having problems with depression or schizophrenia in the future? As is the case with other chronic illnesses, short intensive treatments may be necessary at times, but when provided alone they usually have very little lasting impact on the course of addictive diseases. Patients will require ongoing care, and will cycle through periods in which control of their addiction improves or worsens. Therefore, managing addiction in the office setting requires the same ongoing monitoring and care needed for managing any other chronic medical or psychiatric condition. Fortunately, all of the steps that providers and staff usually take to help a patient get a chronic illness back under control, also help patients with poorly controlled addiction.

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CHRONIC DISEASE MANAGEMENT PRINCIPLES Following the induction and early stabilization phases of treatment, the principles used in managing chronic medical diseases are applicable to buprenorphine treatment: 1. Providers should schedule regular appointments, with visit intervals determined by how well the disease is controlled. Patients struggling to meet treatment goals need to be seen more often, whereas patients who have achieved long-term stability may be seen less often. 2. As with any medication for any condition, most visits begin with the process of reconciling the medication record and updating dosing information for all medications being prescribed. This is followed by reviewing the patient’s use of the medication to evaluate for compliance, effectiveness, safety, and side effects. Is the medication successfully suppressing withdrawal symptoms and craving? How often is the patient taking the medication during the day? Some providers allow patients to dose the medication at whatever interval they prefer as long as they do not exceed a designated daily dose. Other providers insist on once-daily dosing out of concern that multiple daily dosing may simulate drug abuse behaviors and may not be conducive to achieving recovery. Also ask whether there have been any days when the patient has gone without the medication or taken an extra dose. Is the patient experiencing any toxicity that would require an immediate intervention, such as sedation or cognitive impairment? Are there less serious side effects, such as constipation or sweating? And is the patient taking any medication that may interact with buprenorphine or put the patient at risk of impairment or overdose when taken in combination with buprenorphine? 3. The next step is to review to what degree each patient is meeting his or her treatment goals. In diabetes, a provider might review a blood glucose monitoring record or the most recent hemoglobin A1c level. In buprenorphine treatment, drug testing results provide an objective measure of the success of treatment. Abstinence is an essential component, but certainly not the only component of a patient’s recovery. Achieving stable employment, pursuing educational or vocational training opportunities, improving fulfillment of role responsibilities, improving interpersonal relationships, and resolving financial and legal issues all represent some of the important nonmedical outcomes of successful treatment. Improvements in comorbid conditions may also be critically important signs of treatment progress. For patients with co-occurring medical and/or psychiatric conditions, the stabilization of drug abuse may be the first essential step needed to facilitate the treatment of other coexisting conditions (see Chapter 9; Chapter 10,

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“Medical Management”; and Chapter 11, “Management of Acute and Chronic Pain”). As patients and providers integrate treatment for co-occurring disorders into the treatment goals, monitoring for progress in addiction treatment broadens to include monitoring for improvements in other related medical and psychiatric conditions. 4. As with any chronic condition, relapses should be anticipated and do not mean that the patient has failed or that the treatment is ineffective. Providers should pay careful attention to the language used to discuss relapse because patients can become very discouraged when relapse occurs. When providers remain optimistic about the potential for recovery it is much more likely that patients will as well. It is very useful to reframe the relapse episode as a learning opportunity, a chance to identify previously unrecognized high-risk situations or to expose weak elements in the treatment plan. Many patients in early sobriety fail to appreciate the range of changes and the intensity of effort needed to sustain true recovery. It may only be through brief lapses or relapses that patients are able to develop a truly effective recovery plan. It is often helpful for clinicians to point out at the beginning that lapses or relapses “may” occur and to stress the importance of a quick return to treatment while reinforcing the message that patients are always welcome to return despite a relapse. Patients need to learn that being honest about their struggle for recovery will be met with added support and respect and not rejection or disappointment. 5. Participation in nonpharmacological treatment modalities is a critical element in the recovery process. Few medical providers would consider treatment for diabetes or hypertension to be complete if it did not include regular attention to diet, exercise, and other behavioral changes that would positively affect the disease course. Most mental health clinicians recognize that medications are only one component of a comprehensive treatment plan for conditions such as depression or anxiety. Similarly, participation in behavioral treatment modalities is considered essential by most buprenorphine providers, and reviewing a patient’s participation in counseling and/ or 12-step recovery programs is a part of every visit. 6. Motivation enhancement techniques should be an essential component of every visit (see Chapter 8, “Clinical Management II”). In short, motivation enhancement therapy is a way of communicating with patients that helps to increase their motivation to make positive changes and reinforces to patients that they can effectively make those changes in their lives. As medical providers we often focus on what is wrong: abnormal laboratory test results, poorly controlled conditions, and the lack of improvement in patients’ conditions. This information is important, but patients often leave visits discouraged and with little hope or confidence that things will ever

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get better. The motivation enhancement approach reminds providers to recognize and highlight areas where patients have succeeded in making positive changes and to review how those changes were achieved. By reiterating and reinforcing what is working well, it becomes more likely that patients will repeat those productive behaviors. Other unique elements of monitoring buprenorphine treatment that warrant mentioning include dosing technique, dosage tapering, and maintaining safety of medication supplies; these topics are reviewed below.

DOSING TECHNIQUE When reviewing a patient’s buprenorphine dosage, it is important to carefully review the patient’s technique for taking the sublingual tablet. It is especially important to review dosing technique when patients request dose increases or complain that the medication “wears off ” or that the dose “just doesn’t hold me.” Patients unfamiliar with the unique sublingual dosing of buprenorphine, or who for other reasons end up swallowing the tablets or the liquid that forms in the mouth when the tablets first dissolve, receive only a fraction of the medication dose due to first-pass hepatic metabolism. When questioned carefully, patients may reveal that they swallow the sublingual tablets outright or take them with coffee or another beverage to dilute the bitter orange taste. Patients swallowing the sublingual tablets receive only a fraction of the sublingual dose; improving dosing technique may increase serum buprenorphine levels and eliminate the need for an increase in dosage.

TAPERING

THE

DOSAGE

Strategies for tapering buprenorphine doses are covered in Chapter 6, “Clinical Use of Buprenorphine.” In general, dosing levels and tapering plans should be a regular part of treatment planning, even though complete detoxification may not be the goal for many patients. Patients should be encouraged to work toward the lowest dosage that prevents withdrawal symptoms and relapse to drug use. As patients progress in treatment and gain greater degrees of psychosocial stability, it should be expected that they will need less medication to support their sobriety. This approach helps to minimize side effects, maximize cost-effectiveness at each stage of treatment, and encourage patients to actively pursue the skills and support networks they need to maintain recovery. Patients are more willing to attempt dose reductions if they understand that the schedule and amount of any dosage taper is under their control, and that they will have the opportunity to consider returning to the previous dosage should they experience difficulty at a lower dosage.

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MAINTAINING SAFETY

OF

MEDICATION SUPPLIES

As the number of patients receiving buprenorphine has expanded, so has the number of poisoning events due to accidental ingestion of the medication. Even though only a fraction of the medication is absorbed when chewed or swallowed, individuals without preexisting opioid tolerance can experience significant toxicity with oral administration, such as respiratory depression. Children are at particular risk for buprenorphine overdose because the tablets look and smell like orange candy, and children may suck on or hold tablets in their mouths, thus increasing the amount of medication absorbed. All patients should be reminded regularly to keep their medications out of the reach of children, preferably in a locked container or a safe.

Managing Problem Behaviors Time invested in reviewing treatment agreements, establishing strong therapeutic relationships, and developing clear treatment plans will prevent many problem behaviors. That being said, it is helpful to plan ahead and prepare providers and support staff to provide clear, consistent responses when problems do occur. In all situations, safety is the most important priority. Providers must respond immediately to any behavior that seriously compromises the safety of patients or those around them. For example, threatening behavior against other patients or staff, or criminal behavior such as selling drugs or forging prescriptions, would usually result in immediate dismissal. Short of serious safety concerns, however, it is important to remember that change is a process that happens gradually and often involves both steps forward and steps backward in order to make progress. Prompt, graded responses to less serious behaviors, coupled with motivation enhancement, will maintain safety and retain patients in treatment. Minimal problems, such as a missed counseling visit, may be easily managed by a focused discussion with the treating physician. A brief relapse may require a temporary increase in the frequency of monitoring visits and urine screens, and possibly a dosage adjustment. A more serious relapse may indicate the need for a major review of the treatment plan, with the addition of more counseling services and/or a significant increase in participation in mutual support groups, as described below. Problem behaviors fall into five general categories: 1. Violations of office policies, including inappropriate interactions with office staff, noncompliance with financial responsibilities associated with treatment, calling in to report lost or stolen medications, calls for early refills, and nonemergency calls after office hours

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2. Noncompliance with treatment plans, including unapproved increases in buprenorphine dosing, missed office appointments or missed visits with consultants, declining to allow communication with other treatment providers, failing to provide urine samples for drug screening, and failing to participate in behavioral treatment as requested 3. Continued use of opioids, including unapproved use of opioid pain medications 4. Abuse of nonopioid illegal drugs such as marijuana or cocaine, problem alcohol use, and unapproved use of other medications with abuse potential 5. Criminal behavior such as alteration of prescriptions, diversion of prescribed buprenorphine, selling or sharing other medications or illegal drugs, and theft. When problem behaviors arise that do not cause immediate safety concerns, it is important to verify and document the behavior, and review this information with the patient. Many clinicians begin by reviewing the details of the problematic behavior along with the treatment agreement and the most recent treatment plan to make sure that all parties have the same expectations and goals. Patients should also have the opportunity to tell their side of the story. In specialty behavioral and substance abuse treatment settings, it is common to implement a written behavior contract, which identifies the problem behavior, the expected remedy, the time period in which it is expected that the situation will be remedied, and the consequences if insufficient action is taken. In physicians’ offices where this formal process may be too time consuming, or with less serious problems, a verbal review of similar information documented in the progress note may be more practical. As with chronic illnesses such as diabetes or depression, when patients are nonadherent or not meeting treatment goals the most common responses are to increase monitoring and increase the intensity of treatment. Patients might be seen once or twice a week for a time, with more frequent drug screens and limited medication supplies. Providers can mandate participation in 12-step programs or other formal behavioral or psychiatric treatment. For patients struggling to stabilize substance abuse or mental health symptoms, participation in structured intensive outpatient programs or inpatient hospitalization may be required. It is important to explain that any increase in the intensity and requirements of treatment is not punitive and is primarily to ensure the patient’s ultimate success in treatment. Occasional opioid use during the first week or two of treatment is not unusual and may require a dosage adjustment, but it rarely implies a serious treatment problem. However, ongoing use of opioids should prompt a careful review of adherence to buprenorphine dosing, the adequacy of that dose, med-

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ication dosing technique, and the adequacy of counseling or other recovery activities. Relapses to opioid use after a period of stability typically occur in response to some unexpected stressor. A review of the circumstances may reveal some previously unidentified risk factors and suggest some needed improvements to the treatment plan. A temporary intensification of treatment services may be adequate to help the patient restore his or her previous level of functioning. Behavior associated with buprenorphine diversion should lead to increased frequency of visits and screening tests to monitor drug use, shortinterval prescriptions, and random callbacks to count the number of pills left in the patient’s bottle. It is not uncommon for some patients to stop all use of opioids (other than buprenorphine) but then present evidence of a new or intensified problem with alcohol or other drugs. These problems are best managed by counseling and participation in a 12-step program. Patients should be told that sobriety from all drugs of abuse is the goal of treatment and that the ongoing use or abuse of alcohol and other drugs is likely to undermine the success of their buprenorphine treatment program. That being said, occasional social drinking or marijuana use should not be grounds for the termination of buprenorphine treatment. Some patients may take months or even years to establish complete sobriety. The clinician should look for signs of progress toward full recovery and sobriety, but recognize that progress may be slow and occur at different rates with different substances. Unfortunately, ongoing problematic use of alcohol and benzodiazepines poses the additional risk of respiratory suppression, overdose, withdrawal, and seizures. Patients with problematic alcohol and/or benzodiazepine use may require referral for detoxification services. Failure to resolve problems with ongoing dependence on alcohol or other classes of drugs may require a review of the patient’s basic suitability for buprenorphine therapy or for office-based treatment. Ultimately, providers will need to weigh the risks and benefits of officebased treatment with buprenorphine for each patient and determine whether it is both safe and appropriate to continue. Except in the most unusual or extreme circumstances, termination of office-based buprenorphine treatment should be the last response to behavioral problems. However, providers must be realistic about the complexity of problems that they can manage in their office setting. Patients who cannot take or store buprenorphine safely, or who are engaged in criminal behavior, should be referred immediately to a higher level of care. Patients who, after a series of interventions to intensify treatment and monitoring, are unable to meet treatment goals or adhere to treatment expectations should also be referred to a higher level of care. Most commonly, patients doing poorly in office-based buprenorphine treatment are referred to higher-intensity specialty substance abuse services, such as inpatient detoxification centers,

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methadone maintenance treatment, and/or residential treatment programs. Continued buprenorphine treatment within the structure of a methadone program or a residential therapeutic community may also be an option for some patients. Questions often arise about how to transition patients to higher levels of care. Programs may have long waiting periods, and patients may be reluctant to change treatment modalities. Except in cases where there are serious safety concerns or criminal activity, it is important to avoid abruptly stopping treatment. The current standard of care is to provide patients, in writing, with the reasons why you are recommending the change in treatment, a warning about the potential for withdrawal symptoms and the risks associated with relapse to drug use, contact information for local substance abuse treatment centers, and a transitional supply of medication to cover the patient for a reasonable period of time while he or she is seeking other treatment. Alternatively, the medication can be tapered over the course of a few weeks and then discontinued. If a patient becomes unstable, admission to a detoxification center or other inpatient unit may be needed to ensure the patient’s safety and facilitate the beginning of another form of treatment. Patients should always be reminded to seek emergency care in case of crisis.

Screening for Drugs of Abuse Regular screening for opioids and other drugs of abuse is an essential component of office-based buprenorphine treatment. Although some patients may complain that drug screening feels like an invasion of privacy, others express appreciation for the monitoring and request that it be performed regularly. The manner in which drug screening is presented may impact how well it is accepted by patients. Include drug testing expectations in the initial treatment agreement, and use language that normalizes this testing as a standard part of monitoring for the safety and effectiveness of buprenorphine treatment. If concerns arise, comparisons to the management of other medical conditions may also help. No patient would have confidence in a physician’s care if he or she prescribed insulin without regularly checking blood glucose measurements and hemoglobin A 1c levels, or lithium without measuring serum lithium levels. Similarly, it would be irresponsible and unsafe to provide addiction treatment without monitoring for ongoing drug abuse.

BASIC DRUG SCREENING TECHNIQUES The two most commonly utilized methods for drug screening are immunoassays and gas chromatography–mass spectrometry (GC-MS) (Moeller et al. 2008). Drug screening in office-based buprenorphine treatment is most often

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performed using urine samples, although oral swabs for saliva testing are becoming more popular. Immunoassays work in the same way that dipstick pregnancy tests and rapid strep screens do. An antibody to the drug metabolite is linked to a color indicator and then bonded to elution paper. When the paper absorbs a liquid that contains drug metabolites, these metabolites bind to the antibodies and cause the indicator to change color, which represents a positive result. There are many benefits to this type of testing. Immunoassays are inexpensive, easy to perform, and can be used in many clinical settings including physicians’ offices and other outpatient treatment program settings. Specific tests have been developed for a number of opioids, including oxycodone, methadone, and buprenorphine.

INTERPRETING DRUG TEST RESULTS There are, however, a number of limitations to immunoassay drug testing. First, immunoassays are qualitative tests, providing only a positive or negative result. They provide no information about the level of drug metabolite in a sample, and only read positive when the amount of drug metabolite in the fluid tested reaches a certain threshold level, or cutoff. The cutoff for opioid metabolites is set quite high in many standard screens, meaning that a patient may demonstrate a false-negative result when lower levels of metabolite are present. Table 7–1 shows the threshold levels for drug metabolites used in U.S. Department of Transportation testing, and the average time it takes after drug use for the metabolites to be detected in urine. Cutoffs vary for commercial drug testing kits that are not used for testing under federal guidelines. Note that the cutoff levels for opioid metabolites are set quite high to prevent false-positive screening results from opiates found in low levels in some foods (e.g., poppy seeds). It is also possible to have false-positive results due to the presence of other substances and medications that cross-react with the components of the immunoassay. Table 7–2 lists some common substances that may cause false-positive immunoassay screening results. This list is not exhaustive; please see Manchikanti et al. 2008 and Moeller et al. 2008 for more detailed information. Providers should note that although many agents cross-react with the amphetamine screen, the metabolite for cocaine, benzoylecgonine, is unique. Only cocaine and medications that contain cocaine, and not other topical anesthetics, should cause a positive result. Most buprenorphine providers have mechanisms in place to follow up any questionable positive results by confirming or clearing them with GC-MS testing. Finally, it is important to recognize that standard opiate immunoassay screens detect only morphine and drugs that are metabolized to morphine: heroin, codeine, and all morphine products. Semisynthetic opioids such as the

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TABLE 7–1.

141

Federal workplace drug testing cutoff valuesa and detection time in urine Initial cutoff level Confirmatory Typical detection by immunoassay level by GC-MS time in urine (days) (ng/mL) (ng/mL)

Opioid metabolites (morphine, heroin) Cocaine metabolite (benzoylecgonine) Marijuana metabolite (∆-9-THC) Amphetamines Phencyclidine

2,000

2,000

2–3

300

150

2–4

50

15

3–30

1,000

500

2

25

25

8

Note. GC-MS=gas chromatography–mass spectrometry; ∆-9-THC=∆-9-tetrahydrocannabinol. aValues used in U.S. Department of Transportation testing. Source. Adapted from Moeller et al. 2008.

commonly abused pharmaceutical opioids oxycodone and hydrocodone occasionally, but not reliably, cross-react and give a positive opiate screening result. Specific testing should be done to detect semisynthetic opioids. Fully synthetic opioids, such as methadone and fentanyl, are not detected by standard opiate screens, and also require testing specifically for these agents. Similarly, buprenorphine is not detected in opiate screens. Providers should consider regular testing for buprenorphine but must order buprenorphine testing specifically and be sure to test for the buprenorphine metabolite norbuprenorphine to provide some objective evidence that patients are taking the medication on a regular basis. Table 7–3 lists the most prevalent metabolites of the most common opioid agents. These metabolites are noted specifically only if GC-MS testing is performed. Urine drug testing also presents a number of logistical issues that buprenorphine providers must consider: • • • •

Will testing be done on-site or at a referral laboratory? If testing is done on-site, will patients be observed while providing the samples to prevent substitution? Will other quality control measures such as urine temperature, specific gravity, and creatinine levels be available? By what mechanism, and in what circumstances, will screening immunoassays be sent for GC-MS confirmation?

Common substances and medications that may cause false-positive immunoassay results

Opiates

Benzodiazepines

Marijuana

Amphetamines

Phencyclidine

Dextromethorphan

Oxaprozin

Dronabinol

Bupropion

Dextromethorphan

Diphenhydraminea

Sertraline

Efavirenz

Chlorpromazine

Diphenhydramine

Quinine

Hemp-containing foods

Ephedrine

Doxylamine

Quinolones

NSAIDs

Phenylephrine

Ibuprofen

Rifampin

Proton pump inhibitors

Phenylpropanolamine

Imipramine

Verapamila

Riboflavin

Pseudoephedrine

Ketamine

Promethazine

Meperidine

Ranitidine

Tramadol

Selegiline

Venlafaxine

Trazodone Note. NSAIDs=nonsteroidal anti-inflammatory drugs. aFalse-positive result on methadone screen only. Source. Adapted from Moeller et al. 2008.

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TABLE 7–2.

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TABLE 7–3.

143

Common opioids and their most prevalent metabolites

Drug

Metabolites

Morphine

Morphine, morphine glucuronides

Heroin (diacetylmorphine)

6-Monoacetylmorphine, morphine

Codeine

Norcodeine, morphine

Oxycodone

Noroxycodone, oxymorphone, oxycodol

Hydrocodone

Norhydrocodone, hydromorphone, hydrocodol

Hydromorphone

Hydromorphone glucuronides

Buprenorphine

Norbuprenorphine, buprenorphine glucuronides

Methadone

EDDP

Meperidine

Normeperidine

Propoxyphene

Norpropoxyphene

Fentanyl

Norfentanyl

Note. EDDP=2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine. Source. Adapted from Manchikanti et al. 2008; Nagar and Raffa 2008.

• • •

Will testing be done randomly, or only at the time of office visits? What will happen if the patient is found to have substituted a urine sample? How will patients pay for this monitoring if they are uninsured, or if their insurance does not pay for this service?

In any circumstance, it is helpful to develop relationships with a referral laboratory, preferably one with some experience in drug testing. Providers with links to hospital labs may be able to call on the hospital lab staff with questions. In many areas, there are private drug testing companies with professional toxicologists that will manage the entire testing process. Providers should monitor testing procedures, however, because many labs charge per item tested, and the cost of each screening can get quite high.

TESTING

FOR

BUPRENORPHINE

Testing procedures for buprenorphine deserve a quick final comment. Immunoassays that detect buprenorphine are available commercially, and have the same limitations as immunoassays for other substances. These tests can be managed in the office, but false-positive results are possible due to cross-reactivity with other

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substances, and false-negative results are possible if the level in the patient’s urine falls below the cutoff point. Many providers are using GC-MS testing to measure levels of buprenorphine and its primary metabolite, norbuprenorphine. Patients initiating buprenorphine treatment show higher levels of the parent compound buprenorphine, but patients who are taking the medication steadily should have levels of norbuprenorphine well above that of the parent compound. Very high levels of the unchanged parent compound with very low or absent levels of the metabolite may indicate that a patient has dissolved a tablet into the urine sample. Unfortunately, urine buprenorphine levels vary widely and there is no reliable way to determine how much buprenorphine a person is taking by looking at drug levels. This testing may be most helpful to identify patients who have no buprenorphine in their system, or to provide additional information in the evaluation of patients who are not meeting treatment goals or who complain of inadequate dosing.

Conclusion Treatment with buprenorphine in office-based settings is safe and effective, and has greatly expanded the availability of agonist treatment for opioid addiction at a time of critical need for additional treatment resources in this country. Most providers find that, with a bit of preparation, buprenorphine treatment integrates well into any office setting that is experienced in managing other chronic medical or psychiatric conditions. The tools and guidelines provided in this chapter are intended to help providers cultivate a therapeutic environment for treating opioid addiction that minimizes problem behaviors and optimizes treatment outcomes. Although offering this new treatment modality does require some additional effort and resources, I believe providers will find it well worth the effort to have such a positive impact on the lives of patients, families, and communities experiencing the consequences of opioid addiction.

Clinical Pearls • Opioid addiction shares many features with other chronic medical and psychiatric conditions and the principles used in managing chronic diseases in office-based settings are applicable to buprenorphine treatment. • Time invested in reviewing informed consent and treatment agreements, establishing strong therapeutic relationships, and developing clear treatment plans will prevent many problems. • We all learn from our mistakes—relapse is a part of the natural history of any chronic disease and should be considered as an

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opportunity to intensify treatment, review treatment goals, and develop new strategies for working toward sustained recovery. • Prompt, graded responses to problem behaviors coupled with motivation enhancement strategies and other behavioral treatment modalities will maintain safety and retain patients in treatment. • Regular screening for opioids and other drugs of abuse is an essential component of office-based buprenorphine treatment, but providers must consider the limitations of the different testing techniques when reviewing test results.

CASE 2 Mark is a married 45-year-old postal worker who comes to your office saying: “Someone told me you write for BUP.” He has been receiving methadone treatment for the last 5 years but has a new postal route and tells you: “I can’t make it to the clinic and keep my job. I’ve been on 120 mg of methadone and have been clean for the last 3 years.” He says you can call the clinic to verify that he has been compliant. “I have to be on time for work!” he adds. He does not attend Alcoholics Anonymous, Narcotics Anonymous, or any other supportive group meetings.

1. What steps are recommended to convert someone from methadone treatment to buprenorphine treatment? 2. If this patient recently converted to buprenorphine treatment under the care of a different physician but complains of the other prescriber’s “requirements,” would you feel comfortable prescribing buprenorphine? 3. What are your requirements (ancillary therapy/support in and out of your office), if any, of someone for whom you are prescribing buprenorphine?

♦ ♦

♦

♦

♦ ♦

♦

Mark has been coming to your “BUP group” fairly consistently for the past 3 months. He had a positive test result for cocaine on his urine toxicology screen 2 weeks ago. He also missed coming to his group meeting last week.

1. Did you ask Mark to sign a treatment agreement when you took over his case? 2. Did you delineate your limits for exclusion from your practice? 3. Is this a rule violation? 4. Is this a clinical problem? 5. What will be your next step?

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References Bodenheimer T, Wagner EH, Grumbach K: Improving primary care for patients with chronic illness. JAMA 288:1775–1779, 2002a Bodenheimer T, Wagner EH, Grumbach K: Improving primary care for patients with chronic illness: the chronic care model, Part 2. JAMA. 288:1909–1914, 2002b Dole VP: Implications of methadone maintenance for theories of narcotic addiction. JAMA 260:3025–3029, 1988 Magura S, Rosenblum A: Leaving methadone treatment: lessons learned, lessons forgotten, lessons ignored. Mt Sinai J Med 68:62–74, 2001 Manchikanti L, Atluri S, Trescot AM, et al: Monitoring opioid adherence in chronic pain patients: tools, techniques, and utility. Pain Physician 11 (suppl):s155–s180, 2008 McLellan AT, Lewis DC, O’Brien CP, et al: Drug dependence, a chronic medical illness: implications for treatment, insurance, and outcomes evaluation. JAMA 284:1689–1695, 2000 Moeller KE, Lee KC, Kissack JC: Urine drug screening: practical guide for clinicians. Mayo Clin Proc 83:66–76, 2008 Nagar S, Raffa RB: Looking beyond the administered drug: metabolites of opioid analgesics. Current Clinical Practice 57 (suppl):s1–s8, 2008 National Consensus Development Panel on Effective Medical Treatment of Opiate Addiction: Effective medical treatment of opiate addiction. JAMA 280:1936– 1943, 1998 Saitz R, Larson MJ, Labelle C, et al: The Case for Chronic Disease Management for Addiction. J Addict Med 2:55–65, 2008 Sees KL, Delucchi KL, Masson C, et al: Methadone maintenance vs 180-day psychosocially enriched detoxification for treatment of opioid dependence: a randomized controlled trial. JAMA 283:1303–1310, 2000 Zanis DA, Woody GE: One-year mortality rates following methadone treatment discharge. Drug Alcohol Depend 52:257–260, 1998

8 Clinical Management II PSYCHOSOCIAL AND SUPPORTIVE TREATMENT Peter D. Friedmann, M.D., M.P.H. Patricia A. Cioe, M.S., R.N.P.

OPIOID DEPENDENCE is a complex behavioral disorder that affects multiple dimensions of a person’s life, so it is no surprise that its treatment is a complex, multidimensional intervention. Long-term recovery requires a level of commitment and effort that goes far beyond simple compliance with buprenorphine treatment, and experienced buprenorphine providers have learned that psychosocial counseling is an essential part of office-based treatment. Patients should be educated that buprenorphine alone is not enough, and that patients who participate in counseling have the best outcomes (Stein et al. 2005). The most successful patients typically invest in a range of therapeutic activities that include individual and/or group counseling and participation in self-help recovery programs. In this chapter, we give an overview of treatment options for ambulatory patients who receive office-based buprenorphine therapy. Counseling can take several forms; not all are equally effective, and even 147

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evidence-based treatments are not effective for all patients at all times. So trial and error and multiple “doses of treatment” over a long period of time are often necessary to facilitate lasting behavioral change. A basic understanding of the available treatment options is essential to assist patients in achieving the most favorable outcomes. Cases are presented at the end of this chapter, including related questions for additional consideration. For discussion of these cases, please see Chapter 14, “Comments on the Case Vignettes.”

Professional Counseling Improves Outcome Research on the efficacy of psychosocial counseling for patients receiving methadone maintenance therapy first identified the relationship between treatment improvement and professional counseling (McLellan 1993). Patients who met with skilled professional counselors were shown to have better outcomes then those who met with untrained drug counselors. It was eventually determined that confrontational counseling, nonspecific drug counseling, and nonspecific psychotherapy are ineffective, whereas cognitive-behavioral therapy (CBT), contingency management, and other manual-guided behavioral therapies such as motivation enhancement therapy (MET), 12-step facilitation (TSF), and behavioral marital therapy are associated with significant improvements in treatment (Miller and Wilbourne 2002; O’Farrell and Fals-Stewart 2002). The largest and most scientifically rigorous random assignment trial comparing the effect of different types of psychosocial treatments in substance use disorders was Project MATCH (Matching Alcoholism Treatments to Client Heterogeneity), funded by the National Institute on Alcohol Abuse and Alcoholism (NIAAA). Although this study focused on individuals with alcohol dependence and not opioid dependence, its findings are commonly accepted as relevant across the addictive disorders. Individuals in Project MATCH were randomly assigned to manual-guided individual CBT, MET, or TSF therapy. All of the subjects showed significant improvement, and the three counseling approaches were thought to be equally effective. Among buprenorphine-naloxone patients, receipt of any counseling has been associated with better treatment retention (Stein et al. 2005). However, the intensity of counseling might not matter. In a study of three levels of counseling intensity, patients randomly assigned to 40 minutes weekly did no better than those who received 20 minutes weekly (Fiellin et al. 2006), and those receiving less intensive counseling were more satisfied (Barry et al. 2007). Al-

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though counseling must be available to buprenorphine patients, 40% or more patients do not attend formal counseling (Finch et al. 2007), and many choose self-help groups only. Although existing research has not identified any one counseling approach as being the most effective, it supports the efficacy of a variety of manual-guided individual and group therapies as delivered by professionally trained therapists. We describe a number of these approaches below.

ASSESSMENT

FOR

PROFESSIONAL TREATMENT

Many treatment programs use the American Society of Addiction Medicine Patient Placement Criteria to determine the appropriate intensity of treatment services. These criteria assess patients’ severity of illness in six dimensions: 1. 2. 3. 4. 5. 6.

Acute intoxication/withdrawal potential Medical condition that may distract from or complicate recovery Comorbid emotional/behavioral problems Treatment acceptance and resistance (insight/compliance) Relapse potential (craving/history of relapses) Recovery environment (structured/supportive).

Arguably the most important dimensions for deciding on the setting and intensity of rehabilitative services are the comorbid emotional/behavioral problems and recovery environment. Comorbid emotional/behavioral problems, whether or not they fulfill the criteria for a psychiatric disorder in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR; American Psychiatric Association 2000), are endemic among substance-using patients. Recovery environment refers to whether the individual has a supportive place to live (i.e., a drug-free environment) and a structured daily routine (e.g., a job, school, or even attending daily Alcoholics Anonymous [AA] meetings). Often, patients with co-occurring disorders or unstable recovery environments require more intensive treatment settings such as intensive outpatient treatment/partial hospitalization (9–25 hours/week) or residential treatment. Patients with limited emotional/behavioral comorbidity, a structured daily routine, and a supportive environment can usually receive outpatient treatment (<9 hours/week). Assessment by a qualified addiction treatment professional is usually necessary to determine the appropriate level of care; this type of assessment and referral is an integral part of most detoxification and intake programs. Patients who apply for outpatient buprenorphine treatment should be assessed from this perspective to determine whether they are stable enough for outpatient care and whether they require a higher level of intensity of care (see Chapter 5, “Patient Assessment”).

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PROFESSIONAL TREATMENT VERSUS RECOVERY GROUPS The addiction treatment system includes both professional treatment programs that are full-fledged health care entities and informal recovery groups, most of which are based on the 12 steps. It is a common misconception that recovery groups such as AA and Narcotics Anonymous (NA) are alone a form of addiction treatment. Although referral to recovery groups is an important component of the overall treatment plan, involvement in these groups alone does not constitute optimal treatment. Recovery groups are the most cost-effective and widely available secular source of social support available to recovering persons. Clinicians are urged to encourage involvement in these groups as an essential source of social support and practical advice about living with the disease and controlling its symptoms. That said, some recovery groups have philosophies that buprenorphine patients sometimes find difficult to accept. In some communities, care from a buprenorphine clinician along with recovery group involvement may be the only available treatment options. However, formal treatment by trained counseling staff is preferred where it is available.

Residential and Intensive Outpatient Programs Selecting an appropriate setting for addiction treatment depends on the recovery environment. For example, patients who are homeless will likely benefit most from a residential program. Short-term (e.g., 28-day) inpatient programs are often modeled after the Minnesota Model, which focuses on initiation of recovery using a 12-step orientation. Long-term residential programs (lasting ≥3 months) commonly use elements from the well-known therapeutic community model developed by programs such as Phoenix House (www.phoenixhouse.org) and Daytop Village (www.daytop.org). Modified therapeutic communities are also prevalent in prisons and correctional transitional programs. Therapeutic communities create a highly structured therapeutic milieu in which group and individual therapy are delivered along with behavioral modification through progressive responsibilities and freedom, a hierarchy of jobs, and comprehensive rehabilitative services. These programs reduce crime and drug use and increase employment among individuals who complete them (National Institute on Drug Abuse 2002), but attrition is high—only 15%–25% of patients complete the full course of treatment (Keen et al. 2001). All addiction treatment programs offer some combination of group, individual, and/or family therapy. Many programs offer groups that focus on insight

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building and education, though little evidence supports their effectiveness. In general, quality programs offer group treatment and individual treatment that have one or more of the following components: 1. Recovery orientation focused on initiation of the 12 steps 2. Cognitive-behavioral orientation with a focus on understanding, avoiding, and coping with triggers for relapse 3. Motivation enhancement orientation with a focus on resolving ambivalence and increasing readiness for behavioral change. Some programs offer family or marital therapy to reduce negative family dynamics and codependence that could lead to relapse. In looking for quality programs, these evidence-based counseling methods are preferable to supportive care or solely psychoeducational approaches. Concerns about cost have led to a decline in the availability of inpatient and residential treatment. Nonetheless, patients with neither a structured daily routine (e.g., being unemployed) nor a supportive environment (e.g., being homeless, living in a drug-encouraging neighborhood, or having an addicted significant other) require a treatment plan that provides the needed structure and support. The result is that many patients who formerly received inpatient services are now housed in either sober houses or shelters, with outpatient treatment. Intensive outpatient or daytime hospital programs can provide a fully structured plan of activities and a supportive therapeutic milieu. For patients without access to formal treatment, attending an AA or NA meeting every day for 90 days (“making the 90-in-90”), can provide some measure of structure and support. Toxicological monitoring is an important aspect of the structure in formal treatment programs. In some modalities, such as therapeutic communities or methadone treatment programs, verified progress in treatment leads to increased privileges, such as unsupervised visitation or methadone take-home doses. Objective testing for substance use is essential to verify self-reports and facilitate and monitor progress. Case management with access to psychological, medical, and psychiatric consultation and employment assistance is another evidence-based practice to look for in quality programs.

CHOOSING A PROFESSIONAL TREATMENT PROGRAM The Substance Abuse and Mental Health Services Administration’s Substance Abuse Treatment Facility Locator (which can be found online at http:// dasis3.samhsa.gov) and local directories maintained by state departments of

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health or state substance abuse agencies are helpful tools for selecting qualified programs. However, just like choosing any specialist for your patient, selecting quality substance abuse treatment providers is neither trivial nor easy. As with selecting other specialists, asking knowledgeable colleagues, patients, and their families for recommendations is advisable. Ideally, one should search for programs with a multidisciplinary approach, with treatment providers who are comfortable with addiction pharmacotherapy, that combines the following: • • • • •

Evidence-based counseling A longitudinal approach across the entire continuum of care Case management A comprehensive array of psychosocial services either on-site or via referral A patient-centered approach that recognizes the importance of evening hours, transportation, and child care to facilitate access.

High-quality programs routinely include screening for co-occurring psychiatric conditions and, if needed, provide referral or treatment on site. Once the patient accesses the program, it is essential that the patient sign a release of information statement so that the clinician can proactively establish communication with the primary treatment counselor. This communication allows clarification of roles in the formulation and implementation of a treatment plan, care coordination, and ongoing sharing of information relevant to treatment progress (e.g., toxicology results and treatment participation). If documented in the chart, time spent in these coordination activities can be used to justify Current Procedural Terminology evaluation and management coding (see Chapter 13, “Logistics of Office-Based Buprenorphine Treatment”).

Facilitating Outpatient Treatment and/or Recovery Group Involvement HANDLING RESISTANCE TO TREATMENT: MOTIVATION ENHANCEMENT THERAPY Often patients resist recommendations for counseling or 12-step involvement. MET approaches offer a very powerful method for dealing with resistant or ambivalent patients. Based on the stages of change paradigm (see Chapter 5), this approach to counseling recognizes that ambivalence is a normal part of the change/recovery process and that the clinician’s behavior can either facilitate or impede progress toward recovery. A supportive, nonjudgmental

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patient-clinician relationship is especially important in these cases. Because of the negative interactions many such patients have had with the health care system, they are often guarded and quick to sense disrespect from health care providers. Interview style may be as important as content. With a resistant patient, the clinician should convey concern, empathy, and respect through the use of open-ended questions, active listening, and repeating back the patient’s words and ideas so that he or she knows the clinician has listened (reflective listening) (Miller and Rollnick 2002). Affirmation of the patient’s positive statements and modest successes (arriving at the appointment, duration of abstinence, challenges overcome, improvements in health, and positive lifestyle changes) will build both the therapeutic relationship and the patient’s selfefficacy (Barnes and Samet 1997). Resistance should be viewed as a natural response whenever someone is being asked to change behaviors. When patients resist going to counseling or meetings, the clinician needs to explore motivation and attitudes toward recovery and negotiate for acceptable alternatives in a motivational style (Barnes and Samet 1997; Miller and Rollnick 2002). The clinician should accept that he or she cannot impose his or her personal views on the patient but must invite the patient to consider new perspectives. Resistance should be a clue for the clinician to change strategy: to ask more open-ended questions, listen more, emphasize respect for the patient, ask for the patient’s perspective on the problem, ask the patient to suggest solutions, and discuss the pros and cons of change. Finally, it is important to emphasize the personal responsibility of the patient, because in the final analysis, the patient must accept and carry out the recovery plan. In this respect, the clinician serves as a coach on the sideline, helping to instill motivation and offering strategy, but the patient is the one on the field. For patients who lack self-efficacy, especially those with prior failed attempts at change, the clinician is an important source of hope, support, encouragement, and alternative strategies. The MET approach was incorporated as one of the manual-guided behavioral therapies employed in Project MATCH; copies of the manual (Miller et al. 1995) are available from NIAAA (http:// pubs.niaaa.nih.gov/publications/match.htm, NIH Publ. No. 94-3723, 1994). The Miller and Rollnick text (2002) is also a valuable and highly accessible resource for the buprenorphine practitioner. The clinician should assess and take seriously the patient’s agenda. However, a patient-centered approach does not mean the absence of disagreement; on the contrary, it can make confrontation more effective. For example, if the clinician believes that the lack of counseling places the recovering patient at risk for relapse, that should be stated directly and the patient should be asked to respond. Recommendations should be framed as specific responses to needs. Patients should be reminded that buprenorphine treatment alone is not enough, and that patients who participate in counseling have the greatest success (Stein

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et al. 2005). Feedback should reinforce the areas in which the patient is doing well, express direct concern about overconfidence and the relationship between the concerning behavior and possible consequences, and seek the patient’s reaction. If the patient disagrees, management should be negotiated with the same concern used in addressing patients with coronary artery disease who resist changing a sedentary lifestyle. In both cases, judgmental, hard-line approaches produce no clinical benefit and may alienate the patient. A menu of possible options should be presented, and the clinician should negotiate to reach a solution that is acceptable to both clinician and patient. In the final analysis, behavior change is hard work and the patient should be applauded and supported for any positive change. In a supportive, ongoing relationship, future meetings hold the possibility of helping the resistant patient recognize and address his or her risky behaviors.

WORKING WITH 12-STEP RECOVERY GROUPS Twelve-step fellowships like AA and NA are the most widely available form of long-term support for recovery. The 12 steps outline a process of personal change. The steps move the recovering person from initial acceptance of the diagnosis through self-exploration and on to action. Because one of the most difficult tasks of recovery is breaking loose from perceived “friends” who use alcohol or other drugs, 12-step groups, in addition to focusing on the personal changes necessary for recovery, help establish substance-free social networks. Some therapists offer specific treatment designed to assist patients in the process of connecting to mutual support programs. The TSF manual that was used in Project MATCH is available from NIAAA (http://pubs.niaaa.nih.gov/ publications/match.htm, NIH Publ. No. 94-3722, 1995) and provides more details on some of the recommendations described below (Nowinski et al. 1995).

Facilitating Involvement in 12-Step Groups By encouraging involvement in 12-step groups, the clinician can have an effective role in facilitating recovery (Friedmann et al. 1998). Even though NA focuses on heroin and other opioids, some buprenorphine patients are more comfortable at AA meetings. This circumstance is understandable because of concerns about encountering the “wrong people” at NA meetings and because some NA groups do not recognize buprenorphine patients as being in recovery. In general, contemporary AA groups are accustomed to polysubstance use and welcome anyone who seeks recovery. Occasionally buprenorphine patients encounter other AA/NA members who challenge their buprenorphine treatment and insist that the patient is not legitimately sober. Our patients should be in-

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formed that this is not the official position of AA or NA and that these organizations specifically support members who are taking medication under their physician’s supervision. The clinician should encourage the patient to look for a home group in which he or she feels comfortable. The patient should be reminded that every group is different and to try different meetings until one feels right. The patient should be encouraged to regularly participate in the home group and to search for a sponsor and gather a list of telephone numbers from group members. The sponsor: an important, ongoing source of support. The clinician should strongly support a recovering patient’s search for a sponsor (Nowinski et al. 1995). The sponsor, an AA/NA member who has been abstinent for a year or more, is a role model and informal guide to the program. It is important to explain to the patient that the use of sponsors is one of the oldest and most important and effective traditions in 12-step programs. The sponsor will support recovery and confront behavior indicative of imminent relapse. The sponsor should be of the same gender as the patient (or the opposite gender of a homosexual patient) and the same age or older. If the patient is having trouble finding a sponsor, he or she should continue to attend meetings, wait for announcements, and state simply that he or she needs a sponsor. A patient who has difficulty speaking in front of a group should be encouraged to arrive early and stay late, and casually let people know that he or she is looking for a sponsor. The telephone list: an essential tool for managing high-risk situations and slips. The telephone list is especially important for new members and for those without a sponsor. The clinician should urge the patient to gather a list of telephone numbers from other members who are prepared to give their contact information to new members. Using the telephone is one of the cornerstones of 12-step therapy. Reassure the patient that members expect to give out their telephone numbers and expect to get calls. The clinician should remind patients to call these telephone numbers or their sponsor whenever they have an urge to drink or use drugs, whenever they feel lonely, angry, tired, or other negative feelings, whenever they feel overly good (and perhaps complacent) about their sobriety, and as soon as possible after a relapse. Often there is no need to explain the reason for calling. A telephone list can also include supportive sober friends or family. At each visit the clinician should ask in a nonjudgmental manner about the number of meetings per week the patient is attending, the level of participation in the meetings, and any contact with a sponsor. Clinician concern about a sudden drop-off in meeting attendance, a lack of participation, loss of contact with the sponsor, or possible signs of relapse should be expressed in a direct and empathic manner.

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Addressing Resistance to AA/NA Resistance to AA/NA is common. Some patients genuinely take issue with 12step groups, typically complaining that they do not like the religiosity of traditional groups, that they cannot tolerate the cigarette smoke, or that their substance problem is not severe enough to need AA/NA. The clinician should have a repertoire of appropriate responses for reluctant patients. Patients who object to smoking should be directed to the growing number of nonsmoking meetings. The clinician needs to urge patients who object to spirituality to seek out meetings with a less overtly spiritual tone, atheist meetings, or where available, Rational Recovery (https://rational.org) or similar secular recovery groups. The clinician should explain that belief in the 12 steps or in a higher power is less important than simply going to meetings and seeking supportive, nonusing friends. For patients uncomfortable with the spiritual aspects of a 12step program, clinicians need to emphasize the practical wisdom reflected in its many slogans, a few of which are discussed below (Nowinski et al. 1995): •

•

•

One day at a time. This slogan is useful for patients who get caught up in lamenting the past or planning the future. It emphasizes that the key to sobriety is to focus on the present situation and to avoid drug use today. Though anniversaries of sobriety are important, what is most important is whether you drink or use drugs today, not whether you drank or used drugs yesterday or will drink or use drugs tomorrow. First things first. This slogan says that if the patient does not stay sober, nothing else will matter. This is useful for patients who get distracted from their recovery work by other life problems and responsibilities. It is important to emphasize that all people have multiple obligations, but sobriety must be the first commitment. Fake it till you make it. Twelve-step groups acknowledge that many of their suggestions may not appeal or make sense to the newly recovering person. This slogan asks the member to accept on faith that the advice will make sense eventually. This slogan is useful with patients who resist going to meetings, working the steps, and following the sponsor’s advice. A related slogan, Take what you need and leave the rest, encourages patients to derive from these groups the ideas and support that they think will aid their recovery and to ignore the unhelpful aspects of the program.

Even so, 12-step groups are not for everyone, and the clinician should reassure patients that meeting attendance is neither essential to continuing the patient-clinician relationship nor the only path to recovery.

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COGNITIVE-BEHAVIORAL THERAPY AND RELAPSE PREVENTION COUNSELING Relapse is a process in which the return to alcohol or drug use results from a series of maladaptive responses to stressors or stimuli (Marlatt and Gordon 1985). The initial return to use (a lapse or slip) results when the recovering person inadequately copes with emotions, situations, or cues that create craving— an inner need or desire for the substance. The predominant triggers for relapse are negative affective states (e.g., frustration, anger, fatigue, boredom, or stress), family conflict (e.g., marital fights), social pressure like that at parties and in bars, and social isolation (Connors et al. 1996; Miller 1996). Twelve-step groups use the expressions people, places, and things and HALT: don’t get Hungry, Angry, Lonely, or Tired to express this idea. After the first instance of drug use, the individual may experience guilt, shame, and/or anxiety. These negative feelings can lead to an attitude that there is nothing more to lose, resulting in relapse to heavy use to assuage the negative feelings. Although the term slipping used by 12-step groups does not differentiate between an initial lapse and fullblown relapse, the recovering patient should be urged to see past the negative feelings brought on by initial use and understand their potential for harm. The clinician is in a position to educate the patient to recognize high-risk situations, craving, and slips and to help develop a coping plan.

Plan to Cope With Emergencies: High-Risk Situations, Craving, and Slips CBT approaches have proved particularly effective in helping patients avoid relapse and build successful and healthy coping skills. Recovering patients commonly experience high-risk situations, such as life crises, drug offers, craving, and slips, as they struggle to maintain sobriety (Kadden et al. 1995). Craving can be triggered by negative or positive emotions, physical distress, or people, places, and things that remind the patient of drugs. The clinician should emphasize that craving is an uncomfortable but normal part of recovery and is nothing to be ashamed of. The clinician should counsel patients that cravings last only a few minutes to hours and eventually weaken and disappear if they do not give in. While advocating avoidance of high-risk situations and people, the clinician must acknowledge that avoidance is not always possible. For example, major life changes and crises are inevitable. Thus, coping skills and planning are essential for stable recovery.

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Relapse prevention counseling with an addiction professional is the best means to obtain improved coping skills. However, this type of counseling is not available in some communities and, where available, some patients may be unwilling or unable to access it. The buprenorphine clinician should be prepared to use brief counseling and/or role-play to ensure that patients have ways to cope with the normal exigencies of life without resorting to drug use. Counseling in this context involves brainstorming and problem solving with the patient regarding how he or she plans to manage high-risk situations, moods, craving, and slips. In this regard, useful lines of inquiry include the following: • • • • • • •

“In what kinds of situations (do/did) you use (drugs)?” “What (are/were) your triggers for using?” “During previous abstinent periods, what set you off to use again?” “How do you plan to cope with these situations this time?” “How do you plan to cope with major life crises or peer pressure to use?” “What would you do if you had a slip?” “Do you feel confident that you can manage these situations without using?”

The clinician should instruct the patient to write an emergency plan of responses. The plan should formalize any specific coping mechanisms identified by the patient. If the patient cannot identify any coping mechanisms, suggest simple strategies such as the following: •

• • • •

Talking it through with a sponsor, another recovery group member on the patient’s telephone list, or a supportive family member or friend—or call the AA hotline Going to an AA or other recovery group meeting Getting involved in a distracting activity, such as reading, a hobby, going to a movie, or exercising Engaging in prayer or meditation Employing behavioral methods learned in a treatment or aftercare program.

The plan should specify that the patient will leave the situation, and if necessary, seek help immediately. The social relationships of drug users revolve around substances. Their peer group has been populated with others who support and reinforce drug use. Being with drug-using friends, family members, or associates increases the risk of relapse through indirect social pressure; the result of the availability of drugs; the conditioned craving and feelings associated with people, places, and things; and direct social pressure to use, as when someone offers the individual drugs or alcohol (Kadden et al. 1995; McKay 1999). Thus, patients must be able to fend off pressure to use as quickly and convincingly as possible (Monti et al.

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1989). For patients facing the likely prospect of peer pressure to use or highrisk social environments such as parties, the clinician can help the patient roleplay what he or she would say to refuse the offer. At the very least, the clinician can ask the patient how he or she would respond if offered drugs. The patient should be clear that he or she is in recovery and avoid excuses (e.g., saying “I’m on medication”) or vague answers (e.g., “not tonight”) that imply that he or she might use in the future. Patients should be asked to consider how someone might react to such a refusal and be advised that they are not hurting anyone by not using drugs, so they should not feel guilty. Despite their best efforts many recovering persons do use again. After an initial return to use, the individual may experience guilt and shame. These negative feelings can lead to an attitude that there is nothing more to lose, resulting in a return to heavy substance use to assuage the negative feelings. Patients should be urged not to beat themselves up after initial use and to understand the potential for negative feelings to lead to even more drug use. Marlatt and Gordon have described this as the abstinence violation effect (Marlatt and Gordon 1985). The clinician should remind the recovering person that craving and slips are expected parts of the recovery process and present opportunities for patients to learn about their triggers and to practice their coping plan. The clinician can facilitate a positive approach to recovery as a learning process, with slips providing valuable lessons. That said, the clinician should be mindful of a fine line between helping patients see relapse as a learning opportunity and conveying the message that some use is acceptable. The clinician must make it clear that abstinence is the goal for the majority of patients and that continued use will likely require more intensive treatment (e.g., more counseling, more monitoring, or referral to a more intensive level of care). However, the goal of abstinence should not prevent the patient from returning to see the clinician or seeking help following a slip because of the guilt and/or shame that could result if the patient interpreted any use as failure (Monti et al. 1989). If the patient needs or desires other ways to cope with urges and craving, refer the patient to a relapse prevention therapist, an expert in CBT, or a CBT group, if these options are available and acceptable. CBT is based on the premise that substance abuse is a functional problem related to deficits in coping skills. Typically CBT is provided in the form of group or individual, manual-guided therapy that aims to build cognitive and behavioral skills that support recovery. As originally conceived it comprises 12 sessions, each of which focuses on specific skill sets such as anger management, coping with craving, and resisting peer pressure. A very useful resource for clinicians is the CBT manual developed by NIAAA (http://pubs.niaaa.nih.gov/publications/ MATCHSeries3/index.htm), which can be obtained free of charge as part of the Project MATCH Series (Kadden et al. 1995).

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Conclusion Psychosocial counseling is an essential part of office-based treatment with buprenorphine. The clinician should specifically educate patients that buprenorphine treatment alone is not enough and that patients who participate in counseling have the best outcomes. In selecting quality substance abuse counselors, ask knowledgeable colleagues, patients, and their families to suggest therapists or programs that include evidence-based counseling and pharmacotherapeutic practices; a longitudinal approach across the entire continuum of care; case management; a comprehensive array of psychosocial services; and a patient-centered approach that recognizes the importance of evening hours and transportation to facilitate access. In making the referral, coordination with local treatment providers is important to quality care and signed release of information forms are essential to enable communication among treatment providers. Buprenorphine clinicians should also facilitate patients’ involvement with recovery groups. Recommendations for counseling and 12-step involvement should be made in a motivational style that recognizes that resistance is common and expected. For the resistant patient, a menu of possible options should be presented and the clinician should negotiate a solution that is acceptable to both parties. In general, patients need to develop new drug-free social networks, and 12-step groups should be encouraged as a way to establish these relationships. Although formal relapse prevention counseling is the best means to develop coping skills, buprenorphine clinicians should also be prepared to help patients identify triggers and develop a coping plan as part of their routine medication supervision visits.

Clinical Pearls • Counseling is an essential component of quality buprenorphine treatment. Clinicians should emphasize that treatment is “more than just a pill.” • A basic understanding of the dimensions of assessment and available treatment options will help ensure that the buprenorphine patient receives the appropriate intensity of care. • Getting to know the competent therapists and quality programs in your community is no different than getting to know quality specialists in other arenas. Inquiries to knowledgeable colleagues and patients can help. Clinicians should locate therapists trained in CBT, MET, and TSF. • Release of information and care coordination with treatment counselors are essential to quality buprenorphine treatment.

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• Twelve-step groups like AA and NA are cost-effective and widely available. The clinician can have an important role in facilitating the patient’s involvement in these groups. • Resistance to counseling and 12-step groups is common and to be expected. It should be addressed by counseling in a motivational style. • The buprenorphine clinician should encourage patients to develop a plan to cope with high-risk situations, craving, and relapse.

CASE 3 Eddie is a 25-year-old cab driver who initiated buprenorphine 6 months ago. He began using intravenous heroin in his teens and has a history of truancy but denies any history of criminal behavior. He has been driving his cab for 3 years. Nonetheless, you never feel quite comfortable when he is on your appointment schedule. He “lost” one of his prescriptions 2 months ago, and you agreed to replace it but warned him that you would not do it again. As he walks into your office, you see that his last urine test was positive for morphine. He becomes defensive and angry when you ask him about his urine test results. “No way, doc! It’s a mistake in your test....”

1. What are your strengths and weaknesses in understanding and interpreting toxicology? 2. What do you do now? 3. What interview style do you use if you perceive your patient as resistant? 4. What action will you take? 5. Is transfer to a more structured program (possibly a methadone clinic) the next step?

CASE 4 Martha is a 35-year-old housewife who started buprenorphine therapy 4 months ago after years of taking oral opioids for back pain related to a herniated disc. She has been a “perfect patient” in many respects but now reports that her AA sponsor insists she “isn’t clean.” She is confused—you had suggested 12-step groups as a reliable support system. She feels that she has benefited from “working the steps” but now doesn’t know where to turn. She doesn’t feel that alcohol was ever “really the problem.” She says: “I’ll just stop going. I don’t need the stress. I can get sober on my own.”

1. How would you respond to this patient’s last statement? 2. How important is a sponsor in a 12-step program? 3. What is AA’s stance on prescribed medicines and psychiatric treatment?

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4. How do you get a sense of your patient’s involvement in AA? 5. Are there are other self-help groups available? Are there other treatment options? Note: This case is continued at the end of Chapter 11, “Management of Acute and Chronic Pain.”

CASE 5 Henrietta is a 43-year-old auto mechanic who has been in your clinic for a year. She comes to your Thursday evening buprenorphine group and says that she’s “back on track”—by this she means that she is back to work, paying her bills, and rebuilding her repair shop business. She admits that she drinks to relax at the end of the day. Exploration of her alcohol intake reveals that she drinks four or five beers every evening. She adds, “I finish off a case on weekends but drinking has never been a problem, doc.” She does not attend AA or NA. “All they talk about is problems—I’m all set.” She has a husband and three children, ages 5–9. She is happy with her work, but her husband has told her that she should cut back on her drinking or he might have to leave “again.”

1. Is her drinking a problem? 2. Should she undergo detoxification from alcohol? 3. If you continue buprenorphine therapy, would you change her treatment plan? 4. How would you address attendance at AA meetings? 5. Would 12-step facilitation be effective in this case? Note: This case is continued at the end of Chapter 9, “Psychiatric Comorbidity.”

References American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision. Washington, DC, American Psychiatric Association, 2000 Barnes HN, Samet JH: Brief interventions with substance-abusing patients. Med Clin North Am 81:867–879, 1997 Barry DT, Moore BA, Pantalon MV, et al: Patient satisfaction with primary care officebased buprenorphine/naloxone treatment. J Gen Intern Med 22:242–245, 2007 Connors GJ, Longabaugh R, Miller WR: Looking forward and back to relapse: implications for research and practice. Addiction 91(suppl):S191–S196, 1996 Fiellin DA, Pantalon MV, Chawarski MC, et al: Counseling plus buprenorphinenaloxone maintenance therapy for opioid dependence. N Engl J Med 355:365– 374, 2006 Finch JW, Kamien JB, Amass L: Two-year experience with buprenorphine-naloxone (Suboxone) for maintenance treatment of opioid dependence within a private practice setting. J Addict Med 1:104–110, 2007

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Friedmann PD, Saitz R, Samet JH: Management of adults recovering from alcohol or other drug problems: relapse prevention in primary care. JAMA 279:1227–1231, 1998 Kadden R, Carroll K, Donovan D, et al: Cognitive-Behavioral Coping Skills Therapy Manual: A Clinical Research Guide for Therapists Treating Individuals With Alcohol Abuse and Dependence. Project MATCH Monograph Series, Vol 3 (NIH Publ No 94-3724). Rockville, MD, National Institute on Alcohol Abuse and Alcoholism, 1995. Available at: http://pubs.niaaa.nih.gov/publications/ MATCHSeries3/index.htm. Accessed May 3, 2010. Keen J, Oliver P, Rowse R, et al: Residential rehabilitation for drug users: a review of 13 months’ intake to a therapeutic community. Fam Pract 18:545–548, 2001 Marlatt GA, Gordon JRE: Relapse Prevention: Maintenance Strategies in the Treatment of Addictive Behaviors. New York, Guilford, 1985 McKay JR: Studies of factors in relapse to alcohol, drug and nicotine use: a critical review of methodologies and findings. J Stud Alcohol 60:566–576, 1999 McLellan AT, Arndt IO, Metzger DS, et al: The effects of psychosocial services in substance abuse treatment. JAMA 269:1953–1959, 1993 Miller WR: What is a relapse? Fifty ways to leave the wagon. Addiction 91(suppl):S15– S27, 1996 Miller WR, Rollnick S: Motivational Interviewing: Preparing People for Change, 2nd Edition. New York, Guilford, 2002 Miller WR, Wilbourne PL: Mesa Grande: a methodological analysis of clinical trials of treatments for alcohol use disorders. Addiction 97:265–277, 2002 Miller WR, Zweben A, DiClemente CC, et al: Motivational Enhancement Therapy Manual: A Clinical Research Guide for Therapists Treating Individuals With Alcohol Abuse and Dependence. Project MATCH Monograph Series, Vol 2 (NIH Publ No 94-3723). Rockville, MD, National Institute on Alcohol Abuse and Alcoholism, 1995 Monti P, Abrams D, Kadden R, et al: Treating Alcohol Dependence: A Coping Skills Training Guide. New York, Guilford, 1989 National Institute on Drug Abuse: Therapeutic Community (NIDA Research Reports Series, NIH Publ No 02-4877). Rockville, MD, National Institute on Drug Abuse, August 2002. Available at: www.nida.nih.gov/PDF/RRTherapeutic.pdf. Accessed July 18, 2008. Nowinski J, Baker S, Carroll K: Twelve Step Facilitation Therapy Manual: A Clinical Research Guide for Therapists Treating Individuals With Alcohol Abuse or Dependence. Project MATCH Monograph Series, Vol 1 (NIH Publ No 94-3722). Rockville, MD, National Institute on Alcohol Abuse and Alcoholism, 1995 O’Farrell TJ, Fals-Stewart W: Behavioral couples and family therapy for substance abusers. Curr Psychiatric Rep 4:371–376, 2002 Stein MD, Cioe P, Friedmann PD: Buprenorphine retention in primary care. J Gen Intern Med 20:1038–1041, 2005

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9 Psychiatric Comorbidity Elinore F. McCance-Katz, M.D., Ph.D.

PSYCHIATRIC SYMPTOMS are common in opioid-dependent patients. In this chapter, I review how to differentiate substance-induced psychiatric disorders from independent psychiatric disorders and how to determine which patients can be successfully managed in specific office settings. The complexities of pharmacotherapy and clinical management of co-occurring psychiatric disorders in buprenorphine-treated patients are considered, and the recommendations for managing some of the more common clinical problems also are discussed. Cases are presented at the end of this chapter, including related questions for additional consideration. For discussion of these cases, please see Chapter 14, “Comments on the Case Vignettes.”

Epidemiology Mental disorders co-occur frequently in patients with opioid dependence. In particular, significant rates of co-occurring affective disorders, particularly major depression, anxiety disorders, posttraumatic stress disorder (PTSD), attentiondeficit/hyperactivity disorder (ADHD), antisocial personality disorder—as well as other psychiatric disorders—occur in this population (Regier et al. 1988). In addition, substance-induced mental disorders are common in the patient presenting 165

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for treatment of opioid dependence. Key to providing effective treatment is accurately diagnosing and implementing appropriate treatment for these conditions. The underlying etiology for the high rates of comorbidity in opioid-dependent patients is likely to be multifactorial. Similar to the use of other substances with abuse liability, the use of opioids is associated with increases in dopamine in the nucleus accumbens. This is thought to be the mediator of the euphoria related to substance use. The chronic abuse of opioids leads to changes in the brain, including the nucleus accumbens, such that there is decreased ability to experience pleasure without the presence of opioids. Over time this may contribute to the depression that many patients complain of when presenting for treatment of opioid addiction. Alternatively, those with vulnerability to developing a mental disorder such as depression may hasten its onset as a result of changes that occur with chronic exposure to opioids, although this mechanism has not been well defined to date. There may be other neurophysiological changes that occur following chronic exposure to opioids that might render an individual vulnerable to the development of other mental disorders as well. It is also possible that those with disturbing psychiatric symptoms have attempted to self-medicate these symptoms with illicit drugs such as opioids. This can eventually lead to physical dependence and addiction. Unfortunately, substance abuse does not provide adequate relief of the target symptoms that the patient attempted to medicate and may ultimately aggravate their symptoms. Given the complex etiologies of co-occurring mental illness in those with opioid dependence, it is clear that careful evaluation over time is needed to fully understand the psychopathology of the patient in order to accurately diagnose his or her condition and provide appropriate treatment. In evaluating the co-occurrence of psychiatric symptoms and syndromes in patients with a history of chronic substance abuse, it is important not to assume that all symptoms reported are related to an independent mental disorder, even if a patient states that such symptoms predated drug abuse. The symptoms associated with intoxication and withdrawal can mimic virtually any mental disorder. Patients often have a need to rationalize their substance abuse by attributing it to another problem or disorder. Therefore, careful evaluation over time is required to fully understand the relationship between opioid dependence and other reported psychiatric symptoms. Anxiety and/or panic symptoms are frequent complaints in those with opioid dependence and they must be carefully evaluated. Anxiety is a common symptom of opioid withdrawal. Anxiety may also occur as part of a syndrome of withdrawal from other substances. When evaluating for co-occurring disorders, it is important for clinicians to understand that opioid withdrawal is ubiquitous in those with opioid addiction, whether the patient endorses this or not. It is simply a fact that opioid dependence is characterized by the ongoing and frequent use of opioids and is driven by the withdrawal symptoms that occur as blood levels of opioids

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decline. Part of that constellation of withdrawal symptoms is anxiety. Further, patients frequently lack the insight to make the connection between the onset of opioid withdrawal and the temporal relationship of anxiety symptoms. Rather, patients often ask for anxiolytic medications (usually benzodiazepines), which have abuse liability and can enhance the effects of prescribed opioids (methadone, buprenorphine)—certainly unwanted effects in the treatment of such patients. The goal of opioid therapy is to stabilize the patient’s condition so that his or her life does not revolve around the abuse of opioids, including intoxication and withdrawal with constant drug seeking. Therefore, the use of anxiolytic medications— which may contribute to intoxication—is not therapeutic and could be dangerous to the patient and to others. In addition, the presence and characterization of drug interactions between benzodiazepines and opioids such as buprenorphine have not been well defined as yet, but significant adverse events are possible. Although benzodiazepines are not absolutely contraindicated in those with opioid dependence, evaluation must be thorough and thoughtful prior to prescription of these medications for anxiety in opioid-addicted patients receiving opioid agonist therapy. Independent anxiety disorders may also occur in those with opioid dependence, and in such cases pharmacotherapy for the anxiety is necessary. PTSD is also a frequently co-occurring mental illness in patients with opioid dependence, particularly women. Up to 80% of women with substance use disorders report having experienced trauma, either physical or sexual. Further, it has been reported that PTSD occurs in 30%–59% of women with substance use disorders (Najavits et al. 1997). The drug-abusing lifestyle can be quite conducive to trauma given the illegal activities related to drug procurement and abuse. Individuals often engage in risky activities or are victimized in the context of drug use. Intoxication also renders an individual more vulnerable to traumatic events. Such occurrences may lead to the onset of PTSD, which may only be detected when the patient comes to treatment. As with other psychiatric disorders, untreated PTSD negatively impacts the overall response to drug abuse treatment. ADHD is a diagnosis that has been made with increasing frequency over the past few years. The Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR; American Psychiatric Association 2000) requires that some symptoms of ADHD—characterized by impulsivity, inattentiveness, and increased nonproductive activity levels—start before age 7. However, more recent work indicates the validity of the diagnosis (ADHD not otherwise specified) in adults who do not have a clear record of the symptoms before age 7 (Faraone et al. 2007). The most current data from the Centers for Disease Control and Prevention (2005) indicate that the diagnosis is missed in at least half of cases. It has been shown that development of substance use disorders in adolescence is less likely in a child with ADHD who receives appropriate pharmacotherapy in childhood (Wilens et al. 2008), underscoring the importance of accurate diagnosis and treatment of ADHD. With opioid-addicted patients, it is impor-

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tant to remember that impulsivity and inattentiveness are often directly related to the effects of the abused substances. A reasonable period of verified abstinence is suggested before making the diagnosis of ADHD in an individual with any substance use disorder, to help distinguish ADHD from subacute effects of substances of abuse. Antisocial personality disorder is the most common personality disorder seen in those with opioid dependence (and substance use disorders in general). Antisocial behaviors such as lying, cheating, and stealing are common in those who must support a costly drug habit. Such behaviors often resolve with appropriate treatment of addiction such as opioid agonist therapy and counseling. The major differential in an opioid-dependent individual with a history of antisocial behavior is whether there is a true underlying antisocial personality disorder or whether the behavior was induced secondary to the addiction. Clues to this question often lie in the developmental history of the patient. For example, those exhibiting conduct disorder in childhood and adolescence before the onset of substance abuse are more likely to have antisocial personality disorder. Further, a history of property destruction or cruelty to others or animals, diagnostic criteria for antisocial personality disorder, are not generally associated with addiction. It is important to know that most individuals with opioid addiction do not have true antisocial personality disorder, but rather present the symptoms of substance-induced sociopathy necessary to procure and use drugs. Such patients respond well to opioid therapies, including buprenorphine. Further, such patients can be effectively treated in office-based settings. To conclude, mental disorders co-occur at significant rates in those with opioid dependence. These mental disorders can be either substance induced or independent of the opioid dependence. It is important to differentiate between substance-induced and independent disorders because the treatments are quite different. Substance-induced disorders resolve with appropriate treatment of opioid dependence (and other co-occurring substance use disorders when present). Independent mental disorders do not, and may possibly worsen as psychopathology is unmasked with treatment of the addiction. Individuals with these co-occurring conditions require integrated treatment of both disorders to establish any meaningful recovery from their substance abuse. The following sections provide guidance on how to evaluate and treat the opioiddependent patient with co-occurring mental illness.

Evaluation Evaluation of the patient with opioid dependence requires attention to the history of opioid abuse and to the history of other substance abuse, medical illnesses, and psychiatric symptoms. The history is critical to arriving at the appropriate di-

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agnoses and treatment plans. Patients with opioid addiction may be uncomfortable answering some of these questions; therefore the approach of the clinician is important to determining how much of the relevant information can be gathered (see Chapter 5, “Patient Assessment”; Chapter 7, “Clinical Management I”; and Chapter 8, “Clinical Management II”). A nonjudgmental approach, the use of open-ended questions with follow-up questions to clarify responses as needed, and reassurance regarding confidentiality are all important parts of the interview. It is also important to obtain consent to speak with important significant others in the patient’s life who can provide additional information about the patient’s history and progress reports over the course of treatment.

ASSESSING

THE

ABUSE

OF

OTHER SUBSTANCES

Determination of opioid addiction and determining the presence of other substance use disorders have been discussed in more detail in Chapter 5. It is worth reiterating, however, the importance of assuring that the patient is opioid dependent through assessment of the patient’s history, medical records, signs on physical examination (e.g., needle track marks, signs of opioid withdrawal), and urine drug screening results. It is important to ask about the use of street opioids (e.g., heroin, opium) as well as prescription opioids (see Chapter 5, Table 5–1, “Commonly abused opioids”). Prescription opioid abuse has rapidly increased in the last 10 years and is characterized by aberrant drug-taking behaviors including the following: • • • • • • •

Compulsive use of opioid analgesics with unauthorized dose increases Using the drugs to get “high,” relieve stress, or sleep Obtaining prescriptions from multiple physicians Frequenting emergency departments seeking opioids Forging prescriptions Taking drugs from friends and/or family members Buying or selling drugs.

The number of people with prescription opioid abuse or dependence now far exceeds the number of heroin addicts in the United States. The number of new misusers of prescription opioids now approximates the number of new cannabis users (Substance Abuse and Mental Health Services Administration 2009; see also Chapter 1, “Opioid Dependence in America,” Figure 1–3). These findings underscore the need for office-based treatment of opioid dependence in order to increase access to treatment for the burgeoning numbers of opioid-addicted individuals. It is also important to screen for other substance use disorders because the patient may require treatment for those as well. If the patient is alcohol dependent or benzodiazepine dependent, he or she should be admitted to a facility

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for medically supervised detoxification treatment. Such a patient would likely not be an appropriate candidate for office-based buprenorphine treatment due to the risk of adverse events (see “Drug Interactions With Buprenorphine” later in this chapter) should they reinitiate alcohol and/or benzodiazepine use. The abuse of stimulants such as cocaine or methamphetamine predicts a poor course for buprenorphine-treated individuals if they receive no treatment specific for stimulant dependence. There is now also evidence that cocaine abuse can adversely impact buprenorphine pharmacokinetics (McCance-Katz et al. 2010), adding another layer of complexity to the treatment of such patients. Nicotine dependence is a common problem in opioid-dependent patients. All patients should be strongly encouraged to stop smoking and treatment should be provided if the patient is interested. Cigarette smoking is strongly linked to relapse to other substance use, and effective pharmacotherapies to help patients quit smoking are now available. It is important to query patients regarding other substance use as well, although the most common co-occurrence of substance use with opioids is alcohol, sedatives, hypnotics, stimulants, and nicotine. In Chapter 5, Table 5–2 (“Other commonly abused substances”) includes a list of abused substances that should be asked about in the evaluation of the opioiddependent patient and that should be tested with urine drug screening. Evaluating for medical illnesses is an important component of the overall evaluation of the opioid-dependent patient. Patients with opioid dependence often have co-occurring medical illness (as well as psychiatric illness) as a result of risky behaviors related to the development and maintenance of opioid addiction. Individuals who inject opioids are at high risk for HIV infection, hepatitis B and C virus infection, cellulitis, abscesses, emboli, thromboses, and other medical problems that require acute and possibly ongoing medical care (see Chapter 10, “Medical Management”). The medical needs of an opioid-addicted patient are an important consideration in determining the most appropriate setting for office-based treatment with buprenorphine-naloxone.

ASSESSING CO-OCCURRING PSYCHIATRIC DISORDERS Evaluation for the presence of co-occurring psychiatric disorders is critically important to instituting effective treatment for opioid dependence in any clinical setting, but can take on special importance when treatment is provided in an office-based setting. It is imperative that the treating physician understand the patient’s mental health history, understand the patient’s current problems, and determine the patient’s prognosis because all of these factors are important to determining whether office-based treatment of opioid dependence with buprenorphine is appropriate for the patient.

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Specific current psychiatric symptoms as well as past psychiatric history must be reviewed before the decision to begin buprenorphine-naloxone treatment because these issues are a significant part of the decision as to whether an opioid-dependent patient is a good candidate for office-based treatment of opioid dependence. Table 9–1 provides an outline for obtaining the most important parts of the mental health history, both most recent and further past. Obtaining the information outlined in Table 9–1 and following up on other relevant areas brought up by the patient should provide the information the physician needs to determine whether this is a patient that could be appropriately managed in the physician’s practice. For example, a primary care physician may be uncomfortable treating an opioid-dependent patient with significant mental illness, whereas a psychiatrist offering office-based treatment of opioid dependence may judge the patient to be a good fit for his or her practice. Alternatively, a patient with a history of co-occurring HIV infection or AIDS and opioid dependence may be one that a primary care physician would find appropriate for his or her practice, whereas a psychiatrist may refer such a patient to a physician with expertise in the treatment of HIV infection and AIDS while treating only the opioid dependence, or may refer the patient to a physician who can offer treatment for both conditions. Patients should be informed that the evaluation does not guarantee acceptance into the physician’s practice but that the physician will provide appropriate referrals for treatment should the patient’s condition be one that the evaluating physician does not believe to be a good fit for his or her practice. It is also important not to rely on information gleaned from a telephone screening done by an office staff member. Although it may be beneficial to have an office staff member do a cursory initial screen to exclude patients who require services not available through your practice (e.g., an opioid-addicted patient with a long-standing history of schizoaffective disorder and noncompliance with psychotropic medications who calls a primary care doctor requesting office-based treatment of opioid dependence), it is imperative that the physician take a thorough history to evaluate the patient. Untrained staff do not have the expertise to ask the questions that would be likely to clarify a complicated history. As previously mentioned, the most frequently occurring psychiatric disorders in this population are depression, anxiety, and personality disorders. Knowledge of the status of any patient regarding these disorders is essential to determining appropriateness for office-based treatment. Certain mental conditions render some individuals poor candidates for office-based treatment using buprenorphine (Table 9– 2). For any patient showing signs of active psychosis including hallucinations (either auditory or visual) or delusions, buprenorphine-naloxone should not be inducted. Any individual who endorses active suicidal or homicidal ideation should not be considered for office-based treatment. Any individual who appears to have significant cognitive impairment or dementia is also not a candidate for office-

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TABLE 9–1.

Taking the mental health history

History of substance abuse Opioids Alcohol Benzodiazepines Cocaine Methamphetamine

Cannabis Tobacco Steroids Other street drugs Other prescription drugs

History of mental health problems Depression Trauma Anxiety Criminal history, including property damage, truancy, aggression toward Psychosis other people or animals, violent behavior Has the patient ever been under the care of a psychiatrist or therapist? Was a diagnosis ever given? Was the patient ever referred for psychotherapy? What type? Was medication treatment ever recommended? What medications have been prescribed in the past? Currently? What do the medications help with? Does the patient feel the medications are effective? Does the patient take the medications as prescribed? Has the patient ever been hospitalized for a psychiatric condition? Are there current symptoms of mental illness? Ask about current depression, anxiety, psychotic thinking Assess cognition (orientation, memory [ask questions that you know you have correct answers for], concentration, abstracting ability, fund of knowledge, judgment, insight) Suicidal thoughts Current plans Past attempt(s) made and description (assess lethality) Means available to act (e.g., guns in the home, medications to overdose) Were suicide attempts impulsive or well planned? Supports in the home Homicidality Current plans Specific target? Past events

Means available to act Planned or impulsive?

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TABLE 9–2.

173

Psychiatric contraindications to office-based treatment of opioid dependence

Absolute contraindications Active psychosis Active suicidal or homicidal ideation Cognitive impairment or dementia Relative contraindications Psychosis (if not well controlled with medication) History of suicidality History of homicidality based treatment. In addition to eliciting the patient’s recent history of such issues, it is important for the clinician to review the past history of such problems. For example, a patient who is not currently suicidal but who has a history of suicide attempts may be more suitably treated in a methadone maintenance program due to the additional structure and observation available in that setting. What are the options for patients with opioid dependence who are not good candidates for office-based treatment? Depending on the setting in which the patient is evaluated, several options are available. For the patient with significant psychiatric symptoms who is evaluated in a primary care setting, the options include referral to a psychiatrist who may be more comfortable providing buprenorphine treatment in an office-based practice setting or to a program capable of providing treatment for both opioid addiction and psychiatric disorders. Some methadone maintenance programs can provide these services. Referral of such patients to community or clinic-based substance abuse and/or mental health services may, in some cases, be appropriate. In these settings, choices for treatment of opioid dependence may include methadone maintenance or medically assisted withdrawal. Another possibility is referral to a program where buprenorphine can be administered on site, eliminating the need to provide take-home medication. Because of buprenorphine’s long half-life and the even longer half-life of its active metabolite norbuprenorphine, this medication can be dosed thrice weekly and provide effective treatment for opioid dependence. If the community in which the physician is practicing has good, supportive treatment services as described above, it may be possible for the doctor to provide office-based treatment of opioid dependence with buprenorphine-naloxone while the patient also attends another appropriate psychiatric treatment facility. Patients with severe psychopathology who are judged not to be good candidates for office-based treatment of opioid dependence should be referred to a methadone maintenance program, which can offer greater structure and individual attention.

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HOW TO DIFFERENTIATE SUBSTANCE-INDUCED FROM INDEPENDENT PSYCHIATRIC DISORDERS Differentiating substance-induced psychiatric disorders from independent psychiatric disorders can be a challenge even for very experienced addiction psychiatrists. Important to this differentiation are the patient’s history, the patient’s family history, and the course of symptoms following cessation of substance abuse. Obtaining an accurate history regarding the temporal relationship of psychiatric symptoms to the substance abuse can be very illuminating. A patient who describes having anxiety and/or depression, but only since the onset of substance abuse, is more likely to have a substance-induced disorder. Similarly, the individual whose symptoms abate as the length of sobriety increases also has a substance-induced disorder. As a general rule, substance-induced disorders resolve fairly rapidly following cessation of substance abuse. Improvement can be seen in days to weeks following completion of medical withdrawal or stabilization with opioid agonist therapy. If symptoms worsen with abstinence or do not abate after 30 days, it is more likely that the individual has an independent psychiatric disorder and appropriate treatment should be instituted. Those with a family history of major mental disorders or who have a documented history of onset of a psychiatric disorder before the onset of substance abuse are more likely to have an independent psychiatric disorder. Another set of important questions has to do with determining when psychiatric symptoms occurred once substance abuse and dependence was initiated. For example, the patient with a history of mental illness occurring during extended periods of sobriety has an independent psychiatric disorder. Review of the patient’s medical records is important to determining the relationship of psychiatric symptoms to the cessation of substance use and sobriety. It is also important to know all of the substances being abused by the patient. For example, a patient who is dependent on opioids may have had several episodes of medical withdrawal followed by periods of opioid abstinence. However, if that patient also abused other substances (e.g., alcohol, stimulants) and these issues were not addressed, and there was no sobriety from all abused substances, then a diagnosis of an independent psychiatric disorder would not be appropriate. It is often difficult to be certain whether all substance abuse disorders have been identified and treated. Unfortunately, some substance abuse treatment facilities focus on the identified primary substance use disorder and ignore other abuse problems. Similarly, when a substance-abusing patient enters the mental health system, substance abuse may be neither identified nor treated, in favor of a focus on other psychiatric disorders. The more conservative approach of delaying the treatment of mental disorders until they can be observed going forward is often the best approach.

Psychiatric Comorbidity

IMPORTANCE

OF

175

REEVALUATION

The previous sections emphasize the need to do a thorough initial evaluation to determine immediate diagnoses and to initiate appropriate treatment. The prevalence of symptoms of mental illness in opioid-dependent patients is quite high. Clearly, the abuse of substances produces psychiatric symptoms regardless of the presence of an independent mental disorder. Those with substance dependence, by diagnostic definition, have had the substance abuse make a significant impact on their lives. Problems with significant others, children, and other family members and problems with employment, finances, and legal issues are common. Such issues would be expected to produce depression and anxiety. Indeed, such responses would be normal and lack of concern about such issues could also be indicative of a current psychiatric disorder. Therefore, it is important not to make the diagnosis of a psychiatric disorder prematurely or to immediately initiate treatment with psychotropic medications. In such circumstances, it is prudent to follow the symptoms over time. These patients should be reevaluated again after their opioid dependence has been stabilized with buprenorphine; changes in symptoms over time, partial or full resolution, or worsening despite abstinence from illicit drugs will provide the data needed to make the appropriate diagnosis and to institute treatment.

A WORD TO THE WISE: DO NOT EVALUATE INTOXICATED PATIENTS Patients who come to the office for evaluation and who appear to be intoxicated more than likely are intoxicated, and they are not capable of giving an accurate history or providing informed consent for the treatment. Essentially, evaluating such a patient (or speaking to them on the telephone as office staff frequently do) is a waste of time and bodes poorly for that patient’s course in treatment were you to admit the patient. Office staff may wonder whether a patient who is an opioid addict isn’t constantly intoxicated and therefore unable to come to an appointment before initiating buprenorphine-naloxone treatment at a time when the patient is not intoxicated. The answer is that a patient who is opioid dependent, and therefore has substantial tolerance to the effects of opioids, is quite capable of coming to an appointment when he or she does not show obvious signs of intoxication. Opioid-addicted individuals experience opioid intoxication for only a brief period after use (hours or less) once they have become physically dependent. They spend far more time trying to find that next dose of heroin or pain pills and experiencing the onset of withdrawal symptoms than they do with actual gross intoxication. Often, opioid-addicted patients abuse other

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drugs in combination with heroin and/or opioid analgesics in order to potentiate the euphoric effects of the opioids. Maintaining their desired level of euphoria becomes increasingly difficult as they become more and more tolerant to the effects of the opioids. This is why it is so important to evaluate for other substance use disorders in this population and why effective treatment must focus on abstinence from all substances of abuse. Patients should be told that they must not come to office appointments intoxicated and that if they show evidence of intoxication, the appointment will be terminated. This brings up another important issue in the assessment of any alcohol- or drug-abusing individual. If the patient appears to be intoxicated (e.g., has altered cognition, has slurred or excessively slow speech, gives answers that do not make sense or are not appropriate to the question asked, or shows evidence of sedation or motor incoordination), an intervention must be made to protect both the patient and the public. There is liability for the physician who does not intervene if the patient drives away and has an accident that harms the patient or others. The following is recommended if it is suspected that the patient is intoxicated: •

• •

•

•

•

Ask the patient when he or she last used drugs or alcohol (if the patient endorses drinking alcohol, a breath alcohol test can be done with a breathalyzer). Ask the patient if he or she wishes to be referred for medical withdrawal treatment; if so, arrange for an admission. Inquire about suicidal or homicidal ideation. If an intoxicated individual admits to such thoughts, the patient must be carefully assessed and hospitalized if necessary (see the sections “Acute Suicidal Ideation” and “Acute Homicidal Ideation” later in this chapter). If the patient denies any suicidal or homicidal ideation, and does not wish to be hospitalized for medical withdrawal, ask the patient how he or she arrived at the appointment. If another person brought the patient, nothing further needs to be done except to document that you ascertained that the person would not be driving. If the patient arrived by public transportation, the patient cannot be permitted to leave until he or she is sober enough to safely manage on his or her own. If the patient drove to your office, tell the person that it is not safe for him or her to drive away. Ask the patient to give you the phone number for someone who can be called to come to pick the patient up, or offer the patient a seat in the waiting room until he or she is no longer intoxicated. If the patient leaves with the intent of driving away, if possible have a staff member escort the patient out and observe which car the patient drives. This should be reported to the police. This is not in violation of the Code of Federal Regulations Title 42 (66 Federal Register 4076–4102) because

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•

•

177

you will not tell the police why the individual was at your office, only that he or she may be intoxicated while driving. No other information should be given out regarding the patient’s history. If the person is grossly intoxicated, hospitalization may be required, even on an involuntary basis. The physician can be held responsible for permitting a grossly impaired individual to leave before the person is deemed sober enough to safely manage on his or her own. Document the interaction thoroughly.

Having said all of this is precautionary. I have worked for 18 years in substance abuse treatment settings and the situation where the police were informed of a possible intoxicated driver has occurred only once. Furthermore, individuals who wish to obtain buprenorphine-naloxone for treatment of opioid dependence are generally quite cooperative and eager to get treatment and will do whatever is asked of them. This information is detailed only because it is a potential liability for the physician should it occur, and how the clinician will handle such situations should be considered before engaging in this form of treatment.

MANAGING PATIENTS WHO SHOW UP IN ACUTE W ITHDRAWAL It is also possible that an opioid-addicted patient will show up for the first appointment in withdrawal, expecting treatment to begin with the first visit. This can generally be avoided by informing the patient before the first appointment that the patient will not receive treatment on the first visit. Make sure that staff members explain that the first visit is to determine whether the patient should be treated with buprenorphine-naloxone (or whether another form of treatment for opioid dependence would be more appropriate) and whether the patient has any other physical or mental health problems that might need a higher level of care than can be provided in the physician’s office. If the patient is not an appropriate candidate for the services that the physician offers, the patient should be given a referral to another treatment provider in the community. In my practice, patients are also given a copy of any laboratory results to take to another provider. This can help to inform the next provider about the patient and reduce the cost of care by avoiding a repeat of laboratory tests. If a patient does show up in withdrawal, it should be reiterated that treatment will not occur on that visit. An adequate, comprehensive evaluation cannot be completed when a patient is either intoxicated or in the midst of severe withdrawal. The appointment should be rescheduled for the patient to come back at a time when he or she can be assessed appropriately.

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Managing Co-Occurring Psychiatric Disorders GUIDELINES 1. Do not assume that a patient with an independent psychiatric disorder cannot be treated in an office-based practice setting or is not a candidate for buprenorphine treatment. 2. Determine the severity of the psychiatric disorder and the patient’s treatment needs to decide whether office-based treatment of opioid dependence is in the best interest of the patient. 3. Always insist on psychosocial therapies in conjunction with buprenorphine-naloxone treatment. 4. Nonpsychiatrists should have a psychiatry colleague with experience in addiction psychiatry assist with the evaluation as needed. 5. Refer the patient for any other indicated mental health services that can be given in the most appropriate treatment setting. Be sure to obtain signed information release forms so you can communicate with all treatment providers, to ensure that all are aware of the patient’s condition at any point in time. Use of the above guidelines will help the physician think through which patients with independent psychiatric disorders can be managed in the physician’s practice and under what conditions such patients should be treated. Not all independent psychiatric disorders dictate treatment by a psychiatrist. A patient with uncomplicated major depression, for example, might be managed by a primary care physician, whereas a clear history of bipolar disorder is an indication for treatment by a psychiatrist with experience in the treatment of substance use disorders. The patient’s history will help the physician develop the best treatment plan for the patient. It must be strongly emphasized that all patients (with or without co-occurring mental illness) who receive office-based treatment of opioid dependence with buprenorphine-naloxone require ancillary counseling (see Chapters 7 and 8). Counseling is a critical part of addiction treatment as well as treatment for other psychiatric disorders. Many studies have shown that physician advice with pharmacotherapy alone is not sufficient for effective treatment of these disorders. For uncomplicated addiction, group therapy addressing addiction and recovery issues is the minimal additional treatment. If no group therapy is available in the physician’s community, then individual counseling is required. For those with additional psychopathology, individual therapy is generally indicated and specialized group therapy for those with the same co-occurring

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disorder is beneficial. For many years, there was no consensus on the appropriate management of these patients. The standard professional therapies (cognitive-behavioral therapy, motivation enhancement therapy, and 12-step facilitation) were designed for patients with no co-occurring conditions, and professionals disagreed on the sequencing and coordination of treatments for these patients. Making the situation even more problematic, patients with cooccurring conditions were often excluded from standard treatment programs. In the last decade, new treatment models have been developed to remedy this problem. One of the most successful new evidence-based approaches for treating dual-diagnosis patients is the Seeking Safety protocol (Najavits 2002). Originally conceived as a 25-session, manual-guided group therapy to provide integrated treatment for women with PTSD and co-occurring substance use disorders, Seeking Safety has proved highly useful for the treatment of both men and women with a wide variety of co-occurring psychiatric and substance use disorders. Seeking Safety combines elements of cognitive-behavioral therapy that have been shown to be effective treating substance use disorders and other psychiatric conditions. It focuses specifically on safety issues such as avoiding substance use, sexual acting out, and circumstances likely to risk repetition of traumatic events. Given the high incidence of PTSD and other psychiatric disorders in opioid-dependent individuals, clinicians planning to provide buprenorphine treatment should attempt to identify therapists in their community who are trained in the Seeking Safety protocol and should establish appropriate referral relationships. Many patients benefit also from referral to 12-step groups, although some 12-step groups may be less accepting of medication therapy for addiction than others. Groups that do not accept the concept of medication treatment for substance use disorders (and/or psychiatric disorders) can actually be detrimental to the patient by discouraging adherence to needed treatment. The physician should attempt to identify groups in the community that are supportive of patients taking medication and should encourage patients to participate actively. Office-based treatment of opioid dependence should not be started in any patient who is unwilling to obtain ongoing counseling. The aberrant behaviors that characterize addiction are not treated by any medication and require ongoing counseling to help the patient gain insight into his or her disease. Patients with more severe psychiatric disorders should be considered for treatment programs that provide greater structure, at least initially. Two possibilities are discussed briefly here: 1. For a patient who does not appear to be a good candidate for office-based treatment of opioid dependence but is felt to need opioid agonist therapy, referral to methadone maintenance programs is the best option. Methadone maintenance programs provide much more structure than office-based treat-

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ment. Federal regulations limit the amount of take-home medication that can be provided in methadone maintenance programs, with relatively few doses available in the early treatment period. Many methadone programs provide medical and psychiatric care for patients with co-occurring disorders, and thus make it possible for a patient to obtain treatment for multiple problems in one treatment setting. Methadone maintenance programs provide observed methadone dosing and may also provide observed dosing of other prescribed medications (e.g., psychotropic medications, antiretroviral medications, tuberculosis medications), making methadone maintenance a potentially better choice for patients with a history of difficulty adhering to prescribed regimens. 2. Buprenorphine-naloxone doses may also be administered in some intensive outpatient programs, eliminating the need for take-home medication. Thrice-weekly dosing of buprenorphine-naloxone has been shown to be effective in the treatment of opioid dependence (Schottenfeld et al. 2000) and can provide a means of delivering both substance abuse and psychiatric treatment to patients.

MANAGEMENT OF SPECIFIC PSYCHIATRIC ISSUES: WHO SHOULD PRESCRIBE? As mentioned above, the decision regarding who should be the prescribing physician for patients needing psychotropic medication depends on each physician’s level of expertise in managing psychiatric disorders. If a physician is uncomfortable treating co-occurring mental disorders, other options include referral to a psychiatrist who can provide all necessary care, or a referral to a psychiatrist who can treat the non–substance use mental disorders in conjunction with the physician prescribing buprenorphine-naloxone. Alternatively, patients can be referred to a program that specializes in the treatment of cooccurring disorders.

WHEN

TO

REFER

OR

HOSPITALIZE

Acute Suicidal Ideation Any patient receiving treatment for opioid dependence in an office-based practice must have a way to contact the treating physician (or covering physician) 24 hours a day, 7 days per week. Patients should be informed that acute suicidal ideation is a reason to call the treating physician. Critical elements in the evaluation of suicidal ideation are listed in Table 9–1. Patients with suicidal ideation having intent and a plan should be admitted to an inpatient facility that

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can provide constant care and observation. Such a referral generally begins with an evaluation either in the treating physician’s office or in the local hospital emergency department. If the patient is being interviewed on the telephone, it is important to get information from the patient about his or her current location and whether any supportive individuals are present, in case the patient refuses an evaluation that the physician believes to be indicated. In such a case, significant others can be enlisted to assist the patient or the police can be asked to intervene to help get the individual to an emergency department where the safety of the patient can be addressed. A patient without the intent or a plan to commit suicide may need more frequent visits to provide support and structure while working through the difficulties contributing to the suicidal thoughts. Such episodes require an updated treatment plan and possible reevaluation to determine whether office-based treatment of opioid dependence continues to be appropriate for the patient.

Acute Homicidal Ideation As with suicidal ideation, the occurrence of acute homicidal ideation requires immediate attention from the physician. The assessment is similar to that described for acute suicidal ideation. Patients experiencing homicidal ideation may require an inpatient level of care for their safety and for the safety of others. If there is an identified intended victim and the physician believes the threat to be serious and imminent, the physician has a duty to warn the intended victim. It is important to have such a patient admitted to the hospital for a more thorough evaluation and consultation with a treatment team and legal experts to determine the most appropriate course of action. Again, such patients will require reevaluation to determine whether they are appropriate candidates for continued office-based treatment of opioid dependence.

ADHERENCE

TO

PRESCRIBED MEDICATIONS

It is difficult to successfully treat a patient who does not take medications as prescribed. There are two immediate issues that can arise in office-based treatment of opioid dependence with buprenorphine-naloxone. The first is that of prescribing more medication than is needed, resulting in misuse or diversion. The second is deliberate nonadherence on particular days so that opioid abuse will provide the euphoria being sought. In the former case, it is worth emphasizing that 16 mg of buprenorphine daily has been shown to bind to 79%–95% of µ opioid receptors (Greenwald et al. 2003, 2007). Therefore, one needs to question why a patient would need dosages higher than those typically recommended for the treatment of opioid dependence (using the combination buprenorphine-naloxone tablets, 12 mg buprenorphine/3 mg naloxone daily or

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16 mg buprenorphine/4 mg naloxone daily) and whether a higher dosage is really providing a therapeutic response. Further, the long half-lives of buprenorphine and its active metabolite, norbuprenorphine (Zhang et al. 2003), mean that the drug requires at least 12 days of use to reach steady-state levels. Therefore, dosage changes in close succession are not indicated. To address cases in which the patient reduces the dosage of or stops taking the medication for a day or two in order to abuse opioids (buprenorphine-naloxone can blunt the effect of other abused opioids), it may be helpful to ask patients to periodically bring in their prescription bottles so that the pills can be counted. This will provide additional evidence as to whether the medication is being taken as prescribed. Urine toxicology screens are not sufficient because although the buprenorphine metabolite will be detected, this does not tell the clinician how much of the drug is being taken. It is also important to ascertain whether the patient is taking prescribed psychotropic medication as well (see the section “Pharmacotherapy” later in this chapter). For patients whose psychiatric conditions do not improve, it is important to consider whether the prescribed medication is not being taken or is not being taken as prescribed. It is necessary to address these issues directly with the patient—the patient may be experiencing side effects that he or she finds intolerable, but which the patient may not mention unless asked. The patient may also lack insight into his or her psychiatric condition and not wish to take psychotropic medication. It may also be helpful to ask the patient to bring in prescribed psychotropic medications so that those pills can be counted because this will help to determine whether the patient is adherent. It is also important to determine whether other substances are being abused by the patient who is nonadherent with prescribed medications. Undetected substance abuse can lead to nonadherence and poor treatment outcomes.

COMPLIANCE WITH PSYCHOTHERAPEUTIC INTERVENTIONS Some patients with substance use disorders are quite resistant to participating in psychosocial therapies that support the pharmacotherapy being provided by the physician. Substance abuse is a disorder of behavior. Opioid abuse produces physical dependence that can be effectively treated with long-acting opioids. However, although physical dependence (and the associated withdrawal) may be at the top of the list of problems the patient wants addressed, the bottom line is that addiction is characterized by aberrant behaviors that spill over into many facets of life. These problems can be best addressed in psychotherapy, counseling, and/or participation in self-help groups like Alcoholics Anonymous or Narcotics Anonymous. For most patients, medication alone is not

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enough to treat the addiction. If the patient requires counseling or psychotherapy but the treating physician is not able to provide it, the physician should refer the patient to another clinician who can provide that intervention (see Chapters 7 and 8).

CONTINUED SUBSTANCE ABUSE When patients with opioid dependence enter any treatment setting, but particularly when they enter less structured, office-based treatment, one question that always arises is what to do if abuse of substances continues. The first thing to understand is that in addicted patients it is commonplace for substance abuse to occur at least sporadically, particularly in the initial phases of treatment. Most patients will “test” buprenorphine-naloxone to determine what occurs when they use opioids again (most find that they do not get the effect that they are accustomed to). Furthermore, most addicted patients need time to stabilize in treatment before they are able to stop abusing other drugs and/or alcohol. This fact underscores the importance of several components of treatment. Psychosocial therapies are important to help patients discontinue the behaviors that place them at risk for relapse and to help them develop more adaptive coping mechanisms. Psychoeducation is important to inform the patient about the possibility of adverse drug interactions and the side effects of buprenorphinenaloxone. Once the patient’s condition stabilizes with buprenorphine-naloxone, and the patient is established in the psychotherapeutic environment recommended, it will be easier for him or her to stop abusing drugs and alcohol. It is also important to undertake regular, but random, urine drug screening so that ongoing substance use can be followed (for a patient with a history of alcohol abuse, ethyl glucuronide will provide information about recent alcohol use, but this test is not currently available as an immunoassay on a dipstick). Each patient needs to be individually evaluated, and a patient with chronic, unremitting substance use will likely need to be referred to a higher level of care. This might include hospitalization for medical withdrawal from other substances or to stabilize co-occurring psychiatric disorders. For a patient with less severe problems, but ongoing substance abuse, referral to a more structured program such as methadone maintenance or an intensive outpatient treatment program may be indicated.

PHARMACOTHERAPY A frequently asked question regarding the treatment of patients with co-occurring opioid dependence and psychiatric disorders is whether they can be treated with the standard psychiatric treatments that have an evidence base, but were obviously not developed for patients with opioid dependence and those receiving buprenor-

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phine-naloxone treatment. The simple answer to this question is that there is no evidence base for treatment of psychiatric disorders in this population. On the other hand, there is no evidence that standard treatments are not effective. Therefore, with a few caveats, standard pharmacotherapy and psychotherapy interventions should be utilized in the treatment of mental disorders in patients with opioid dependence who receive buprenorphine-naloxone pharmacotherapy.

Major Depression and Anxiety Disorders In the treatment of major depression and anxiety disorders, the first-line treatments are selective serotonin reuptake inhibitors (SSRIs). These drugs are better choices for treating the anxiety disorders than benzodiazepines, which if injected, have resulted in deaths and can also be used to “bump” the effect of buprenorphine-naloxone or methadone. Although adverse events with the use of SSRIs have not been reported, several SSRIs may result in drug-drug interactions, at least hypothetically (see the section “Drug Interactions With Buprenorphine” later in this chapter); therefore, when possible, other choices should be made. If the SSRIs are found to be ineffective, then the selective norepinephrine reuptake inhibitors or bupropion may be tried. The tricyclic antidepressants may be effective in some patients, but their use requires greater monitoring for side effects.

Attention-Deficit/Hyperactivity Disorder Pharmacotherapy for ADHD requires careful consideration in any individual with a substance abuse history. ADHD medications generally should be started after the patient has had a period of abstinence from illicit drugs and the diagnosis has been reconfirmed. Because of concerns about diversion and misuse— and given that some stimulants in combination with opioids produce a “speedball” effect (Foltin and Fischman 1994) (i.e., a combination of stimulant and central nervous system depressant effects that some individuals find very reinforcing and prefer to either class of drugs alone)—unless the patient has a welldocumented history of childhood-onset ADHD that has responded positively to treatment with stimulants, it is recommended that nonstimulants such as atomoxetine or bupropion be prescribed for patients receiving buprenorphinenaloxone. Extended-release stimulants can be considered in well-stabilized buprenorphine recipients, but such patients should be observed carefully for the emergence of euphoria or other behaviors suggestive of medication abuse.

Insomnia Another common complaint with any substance-abusing patient, including opioid-addicted patients, is disrupted sleep. Many ask for sleep medication. It

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has become commonplace for physicians to prescribe some atypical antipsychotics for this purpose. In general, the antipsychotics have enough major adverse side effects that they should be avoided except for their approved indication(s). Quetiapine is sometimes prescribed for sleep, but its metabolism by cytochrome P450 3A4 (CYP3A4)—which is also the main means for buprenorphine metabolism—could hypothetically alter metabolism of both drugs. Quetiapine is also a sedating medication that may have a pharmacodynamic interaction with buprenorphine. Quetiapine also has been reported to be abused by some (Hanley and Kenna 2008). Sleep hygiene techniques should be taught to all opioid-dependent patients and avoidance of sleep medications should be the standard. If the problem is so severe that prescribed medication is needed, small amounts of diphenhydramine, trazodone, or ramelteon can be tried for brief periods. However, it is important to not prescribe medication for every complaint because this feeds into the pathology of the addict.

Drug Interactions With Buprenorphine Remarkably little information is available on pharmacokinetic and pharmacodynamic interactions between buprenorphine and other drugs. Most of the studies to date have examined the interaction of buprenorphine with HIV medications (McCance-Katz et al. 2006a, 2006b, 2007) or have compared the extent of interactions between HIV medications and methadone or buprenorphine (McCance-Katz 2005). Buprenorphine is predominantly a substrate of the CYP3A4 isoenzyme. Therefore, drugs that alter CYP3A4 function might alter buprenorphine and, to a lesser extent, methadone exposure and thus their effectiveness in the treatment of opioid dependence. However, buprenorphine has an advantage in its clinical pharmacology that methadone does not have: methadone is metabolized to an inactive metabolite, whereas buprenorphine is metabolized to norbuprenorphine, which is also a µ opioid receptor agonist. In the presence of drugs that can induce buprenorphine metabolism, this can help to prevent the onset of withdrawal, which has been observed with methadone and some drugs that induce CYP3A4 enzymes. However, this effect remains to be demonstrated adequately. With some HIV medications that induce CYP3A4 enzymes, buprenorphine-treated study participants have not experienced withdrawal symptoms, although it is worth noting that these studies have been short in duration. With clinical treatment results may differ, and patients taking drugs that alter CYP3A4 function need to be monitored for adverse effects. The anticonvulsant medication often used as a mood stabilizer, carbamazepine, can induce the CYP3A4 enzyme system. When possible, the

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choice of another mood-stabilizing drug such as valproate might be a better choice in patients treated with buprenorphine-naloxone. Some drugs have the potential to inhibit buprenorphine metabolism by inhibiting the action of CYP3A4. There has been a case report of cognitive impairment in patients with HIV disease treated with atazanavir plus ritonavir (Bruce and Altice 2006), and buprenorphine and norbuprenorphine levels were significantly increased in those receiving that drug combination (McCanceKatz et al. 2007). Again, patients receiving treatment with medications that might inhibit buprenorphine metabolism should be observed and monitored for adverse opioid effects. Psychotropic medications known to inhibit CYP3A4 include fluvoxamine and nefazodone. There may also be drugs that do not have a direct effect on buprenorphine metabolism, but that may have a pharmacodynamic interaction with buprenorphine. For example, the benzodiazepine diazepam has been shown to be associated with increased sedation and memory deficits when given in combination with buprenorphine. Sedating drugs should be avoided when possible in the patient being treated with buprenorphinenaloxone (or methadone, for that matter). Finally, buprenorphine is not itself known to alter drug metabolism and has not been found, to date, to substantially alter exposure to other drugs taken concomitantly. Because of its clinical pharmacology, buprenorphine may be a better choice than methadone for opioid agonist therapy in patients who must also take other medications for cooccurring conditions.

Conclusion Mental illness occurs frequently in opioid-addicted patients. The safe and effective treatment of these patients requires thorough patient evaluation, differentiation of substance-induced versus independent mental disorders, and institution of the most appropriate treatment for all current mental disorders in the most appropriate clinical setting. Buprenorphine-naloxone treatment can be undertaken in patients with co-occurring psychiatric disorders, but for some severely ill patients the best care for opioid dependence and other co-occurring psychiatric disorders is a setting other than a physician’s office-based practice. The considerations and practices outlined in this chapter will help physicians help patients to engage in the most effective treatment interventions for these complex illnesses.

Clinical Pearls • Evaluate and provide treatment for all of the substance abuse problems that the patient has. It is relatively rare to evaluate an

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opioid-addicted patient who has no other substance-related problems. Failure to treat all of the patients’ substance abuse problems places them at high risk for relapse. • Differentiate substance-induced from independent psychiatric disorders because the former resolve with treatment of opioid addiction whereas the latter require a specific treatment plan that often includes use of psychotropic medications. • Opioid-dependent patients with co-occurring psychiatric disorders respond to the standard first-line treatments for these conditions. • Avoid the use of medications with abuse liability in opioid-addicted patients (e.g., quetiapine and benzodiazepines). There are other first-line medications for anxiety disorders that do not have abuse liability. Patients resistant to such medications and/or insistent on prescription of controlled substances should be carefully evaluated to determine whether their behaviors are drug seeking rather than symptoms of a co-occurring psychiatric disorder. • Consider the possible drug interactions that might occur when buprenorphine or methadone are prescribed to treat opioid dependence (for review, see McCance-Katz et al. 2010). • Know the referral sources in your community before you start office-based treatment of opioid dependence.

CASE 5

(CONTINUED

FROM

CHAPTER 8)

Henrietta, the 43-year-old auto mechanic who said “drinking has never been a problem,” has not paid her bill for a month. She has cut back on her drinking and has been attending group psychotherapy meetings weekly while maintaining negative urine toxicology screens. Today, when she arrives at the office she is belligerent, and it is very clear that she is intoxicated with alcohol.

1. How would you expect your staff to treat her? 2. She refuses to be admitted for alcohol detoxification and insists on driving herself home. How would you respond? 3. How do you address the nonpayment issue?

CASE 6 Maria is a 31-year-old single woman who is referred to your office with the chief complaint: “My work Employee Assistance Program wants me to get an evaluation.” She is a talented graphics design artist but has been reported as “erratic” and “hotheaded” at work.

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The Employee Assistance Program office reports that two urine tests have been positive for opioids. She admits to using heroin from time to time but refuses to go into detail—“I’m not hurting anybody.” She insists that her only problem is controlling her temper. After you obtain another positive urine test result, she admits that her heroin use is out of control and agrees to buprenorphine treatment and weekly group therapy. Her buprenorphine induction goes smoothly, but during her first group session she engages in a heated argument with several group members and then reveals that she was molested repeatedly as a child.

1. Should this patient have a psychiatric evaluation? What is the most likely diagnosis or diagnoses? 2. Would a more specialized type of therapy group or individual counseling be useful? 3. In this case, would you consider motivation enhancement therapy? 4. Is the Seeking Safety program a better option for this patient?

CASE 7 Karen is a 28-year-old woman who has been gainfully employed as a receptionist for the past year. She started using opioids in her teens and eventually became addicted to intravenous heroin. She has been taking buprenorphine for 2 years. Karen had a few problems with opioids and benzodiazepines during the first year of treatment but sustained sobriety has been the trend for the past 12 months. She calls, very upset: “They closed our office and fired everyone!” She has been living in a drug- and alcohol-free residential facility in the community but now has to leave because she can no longer afford the rent. Fortunately, she is able to move in with a sober woman friend from Narcotics Anonymous, but she is feeling anxious and discouraged. She says: “I’m scared of becoming homeless, and I think I’m depressed again.” She carries the diagnosis of major depressive disorder and generalized anxiety disorder, for which she takes citalopram and trazodone.

1. What helps determine whether her psychiatric symptoms are secondary to her opioid use or represent independent psychiatric disorders? 2. What elements of her history would clarify this diagnostic question? 3. Would you change her psychiatric medications at this time? 4. Given her dual diagnosis, would she be manageable in your office setting? 5. Does it matter which antidepressant is used? 6. If she reports clear evidence of a panic attack would you consider adding a benzodiazepine? 7. In what ways might benzodiazepines be a problem in this case?

CASE 8 You cover the psychiatric service for a community hospital on some weekends. When you get to the emergency department, you are asked to evaluate a 28-

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year-old Iraq combat veteran for suicidal ideation. He says that he “can’t live like this” any longer. He has been taking 3–4 OxyContin 80-mg pills daily for the last 4 months, has been unable to stop, and now realizes that he is addicted. You determine that he meets the threshold for active risk of self-harm and you admit him to the hospital. During your evaluation, you find that he also meets all of the DSM-IV-TR criteria for PTSD. He also says that he has anger issues about his war experience and sometimes “wants to take everybody out....”

1. How do you determine whether the suicidal ideation is secondary to his drug problem or related to his PTSD? How should this be handled? 2. Would you recommend inpatient detoxification or would you consider him a candidate for opioid agonist therapy? 3. How do you address his homicidal language? 4. Is buprenorphine a reasonable choice? 5. How will you incorporate treatment for PTSD into his treatment plan?

References 66 Federal Register 4076–4102/Vol 66, No 11, Wednesday, January 17, 2001/Rules and Regulations: Opioid drugs in maintenance and detoxification treatment of opiate addiction; final rule, part II. Department of Health and Human Services, 42 CFR Part 8, RIN 0910-AA52 American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision. Washington, DC, American Psychiatric Association, 2000 Bruce RD, Altice FL: Three case reports of a clinical pharmacokinetic interaction with buprenorphine and atazanavir plus ritonavir. AIDS 20:783–784, 2006 Centers for Disease Control and Prevention (CDC): Mental health in the United States: prevalence of diagnosis and medication treatment for attention-deficit/ hyperactivity disorder—United States, 2003. MMWR Morb Mortal Wkly Rep 54:842–847, 2005 Faraone SV, Wilens TE, Petty C, et al: Substance use among ADHD adults: implications of late onset and subthreshold diagnoses. Am J Addict 16 (suppl 1):24–32; quiz 33–34, 2007 Foltin RW, Fischman MW: Effects of buprenorphine on the self-administration of cocaine by humans. Behav Pharmacol 1994;5(1):79–89, 1994 Greenwald MK, Johanson CE, Moody DE, et al: Effects of buprenorphine maintenance dose on mu-opioid receptor availability, plasma concentrations, and antagonist blockade in heroin-dependent volunteers. Neuropsychopharmacology 28:2000–2009, 2003 Greenwald M, Johanson CE, Bueller J, et al: Buprenorphine duration of action: muopioid receptor availability and pharmacokinetic and behavioral indices. Biol Psychiatry 61:101–110, 2007 Hanley MJ, Kenna GA: Quetiapine: treatment for substance abuse and drug of abuse. Am J Health Syst Pharm 65:611–618, 2008 McCance-Katz EF: Treatment of opioid dependence and HIV/HCV co-infection in opioid dependent patients: the importance of drug interactions between opioids and antiretroviral medications. Clin Infect Dis 41:S89–S95, 2005

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McCance-Katz EF, Moody DE, Morse GD, et al: Interactions between buprenorphine and antiretrovirals: I: the nonnucleoside reverse-transcriptase inhibitors efavirenz and delavirdine. Clin Infect Dis 43 (suppl 4):S224–S234, 2006a McCance-Katz EF, Moody DE, Morse G, et al: Interactions between buprenorphine and antiretrovirals: II: the protease inhibitors nelfinavir, lopinavir/ritonavir, and ritonavir. Clin Infect Dis 43 (suppl 4):S235–S246, 2006b McCance-Katz EF, Moody DE, Morse GD, et al: Interaction between buprenorphine and atazanavir or atazanavir/ritonavir. Drug Alcohol Depend 91:269–278, 2007 McCance-Katz EF, Rainey PM, Moody DE: Effect of cocaine use on buprenorphine pharmacokinetics in humans. Am J Addict 19:38–46, 2010 Najavits LM: Seeking Safety: A Treatment Manual for PTSD and Substance Abuse. New York, Guilford, 2002 Najavits LM, Weiss RD, Shaw SR: The link between substance abuse and posttraumatic stress disorder in women: a research review. Am J Addict 6:273–283, 1997 Regier DA, Boyd JH, Burke JD Jr, et al: One-month prevalence of mental disorders in the United States: based on five Epidemiologic Catchment Area sites. Arch Gen Psychiatry 45:977–986, 1988 Schottenfeld RS, Pakes J, O’Connor P, et al: Thrice-weekly versus daily buprenorphine maintenance. Biol Psychiatry 47:1072–1079, 2000 Substance Abuse and Mental Health Services Administration: Results From the 2008 National Survey on Drug Use and Health: National Findings (Office of Applied Studies, NSDUH Series H-36, DHHS Publ No SMA 09-4434). Rockville, MD, Substance Abuse and Mental Health Services Administration, 2009. Available at: http://www.oas.samhsa.gov/nsduh/2k8nsduh/2k8Results.cfm. Accessed April 29, 2010. Wilens TE, Adamson J, Monuteaux MC, et al: Effect of prior stimulant treatment for attention-deficit/hyperactivity disorder on subsequent risk for cigarette smoking and alcohol and drug use disorders in adolescents. Arch Pediatr Adolesc Med 162:916–921, 2008 Zhang W, Ramamoorthy Y, Tyndale RF, et al: Interaction of buprenorphine and its metabolite norbuprenorphine with cytochromes p450 in vitro. Drug Metab Dispos 31:768–772, 2003

10 Medical Management Jeanette M. Tetrault, M.D. Lynn E. Sullivan, M.D. David A. Fiellin, M.D.

OPIOID-DEPENDENT patients who present for treatment often have other medical problems. These medical conditions can result from both past and current high-risk behaviors. For instance, both injection and noninjection drug use are associated with infectious complications. It is important for clinicians who treat opioid-dependent patients with buprenorphine to screen for and treat (or refer for treatment of ) common comorbid medical conditions. Office-based buprenorphine treatment provides the opportunity to integrate the delivery of substance abuse treatment with screening for and treatment of comorbid medical conditions. In addition, this setting allows the clinician to discuss appropriate preventive measures pertinent for this patient population. The purpose of this chapter is to provide the clinician with an overview of the approach to the medical treatment of patients with opioid dependence, to discuss common comorbid medical conditions found in opioid-dependent patients, and to review the features of preventive health care for these patients. Additionally, the clinician must consider potential interactions of buprenorphine with some medications used in the treatment of comorbid medical conditions. It is important to know about these topics because integration of 191

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screening and treatment of these comorbidities with office-based buprenorphine can improve the health of patients being treated with buprenorphine. We address the following topics in this chapter: admission procedures and referral to primary care; routine preventive care; comorbid hepatitis B, hepatitis C, HIV infection/AIDS, and tuberculosis; and buprenorphine treatment in special populations. A case is presented at the end of this chapter, including related questions for additional consideration. For discussion of this case, please see Chapter 14, “Comments on the Case Vignettes.”

Admission Procedures and Referral to Primary Care All patients with opioid dependence should have a medical history taken before treatment initiation. At this visit, the clinician should review the patient’s medical, surgical, psychiatric, and substance use history; medication list; prior substance abuse treatment; and the basic support systems the patient has in place. Clinicians should have the ability to perform, or refer the patient for, a targeted or complete physical examination with attention to potential stigmata of drug use—with careful inspection of skin and soft tissue (especially at sites of injection), lymph node examination, assessment of liver size and contour, cardiac examination with auscultation for murmurs, and a full neurological exam. Because of potential buprenorphine-related hepatotoxicity and the high prevalence of hepatitis in opioiddependent patients, liver function tests should be performed at baseline; if enzyme levels are elevated, liver function should be monitored throughout the course of treatment (Berson et al. 2001a, 2001b; Fudala et al. 2003; Petry et al. 2000). Clinicians should also take this time to review the options for the treatment of opioid dependence with the patient. This discussion should review principles of detoxification versus maintenance therapy as well as reviewing all pharmacological and nonpharmacological approaches to the treatment of opioid dependence (Fiellin and O’Connor 2002). Any patient with chronic underlying medical conditions or a new diagnosis of an acute or chronic infection should be referred for ongoing primary care. Patients with chronic pain and opioid dependence may also present unique challenges and require a primary care or more specialized referral (see Chapter 11, “Management of Acute and Chronic Pain”).

Routine Preventive Care The clinician should consider testing for hepatitis B virus (HBV) infection, hepatitis C virus (HCV) infection, latent tuberculosis infection (LTBI), and

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syphilis in all patients with opioid dependence. The Centers for Disease Control and Prevention (CDC) recently released guidelines that all patients between the ages of 13 and 64 years should be tested for HIV infection in an opt-out fashion (Bartlett et al. 2008). Patients who have not been exposed to or vaccinated against HBV should receive the hepatitis B vaccination series. The recommended vaccination schedule is a series of three shots administered at age 0, 1, and 6 months (Advisory Committee on Immunization Practices 2009). Patients with underlying liver disease or HCV infection should be vaccinated against the hepatitis A virus if they have not been exposed or immunized previously. Hepatitis A and hepatitis B vaccinations may be administered using a combination formulation, Twinrix. Patients may be offered vaccination against influenza yearly and receive a tetanus-diphtheria booster every 10 years, and at least one dose should be a tetanus-diphtheria-pertussis vaccine (Advisory Committee on Immunization Practices 2009). Recent guidelines suggest that all smokers should receive the pneumococcal vaccine once before age 65 and once after that (Kuehn 2008).

Hepatitis B EPIDEMIOLOGY HBV is an important cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma, leading to one million deaths per year worldwide. In the United States, there are 1.25 million individuals with chronic HBV infection and approximately 300,000 new HBV infections per year; 15,000–30,000 of the latter progress to chronic infection each year, and 2–3 patients per 1,000 die annually secondary to fulminant hepatitis (Dienstag 2008; Imperial 1999). Approximately 25% of carriers develop chronic active hepatitis, which in most cases leads to cirrhosis (“Protection Against Viral Hepatitis” 1990). Acute liver failure develops in approximately 1% of patients with acute HBV infection (Lee 1993). HBV infection is contracted primarily via blood or other bodily fluids. Although vertical transmission from mother to child is a significant risk factor worldwide, it plays a less important role in the United States. The majority of the cases in the United States are secondary to sexual contact (41%) or injection drug use (15%), with occupational exposure, hemodialysis, household contact with an infected person, blood transfusion, and organ transplantation constituting the less common sources of infection. With injection drug use being a major risk factor for the transmission of HBV, as seen with HCV infection, there was a 70%–85% decrease in the number of cases of acute HBV from 1989 to 1993 (Centers for Disease Control and Prevention

194 Handbook of Office-Based Buprenorphine Treatment of Opioid Dependence

2005). Still, it is estimated that 50% of active injection drug users have serological evidence of prior exposure to HBV, and the majority of these cases show evidence of active viral infection. In addition, approximately 50% of injection drug users were exposed to HBV within the first year of injecting drugs (Garfein et al. 1996).

LABORATORY DIAGNOSIS All patients with symptoms consistent with hepatitis or with risk factors for the development of hepatitis B should be tested. Typical screening includes liver function tests and hepatitis serologies including serology for hepatitis A, B, and C. With hepatitis B, liver function tests typically reveal elevated transaminase levels, with the alanine aminotransferase (ALT) level being greater than the aspartate aminotransferase (AST) level. The peak levels of these enzymes typically precede the onset of jaundice. Transaminase levels usually return to the normal range once the acute illness resolves. As shown in Figure 10–1, serologies used to test for hepatitis B include serologies for hepatitis B surface antigen (HBsAg), for antibody to HBsAg (antiHBs), and for immunoglobulin M antibody to hepatitis B core antigen (IgM anti-HBc). The presence of HBsAg in the serum can indicate either acute or chronic infection. HBsAg is detected in the serum as early as 1 week to as late as 12 weeks after exposure to the virus (Younossi 2000). HBsAg typically clears within 3–6 months in individuals whose condition does not progress to chronic infection, and the loss of HBsAg and the appearance of anti-HBs signals recovery and protective immunity from reinfection (Ganem and Prince 2004; Lee 1993). Anti-HBs can be seen both in cases of recovery from acute infection and in cases of HBV vaccination (Lee 1993). Detection of IgM anti-HBc indicates acute infection and usually coincides with elevation in the transaminase levels. This antibody is typically found in the serum at the time of onset of clinical symptoms and then disappears within 6 months. IgM anti-HBc, which persists permanently as an indicator of past infection, does not confer protective immunity as anti-HBs does (Lee 1993). The HBV e antigen (HBeAg), HBV DNA, and virion DNA polymerase are also early markers of infection; they appear in the serum within days of the appearance of HBsAg, signify active viral replication and increased infectivity, and may be undetectable at the time of peak clinical illness (Lee 1993). Antibody to HBeAg (anti-HBe) develops in most cases and indicates the loss of actively replicating virus and decreased infectivity.

ACUTE HBV INFECTION Approximately 25% of people infected with HBV present with symptoms—typically nausea, fatigue, malaise, and anorexia—followed by jaundice (Davis 1997;

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Symptoms HBeAg

Anti-HBe

Titer

Total anti-HBc

HBsAg

0

4

IgM anti-HBc

8

12

16

20

24

28

32

Anti-HBs

36

52

100

Number of weeks after exposure FIGURE 10–1.

Hepatitis B serology.

Anti-HBc =antibody to hepatitis B core antigen (HBcAg); anti-HBe=antibody to hepatitis B envelope antigen (HBeAg); anti-HBs=antibody to hepatitis B surface antigen (HBsAg); IgM anti-HBc =immunoglobulin M antibody to HBcAg. Source. Courtesy of Centers for Disease Control and Prevention, Division of Viral Hepatitis.

Imperial 1999; Younossi 2000). The onset of symptoms is insidious, with malaise being the earliest and most common complaint reported by patients. Jaundice is reported as a clinical sign in approximately 80% of cases. Other signs and symptoms include vomiting, headache, fever, arthralgias, abdominal or right upper quadrant pain, hepatomegaly, and, less commonly, splenomegaly.

CHRONIC HBV INFECTION In patients with HBV, the risk of chronic infection and the likelihood of symptoms correlate, in part, with the patient’s age. Of adults infected with HBV, 30%– 50% exhibit symptoms. In contrast to adults with HCV infection, the majority of adults with acute HBV infection recover from infection, with clearance of HBsAg from the blood and the development of the antibody to the surface antigen (anti-HBs); and a much smaller percentage, only 2%–10%, progress to chronic infection (Centers for Disease Control and Prevention 2005). The progression from acute to chronic infection is related to viral factors and the mode of acquisition, as well as host factors such as the individual’s age and immune status (Fattovich et al. 1991). The definition of a chronic carrier

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is a person who has detectable levels of HBsAg documented at least 6 months apart, or who has detectable HBsAg with no evidence of IgM anti-HBc antibody (“Protection Against Viral Hepatitis” 1990). In contrast to patients with acute HBV infection, patients with chronic HBV infection may complain of nonspecific symptoms such as fatigue or malaise, but typically are relatively asymptomatic unless they exhibit signs of cirrhosis or end-stage liver disease.

PREVENTION

AND

TREATMENT

No guidelines currently exist for the pharmacological treatment of acute HBV infection; the clinical management of acute HBV is therefore primarily one of conservative supportive measures, although lamivudine may play a role. All patients with chronic HBV infection, like chronic HCV infection, are instructed to avoid hepatotoxins, including alcohol. In contrast to HCV, HBV is often transmitted through sexual contact and partners of infected patients are instructed to be vaccinated. Barrier protection is recommended for patients with multiple partners (Wasley et al. 2008). The objective of treatment of chronic HBV infection is to eradicate active replication, thereby decreasing hepatic injury. Therefore, evidence of viral replication provides the rationale for treatment, and this includes the presence of HBsAg, HBeAg, and HBV DNA for at least 6 months; persistently elevated serum ALT or AST levels; biopsy evidence of chronic hepatitis; and compensated liver disease (Malik and Lee 2000). Pharmacological treatment options include interferon α; pegylated interferon α-2a; nucleoside analogues lamivudine, telbivudine, and entecavir; and nucleotide analogues adefovir and tenofovir (Table 10–1). Treatment usually lasts for 1 year (or longer in HBeAgpositive infected patients) and results in a reduction in serum HBV DNA levels by 3.5 to 6.9 log 10, which results in undetectability in 13%–95% of patients (Dienstag 2008).

HBV INFECTION AND OPIOID AGONIST TREATMENT There appear to be few unique precautions that need to be adhered to in patients receiving buprenorphine who are infected with HBV. There are no known interactions between buprenorphine or methadone and any of the antiviral medications used to treat hepatitis B. However, if interferon treatment is used, patients should be monitored closely for relapse to drug use because the flu-like syndrome that often accompanies interferon treatment may mimic symptoms of opioid withdrawal. Depression is also a common side effect of interferon treatment and may increase the risk for relapse in some patients. Pa-

Class

Medication

Immunosuppressant Standard interferon α†

Nucleoside analogues

Dosage

Advantages

May reduce disease 5 million units SQ progression daily or 10 million units SQ three times per week for 12–24 weeks

Side effects Flu-like symptoms, autoimmune disorders, depression

Resistance is unlikely

Flu-like symptoms, autoimmune disorders, depression

Entecavir

0.5 mg/day PO

Potent viral suppression

Black box warning: lactic acidosis and hepatomegaly; severe, acute exacerbation of hepatitis B may occur on discontinuation Cross-resistance may occur in patients failing lamivudine

Lamivudine

100 mg/day PO

Well tolerated

High rate of resistance

Telbivudine

600 mg/day PO

Generally well tolerated

Cross-resistance with lamivudine; rhabdomyolysis and peripheral neuropathy rare but may occur

197

Pegylated 180 µg/week SQ interferon α−2a

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TABLE 10–1. Pharmacological options available for the treatment of chronic hepatitis B virus infection

Pharmacological options available for the treatment of chronic hepatitis B virus infection (continued)

Class

Medication

Dosage

Advantages

Side effects

Nucleotide analogues

Adefovir

10 mg/day PO

Activity against lamivudine-resistant virus

Potential nephrotoxicity (creatinine monitoring advisable), slow viral suppression

Tenofovir

300 mg/day PO

Generally well tolerated

Potential nephrotoxicity (creatinine monitoring advisable)

Note. PO=orally; SQ=subcutaneously. †For hepatitis B envelope antigen (HBeAg)–positive chronic hepatitis B.

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TABLE 10–1.

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tients with a prior history of depression should begin taking antidepressants before beginning interferon treatment.

Hepatitis C EPIDEMIOLOGY Nearly 4 million people in the United States are infected with HCV and roughly 35,000 new cases occur annually. Upward of 85% of incident cases of HCV go on to become chronic infection. HCV is the leading cause of chronic liver disease, cirrhosis, liver cancer, and liver transplantation in the United States (Centers for Disease Control and Prevention 2008b). Injection drug use remains the most common cause of HCV seroconversion in the United States, with more than 60% of all new infections occurring as a result of injection drug use (Lauer and Walker 2001). It is important to remember that HCV is transmitted not only through sharing needles but also through sharing “works” (tubing, syringe, wastewater, and so forth) with an infected individual. Sexual transmission of HCV is inefficient; it is estimated that in long-term monogamous couples, the rate of sexual transmission is 0.6% per year. Only patients practicing high-risk sexual behavior or those with multiple sexual partners are instructed to use barrier methods of contraception. Other causes of HCV transmission include needlestick injuries, receipt of a blood transfusion before 1992, and infrequently, mother-to-child transmission.

NATURAL HISTORY Although acute HCV infection can cause severe hepatic injury, it is most often relatively benign and usually lasts between 4 and 12 weeks. Because patients often have only mild symptoms, the diagnosis of acute infection can be very difficult to capture. Exposure to HCV generally results in development of an antiHCV antibody roughly 10–12 weeks after exposure. However, this antibody does not confer protection. After acute infection, in 15%–20% of individuals, the infection resolves spontaneously, whereas 80%–85% of patients will develop chronic hepatitis C with varying degrees of fibrosis. Of those who develop chronic infection, 10%–15% develop progressive liver fibrosis and cirrhosis, which may lead to liver failure or hepatocellular carcinoma. Development of cirrhosis often occurs 15–20 years after infection. It is not possible to determine which patients will go on to develop complications from HCV infection. However, several factors are known to affect disease progression. These include male gender; older age at onset of disease; presence of other comorbid conditions including HIV infection, hepatitis B, or fatty liver disease; and alcohol consump-

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tion (Fattovich et al. 1997). Clinicians should therefore counsel their patients with HCV to avoid behaviors that put them at risk of HIV transmission, to be vaccinated against the hepatitis A virus and HBV, to control their weight and diabetes (when applicable), and to avoid alcohol. The common clinical manifestations of chronic HCV infection tend to be nonspecific and include fatigue, muscle or joint aches, low-grade fever, depressive symptoms, and mild gastrointestinal complaints.

LABORATORY DIAGNOSIS Screening for HCV infection rests with measurement of serum anti-HCV. Once a detectable level of antibody is noted, a qualitative HCV RNA test should be performed to confirm viremia. For patients considering treatment, a genotype and quantitative HCV RNA should be obtained. These two virologic tests are important in terms of treatment initiation and response. There are six different genotypes of HCV with multiple subtypes. Genotype 1 is the most common type in the United States, with genotypes 2, 3, and 4 being less common. The most important clinical distinction is between genotype 1 and genotypes 2 and 3 because treatment for genotype 1 (or any genotype in a patient coinfected with HIV) lasts 48 weeks whereas treatment for genotypes 2 and 3 lasts 24 weeks (Lauer and Walker 2001). Quantitative HCV RNA, or HCV viral load, is used to determine treatment response. Transaminase levels are nonspecific and should not be used for screening purposes. ALT levels may be elevated, may be normal, or may fluctuate throughout the course of disease (Inglesby et al. 1999). Histological specimens obtained via liver biopsy are often necessary in order to determine the degree of liver fibrosis and therefore optimal timing of treatment.

TREATMENT

OF

CHRONIC HCV INFECTION

It is important to note that all patients with chronic HCV infection and fibrosis as shown on liver biopsy are potential treatment candidates. According to the 2002 National Institutes of Health consensus statement, treatment should not be withheld from patients with opioid dependence, and treatment of active users of drugs and alcohol should be considered on a case-by-case basis (“Recommendations From the National Institutes of Health Consensus Development Conference Statement” 2002). The mainstay of treatment is combination therapy with weekly injections of pegylated interferon α-2a or α-2b plus twice-daily ribavirin. Treatment duration depends on HCV genotype. The goal of treatment is to achieve a sustained virologic response (SVR), which is defined as an undetectable HCV viral load at the end of treatment and 24 weeks after the end of treatment. SVR

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is achieved in 40%–45% of patients with genotype 1 virus and in 70%–80% of patients with genotypes 2 and 3 virus who undergo appropriate treatment (Fried et al. 2002; Manns et al. 2001).

HCV INFECTION AND OPIOID AGONIST TREATMENT As with patients who are infected with HBV, there appear to be few unique precautions that need to be adhered to in patients receiving buprenorphine who are infected with HCV. There are no known interactions between buprenorphine or methadone and pegylated interferon or ribavirin used in the treatment of HCV. The feasibility of HCV treatment in patients receiving methadone maintenance treatment has been examined. One study (Mauss et al. 2004) included 100 opioid-dependent patients with chronic hepatitis C, half of whom were receiving methadone maintenance therapy and half of whom had had no injection drug use or methadone maintenance therapy for at least 5 years (the control group). Both groups received standard treatment with pegylated interferon α-2b and ribavirin. The primary end point of the study was the rate of SVR. At the end of treatment, 50% of subjects in the methadone group and 76% in the control group had undetectable HCV RNA levels. The difference between the two groups was statistically significant (P= 0.01). However, the SVR rate did not vary significantly between subjects receiving methadone (42%) and subjects in the control group (56%), demonstrating that treatment is as effective in HCV-positive, opioid-dependent patients receiving methadone maintenance therapy as in control subjects (Mauss et al. 2004). Other studies have shown that adherence to HCV treatment and treatment outcomes are favorable in patients maintained with methadone (Sylvestre 2002; Sylvestre and Clements 2007). Similarly, preliminary data suggest that HCV-positive patients maintained with buprenorphine have response rates to HCV treatment comparable to rates in control subjects, and that administration of buprenorphine to patients with HCV and elevated liver enzyme levels is safe (Bruce and Altice 2007; Sulkowski 2007). The side effects of interferon treatment in HCV-positive patients are similar to those described above for patients with HBV.

HIV Infection/AIDS EPIDEMIOLOGY HIV is a blood-borne retroviral infection caused by the human immunodeficiency virus. Transmission occurs through sexual contact, parenteral exposure,

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perinatal exposure, and breast-feeding. It is estimated that there are roughly 1.1 million individuals living with HIV and/or AIDS in the United States, and 25% are unaware of their infection. Of all individuals diagnosed with HIV, 3.4% meet the definition of having AIDS. AIDS is defined as a CD4 cell (helper T lymphocyte) count of less than 200 cells/mm3 (normal range, 800– 1,050 cells/mm3) or the presence of an opportunistic infection known to be associated with HIV infection (Centers for Disease Control and Prevention 2007). Twelve percent of the more than 56,000 new infections each year occur through injection drug use (Centers for Disease Control and Prevention 2008c). In addition to direct transmission through injection drug use, HIV transmission through high-risk sexual contact is another risk for opioid-dependent individuals (Sullivan et al. 2008).

NATURAL HISTORY The course of HIV disease is followed clinically with the CD4 count and the viral RNA level (viral load). Low CD4 count is the strongest predictor of the development of opportunistic infections. Most opportunistic infections occur at a CD4 count of less than 50 cells/mm3. High viral load remains an independent predictor of disease progression, and the goal of treatment is to suppress the viral load to undetectable levels. In the setting of untreated infection, patients become increasingly immunocompromised and ultimately succumb to overwhelming infection.

LABORATORY DIAGNOSIS The primary screening test for HIV is an enzyme immunoassay. All positive tests must be confirmed by Western blot analysis. The accuracy rate of enzyme immunoassay testing is very high, and the predictive value depends on the seroprevalence in the population being tested. False-negative test results may occur and are often due to screening during the window period. The window period is the time from infection to the development of antibodies and generally ranges from 30 days to 6 months. Patients who have engaged in risky behavior and obtain a negative test result are encouraged to have repeat testing 3–6 months after the initial test. Rapid testing has recently become available and is considered to have diagnostic accuracy similar to that of standard testing. However, recent reports have raised concern over use of these tests in certain clinical situations, such as in emergency departments (Centers for Disease Control and Prevention 2008a; Walensky et al. 2008). Once a positive HIV test result is confirmed by Western blot testing, the patient should undergo a battery of staging tests including HIV genotype, CD4 count, and HIV viral load assessment. Patients should be referred to an HIV specialist for treatment.

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TREATMENT The mainstay of treatment is highly active antiretroviral therapy (HAART), a regimen consisting of at least three medications from several potential drug classes. All patients with a CD4 count of less than 200 cells/mm3 or with a history of an AIDS-defining illness should begin receiving HAART. Several classes of medications are used in the treatment of HIV, and new drug development has created an ever-changing landscape of possible combinations. Table 10–2 shows the medications currently used for HIV treatment.

HIV INFECTION

AND

OPIOID AGONIST TREATMENT

There appear to be few unique precautions that need to be adhered to in patients receiving buprenorphine who are HIV infected. It is established that methadone maintenance therapy reduces HIV risk transmission and improves HIV medication adherence and outcomes (Gowing et al. 2006; Sullivan et al. 2005). Other work has also suggested that buprenorphine therapy has a similar impact on HIV transmission, medication adherence, and outcomes (Carrieri et al. 2000; Moatti et al. 2000; Sullivan and Fiellin 2005; Sullivan et al. 2006, 2008). Several medication interactions occur between antiretroviral medications and methadone. These interactions often involve the cytochrome P450 pathway and may result in the need to adjust the dosage of either methadone or the antiretroviral medication (Gourevitch and Friedland 2000). The only clinically significant interaction between buprenorphine and antiretrovirals is its potential interaction with the commonly used protease inhibitors atazanavir and ritonavir. Atazanavir plus ritonavir used in combination may increase buprenorphine concentrations and cause sedation (McCance-Katz et al. 2007). Therefore, the clinician may need to decrease the buprenorphine dosage (see the section “Drug-Drug Interactions” in Chapter 6, “Clinical Use of Buprenorphine,” and Chapter 9, “Psychiatric Comorbidity,” for further discussion of drug interactions with buprenorphine).

Tuberculosis All patients with opioid dependence should be screened for exposure to tuberculosis with the purified protein derivative (PPD) skin test (American Thoracic Society 2000). A positive test result indicates exposure to tuberculosis or LTBI. Any individual testing positive for LTBI (area of induration >10 mm, or >5 mm in HIVpositive patients, at 48–72 hours after PPD skin testing) should be further tested for signs of active pulmonary or extrapulmonary infection and, if results are negative, should be considered or referred for treatment for LTBI. For patients exposed to bacillus Calmette-Guérin (BCV) vaccination, the test should be performed and

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TABLE 10–2.

Medications used for treatment of HIV infection Medication

Class

Generic name

Other namesa

NNRTIs

delavirdine efavirenz etravirine nevirapine rilpivirine abacavir abacavir+lamivudine abacavir+lamivudine+zidovudine didanosine emtricitabine lamivudine lamivudine+zidovudine stavudine tenofovir DF tenofovir DF+emtricitabine zalcitabine zidovudine amprenavir atazanavir darunavir fosamprenavir indinavir lopinavir+ritonavir nelfinavir ritonavir saquinavir tipranavir enfuvirtide maraviroc

Rescriptor, DLV Sustiva, EFV Intelence, TMC125 Viramune, NVP TMC278 Ziagen, ABC Epzicom Trizivir Videx, Videx EC, ddI Emtriva, FTC Epivir, 3TC Combivir Zerit, d4T Viread, TDF Truvada Hivid, ddC Retrovir, AZT, ZDV Agenerase, APV Reyataz, ATV Prezista, DRV Lexiva, FPV Crixivan, IDV Kaletra, LPV/r Viracept, NFV Norvir, RTV Invirase, SQV Aptivus Fuzeon, T20 Selzentry, UK-427,857 SCH417690

NRTIs

Protease inhibitors

Entry inhibitors

vicriviroc Integrase inhibitors elvitegravir raltegravir Maturation inhibitor bevirimat Combination tenofovir DF+emtricitabine (NRTIs)+efavirenz (an NNRTI)

GS-9137 Isentress, MK-0518 PA-457 Atripla

Note. AZT=azidothymidine; ddC=dideoxycytidine; NNRTIs=nonnucleoside reverse transcriptase inhibitors; NRTIs=nucleoside reverse transcriptase inhibitors; tenofovir DF=tenofovir disoproxil fumarate; Videx EC=Videx enteric-coated (extended-release) capsules. aTrade

names, abbreviations, code designations.

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interpreted as it is for unvaccinated persons. For those with chest X-ray findings or other findings consistent with active infection, specialty referral to a pulmonologist and possible hospitalization need to occur as soon as possible. The goal of LTBI treatment is to prevent development or reactivation of active infection. Treatment of LTBI requires 9 months of administration of isoniazid (isonicotinic acid hydrazide; INH) 300 mg/day coupled with pyridoxine 10–50 mg/day to prevent the potential side effect of neuropathy. Patients should be followed throughout treatment for signs or symptoms of hepatotoxicity. If a patient’s liver function test results show enzyme levels increased to three times the upper limit of normal, therapy should be discontinued. Adherence to treatment is a common concern and directly observed therapy can be instituted as a means to increase treatment adherence. Methadone programs have been effective for linking opioid agonist treatment to INH chemoprophylaxis and increasing medication adherence (Batki et al. 2002; O’Connor et al. 1999). Though INH may decrease serum methadone levels, this interaction does not appear to be clinically significant (Raistrick et al. 1996). There are no published reports to date regarding buprenorphine treatment coupled with INH therapy for the treatment of LTBI.

Buprenorphine Treatment in Special Populations ADOLESCENT PATIENTS Limited data have been published on the use of buprenorphine in adolescent patients, and treatment protocols have mostly mimicked those protocols used in adults. Adolescent patients are often funneled into detoxification protocols rather than programs with longer-term maintenance strategies. However, a recent report has shown that adolescent patients receiving longer-term treatment (12 weeks) had improved outcomes compared with subjects randomly assigned to a 14-day detoxification strategy (Woody et al. 2008). Another issue to consider in this patient population is the involvement of parents in the overall treatment approach. In general, it is important to review state laws on parental consent before treatment of adolescent patients. Often, the approach should be individualized with regard to supervised dosing, parental involvement in doctor visits, and so on (see Chapter 12, “Opioid Use by Adolescents”).

GERIATRIC PATIENTS To date, there are no published data on the use of buprenorphine for the treatment of opioid dependence in patients over age 65 years. In fact, there is little

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known about the use of illicit substances in this population. Pain control in the elderly is an emerging area of study, and there is concern over appropriately defining prescription opioid misuse in this population. If buprenorphine treatment is considered, gradual dose escalation and monitoring for medication interactions and for transaminase elevations should be undertaken.

PREGNANT WOMEN In the United States, roughly 5,000–10,000 infants are born to opioid-dependent mothers annually. One major clinical concern is the development of neonatal abstinence syndrome, which occurs in 40%–95% of infants exposed to opioids in utero (Doberczak et al. 1991). There is substantial experience treating opioid-dependent pregnant patients with methadone and for this reason methadone remains the standard of care. The role of buprenorphine in the treatment of this population continues to emerge. Both methadone and buprenorphine are pregnancy category C drugs. Infants exposed to buprenorphine in utero seem to experience milder neonatal abstinence syndrome (Johnson et al. 2001). Because of the potential teratogenicity associated with naloxone, patients who become pregnant while receiving buprenorphinenaloxone treatment should be switched to either methadone or to the buprenorphine-only tablet during pregnancy. Pregnant, opioid-dependent patients should be comanaged with an obstetrician who has experience treating opioid-dependent patients (see “Buprenorphine and Pregnant Patients” in Chapter 12).

OTHER SPECIAL POPULATIONS In patients with renal insufficiency, buprenorphine levels are not altered and at present no dose adjustment is recommended (Elkader and Sproule 2005; Filitz et al. 2006). In patients with significant liver disease and transaminase levels greater than five times the upper limit of normal, the clinician should consider decreasing the dosage of buprenorphine or discontinuing its use and should refer the patient to a liver specialist (Saxon 2005). Cardiac arrhythmias have been noted in patients maintained with methadone and L -α-acetylmethadol (LAAM); however, there is no evidence to support that QTc interval prolongation occurs in patients taking buprenorphine (Baker et al. 2006).

Conclusion Patients with opioid dependence frequently have comorbid medical conditions, especially infectious diseases. Screening for and treatment of these comorbid conditions is of paramount importance in order to provide the best possible

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care for this patient population. Knowledge of these potential comorbid conditions is important for any clinician treating patients with opioid agonists. Office-based buprenorphine treatment allows for linkage of substance abuse treatment with comprehensive medical care. Use of buprenorphine to treat opioid dependence may need to be individualized in certain populations.

Clinical Pearls • Patients accepted for buprenorphine treatment should have a comprehensive history taken and a targeted physical examination as well as evaluation of urine toxicology and baseline liver function tests. • Clinicians treating patients with opioid agonist treatment should consider screening patients for HIV infection, hepatitis B, hepatitis C, tuberculosis, and syphilis, as well as offering immunizations against hepatitis A and B viruses, influenza, pneumonia, and tetanus, if appropriate. • Treatment modalities for hepatitis B, hepatitis C, and HIV infection are complex and continue to emerge. Physicians caring for patients with these comorbid conditions should have an understanding of potential treatment options and their potential interactions with buprenorphine. • Hepatitis B, hepatitis C, and HIV infection are not contraindications to office-based treatment with buprenorphine. • Adolescent, geriatric, and pregnant patients with opioid dependence may require an individualized treatment approach, and further guidance identifying proper strategies for the care of these special populations will likely emerge over time.

CASE 9 Ellie is a 56-year-old homeless woman who has been receiving buprenorphine therapy in your mental health clinic for the past 2 years. She had a “hard life on the streets” and was diagnosed with HCV infection 10 years ago. She has not considered doing anything about it because “nobody offered.” Her AST and ALT levels have been running at 1½ times the high-normal values. She says that she always has one drink a day and smokes one pack of cigarettes a day. She calls and says, “My eyes look kind of yellow, and I don’t feel so great....” You obtain lab test results that reveal AST and ALT levels are five times the highnormal value, with an AST:ALT ratio of greater than 1 and a total bilirubin level of 3 mg/dL (normal range, 0.3–1.9 mg/dL).

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1. What are the possible causes of her jaundice? Is this likely to be related to her buprenorphine treatment? 2. Should you stop the buprenorphine treatment? 3. Would she be an appropriate candidate for interferon and ribavirin therapy? What is your mechanism for referral to a gastroenterologist?

References Advisory Committee on Immunization Practices: Recommended adult immunization schedule: United States, 2009. Ann Intern Med 150:40–44, 2009 American Thoracic Society: Targeted tuberculin testing and treatment of latent tuberculosis infection. MMWR Recomm Rep 49:1–51, 2000 Baker JR, Best AM, Pade PA, et al: Effect of buprenorphine and antiretroviral agents on the QT interval in opioid-dependent patients. Ann Pharmacother 40:392–396, 2006 Bartlett JG, Branson BM, Fenton K, et al: Opt-out testing for human immunodeficiency virus in the United States: progress and challenges. JAMA 300:945–951, 2008 Batki SL, Grube VA, Bradley JM, et al: A controlled trial of methadone treatment combined with directly observed isoniazid for tuberculosis prevention in injection drug users. Drug Alcohol Depend 66:283–293, 2002 Berson A, Fau D, Fornacciari R, et al: Mechanisms for experimental buprenorphine hepatotoxicity: major role of mitochondrial dysfunction versus metabolic activation (see comment). J Hepatol 34:261–269, 2001a Berson A, Gervais A, Cazals D, et al: Hepatitis after intravenous buprenorphine misuse in heroin addicts (see comment). J Hepatol 34:346–350, 2001b Bruce RD, Altice FL: Case series on the safe use of buprenorphine/naloxone in individuals with acute hepatitis C infection and abnormal hepatic liver transaminases. Am J Drug Alcohol Abuse 33:869–874, 2007 Carrieri MP, Vlahov D, Dellamonica P, et al: Use of buprenorphine in HIV-infected injection drug users: negligible impact on virologic response to HAART: the Manif2000 Study Group. Drug Alcohol Depend 60:51–54, 2000 Centers for Disease Control and Prevention: Guidelines for Viral Hepatitis Surveillance and Case Management. Atlanta, GA, Centers for Disease Control and Prevention, 2005. Available at: http://www.cdc.gov/hepatitis/SurveillanceGuidelines. htm. Accessed July 6, 2010. Centers for Disease Control and Prevention: HIV/AIDS Surveillance Report: Cases of HIV Infection and AIDS in the United States and Dependent Areas, 2007. Available at: http://www.cdc.gov/hiv/topics/surveillance/resources/reports/2007report/ default.htm. Accessed May 30, 2010. Centers for Disease Control and Prevention: False-positive oral fluid rapid HIV tests— New York City, 2005–2008. MMWR Morb Mortal Wkly Rep 57:660–665, 2008a Centers for Disease Control and Prevention: Hepatitis C Information for Health Professionals, July 8, 2008b. Available at: http://www.cdc.gov/hepatitis/HCV/ index.htm. Accessed January 8, 2009. Centers for Disease Control and Prevention: HIV Incidence, September 11, 2008c. Available at: http://www.cdc.gov/HIV/topics/surveillance/incidence.htm. Accessed May 30, 2010.

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Davis GL: Hepatitis B: diagnosis and treatment. South Med J 90:866–870; quiz 871, 1997 Dienstag JL: Hepatitis B virus infection (see comment). N Engl J Med 359:1486–1500, 2008 Doberczak TM, Kandall SR, Wilets I: Neonatal opiate abstinence syndrome in term and preterm infants. J Pediatr 118:933–937, 1991 Elkader A, Sproule B: Buprenorphine: clinical pharmacokinetics in the treatment of opioid dependence. Clin Pharmacokinet 44:661–680, 2005 Fattovich G, Brollo L, Giustina G, et al: Natural history and prognostic factors for chronic hepatitis type B. Gut 32:294–298, 1991 Fattovich G, Giustina G, Degos F, et al: Morbidity and mortality in compensated cirrhosis type C: a retrospective follow-up study of 384 patients (see comment). Gastroenterology 112:463–472, 1997 Fiellin DA, O’Connor PG: Clinical practice: office-based treatment of opioid-dependent patients (see comment). N Engl J Med 347:817–823, 2002 Filitz J, Griessinger N, Sittl R, et al: Effects of intermittent hemodialysis on buprenorphine and norbuprenorphine plasma concentrations in chronic pain patients treated with transdermal buprenorphine. Eur J Pain 10:743–748, 2006 Fried MW, Shiffman ML, Reddy KR, et al: Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 347:975–982, 2002 Fudala PJ, Bridge TP, Herbert S, et al: Office-based treatment of opiate addiction with a sublingual-tablet formulation of buprenorphine and naloxone (see comment). N Engl J Med 349:949–958, 2003 Ganem D, Prince AM: Hepatitis B virus infection—natural history and clinical consequences (see comment; erratum). N Engl J Med 350:1118–1129, 2004 Garfein RS, Vlahov D, Galai N, et al: Viral infections in short-term injection drug users: the prevalence of the hepatitis C, hepatitis B, human immunodeficiency, and human T-lymphotropic viruses. Am J Public Health 86:655–661, 1996 Gourevitch MN, Friedland GH: Interactions between methadone and medications used to treat HIV infection: a review. Mt Sinai J Med 67:429–436, 2000 Gowing LR, Farrell M, Bornemann R, et al: Brief report: methadone treatment of injecting opioid users for prevention of HIV infection. J Gen Intern Med 21:193– 195, 2006 Imperial JC: Natural history of chronic hepatitis B and C. J Gastroenterol Hepatol 14(suppl):S1–S5, 1999 Inglesby TV, Rai R, Astemborski J, et al: A prospective, community-based evaluation of liver enzymes in individuals with hepatitis C after drug use. Hepatology 29:590– 596, 1999 Johnson RE, Jones HE, Jasinski DR, et al: Buprenorphine treatment of pregnant opioid-dependent women: maternal and neonatal outcomes. Drug Alcohol Depend 63:97–103, 2001 Kuehn B: CDC recommends vaccine for smoking. JAMA 300:2713–2714, 2008 Lauer GM, Walker BD: Hepatitis C virus infection (see comment). N Engl J Med 345:41–52, 2001 Lee WM: Acute liver failure (see comment; erratum). N Engl J Med 329:1862–1872, 1993 Malik AH, Lee WM: Chronic hepatitis B virus infection: treatment strategies for the next millennium. Ann Intern Med 132:723–731, 2000 Manns MP, McHutchison JG, Gordon SC, et al: Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 358:958–965, 2001

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Mauss S, Berger F, Goelz J, et al: A prospective controlled study of interferon-based therapy of chronic hepatitis C in patients on methadone maintenance. Hepatology 40:120–124, 2004 McCance-Katz EF, Moody DE, Morse GD, et al: Interaction between buprenorphine and atazanavir or atazanavir/ritonavir. Drug Alcohol Depend 91:269–278, 2007 Moatti JP, Carrieri MP, Spire B, et al: Adherence to HAART in French HIV-infected injecting drug users: the contribution of buprenorphine drug maintenance treatment: the Manif 2000 study group. AIDS 14:151–155, 2000 O’Connor PG, Shi JM, Henry S, et al: Tuberculosis chemoprophylaxis using a liquid isoniazid-methadone admixture for drug users in methadone maintenance. Addiction 94:1071–1075, 1999 Petry NM, Bickel WK, Piasecki D, et al: Elevated liver enzyme levels in opioid-dependent patients with hepatitis treated with buprenorphine. Am J Addict 9:265–269, 2000 Protection against viral hepatitis. Recommendations of the Immunization Practices Advisory Committee (ACIP). MMWR Recomm Rep 39:1–26, 1990 Raistrick D, Hay A, Wolff K: Methadone maintenance and tuberculosis treatment (see comment). BMJ 313:925–926, 1996 Recommendations from the National Institutes of Health consensus development conference statement: management of hepatitis C: 2002. Hepatology 36:1039, 2002 Saxon AJ: Monitoring of liver function tests and hepatitis in patients receiving buprenorphine/naloxone, in Physicians Clinical Support System–Buprenorphine (PCSS-B), Clinical Guidance. November 22, 2005. Available at: http:// www.pcssbuprenorphine.org/pcss/documents2/PCSS_Hepatitis_052307.pdf. Accessed May 7, 2010.] Sulkowski MS: Management of treatment-naive chronic HCV patients (online only), in Clinical Care Options (http://www.clinicaloptions.com/Hepatitis.aspx). Reston, VA, Clinical Care Options, May 18, 2007 Sullivan LE, Fiellin DA: Buprenorphine: its role in preventing HIV transmission and improving the care of HIV-infected patients with opioid dependence. Clin Infect Dis 41:891–896, 2005 Sullivan LE, Metzger DS, Fudala PJ, et al: Decreasing international HIV transmission: the role of expanding access to opioid agonist therapies for injection drug users. Addiction 100:150–158, 2005 Sullivan LE, Barry D, Moore BA, et al: A trial of integrated buprenorphine/naloxone and HIV clinical care. Clin Infect Dis 43 (suppl 4):S184–S190, 2006 Sullivan LE, Moore BA, Chawarski MC, et al:. Buprenorphine/naloxone treatment in primary care is associated with decreased human immunodeficiency virus risk behaviors. J Subst Abuse Treat 35:87–92, 2008 Sylvestre DL: Treating hepatitis C in methadone maintenance patients: an interim analysis. Drug Alcohol Depend 67:117–123, 2002 Sylvestre DL, Clements BJ: Adherence to hepatitis C treatment in recovering heroin users maintained on methadone. Eur J Gastroenterol Hepatol 19:741–747, 2007 Walensky RP, Arbelaez C, Reichmann WM, et al: Revising expectations from rapid HIV tests in the emergency department (see comment; summary for patients). Ann Intern Med 149:153–160, 2008 Wasley A, Grytdal S, Gallagher K: Surveillance for acute viral hepatitis—United States, 2006. MMWR Surveill Summ 57:1–24, 2008

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Woody GE, Poole SA, Subramaniam G, et al: Extended vs short-term buprenorphinenaloxone for treatment of opioid-addicted youth: a randomized trial (see comment). JAMA 300:2003–2011, 2008 Younossi ZM: Viral hepatitis guide for practicing physicians: Cleveland Clinic of Medicine. Cleve Clin J Med 67 (suppl 1):SI6–SI45, 2000

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11 Management of Acute and Chronic Pain Daniel P. Alford, M.D., M.P.H., F.A.C.P.

ADEQUATE TREATMENT of pain is recognized as an essential dimension of quality medical care. Managing pain is complex when patients also have a history of addiction. Treatment of pain can be particularly challenging in a patient with opioid dependence who is receiving opioid agonist therapy (OAT) (i.e., methadone or buprenorphine) (Alford et al. 2006). Whereas nonopioid analgesics (e.g., nonsteroidal anti-inflammatory drugs [NSAIDs] and acetaminophen) are recommended for treating most pain, moderate to severe pain often requires the use of opioid analgesics. Some of the most often cited reasons for physicians not prescribing opioid analgesics are fear of causing cognitive and psychomotor side effects, fear of causing iatrogenic drug addiction, concerns about prescription drug diversion (Savage 1999), and concerns about regulatory scrutiny (Gallagher 2004). In this chapter, buprenorphine refers to either buprenorphine or to the buprenorphine-naloxone combination tablet unless otherwise specified. A common concern is that the use of opioid analgesics in patients receiving OAT may result in relapse to active drug use. There is no evidence that exposure to opioid analgesics in the presence of pain increases relapse in OAT pa213

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tients. A small retrospective study of methadone-maintained postsurgical patients who received opioid analgesics found no difference in relapse indicators when compared with matched methadone patients (Kantor et al. 1980). Similarly, no evidence of relapse was noted in six methadone-maintained patients treated with opioid analgesics for cancer pain (Manfredi et al. 2001). In fact, relapse prevention theories would suggest that the stress associated with unrelieved pain is more likely to be a trigger for relapse than adequate analgesia. This is supported by a study in which methadone maintenance patients stated that pain played a substantial role in their initiating and continuing illicit opioid use (Karasz et al. 2004). Physicians also express concerns regarding opioid analgesics causing severe respiratory or central nervous system (CNS) depression in patients maintained with OAT. Tolerance to the respiratory and CNS depressant effects of opioids occurs rapidly and reliably (Gutstein and Akil 2006). Cancer patients with worsening pain who require dose escalations typically do not exhibit respiratory and CNS depressant effects with the administration of additional opioids (Manfredi et al. 2001). It has been suggested that acute pain serves as a natural antagonist to opioid-associated respiratory and CNS depression (Eriator 1998). Therefore, the concern about severe drug toxicity with opioid analgesics in patients maintained with OAT is not supported by clinical or empirical experience. Not uncommonly, patients dependent on opioids are perceived by health care providers to be demanding when hospitalized with acute pain. This scenario develops in part because of the patients’ distrust of the medical community, concern about being stigmatized, and fears that their pain will be undertreated or that their OAT may be altered or discontinued (Merrill et al. 2002). Patients’ anxiety related to these concerns, which can be profound and well founded, can complicate provision of adequate pain relief. Physicians’ concern that they are being manipulated by drug-seeking patients is difficult to quantify and is emotion laden. Pain is always subjective, making assessment of its presence and severity difficult. During an initial assessment it is difficult, if not impossible, to differentiate between inappropriate drug-seeking and appropriate pain relief–seeking behaviors. A careful clinical assessment for objective evidence of pain decreases the chance of being manipulated by a drug-seeking patient, and supports the use of opioid analgesics in patients with a history of opioid dependence. It is important to remember that patients maintained with OAT are typically receiving opioid maintenance doses that block the euphoric effects of coadministered opioids, theoretically decreasing the likelihood of opioid analgesic abuse. Complicating the use of opioids in managing pain is the confusing and often misunderstood terminology used in pain management and addiction medicine. Physical dependence and tolerance are typical and predictable physiological

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consequences of opioid exposure. These terms, in and of themselves, do not indicate maladaptive behaviors and do not meet the diagnostic criteria of substance dependence in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR; American Psychiatric Association 2000) without, for example, loss of control or continued use despite harm. Pain medicine specialists and addiction treatment providers commonly operate in separate spheres without much communication or collaboration. The well-described interplay between addiction and pain calls into question this artificial separation. In this chapter, I cover the epidemiology and neurobiology of pain in patients with opioid dependence. I also discuss buprenorphine analgesic pharmacology and review acute and chronic pain management in patients on buprenorphine maintenance therapy. Cases are presented at the end of this chapter, including related questions for additional consideration. For discussion of these cases, please see Chapter 14, “Comments on the Case Vignettes.”

Epidemiology and Neurobiology Pain is common in patients with opioid dependence and those maintained with OAT. One survey reported that 52% of 228 treatment-seeking, opioid-dependent veterans complained of moderate to very severe pain lasting more than 30 days (Trafton et al. 2004). Two cross-sectional surveys suggest that among patients receiving methadone maintenance therapy, the prevalence of chronic pain ranges from 37% to 61% (Jamison et al. 2000; Rosenblum et al. 2003). There are no comparable data for patients receiving buprenorphine maintenance therapy. The clinical conditions of pain and opioid dependence are not unrelated phenomena. Martin and Inglis observed over 40 years ago that self-medicating patients with opioid addiction have “an abnormally low tolerance for painful stimuli” (Martin and Inglis 1965). Opioids, whether administered with analgesic or addictive intent, activate opioid receptors, which provide both analgesia and reward (Compton and Gebhart 2003). The presence of one condition appears to influence the expression of the other. Clinical examples of this include 1) how the presence of acute pain appears to decrease the euphorigenic (pleasurable) qualities of the opioid, and 2) how the presence of addictive disease appears to worsen the experience of pain (Zacny et al. 1996). Regarding the latter, researchers identified over a decade ago that persons with addiction and pain have a “syndrome of pain facilitation” (Savage and Schofferman 1995). Their pain experience is worsened by subtle withdrawal syndromes, intoxication, withdrawal-related sympathetic nervous system arousal, sleep disturbances, and affective changes, all consequences of addictive disease. Supporting a negative effect of addiction on pain tolerance, both stimulant and

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opioid abusers have been shown to be less pain tolerant than peers in remission (Compton 1994).

Buprenorphine Pharmacology Since the 1970s, buprenorphine has been available worldwide as a parenteral and sublingual analgesic. Buprenorphine is a partial opioid agonist at the µ receptor, resulting in supraspinal analgesia, euphoria, miosis, respiratory depression, and decreased gastrointestinal motility. It is also an antagonist at the κ receptor, resulting in limited spinal analgesia, sedation, and dysphoria. Although a ceiling effect on respiratory depression has been demonstrated, there are conflicting data on whether an analgesic ceiling effect exists in animal models, and there are no published data indicating an analgesic ceiling in humans (Cowan 2007). This is in contrast to full opioid agonists (e.g., morphine, oxycodone, methadone), which have no analgesic or respiratory ceiling effect. Buprenorphine’s high affinity at the µ receptor makes it difficult to displace. This effectively blocks the analgesic properties of other coadministered opioid analgesics and also risks displacement of previously administered opioid analgesics. Buprenorphine’s slow dissociation from the µ receptor gives it a relatively long serum half-life and induces a more mild withdrawal. In opioid-naive individuals, sublingual buprenorphine doses of 0.2–0.6 mg provide effective analgesia for postoperative pain, lasting 6–8 hours (Johnson et al. 2005). For opioiddependent and thus tolerant individuals, it is unclear what degree of analgesia is obtained from sublingual buprenorphine and what the optimal dosage for acute pain would be. Pharmacological explanations account for why opioid-dependent patients do not receive adequate analgesia from maintenance buprenorphine therapy prescribed for addiction treatment. Not only do the analgesic and addiction treatment profiles of buprenorphine differ, the neuroplastic changes associated with chronic opioid exposure (i.e., tolerance) may effectively diminish its analgesic effectiveness (White 2004). Buprenorphine’s duration of action for analgesia (6–8 hours) is substantially shorter than its suppression of opioid withdrawal and craving (24–48 hours) (Johnson et al. 2005). Because buprenorphine is usually dosed every 24 hours, the period of even partial pain relief with this medication is small. Tolerance is another factor why these patients derive little analgesia from maintenance buprenorphine therapy. Analgesic tolerance develops for different medications within the opioid class, a phenomenon referred to as cross-tolerance (Collett 1998). Doverty and colleagues (2001) found patients receiving methadone maintenance therapy to be cross-tolerant to the analgesic effects of morphine, and when analgesia was obtained its duration was shorter than expected. Therefore, cross-tolerance between the opi-

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oids used for maintenance therapy and other opioids used for analgesia may explain why patients maintained with OAT often require higher and more frequent doses of opioid analgesics to achieve adequate pain control.

Pain Assessment Because of the complex interplay between pain and addiction, a comprehensive clinical approach to patients with dependence disorders is needed. As with all patients, self-reporting remains the gold standard for assessing pain. Although a number of clinical pain assessment measures exist, none have been validated specifically in patients with addiction disorders, in which anxiety, fear, past experiences, and other psychological elements may impact pain ratings. Simple scales provide estimates of an individual’s intensity of pain cross-sectionally and can be used longitudinally to measure the impact of interventions targeting pain. On a 10-point scale mild pain is typically considered equivalent to a selfreported level of 1–3, moderate pain is in the range of 4–7, and severe pain is anything greater than that (Turk and Melzack 2001). To understand the impact of chronic pain on function, measures such as the Brief Pain Inventory can be used (Tan et al. 2004). In addition, physicians should obtain information and results from prior pain evaluations, including imaging and other testing, treatments tried, past psychiatric therapy, and the impact of these prior interventions on pain and functional abilities.

Acute Pain Management The appropriate treatment of acute pain in patients receiving OAT (i.e., methadone, buprenorphine) includes uninterrupted OAT equivalence to address the patient’s baseline opioid requirement for addiction treatment and aggressive pain management. As with all patients with chronic pain, nonpharmacological and nonopioid pain treatments should be aggressively implemented. However, moderate to severe acute pain often requires opioid analgesics. Literature suggests that undertreating acute pain may lead to decreased responsiveness to opioid analgesics, thus making subsequent pain control more difficult (Mao et al. 1995). To decrease the total amount of opioid given to these patients, multimodal analgesia (e.g., NSAIDs, acetaminophen) and adjuvant analgesics (e.g., antidepressants, anticonvulsants) that enhance opioid effects may be coadministered (Kehlet and Dahl 1993). Continuing the patient’s baseline opioid requirements avoids worsening pain symptoms due to the increased pain sensitivity associated with opioid withdrawal. Thus daily opioid treatment requirements, or the patient’s opioid debt, must be met before attempting to achieve analgesia (Peng et al. 2005). To decrease patients’ anxiety, clinicians should re-

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assure them that their opioid addiction treatment will continue and that their pain will be aggressively treated. Considering the increased pain sensitivity and cross-tolerance with OAT, adequate pain control generally necessitates higher opioid doses at shorter dosing intervals. Analgesic dosing should be continuous or scheduled rather than on an as-needed basis. Allowing pain to reemerge before administering the next dose causes unnecessary suffering and anxiety, and increases tension between the patient and treatment team. Empirical data on the use of patient-controlled analgesia in patients with substance dependence and acute pain are limited. Paige and colleagues (1994) reported that although women receiving methadone maintenance therapy had higher pain scores after cesarean section surgery, there was no statistically significant difference in opioid analgesic usage compared with control subjects. Clinical experience supports consideration of using patient-controlled analgesia in patients receiving OAT; increased patient control over analgesia minimizes patient anxiety over pain management. The pharmacological properties of opioids must be considered when selecting an opioid analgesic for a patient receiving OAT. Although opioids bind to multiple subtypes of opioid receptors in the CNS, binding to the µ receptor subtype is primarily responsible for the analgesic effect. Mixed agonist-antagonist opioid analgesics such as pentazocine (Talwin), nalbuphine (Nubain), and butorphanol (Stadol) must be avoided because they are likely to displace the maintenance opioid from the µ receptor, thus precipitating acute opioid withdrawal in patients receiving OAT (Scimeca et al. 2000). Opioid analgesic combination products containing fixed doses of acetaminophen and an opioid (e.g., Percocet, Vicodin) should be limited to situations not requiring large doses so as to avoid acetaminophen-induced hepatic toxicity. Alternatively, one could prescribe each medication individually at appropriate doses to achieve the desired analgesic effect and avoid hepatic damage. Clinical experience treating acute pain in patients maintained with buprenorphine is limited. Pain treatment with concurrent opioid analgesics is complicated by buprenorphine’s high affinity for the µ receptor. This high affinity risks displacement of, or competition with, full opioid agonist analgesics when administered concurrently or sequentially. However, animal studies have demonstrated additive analgesic effects when combining a full opioid agonist (e.g., morphine, oxycodone) with buprenorphine (Kogel et al. 2005). Several possible approaches exist for treating acute pain requiring opioid analgesia in patients receiving buprenorphine therapy. With such limited clinical experience, the following treatment approaches are based on the available literature, pharmacological principles, and published recommendations (Alford et al. 2006). The most effective approach will be elucidated with increased clinical experience. In all cases, due to highly variable rates of buprenorphine dissociation from the µ receptor, the opioid antagonist naloxone should be

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available, and the level of consciousness and respiration should be monitored frequently. 1. Continue buprenorphine maintenance therapy and titrate a short-acting opioid analgesic to effect. Because higher doses of full opioid agonist analgesics may be required to compete with buprenorphine at the µ receptor, caution should be taken if the patient’s buprenorphine maintenance therapy is abruptly discontinued. Increased sensitivity to the full opioid agonist with respect to CNS and respiratory depression could occur. 2. Divide the buprenorphine daily dose and administer every 6–8 hours to take advantage of its analgesic properties. For example, for buprenorphine 24 mg daily, the split dose would be 8 mg every 8 hours. Because of the apparent lack of analgesic ceiling effect and the presence of a respiratory depression ceiling effect, it is possible to safely administer additional buprenorphine (i.e., parenterally or sublingually) to the patient’s maintenance dose to treat acute pain. One case report described analgesic benefit of time-limited supplemental doses of sublingual buprenorphine of up to 72 mg for acute pain (Book et al. 2007). 3. Discontinue buprenorphine and treat with scheduled full opioid agonist analgesics by titrating to effect to avoid withdrawal and then to achieve analgesia (e.g., sustained-release and immediate-release morphine). With resolution of the acute pain, discontinue the full opioid agonist analgesics, and resume buprenorphine maintenance using an induction protocol. 4. If the patient is hospitalized in acute pain, the patient’s baseline opioid requirement can be managed and thus opioid withdrawal prevented by converting buprenorphine therapy to methadone 30–40 mg daily. Methadone at this dosage will prevent acute withdrawal in most patients, and compared with buprenorphine, binds less tightly to the µ receptor. Thus, responses to additional opioid agonist analgesics will be as expected (i.e., increasing doses will provide increased analgesia). It is recommended that short-acting opioid analgesics be used for easy titration. If opioid withdrawal persists, subsequent daily methadone doses can be increased in 5to 10-mg increments. This method allows titration of opioid agonist analgesics for pain control in the absence of opioid withdrawal. When the acute pain resolves, discontinue the opioid agonist analgesics and methadone, and resume buprenorphine maintenance using an induction protocol. If hospital discharge occurs while opioid agonist analgesics are still required, then discontinue methadone and treat as stated in the third buprenorphine approach above. If buprenorphine therapy needs to be restarted following acute pain management (i.e., third and fourth approaches), it is important to keep in mind that

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buprenorphine induction can precipitate opioid withdrawal. Thus, in a patient receiving a full opioid agonist regularly, the patient should be in mild opioid withdrawal before restarting buprenorphine therapy.

Chronic Pain Management The management of chronic pain in patients receiving OAT is complex. Outcomes in chronic pain management are frequently expressed in terms of improved quality of life and function. Improvements in physical capabilities, social interactions, and health care utilization have been variously used as indicators of good chronic pain management. Similarly, management of chronic pain in patients receiving OAT should be reflected by improved functionality in these domains. It is in the context of well-treated addiction that good pain management outcomes can be expected. Of note, interventions known to improve chronic pain are similar to those effective in managing addiction (e.g., cognitive therapy, behavior modification, involvement of family, treatment of concurrent psychological or psychiatric problems, stress management, and group support). The positive effects of various types of interventions on both chronic pain and addiction suggest that exposure to these types of interventions in either context would yield improvements in the other. Patients maintained with buprenorphine can be managed using nonpharmacological interventions (e.g., acupuncture, cognitive-behavioral therapy, massage, relaxation, physical therapy) and/or nonopioid medications (e.g., acetaminophen, NSAIDs, antidepressants, anticonvulsants). Although methadone-maintained patients with chronic pain may benefit from concurrent treatment with sustained-release opioid analgesics, this approach is not possible with buprenorphine treatment. Buprenorphine’s high µ receptor affinity makes it difficult, if not impossible, to manage chronic pain with concurrent full opioid agonist analgesics. However, due to its inherent analgesic properties, buprenorphine could be dosed every 6–8 hours to treat both opioid dependence (an onlabel indication—i.e., one that is within U.S. Food and Drug Administration– approved drug labeling) and pain (an off-label indication). Malinoff and colleagues (2005) reported that 86% of patients treated with divided doses of sublingual buprenorphine (mean dosage, 8 mg/day) had moderate to substantial pain relief along with improved mood and function. If a patient receiving buprenorphine maintenance therapy requires a full opioid agonist for adequate treatment of chronic pain, the patient must discontinue buprenorphine maintenance treatment. Before taking this step, the physician and patient together need to weigh the risks and benefits of this approach: 1) the risks of prescription medication abuse and potential relapse to drug use without buprenorphine versus 2) the potential improvements in pain and function that might be

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gained from treatment with a full opioid agonist. Alternatively, the patient could be transferred to an opioid treatment program (OTP) for methadone maintenance treatment of his or her addiction, which would allow the patient to receive concurrent opioid analgesic treatment of his or her chronic pain.

Conclusion Addiction elicits neurophysiological, behavioral, and social responses that worsen the pain experience and complicate the provision of adequate analgesia. Treating acute and chronic pain in patients receiving OAT (i.e., methadone, buprenorphine) can be clinically challenging. Patients with a history of opioid dependence most likely experience acute and chronic pain differently than other patients. Moreover, OAT with the drug taken once a day does not provide analgesia to patients in acute or chronic pain. Because of opioid cross-tolerance and increased pain sensitivity in these patients, opioid analgesics often need to be administered in higher doses and at shortened intervals. In treating acute pain in patients receiving buprenorphine maintenance therapy, the clinician should provide 1) reassurance regarding uninterrupted OAT equivalence in order to avoid opioid withdrawal and 2) reassurance regarding aggressive pain management, including patient-controlled analgesia to mitigate patient anxiety and facilitate successful treatment of pain. For patients maintained with buprenorphine who have chronic pain, nonopioid analgesics and nonpharmacological approaches should be tried. If chronic opioid use is required, splitting the buprenorphine dose or transferring the patient to an OTP so the patient can receive methadone maintenance therapy with conconcurrent opioid analgesics may be required.

Clinical Pearls Acute pain management • Reassure the patient that his or her addiction history will not prevent adequate pain management. • Continue the usual or equivalent dose of OAT to avoid opioid withdrawal. • Relieve patient anxiety by discussing, in a nonjudgmental manner, the plan for pain management. •

Try nonopioids and nonpharmacological strategies.

If opioids analgesics are required: • Cross-tolerance will necessitate higher doses at shorter intervals.

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• Prescribe continuous scheduled dosing rather than writing “prn” orders. • Avoid using mixed agonist-antagonist opioids because they will precipitate an acute withdrawal syndrome. Option 1 • Continue buprenorphine maintenance therapy. • Use concurrent short-acting opioid analgesics. Option 2 • Divide the buprenorphine daily dose to take advantage of the drug’s analgesic properties. • You may increase the usual maintenance dosage to achieve increased analgesia. • Return to the usual daily maintenance dosage when pain resolves. Option 3 • Discontinue buprenorphine and treat the patient with scheduled full opioid agonist analgesics by titrating to effect to avoid withdrawal and then to achieve analgesia. • Convert therapy back to buprenorphine when acute pain resolves. Option 4 (if patient is hospitalized) • Convert therapy from buprenorphine to methadone (30– 40 mg/day) to treat opioid dependence. • Use concurrent short-acting opioid analgesics. • Naloxone (Narcan) at bedside. • Convert therapy back to buprenorphine before discharge. Chronic pain management • Try nonopioids and nonpharmacological strategies. If opioid analgesics are required: Option 1 • Divide the daily buprenorphine dose to use every 6- to 8-hour dosing. Option 2 • Refer the patient to an OTP for methadone maintenance therapy to treat opioid dependence and treat chronic pain with sustained-release opioid analgesics.

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Martha, the 35-year-old woman who had trouble reconciling her 12-step program and taking buprenorphine, eventually found them mutually inclusive; she has continued as an active member of Alcoholics Anonymous and is taking 16 mg of buprenorphine per day. She now needs her gallbladder removed; her surgeon calls asking for help managing her medication during the perioperative period. He expects her to be hospitalized for 2 days and to have pain for a week to 10 days.

1. What are the recommendations for the perioperative pain management of a patient taking buprenorphine? 2. Do you have to taper doses until the buprenorphine is completely discontinued? 3. If you taper down to completely discontinue buprenorphine, how do you cross over to another opioid? 4. How do you use methadone in the perioperative period? 5. If the patient is pregnant, what are the recommendations about buprenorphine and pregnancy? (See Chapter 10, “Medical Management,” section “Pregnant Women.”)

CASE 10 Fred is a 44-year-old senior noncommissioned officer who was injured in Iraq by an improvised explosive device 4 years ago and has residual chronic lower extremity and low back pain. He was treated through pain management services at a Veterans Administration medical center with a complicated course that included trials of opioid, nonopioid, regional block, and physical treatments. During the course of treatment, he became addicted to opioids and was eventually referred for buprenorphine treatment. He has achieved excellent control of his opioid problem and “tolerable” control of his pain with sublingual buprenorphine 8 mg/naloxone 2 mg three times a day. He is now successfully pursuing a master of business administration degree. He calls from the emergency department (ED) and tells you that he fell and reinjured his leg. The ED physician wants to prescribe some additional pain medication.

1. 2. 3. 4. 5. 6.

What would be the strategies for addressing acute pain in this client? What are the available nonopioid therapies? What are the available nonpharmacological therapies? When do you seek collaboration with other specialists? Does buprenorphine provide adequate pain relief? Compare and contrast strategies for treating pain in the context of agonist maintenance treatment.

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References Alford DP, Compton P, Samet JH: Acute pain management for patients receiving maintenance methadone or buprenorphine therapy. Ann Intern Med 144:127– 134, 2006 American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision. Washington, DC, American Psychiatric Association, 2000 Book SW, Myrick H, Malcolm R, et al: Buprenorphine for postoperative pain following general surgery in a buprenorphine-maintained patient (letter). Am J Psychiatry 164:979, 2007 Collett BJ: Opioid tolerance: the clinical perspective. Br J Anaesth 81:58–68, 1998 Compton MA: Cold-pressor pain tolerance in opiate and cocaine abusers: correlates of drug type and use status. J Pain Symptom Manage 9:462–473, 1994 Compton P, Gebhart G: The neurophysiology and pain and addiction, in Principles of Addiction, 3rd Edition. Edited by Graham AW, Schultz TK, Mayo-Smith MF, et al. Annapolis, MD, American Society of Addiction Medicine, 2003, pp 1385– 1404 Cowan A: Buprenorphine: the basic pharmacology revisited. J Addict Med 1:68–72, 2007 Doverty M, White JM, Somogyi AA, et al: Hyperalgesic responses in methadone maintenance patients. Pain 90:91–96, 2001 Eriator I: Narcotic analgesics for chronic pain management. Curr Pain Headache Rep 2:193–200, 1998 Gallagher R: Opioids in chronic pain management: navigating the clinical and regulatory challenges. J Fam Pract 53:S23–S32, 2004 Gutstein HB, Akil H: Opioid analgesics, in Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 11th Edition. Edited by Brunton LL, Lazo JS, Parker KL. New York, McGraw-Hill, 2006, pp 547–590 Jamison RN, Kauffman J, Katz NP: Characteristics of methadone maintenance patients with chronic pain. J Pain Symptom Manage 19:53–62, 2000 Johnson RE, Fudala PJ, Payne R: Buprenorphine: considerations for pain management. J Pain Symptom Manage 29:297–326, 2005 Kantor TG, Cantor R, Tom E: A study of hospitalized surgical patients on methadone maintenance. Drug Alcohol Depend 6:163–173, 1980 Karasz A, Zallman L, Berg K, et al: The experience of chronic severe pain in patients undergoing methadone maintenance treatment. J Pain Symptom Manage 28:517– 525, 2004 Kehlet H, Dahl JB: The value of “multimodal” or “balanced analgesia” in postoperative pain treatment. Anesth Analg 77:1048–1056, 1993 Kogel B, Christoph T, Strabburger W, et al: Interaction of the µ-opioid receptor agonist and antagonists with the analgesic effect of buprenorphine in mice. Eur J Pain 9:599–611, 2005 Malinoff HL, Barkin RL, Wilson G: Sublingual buprenorphine is effective in the treatment of chronic pain syndrome. Am J Ther 12:379–384, 2005 Manfredi PL, Gonzales GR, Cheville AL, et al: Methadone analgesia in cancer pain patients on chronic methadone maintenance therapy. J Pain Symptom Manage 21:169–174, 2001

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Mao J, Price DD, Mayer DJ: Mechanisms of hyperalgesia and morphine tolerance: a current view of their possible interactions. Pain 62:259–274, 1995 Martin JE, Inglis J: Pain tolerance and narcotic addiction. Br J Soc Clin Psychol 4:224– 229, 1965 Merrill JO, Rhodes LA, Deyo RA, et al: Mutual mistrust in the medical care of drug users: the keys to the “narc” cabinet. J Gen Intern Med 17:327–333, 2002 Paige D, Proble L, Watrous G, et al: PCA use in cocaine using patients: a pilot study. American Journal of Pain Management 4:101–105, 1994 Peng PW, Tumber PS, Gourlay D: Review article: perioperative pain management of patients on methadone therapy. Can J Anaesth 52:513–523, 2005 Rosenblum A, Joseph H, Fong C, et al: Prevalence and characteristics of chronic pain among chemically dependent patients in methadone maintenance and residential treatment facilities. JAMA 289:2370–2378, 2003 Savage SR: Opioid use in the management of chronic pain. Med Clin North Am 83:761–786, 1999 Savage SR, Schofferman J: Pharmacological therapies of pain in drug and alcohol addictions, in Pharmacological Therapies for Drug and Alcohol Addictions. Edited by Miller N, Gold M. New York, Marcel Dekker, 1995, pp 373–409 Scimeca MM, Savage SR, Portenoy R, et al: Treatment of pain in methadone-maintained patients. Mt Sinai J Med 67:412–422, 2000 Tan G, Jensen MP, Thornby JI, et al: Validation of the Brief Pain Inventory for chronic nonmalignant pain. J Pain 5:133–137, 2004 Trafton JA, Oliva EM, Horst DA, et al: Treatment needs associated with pain in substance use disorder patients: implications for concurrent treatment. Drug Alcohol Depend 73:23–31, 2004 Turk DC, Melzack R (eds): Handbook on Pain Assessment, 2nd Edition. New York, Guilford, 2001 White JM: Pleasure into pain: the consequences of long-term opioid use. Addict Behav 29:1311–1324, 2004 Zacny JP, McKay MA, Toledano AY, et al: The effects of a cold-water immersion stressor on the reinforcing and subjective effects of fentanyl in healthy volunteers. Drug Alcohol Depend 42:133–142, 1996

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12 Opioid Use by Adolescents Ximena Sanchez-Samper, M.D. Sharon Levy, M.D., M.P.H.

SCREENING FOR ALCOHOL abuse and illicit drug use needs to be a standard procedure in any practice that cares for adolescents and young adults. Recent national surveys indicate that prescription pain relievers have replaced marijuana as the most common entry drugs for adolescents beginning to experiment with drugs. In this chapter, we review appropriate screening tools and management approaches for use in this population. We cover standard treatment options with a focus on the treatment of adolescents dependent on heroin or opioid pharmaceuticals and the promising role of buprenorphine in the treatment of this high-risk population. A case is presented at the end of this chapter, including related questions for additional consideration. For discussion of this case, please see Chapter 14, “Comments on the Case Vignettes.”

Epidemiology Opioid abuse among adolescents is a growing problem in the United States. According to data from the National Institute on Drug Abuse’s Monitoring the 227

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Future study, use of “narcotics other than heroin” has doubled among high school students since the year 2000, with marked increases in the use of longacting oxycodone tablets and hydrocodone-acetaminophen combination tablets. In 2007, the annual prevalence for oxycodone and hydrocodone use reached its highest level since these data have been collected, with 1.8%, 3.9%, and 5.2% of eighth, tenth, and twelfth graders, respectively, reporting oxycodone use in the past year and 2.7%, 7.2%, and 9.6% of them, respectively, reporting hydrocodone use in the past year (Johnston et al. 2007). Past-year heroin use without a needle also increased among high school seniors, rising from 0.6% in 2006 to 1.0% in 2007. Survey results also indicate an increased perception of availability, decreased social disapproval, and a decreased perception of risk associated with using opioids; all of these factors suggest that opioid misuse continues to be on the rise (Boyd et al. 2006; Johnston et al. 2007). These reports likely underestimate actual prevalence because data are collected only from teenagers in school on the day of the survey; teens with high rates of absenteeism and those who drop out of school are an even higher-risk group. Teenagers may not fully appreciate the risks of misusing prescription opioids because these drugs are legal and easily accessible (Boyd et al. 2006). Many adolescents who misuse opioids to get high may quickly become addicted and transition to heroin use when they can no longer afford the street price of opioid medications. A decrease in the price of heroin has increased accessibility to teens, and an increase in purity has allowed for nonintravenous administration, which has made the drug more attractive to adolescents (Hopfer et al. 2003). As a result, use of heroin by adolescents has increased substantially and is currently at its highest level since the heroin epidemic of the 1960s (Hughes and Rieche 1995; Johnston et al. 2009). Heroin-related emergency department visits among youths ages 12–17 underwent a fourfold increase between 1991 and 1996 (Greenblatt 1997), and approximately 27% of those reporting first-time heroin use in the year 2000 were under age 18. Although all adolescents are at risk, heroin use is more common among teens with early-onset substance use or those who have developed polysubstance dependence. Boys account for 53%–68% of users (Hopfer et al. 2002) and approximately 80%–97% of users are white. Intravenous use accounts for 45%–57% of all heroin use by adolescents, which raises a significant public health concern due to an increased risk of contracting and spreading HIV infection, hepatitis, and other infectious diseases (Marsch 2005).

Risk and Protective Factors Individual, peer, family, and community factors all impact the likelihood of drug use and the likelihood of progressing to substance use disorders (Oetting

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and Beauvais 1987; Weinberg 2001). Healthy parental attitudes and role modeling decrease the likelihood that teens will try drugs or affiliate with peers who use drugs. Conversely, conflicted parent-child relationships, parental ineffectiveness, insufficient parental monitoring, inconsistent discipline, deprived socioeconomic status, and parental alcohol or drug use have all been robustly correlated with adolescent opioid use (Teichman and Kefir 2000). Lower levels of parental education are also correlated with heroin use by teens, with rates highest among those whose parents did not complete grade school (Catalano et al. 1992). Early-onset substance use predicts a rapid progression to substance use disorders. Early use of nicotine and alcohol increases the risk of developing substance use disorders later in life, including cannabis, stimulant, opioid, and/or alcohol dependence (Hopfer et al. 2002). Teens diagnosed with substance dependence are also more likely than their peers to continue substance use into adulthood (Hingson et al. 2006). Legal problems and co-occurring childhood psychopathology are also risk factors for progression from opioid use to opioid disorders, especially among adolescent females. The most frequently identified antecedent psychiatric disorders include behavioral disorders (conduct disorder, attention-deficit/hyperactivity disorder [ADHD]), mood disorders, anxiety disorders, and learning disabilities (Currie et al. 2005; Goodwin et al. 2002; Wilens et al. 2003).

Substance Use and Co-Occurring Disorders Substance use disorders frequently co-occur with other mental health disorders, and opioid dependence is no exception. The most common comorbidities include mood and anxiety disorders, conduct disorder, oppositional defiant disorder, and ADHD (Currie et al. 2005; Goodwin et al. 2002; Wilens et al. 2004). Adolescents with substance use disorders are also more likely to have been victims of physical or sexual abuse than their peers (Jaycox et al. 2004). Substances of abuse can induce, mimic, or exacerbate underlying mental illness. Opioid-dependent adolescents with comorbid mental health disorders are more likely to require inpatient hospitalization, are less likely to be compliant with medications, are more likely to drop out of treatment, and are at higher risk of relapse. Despite these poor outcomes, simultaneous treatment of the co-occurring mental health disorder helps to alleviate the substance use. Therefore, all adolescents with opioid dependence should be evaluated for cooccurring mental health disorders and should be treated for both disorders simultaneously.

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Screening and Assessment Screening for drug use, including opioids, should occur as part of routine adolescent medical care. Screening is a two-step process—it begins with opening questions about drug use, such as: “During the past 12 months (or since your last appointment), did you drink any alcohol (more than a few sips)? Smoke any marijuana? Use anything else to get high? By ‘anything else’ I mean illegal drugs, over-the-counter and prescription drugs, and things that you sniff or huff ” (Knight et al. 1999). Since 2007, more teens have reported drug initiation with opioid pharmaceuticals than any other class of drugs, including marijuana, making opioids a new gateway drug. Because of this phenomenon, it is important to specifically mention opioids in the opening questions (Johnston et al. 2007). Teens who answer yes to one or more of the opening questions should be further screened with a standardized, developmentally appropriate tool that can distinguish low- versus high-risk substance use. Work by Wilson et al. (2004) has demonstrated that even experienced clinicians significantly underestimate substance use disorders when relying on clinical impressions alone. Several screening tools are available, including the CRAFFT questionnaire (with CRAFFT being a mnemonic for six key terms within the questions: car, relax, alone, forget, family or friends, trouble; Figure 12–1), which has been extensively validated (Knight et al. 1999, 2002) and is recommended by the American Academy of Pediatrics. Every adolescent should receive a brief intervention appropriate to their level of use based on screening results. Readers are referred to the review article “Screening, Brief Intervention, and Referral to Treatment for Adolescents” (Levy and Knight 2008) for a general approach to office-based screening and intervention. Beyond screening, substance use should be considered in the differential diagnosis of any teen who presents with new-onset behavioral, emotional, or school problems, or when an adult suspects substance use because a teen has appeared intoxicated or has been in possession of drugs or paraphernalia. Recognition of the physical and behavioral manifestations of common drugs of abuse can aid in focusing screening questions, testing, and prompt intervention. Physician and family understanding of risk and protective factors may be the single most important element for identifying at-risk youths and intervening early. Adolescents who report any use of opioids (other than as prescribed by a physician) should receive further assessment to determine the motivation and pattern of use, associated problems, attempts at quitting, and previous treatment in order to determine the stage of use and whether a substance use disorder is present. Opioid use occurs on a continuum from misuse to dependence as

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The CRAFFT Screening Questions

Please answer all questions honestly; your answers will be kept confidential.

Part A During the PAST 12 MONTHS, did you: 1. Drink any alcohol (more than a few sips)?

2. Smoke any marijuana or hashish? 3. Use anything else to get high?

No






Yes If you answered NO to ALL (A1, A2, A3) answer only B1






If you answered YES to ANY (A1 to A3) answer B1 to B6

“anything else” includes illegal drugs, over-the-counter and prescription drugs, and things that you sniff or “huff”

Part B

No

Yes

1. Have you ever ridden in a CAR driven by someone (including yourself) who was “high” or had been using alcohol or drugs?







2. Do you ever use alcohol or drugs to RELAX, feel better about yourself, or fit in?







3. Do you ever use alcohol or drugs while you are by yourself, or ALONE?







4. Do you ever FORGET things you did while using alcohol or drugs?







5. Do your FAMILY or FRIENDS ever tell you that you should cut down on your drinking or drug use?







6. Have you ever gotten into TROUBLE while you were using alcohol or drugs?







CONFIDENTIALITY NOTICE: The information on this page may be protected by special federal confidentiality rules (42 CFR Part 2), which prohibit disclosure of this information unless authorized by specific written consent. A general authorization for release of medical information is NOT sufficient.

FIGURE 12–1. CRAFFT screening questionnaire. Source. Reprinted with permission from the Center for Adolescent Substance Abuse Research, CeASAR, Children’s Hospital, Boston, Massachusetts. Copyright © 2009 Children’s Hospital Boston.

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described below. Treatment strategies are most effective when targeted to the stage of use. Opioid misuse is characterized by oral use of opioids without a prescription exclusively for pain relief. Because of the highly addictive nature of opioids, teens using these medications without medical supervision may develop opioid addiction. Problematic opioid use is defined by the occurrence of a single adverse consequence as a result of use, use for reasons other than relief of pain (e.g., to become intoxicated), or use by any route other than oral (e.g., insufflated or injected). Substance-related problems may include decreased school performance, suspensions, relationship problems with parents or peers, motor vehicle accidents, injuries, emergency department visits, physical or sexual assaults, and legal problems. These may be accompanied by significant changes in dress, behavior, and peer group. Opioid abuse refers to continued opioid use in the context of significant problems or impairment in functioning. It is defined in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR; American Psychiatric Association 2000) as a maladaptive pattern of use that causes impairment in social or school functioning, recurrent physical risk or legal problems, and continued use despite harm occurring over a 12-month period, with no diagnosis of dependence. Opioid dependence or addiction refers to loss of control over drug use and is characterized by a maladaptive pattern of compulsive opioid use, preoccupation, and associated negative consequences. Tolerance and withdrawal are nearly universal. Clinical manifestations typically include continual use of substances when available, solitary use, disrupted family relationships, and loss of outside supports. Formal diagnostic criteria are specified in DSM-IV-TR. If a teen denies drug use in the context of substantial evidence to the contrary, the clinician should conduct a confidential interview and ask for an explanation of the reported observations (e.g., “Why is your mother so worried that you are using drugs?” or “Why were you carrying pills in your pocketbook?”). Urine drug testing for opioids may also be a useful part of an assessment, but the procedure has significant limitations. A drug test may be negative in the context of drug use if the window of detection (<72 hours for most opioid preparations) is missed, or if a specimen is adulterated or substituted. Although most standard urine drug screens include an opiate panel that detects morphine and codeine, synthetic opioids are not always detected by these screens, and tests for those substances must be ordered separately (Levy et al 2006; also see Chapter 7, “Clinical Management I”). Conversely, false-positive screening results may occur due to medications or foods cross-reacting with an opiate screening panel; thus all positive results should be confirmed with a definitive test such as gas chromatography–mass spectrometry. Drug testing cannot dif-

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ferentiate use of a medication as prescribed from misuse. Furthermore, a single positive confirmed test result is neither necessary nor sufficient to make the diagnosis of an opioid use disorder. Despite these limitations, a positive test result for opioids in the context of clinical suspicion of drug use may be a useful way to start an honest conversation with an adolescent. A physical examination including assessment of a full set of vital signs should be performed as part of a complete assessment for an opioid use disorder. Signs of acute intoxication or chronic opioid use are rare in adolescents but should be noted if present. Patients who present in opioid withdrawal may benefit from inpatient detoxification for symptomatic relief.

Prevention and Pharmacotherapy NON-OPIOID-DEPENDENT TEENS Primary Prevention When prescribing opioid medications, clinicians should provide anticipatory guidance. Teens and parents should be advised that although pain medications are highly effective and safe when used as prescribed, they are also highly addictive and can be dangerous when misused. Parents should monitor use to ensure that medications are always used as directed. Any leftover medication should be discarded by returning it to the pharmacy. Medications should never be shared or given to anyone other than the patient for whom the prescription was written. Pain medication can be safe for use even in patients with substance use disorders, and pain should not be left untreated because of a history of substance abuse or dependence. However, in these situations clinicians should require increased supervision and monitoring to avoid misuse. Parents should be asked to hold, dispense, and observe all medication doses. When treating chronic pain the clinician should insist on the patient receiving all prescriptions from a single prescriber, open communication among all treating physicians, and use of a single pharmacy to fill all prescriptions. A parent should bring in remaining medication for a pill count at every visit. Early refills should be avoided (Hertz and Knight 2006).

Brief Advice Adolescents who misuse opioids but do not have a substance use disorder may respond to brief counseling and advice. In these cases, the clinician should recommend that the adolescent discontinue use of prescription opioid medications entirely, and briefly discuss the risk of progressing to opioid dependence

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with continued use because of the addictive potential of opioids. An assessment for pain should be conducted if appropriate, and the adolescent should be seen again for a follow-up health visit.

Brief Intervention Adolescents with a diagnosis of opioid abuse but not dependence may benefit from a relatively brief intervention. Motivational techniques that 1) encourage teens to consider the negative consequences they have experienced related to their drug use and 2) explore their ambivalence regarding continued use may be particularly helpful (Knight et al. 2005; Marsch et al. 2005). These teens should be followed closely to ensure that they are able to achieve and maintain abstinence or to refer them for more intensive treatment if they progress to opioid dependence.

OPIOID-DEPENDENT TEENS Adolescents with a diagnosis of opioid dependence require long-term treatment to keep them in stable recovery. Treatment should be comprehensive, and tailored to particular needs; no single approach is suitable for all individuals. Brief opioid detoxification, unless followed by an intensive rehabilitation program or a long-term therapeutic community program, is associated with very high rates of relapse. Similarly, standard drug-free outpatient counseling has minimal efficacy in both adolescents and adults. Few teens at this point in the course of opioid dependence will be able to remain drug free without ongoing treatment, and providing treatment to young patients may present an opportunity to prevent commonly associated biopsychosocial and medical comorbidities. In most cases, effective treatment for dependent adolescents should include opioid agonist therapy in conjunction with evidence-based behavioral therapies. Buprenorphine has added an important new option for the treatment of these high-risk patients.

Role of Pharmacotherapy for Opioid Dependence A large body of evidence has demonstrated that pharmacotherapy is effective in treating opioid-dependent adults, both for detoxification and for long-term maintenance (see Chapter 4, “Efficacy and Safety of Buprenorphine”). Few medication studies have included adolescents, but accumulating evidence suggests that opioid agonist therapy can be effective in reducing relapse rates in adolescent populations by stabilizing neurochemistry, ameliorating withdrawal, and curbing cravings (Fiellin 2008; Woody et al. 2008). However, there is little

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consensus regarding the optimal length of buprenorphine treatment for adolescents. Before describing the use of buprenorphine in adolescents, we review other pharmacotherapy options. Short-term pharmacotherapy (detoxification). Detoxification refers to the medical management of symptoms of withdrawal (see Chapter 6, “Clinical Use of Buprenorphine”). Due to the pharmacological properties of opioids, recurrent use results in upregulation of the µ opioid receptor, intercellular and intracellular dysregulation, activation of the dopamine-based reward system, and development of dependence. If opioid use is discontinued abruptly, adolescents with opioid dependence may experience unpleasant withdrawal symptoms, which is often the precipitating event that brings them into treatment (Rowan et al. 2000). Otherwise-healthy adolescents can tolerate withdrawal without serious medical consequences, although the unpleasant symptoms may lead to relapse to opioid use for symptomatic relief. Inpatient detoxification and medical management of withdrawal symptoms should be offered to all patients who meet criteria for opioid dependence. For adolescents in opioid withdrawal with underlying medical conditions, such as diabetes or cystic fibrosis, or with significant psychiatric comorbidity, inpatient detoxification is the standard of care. Detoxification protocols for adults are well established, and similar protocols can be used for teens. Medication options include brief inpatient treatment with clonidine, methadone, or buprenorphine, or a more gradual outpatient buprenorphine taper. Clonidine is a centrally active α2-adrenergic blocker that decreases sympathetic outflow. It has been used to decrease symptoms associated with opioid withdrawal; it does not bond to the opioid receptor and its abuse potential is limited. A randomized controlled trial conducted among 13- to 18year-olds with opioid dependence compared clonidine detoxification with buprenorphine detoxification. The buprenorphine group had significantly greater retention in treatment (72% vs. 39%), significantly less opioid use (64% vs. 32% of urine samples tested negative for opioids), and significantly greater retention in care after detoxification (61% vs. 5%) (Marsch et al. 2005). These findings, which are comparable to findings of similar detoxification trials in adults, suggest that buprenorphine is clinically more effective than clonidine for the detoxification treatment of opioid dependence. There are no published studies comparing methadone to buprenorphine for detoxification treatment of adolescents. Adolescents should only be discharged from a medical detoxification program once a plan for continued care is in place (Chang and Kosten 2005). Long-term pharmacotherapy. Treatment options include methadone, buprenorphine, and naltrexone. An overview of buprenorphine is provided in this section, and specifics of initiating buprenorphine treatment are discussed later in this chapter, in the section “Buprenorphine Treatment in Adolescents.”

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Methadone maintenance. Patients with opioid dependence may be treated with long-term agonist therapy with the goal of reducing cravings, decreasing relapse rates, and improving overall functioning. Methadone and buprenorphine are currently the only two opioid agonist therapies available in the United States. Methadone maintenance has long been a mainstay of treatment for opioid-dependent adults, although access to treatment is limited (Fiellin et al. 2001). In 2000, Congress passed the Drug Addiction Treatment Act, which permits office-based buprenorphine treatment, thus expanding options and access to opioid agonist therapy (see Chapter 1, “Opioid Dependence in America”). Buprenorphine presents several advantages over methadone for the treatment of adolescents, including an improved safety profile and reduced potential for misuse. However, the treatment of opioid-dependent adolescents presents specific challenges to providers because limited evidence-based research for treatment exists (Rettig and Yarmolinsky 1995; Sees et al. 2000). Methadone is a full agonist of the µ opioid receptor. It has a long half-life, which allows for steady-state dosing without the peaks and troughs associated with euphoria and withdrawal. Methadone maintenance therapy improves functioning, decreases heroin use as evidenced by urine drug testing, leads to reductions in criminal activity, increases treatment retention and employment status, decreases the risk of spreading highly transmissible diseases, and reduces mortality associated with opioid dependence by approximately two-thirds in adult cohorts (Mattick et al. 2003). Although methadone has been approved for use in adolescents younger than age 18 for detoxification, it can only be prescribed for maintenance therapy through specially licensed clinics, which limits its availability for those seeking treatment. Federal regulations limit methadone maintenance treatment to individuals with at least 1 year of dependence, making methadone less accessible to younger users with shorter histories of dependence. Furthermore, U.S. Department of Health and Human Services guidelines specify that methadone clinics cannot accept patients younger than age 18 for maintenance treatment unless they have undergone two unsuccessful attempts at short-term detoxification or drug-free treatment within a 12-month period, and have obtained parental consent (Fudala et al. 2003; Jasinski et al. 1978). Buprenorphine. Buprenorphine is a Schedule III, synthetic partial µ opioid receptor agonist and an antagonist at the κ opioid receptor. Because of its mixed partial agonist-antagonist profile, it has several advantages, including a greater margin of safety than full µ agonists, a less intense abstinence syndrome with fewer autonomic symptoms, lower abuse potential, and an improved safety profile with limited potential for overdose. The agonist activity of buprenorphine has a ceiling effect, and therefore causes less respiratory depression than full agonists (although deaths due to respiratory suppression have been reported when used in combination with alcohol, benzodiazepines, or other cen-

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tral nervous system depressant drugs) (Mattick et al. 2008; see also Chapter 3, “General Opioid Pharmacology,” and Chapter 4, “Efficacy and Safety of Buprenorphine”). Buprenorphine has a higher affinity for opioid receptors than full agonists and displaces full agonists, causing rapid and severe withdrawal symptoms if given to a patient who is dependent on a full µ opioid agonist. When used as maintenance therapy, buprenorphine provides a µ opioid blockade that diminishes a patient’s ability to become intoxicated with other opioids while the µ receptors are saturated (Levy et al. 2007). Because buprenorphine has a long half-life of 24–60 hours, most patients can be maintained with 8–16 mg daily, which can be given in single or divided doses. Physicians who have received a special waiver from the U.S. Food and Drug Administration (FDA) can prescribe buprenorphine in an office-based setting, which reduces stigma and expands treatment access for adolescents (Woody et al. 2008). Buprenorphine is as efficacious as methadone in adults dependent on opioids when equi-effective doses of these medications are provided. It has been approved as opioid agonist therapy for patients ages 16 years and older who meet DSM-IV-TR criteria for opioid dependence. Unlike the federal regulations for methadone maintenance treatment, there is no requirement to document a 1-year history of dependence. This permits the treatment of younger individuals with shorter histories of opioid dependence, a major benefit when treating adolescents. The optimal length of treatment is unknown, although recent evidence suggests that teens can benefit from buprenorphine maintenance therapy. Woody et al. (2008) recently published a randomized cohort study of 152 treatment-seeking adolescents ages 15–21 years who met DSM-IV-TR criteria for opioid dependence. Participants were randomly assigned to receive either 14-day opioid detoxification or 12 weeks of opioid agonist therapy. Patients who received 12 weeks of buprenorphine treatment reported less use of opioids and other illicit substances, had fewer opioid-positive urine test results, and were retained in the study longer. These differences disappeared after medications were discontinued (Woody et al. 2008). Naltrexone. Naltrexone is a µ opioid receptor antagonist with high affinity for the receptor (see Chapter 3). Oral naltrexone has been approved by the FDA for the treatment of both alcohol and opioid dependence, although clinical experience in opioid-dependent patients has been rather disappointing. Many physicians are reluctant to prescribe naltrexone for opioid dependence due to poor patient compliance and high treatment attrition rates. However, a sustained-release depot formulation of naltrexone has received FDA approval for the treatment of alcohol dependence, and a heightened interest has developed for its potential use in treating opioid dependence as well (Comer et al. 2006). There is no published research on the efficacy of naltrexone for opioid dependence in adolescent patients.

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Buprenorphine Treatment in Adolescents Preliminary evaluation. Before beginning opioid agonist therapy, all adolescents should have a complete evaluation including a thorough substance use history assessment; medical, mental health, vocational, and psychosocial history assessments; and a physical examination. The treating clinician must address or refer the patient for treatment of any active problems that would interfere with long-term recovery. All patients should be tested for HIV infection, hepatitis B, hepatitis C, and other infectious diseases as indicated. Symptoms of mild depression or inattention may improve with abstinence and can be monitored if not debilitating. However, all patients should be screened for more significant co-occurring psychiatric symptoms, and comorbidities should be treated simultaneously. Homelessness or living with an active drug user presents special challenges; patients without a stable home and guardian should be referred to social services for support. School dropout and unemployment rates are high among adolescents with opioid dependence and should be addressed as soon as the patient is stable in order to improve long-term outcomes. Setting treatment goals. The optimal length of treatment with opioid substitution therapy has not been scientifically determined, and the risks of long-term exposure to buprenorphine on the still-developing adolescent brain are unknown. Clinicians should therefore discuss the length of treatment with patients, and when appropriate, parents or guardians. Although there is little published evidence, in our clinical practice we recommend that adolescents continue to take buprenorphine until they have been abstinent from illicit opioid use for at least 1 year before considering discontinuation. This approach is consistent with DSM-IV-TR criteria for “opioid dependence in full sustained remission, on replacement therapy,” given that relapse rates for other addictions tend to fall sharply over the course of the first year of abstinence and then begin to level off. Buprenorphine should then be slowly tapered to avoid withdrawal symptoms and/or resurgence of cravings. After buprenorphine is tapered to discontinuation, clinicians should continue to follow adolescents clinically and with drug testing for an extended period to monitor for relapse. The treatment contract. After completing a thorough assessment, the clinician should establish a set of expectations for adolescents beginning buprenorphine treatment. A written contract may be helpful (Figure 12–2). On beginning treatment, adolescents should agree to abstain from all substances including alcohol, which can be dangerous in combination with buprenorphine. All patients who receive buprenorphine treatment should be monitored with random drug tests to assure that they are taking their medication and to monitor for use of opioids, alcohol, or other illicit substances. Patients who are

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unable to achieve abstinence from substances other than opioids should be referred for complementary treatment. Office-based buprenorphine treatment may need to be stopped if a patient is unable to stop using alcohol or sedatives. We recommend that all adolescents with opioid dependence enter counseling to help them identify and avoid triggers for drug use, to learn healthy mechanisms for relieving stress, and to learn other life skills. Some individuals will also need specific counseling to address other issues such as depression, anxiety, and anger. Clinicians treating adolescents should take advantage of the availability of parents or guardians for authority and structure whenever possible. As with treatment-seeking adults who benefit from family involvement, parental participation may improve adolescent treatment adherence, allow for prompt intervention when a relapse occurs, and minimize diversion risk (Dasinger et al. 2004). Getting started: the initial buprenorphine dose. Adolescents should be advised not to use opioids before buprenorphine induction—about 12–24 hours depending on the half-life of their drug of choice (see Chapter 6, “Clinical Use of Buprenorphine”). Buprenorphine therapy may be started at home if a patient (along with a parent or guardian) can be taught to reliably monitor signs of withdrawal and wait until withdrawal has progressed enough to avoid inducing precipitated withdrawal. However, we recommend observed induction for all adolescent patients to give the clinician the opportunity to assess and quantify signs of withdrawal, to teach the teenager to take medications sublingually, to teach a parent or guardian how to observe a medication dose, and to answer questions. Adolescents should be followed closely to monitor for side effects and continued cravings until they are taking a stable dose of buprenorphine. Because of the long half-life of buprenorphine, a single daily dose is effective, although many adolescents prefer divided doses to mimic previous drug use patterns. All patients should be warned to avoid driving for the first few weeks of taking the medication because drowsiness has been reported as a side effect of buprenorphine.

Buprenorphine and Pregnant Patients Buprenorphine is listed as a category C medication in the United States and to date no studies are available to support its safety and efficacy during pregnancy. Methadone continues to be the only FDA-approved medication for maintenance treatment in pregnancy, and buprenorphine monotherapy should be used only if the potential benefit outweighs the risk to the fetus. Neonates should be closely monitored for neonatal abstinence syndrome or signs of respiratory de-

240 Handbook of Office-Based Buprenorphine Treatment of Opioid Dependence

Yes

1. I agree to stop using all drugs, including opiates, alcohol, marijuana, and other street drugs. I will request additional support if I am unable to remain drug free.

Yes

2. I understand that it is dangerous to mix buprenorphine with alcohol or other sedatives (such as Valium, Ativan, Xanax, Klonopin)—so dangerous that it could result in accidental overdose, oversedation, coma, or death. I will not use ALCOHOL or SEDATIVES while I am being treated with buprenorphine.

Yes

3. I agree to cooperate with urine drug testing whenever requested to detect whether I have used alcohol, prescription drugs, or street drugs.

Yes

4. If I slip and use opiates, alcohol, or an illicit drug, I will discuss this honestly with my doctor. 5. I agree that my home supplies of buprenorphine will be kept in the care of my parent or guardian. My parent or guardian will provide me one dose at a time and observe me taking my medication. I will never sell, share, or otherwise distribute my medication. If my medication is taken accidentally by a child or a pet, I will call 911 or Poison Control: _________________ (write phone number).

Yes

Yes

6. I will always take my buprenorphine by placing it under my tongue to dissolve and be absorbed. I will never inject my medication because IV use can lead to sudden and severe opiate withdrawal. I will not skip or alter doses without speaking to my doctor.

Yes

7. I will schedule and keep all recommended appointments. My parent or guardian will accompany me to all of my appointments until I have been cleared to come by myself. If I or my parent/ guardian must reschedule an appointment because of an emergency, I will call as soon as I am aware of the need to change.

Yes

8. My parent or guardian will bring my medication bottle to every visit for a pill count. Once I have been cleared to come by myself, I will give my refill prescriptions directly to my parent or guardian. My parent or guardian will report a pill count by phone whenever requested.

Yes

9. I will report my history and symptoms, including reports of side effects and cravings, honestly.

FIGURE 12–2.

Sample agreement for medication treatment.

Opioid Use by Adolescents

241

Yes 10. I will not drive a car or use dangerous machinery while taking buprenorphine until I have been cleared to do so. I will request medical clearance before resuming any dangerous activities. Yes

11. I will give consent for my doctor to communicate with physicians, therapists, probation officers, and parents or guardian to discuss my treatment and progress, including drug test results.

Yes

12. I will report changes in my medical condition so that all of my treatment can be coordinated. I will discuss pain management before any elective procedure and as soon as possible following any emergency.

Yes

13. I will not try to become pregnant while I am taking buprenorphine because the safety of this medication during pregnancy has not been determined. If I believe that I have become pregnant, I will notify my doctor immediately.

Yes

14. I agree to participate in a counseling program.

Yes

15. If my treatment team determines that I need additional support, I will engage in professional counseling as recommended.

Patient signature: __________________________________ Date: ____________ Parent signature: ___________________________________ Date: ____________ I agree with all of the statements on this page. By my signature above, I further agree that I will closely monitor my child for 24 hours before the first scheduled dose of medication. Staff signature/title: _______________________________ Date: _____________

FIGURE 12–2.

Sample agreement for medication treatment.

(continued)

pression, due to buprenorphine’s ability to cross the placental barrier. Similarly, breast-feeding is not advised because buprenorphine is excreted in breast milk in concentrations similar to those found in maternal serum. Further studies are needed to evaluate the true effect of buprenorphine in infants.

Behavioral Treatments Drug addiction is a complex illness that can impact every aspect of an adolescent’s functioning. Because of the pervasive consequences of drug addiction,

242 Handbook of Office-Based Buprenorphine Treatment of Opioid Dependence

comprehensive treatment involves behavioral therapy in addition to medication. Options for behavioral therapy range from office-based management to hospitalization. The clinician performing an assessment should explore the patient’s readiness for treatment (Drug Strategies 2003; Miller 1998), withdrawal risk, medical complications, psychiatric comorbidities, and home environment in an attempt to determine the least restrictive treatment setting. Manual-driven protocols for psychotherapeutic treatment exist in the form of individual, group, and family therapy. These protocols often implement skills-based approaches via cognitive-behavioral therapy, which can be delivered at various levels of care (in outpatient settings, inpatient settings, or residential treatment programs) (Dasinger et al. 2004; Deas and Brown 2006; Kaminer et al. 2002). Long-term treatments may be provided in outpatient settings, but some patients require greater supervision in settings such as longterm residential facilities in order to achieve and maintain abstinence. The American Academy of Child and Adolescent Psychiatry (Bukstein et al. 2005) has developed a list of principles for adolescent treatment (Table 12– 1). Below is a brief description of typical levels of care at which treatment can be rendered.

OUTPATIENT CARE Outpatient care is the mainstay of substance abuse treatment for adolescents who are medically and behaviorally stable, and may consist of individual, group, or family therapy alone or in combination. A variety of psychosocial therapies have been demonstrated to be effective in the treatment of substance use disorders (Table 12–2). Outpatient care varies in intensity. Day treatment or intensive outpatient programs and partial hospitalization programs are highly structured programs that meet for several hours each day for several weeks and generally combine both individual and group treatment. These programs are usually recommended for adolescents who are transitioning from inpatient care back into the community, or for those who are in the early stages of the recovery process. Office-based management refers to less intensive treatment with patients receiving individual and/or group therapy in sessions range from several times per week to several times per month (Bukstein et al. 2005; Dasinger et al. 2004; Drug Strategies 2003).

PSYCHIATRIC HOSPITALIZATION Psychiatric hospitalization may be warranted for adolescents with unstable cooccurring mental illness. Adolescents should receive a full range of services including assessment and consultation, psychopharmacology, family therapy, and recommendations/referrals for aftercare in an inpatient psychiatric treatment

Opioid Use by Adolescents

TABLE 12–1.

243

Recommendations for the assessment and care of adolescents with substance use disorders (SUDs)

1. The clinician should observe an appropriate level of confidentiality for the adolescent during the assessment and treatment. 2. The mental health assessment of older children and adolescents requires screening questions about the use of alcohol and other substances of abuse. 3. If the screening raises concerns about substance use, the clinician should conduct a more formal evaluation to determine the quantity and frequency of use and consequences of use for each substance used and whether the youth meets criteria for SUD(s). 4. Toxicology, through the collection of bodily fluids or specimens, should be a routine part of the formal evaluation and ongoing assessment of substance use both during and after treatment. 5. Adolescents with SUDs should receive specific treatment for their substance use. 6. Adolescents with SUDs should be treated in the least restrictive setting that is safe and effective. 7. Family therapy or significant family/parental involvement in treatment should be a component of treatment of SUDs. 8. Treatment programs and interventions should develop procedures to minimize treatment dropout and to maximize motivation, compliance, and treatment completion. 9. Medication can be used when indicated for the management of craving and withdrawal and for aversion therapy. 10. Treatment should encourage and develop peer support, especially regarding the nonuse of substances. 11. Twelve-step approaches may be used as a basis for treatment. Attendance at Alcoholics Anonymous (AA) and Narcotics Anonymous (NA) groups is an adjunct to professional treatment of SUDs and should be encouraged. 12. Programs/interventions should attempt to provide comprehensive services in other domains (e.g., vocational, recreational, medical, family, and legal). 13. Adolescents with SUDs should receive thorough evaluation for comorbid psychiatric disorders.

244 Handbook of Office-Based Buprenorphine Treatment of Opioid Dependence

TABLE 12–1.

Recommendations for the assessment and care of adolescents with substance use disorders (SUDs) (continued)

14. Comorbid conditions should be appropriately treated. 15. Programs and interventions should provide or arrange for posttreatment aftercare. Source. Reprinted from Bukstein OG, Bernet W, Arnold V, et al; Work Group on Quality Issues: “Practice Parameter for the Assessment and Treatment of Children and Adolescents With Substance Use Disorders.” Journal of the American Academy of Child and Adolescent Psychiatry 44:609–621, 2005. Copyright © 2005 Elsevier.

facility (Deas and Brown 2006). Once medically stable, an adolescent may be a candidate for a less restrictive acute residential treatment (ART) program as an alternative to prolonged inpatient hospitalization. Based on a multimodal approach and therapeutic milieu model, ART programs work closely with parents and teens to build and strengthen interpersonal relationships, learn more about themselves through group therapy and classroom experience, and reinforce emerging healthy alternative behaviors for managing feelings and impulsive behaviors and avoiding substance use. Further evaluation to address specific concerns such as childhood trauma, eating disorders, learning disabilities, and school conflict can be coordinated as necessary. The goal of an ART program is to promote transition from the therapeutic milieu back to the community (Hawthorne et al. 1999; Stevens and Morral 2003).

LONG-TERM RESIDENTIAL PROGRAMS Long-term residential programs provide services over an average period of 3–12 months, and offer a variety of daily therapeutic sessions including individual, group, and family therapy as well as psychoeducation and psychopharmacology. They can accommodate adolescents with both psychiatric and substance use disorders who have been unable to stop using opioids and/or who have other selfinjurious behaviors. Locked facilities are available for youths at risk of running away (Bukstein et al. 2005).

THERAPEUTIC COMMUNITIES Therapeutic communities are drug-free residential settings that provide treatment for adolescents with addictions and behavioral disorders who have failed to respond to less intensive treatments and are unable to live at home. Adolescents treated in therapeutic community programs are more likely than those in outpatient programs to have prior substance abuse treatment experience and criminal

Therapy

Description

Mechanisms

Psychoeducation

Way of accessing and learning strategies to deal with substance abuse, mental illness, and their effects

•

Designed to teach skills for maintaining abstinence by identifying and modifying thoughts and feelings that precede substance use and trying new ways of behaving

• •

Patient-centered approach aimed at resolving ambivalence about engaging in treatment or stopping drugs

• • •

Cognitive-behavioral therapya

Motivation enhancement therapya

•

• •

•

Used in conjunction with other forms of treatment as a tool for understanding a patient’s illness Helps patients gain self-awareness, identify community resources, and develop a better understanding of the steps of recovery

Opioid Use by Adolescents

TABLE 12–2. Description of various psychosocial therapies

Manual-based, structured therapy Teaches patients to use refusal skills or avoid risky situations Patients record events/feelings/thoughts/behaviors Unrealistic assumptions and habits are identified and changed Stimulates discussion about personal substance use Evokes internally motivated change statements Embraces a dynamic and fluctuating view of willingness/ readiness to change Encourages small steps toward larger goals

245

Description of various psychosocial therapies (continued)

Therapy

Description

Mechanisms

Group therapy

“Safe” environment to examine issues related to peer pressure and relationships; facilitates interpersonal and intrapersonal growth through the use of the group dynamic

• • • •

Offers the feeling of “safety in numbers” for adolescents Developmentally normal preference among adolescents Cost-effective Member must be screened to determine group appropriateness

12-step fellowships (AA/NA/Alateen)

Peer-based support that uses the 12-step model

• • •

Members share their experiences, strengths, and hopes Adolescents should have an appropriate sponsor Adult meetings may not be appropriate for certain adolescents

Multidimensional family therapya

Form of family therapy specifically designed • to treat adolescents with substance abuse and behavioral problems •

Manual-based therapy with up to four individual and family sessions per week Utilizes intensive advocacy and phone contact with the adolescent’s school and the court system

Brief strategic family therapya

Designed to prevent, reduce, and/or treat • adolescent drug use, high-risk sexual behaviors, conduct problems, delinquency, violence, etc.

Sessions aim to improve family functioning (effective, positive parenting) and improve adolescent prosocial behaviors (school attendance and performance)

246 Handbook of Office-Based Buprenorphine Treatment of Opioid Dependence

TABLE 12–2.

Therapy

Description

Multisystemic therapya

• Intensive 4-month program addressing needs of youth at high risk of incarceration or foster care

Contingency management Based on behavioral principles that good behaviors, when rewarded (in a positive and supportive manner), are likely to be repeated Phoenix Academya

Mechanisms

• •

Therapeutic community model enhanced to • meet the developmental needs of teenagers ages 13–17 with substance abuse, mental • health, and behavioral disorders

Integrates comprehensive psychiatric and substance abuse services with in-home family sessions Patients are called weekly, at random, to provide urine specimens and are rewarded for each negative specimen Adolescent-appropriate rewards can include gift certificates, clothing, music, sports equipment, movie theater tickets, etc.

Opioid Use by Adolescents

TABLE 12–2. Description of various psychosocial therapies (continued)

Integrates residential treatment with on-site public school education at the junior high and senior high school level Some programs may include trade or technical training sponsored by local community colleges

Note. AA=Alcoholics Anonymous; NA=Narcotics Anonymous. aIndicates evidence-based practices (EBPs). See www.uncg.edu/csr/asatp/ebpmatrix.pdf for the complete matrix of EBPs with links to more information..

247

248 Handbook of Office-Based Buprenorphine Treatment of Opioid Dependence

justice histories, and are likely to have experienced more severe consequences. These closely supervised programs are typically longer than residential programs (12–24 months) and use a hierarchical model that reflects increased levels of personal and social responsibility that are acquired as progress is made through the various levels of treatment (Morral et al. 2004). Therapeutic communities differ from other treatment approaches mainly through their use of community and peer interactions as a means of learning and assimilating new attitudes, perceptions, and behaviors previously associated with drug use. However, modifications may be required to accommodate adolescent developmental differences, such as including on-site schooling and family support services.

Conclusion Adolescence is a time of physical, emotional, and psychological maturation, and experimentation with risky behaviors is common. Use of opioids by adolescents is on the rise, as is opioid dependence. Physicians should screen all adolescents for opioid use, and make an appropriate level of intervention whenever use is identified. Adolescents who have used opioids but are not opioid dependent may benefit from relatively brief office-based interventions. Adolescents who are opioid dependent should have a thorough assessment before beginning treatment. Although promising treatment interventions are emerging, additional research is needed to evaluate behavioral and pharmacological treatment options. This research will help identify how to best minimize opioid withdrawal symptoms and promote treatment retention and long-term opioid abstinence in the context of the maturing adolescent brain. Few medication studies have included adolescents, but accumulating evidence suggests that buprenorphine can be effective in reducing relapse rates with adolescent populations by stabilizing neurochemistry, ameliorating withdrawal, and curbing cravings.

Clinical Pearls • Since 2000, illicit use of prescription opioids has more than doubled in adolescents. Increased perception of availability, decreased social disapproval, and decreased perception of risk of using opioids are all factors suggesting that opioid misuse continues to be on the rise. • Since 2007, more teens have reported drug initiation with opioid pharmaceuticals than with any other class of drugs, including marijuana, making opioids a new gateway drug. Screening for drug use including opioids should occur as part of routine adolescent medical care.

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• Several screening questionnaires for adolescent substance abuse are available, including the CRAFFT questionnaire. Every adolescent should receive a brief intervention appropriate to his or her level of use based on screening results. • Pain medication can be safe for use even in adolescents with substance use disorders, and pain should not be left untreated because of a history of substance abuse or dependence. However, in these situations clinicians should require increased supervision and monitoring to avoid misuse. • No single approach is suitable for all individuals; treatment should be comprehensive and tailored to particular needs. In most cases, treatment should include opioid agonist therapy in conjunction with evidence-based behavioral therapies. All patients should be screened for co-occurring psychiatric symptoms, and comorbidities should be treated simultaneously. • Few medication studies have included adolescents, but accumulating evidence suggests that buprenorphine can be effective in reducing relapse rates with adolescent populations by stabilizing neurochemistry, ameliorating withdrawal, and curbing cravings. • Comprehensive treatment should incorporate behavioral therapy in addition to medication in settings ranging from office-based management to the hospital level of care. • Substances of abuse can induce, mimic, co-occur with, and/or exacerbate underlying mental illness; therefore, all adolescents with opioid dependence should be evaluated for co-occurring mental health disorders and be treated for both disorders simultaneously.

CASE 11 Tommy is a 16-year-old male who started intravenous heroin use when he was 13. He now uses up to 15 bags of heroin a day, has previously been in two detoxification programs, and has some very serious legal jeopardy hinged on his remaining sober. Both his parents are in Alcoholics Anonymous and oppose “using drugs to treat an addiction.” He smokes marijuana from time to time but does not drink or use other drugs. He was referred to your clinic by the drug court.

1. 2. 3. 4.

How does the approach to addiction differ in an adolescent? Can you legally prescribe buprenorphine to a 16-year-old? Is parental consent a requirement? What is a reasonable treatment goal in this case?

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References American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision. Washington, DC, American Psychiatric Association, 2000 Boyd CJ, McCabe SE, Cranford JA, et al: Adolescents’ motivations to abuse prescription medications. Pediatrics 118:2472–2480, 2006 Bukstein OG, Bernet W, Arnold V, et al; Work Group on Quality Issues: Practice parameter for the assessment and treatment of children and adolescents with substance use disorders. J Am Acad Child Adolesc Psychiatry 44:609–621, 2005 Catalano RF, Morrison DM, Wells EA, et al: Ethnic differences in family factors related to early drug initiation. J Stud Alcohol 53:208–217, 1992 Chang G, Kosten T: Detoxification, in Substance Abuse: A Comprehensive Textbook, 4th Edition. Edited by Lowinson J, Ruiz P, Millman R, et al. New York, Lippincott Williams & Wilkins, 2005, pp 579–586 Comer SD, Sullivan MA, Yu E, et al: Injectable, sustained-release naltrexone for the treatment of opioid dependence: a randomized, placebo-controlled trial. Arch Gen Psychiatry 63:210–218, 2006 Currie SR, Patten SB, Williams JV, et al: Co-morbidity of major depression with substance use disorders. Can J Psychiatry 50:660–666, 2005 Dasinger LK, Shane PA, Martinovich Z: Assessing the effectiveness of communitybased substance abuse treatment for adolescents. J Psychoactive Drugs 36:27–33, 2004 Deas D, Brown ES: Adolescent substance abuse and psychiatric comorbidities (online tutorial). J Clin Psychiatry 67:e02, 2006 Drug Strategies: Treating Teens: A Guide to Adolescent Drug Programs. Washington, DC, Drug Strategies, 2003 Fiellin DA: Treatment of adolescent opioid dependence: no quick fix. JAMA 300:2057–2059, 2008 Fiellin DA, O’Connor PG, Chawarski M, et al: Methadone maintenance in primary care: a randomized controlled trial. JAMA 286:1724–1731, 2001 Fudala PJ, Bridge TP, Herbert S, et al: Office-based treatment of opiate addiction with a sublingual-tablet formulation of buprenorphine and naloxone. N Engl J Med 349:949–958, 2003 Goodwin RD, Stayner DA, Chinman MJ, et al: The relationship between anxiety and substance use disorders among individuals with severe affective disorders. Compr Psychiatry 43:245–252, 2002 Greenblatt J: Year-End Preliminary Estimates From the 1996 Drug Abuse Warning Network (DHHS Publ No SMA 98–3175), Drug Abuse Warning Network series D-3 (Office of Applied Studies). Rockville, MD, Substance Abuse and Mental Health Services Administration, 1997 Hawthorne WB, Green EE, Lohr JB, et al: Comparison of outcome of acute care in short-term residential treatment and psychiatric hospital setting. Psychiatr Serv 50:401–406, 1999 Hertz JA, Knight JR: Prescription drug misuse: a growing national problem. Adolesc Med Clin 17:751–769, 2006 Hingson RW, Heeren T, Winter MR: Age at drinking onset and alcohol dependence: age at onset, duration, and severity. Arch Pediatr Adolesc Med 160:739–746, 2006

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Hopfer CJ, Khuri E, Crowley TJ, et al: Adolescent heroin use: a review of the descriptive and treatment literature. J Subst Abuse Treat 23:231–237, 2002 Hopfer CJ, Khuri E, Crowley TJ: Treating adolescent heroin use. J Am Acad Child Adolesc Psychiatry 42:609–611, 2003 Hughes PH, Rieche O: Heroin epidemics revisited. Epidemiol Rev 17:66–73, 1995 Jasinski DR, Pevnick JS, Griffith JD: Human pharmacology and abuse potential of the analgesic buprenorphine: a potential agent for treating narcotic addiction. Arch Gen Psychiatry 35:501–516, 1978 Jaycox LH, Ebener P, Damesek L, et al: Trauma exposure and retention in adolescent substance abuse treatment. J Trauma Stress 17:113–121, 2004 Johnston LD, O’Malley PM, Bachman JG, et al: 2007 data from in-school surveys of 8th-, 10th-, and 12th-grade students. University of Michigan News Service, Ann Arbor, MI. Available at: http://www.monitoringthefuture.org/data/07data.html. Accessed May 8, 2010. Johnston LD, O'Malley PM, Bachman JG, et al: Monitoring the Future national survey results on drug use, 1975-2008. Volume I: Secondary school students (NIH Publ No 09-7402). Bethesda, MD, National Institute on Drug Abuse, 2009. Available at: http://www.monitoringthefuture.org/pubs/monographs/vol1_2008. Accessed June 21, 2010. Kaminer Y, Burleson JA, Goldberger R: Cognitive-behavioral coping skills and psychoeducation therapies for adolescent substance abuse. J Nerv Ment Dis 190:737– 745, 2002 Knight JR, Shrier LA, Bravender TD, et al: A new brief screen for adolescent substance abuse. Arch Pediatr Adolesc Med 153:591–596, 1999 Knight JR, Sherritt L, Shrier LA, et al: Validity of the CRAFF T substance abuse screening test among adolescent clinic patients. Arch Pediatr Adolesc Med 156:607–614, 2002 Knight JR, Sherritt L, Van Hook S, et al: Motivational interviewing for adolescent substance use: a pilot study. J Adolesc Health 37:167–169, 2005 Levy S, Knight JR: Screening, brief intervention, and referral to treatment for adolescents. J Addict Med 2:215–221, 2008 Levy S, Harris SK, Sherritt L, et al: Drug testing of adolescents in ambulatory medicine: physician practices and knowledge. Arch Pediatr Adolesc Med 160:146–150, 2006 Levy S, Vaughan BL, Angulo M, et al: Buprenorphine replacement therapy for adolescents with opioid dependence: early experience from a children’s hospital-based outpatient treatment program. J Adolesc Health 40:456–461, 2007 Marsch LA: Treatment of adolescents, in The Treatment of Opioid Dependence. Edited by Strain E, Stitzer ML. Baltimore, MD, Johns Hopkins University Press, 2005, pp 497–507 Marsch LA, Bickel WK, Badger GJ, et al: Comparison of pharmacological treatments for opioid-dependent adolescents: a randomized controlled trial. Arch Gen Psychiatry 62:1157–1164, 2005 Mattick RP, Ali R, White JM, et al: Buprenorphine versus methadone maintenance therapy: a randomized double-blind trial with 405 opioid-dependent patients (see comment). Addiction 98:441–452, 2003

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Mattick RP, Kimber J, Breen C, et al: Buprenorphine maintenance versus placebo or methadone maintenance for opioid dependence. Cochrane Database of Systematic Reviews 2008, Issue 2. Art. No.: CD002207. DOI: 10.1002/14651858.CD002207. pub3. Miller WR: Why do people change addictive behavior? The 1996 H. David Archibald Lecture. Addiction 93:163–172, 1998 Morral A, McCaffrey DF, Ridgeway G: Effectiveness of community-based treatment for substance-abusing adolescents: 12-month outcomes of youth entering Phoenix Academy or alternative probation dispositions. Psychol Addict Behav 18:257–268, 2004 Oetting ER, Beauvais F: Peer cluster theory, socialization characteristics, and adolescent drug use: a path analysis. J Couns Psychol 34:205–213, 1987 Rettig R, Yarmolinsky A: Federal Regulation of Methadone Treatment. Washington, DC, National Academy Press, 1995 Rowan AB, Fudala PJ, Mulligan J: The medical management of adolescent heroin dependence. Curr Psychiatry Rep 2:527–530, 2000 Sees KL, Delucchi KL, Masson C, et al: Methadone maintenance vs 180-day psychosocially enriched detoxification for treatment of opioid dependence: a randomized controlled trial. JAMA 283:1303–1310, 2000 Stevens SJ, Morral AR (eds): Adolescent Substance Abuse Treatment in the United States: Exemplary Models from a National Evaluation Study. Binghamton, NY, Haworth, 2003 Teichman M, Kefir E: The effects of perceived parental behaviors, attitudes, and substance-use on adolescent attitudes toward and intent to use psychoactive substances. J Drug Educ 30:193–204, 2000 Weinberg NZ: Risk factors for adolescent substance abuse. J Learn Disabil 34:343–351, 2001 Wilens TE, Faraone SV, Biederman J, et al: Does stimulant therapy of attention-deficit/hyperactivity disorder beget later substance abuse? A meta-analytic review of the literature. Pediatrics 111:179–185, 2003 Wilens TE, Biederman J, Kwon A, et al: Risk of substance use disorders in adolescents with bipolar disorder. J Am Acad Child Adolesc Psychiatry 43:1380–1386, 2004 Wilson CR, Sherritt L, Gates E, et al: Are clinical impressions of adolescent substance use accurate? Pediatrics 114:e536–e540, 2004 Woody GE, Poole SA, Subramaniam G, et al: Extended vs short-term buprenorphinenaloxone for treatment of opioid-addicted youth: a randomized trial. JAMA 300:2003–2011, 2008

13 Logistics of Office-Based Buprenorphine Treatment Joji Suzuki, M.D.

OFFICE-BASED TREATMENT with buprenorphine is an effective treatment for opioid dependence. Buprenorphine prescribers should be aware of the various logistical elements necessary for establishing a successful office-based treatment program. The program can be structured in a wide variety of primary care and psychiatric practice settings. As long as the basic components of the practice are in place, there is a considerable amount of flexibility in meeting the recommendations set forth in various clinical guidelines (Center for Substance Abuse Treatment 2004; Federation of State Medical Boards of the United States 2002; McCance-Katz 2004). In this chapter, I outline the logistics of setting up an office-based treatment program, and discuss referral sources, staffing needs, office needs, documentation requirements, and models of care.

Referral Sources Referral sources should be identified before initiating treatment. Depending on the resources of each particular practice, the need for referral sources will vary. 253

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A private practice physician will have different needs than a substance abuse treatment clinic with multiple prescribers. The following are examples of sources that will refer potential patients for treatment.

INTERNET LISTINGS Online listings are an important source of patient referrals. Patients, their family members, nonwaivered physicians, substance abuse treatment centers, and others use these listings to identify prescribers. Appearing in online listings such as those described below significantly increases the likelihood of reaching potential patients. Conversely, a physician who wishes to limit the number of patients contacting the office may choose to remain off the lists, or choose to remove his or her name after a certain period of time. On completing the requirements for obtaining the waiver to prescribe buprenorphine, a clinician has the option to list his or her information on the Web site maintained by the Substance Abuse and Mental Health Services Administration (SAMHSA). Only when the physician agrees to this option will his or her contact information appear on the list. The online listing can be found at http://buprenorphine.samhsa.gov/bwns_locator. The Web site allows patients to search providers by geographic area, zip code, or name; it then identifies the office address and telephone number of each provider. If the physician does not wish to be on this list, or later decides to go on or come off the list, he or she may call 1-866-BUP-CSAT (1-866-287-2728) or e-mail [email protected] with requests to change his or her listing. The request to change the physician’s contact information can also be found online at http://buprenorphine.samhsa.gov/pls/bwns/updtcntct2$.startup. The buprenorphine-naloxone manufacturer, Reckitt Benckiser, maintains a Web site at www.suboxone.com that allows patients to search for prescribers based on the SAMHSA listing described above. In addition, the company offers a “Here to Help Program,” accessed online at http://heretohelpprogram.com. The program offers patients and their families assistance from “care coaches,” who can provide support, answer questions, and help find a prescriber or therapist. Patients can be referred directly to the prescriber’s practice by the care coaches if the prescriber chooses to participate in this program. To obtain further information about the program, or if interested in participating in this referral system, physicians should go online to http://heretohelpprogram.com/hcp/ physicians/Default.aspx. An enrollment form can be found at the site, which needs to be printed out and faxed to 1-866-239-0976. Physicians can also register their practice with the National Alliance of Advocates for Buprenorphine Treatment (NAABT) at www.naabt.org and join their physician-patient matching system. This matching system allows for physicians to connect with potential patients by matching characteristics that the

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provider can specify. Further instructions on how to use the system are explained in detail on the Web site.

LOCAL PHYSICIANS

AND

CLINICIANS

Frequently, potential patients are identified by physicians who are not waivered to prescribe buprenorphine. These referral sources may appreciate being able to refer patients for buprenorphine maintenance therapy while continuing to provide general medical or psychiatric care. Therefore it is important for waivered physicians to notify other colleagues or therapists that referrals for buprenorphine treatment are being accepted.

TREATMENT FACILITIES Another source of referrals is medical or psychiatric treatment facilities, or other substance abuse treatment programs. A patient may request help in locating a prescriber when admitted to an inpatient detoxification facility, for example. Treatment staff at such facilities may keep a listing of buprenorphine prescribers, which can be provided to care coordinators or directly to the patients. Alternatively, patients can use online resources, if available, so that the process of locating prescribers can begin before discharge.

Staffing Needs Even though successful office-based opioid dependence treatment programs share many common elements, staffing requirements vary with each practice setting. A private practitioner, for example, may decide to perform all the necessary clinical and administrative duties including performing urine toxicology tests, while using community resources for psychosocial treatment. In larger practices, physicians may choose to rely on clinical or administrative personnel to provide coordination of care as well as individual or group counseling onsite. The recommendations for staffing are as follows.

PRESCRIBER All prescribers must be physicians who have obtained the necessary waiver to prescribe buprenorphine (see Chapter 1, “Opioid Dependence in America”). Each physician is initially allowed to provide treatment for up to 30 patients. If the physician chooses to do so, the limit can be raised after 1 year to 100 patients. Information on how to increase the limit can be found at http:// buprenorphine.samhsa.gov/bwns/federal.html, and the submission can be completed online. Alternatively, physicians can contact the SAMHSA Center

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for Substance Abuse Treatment (CSAT) Buprenorphine Information Center by telephone at 1-866-BUP-CSAT (1-866-287-2728) or by e-mail at info@ buprenorphine.samhsa.gov. Resident physicians are eligible to obtain the waiver as long as the resident has a full medical license and is able to obtain a federal Drug Enforcement Administration (DEA) registration number.

NURSE PRACTITIONERS, PHYSICIAN ASSISTANTS, AND REGISTERED NURSES Nurse practitioners, physician assistants, and registered nurses are currently not eligible to obtain the waiver to prescribe buprenorphine (Center for Substance Abuse Treatment 2004). However, nonphysician clinicians can play an important role in the evaluation and ongoing care of patients. These clinicians could perform the initial telephone screens and the initial evaluations. In some settings, for example, a nurse practitioner may be the primary provider who has regular visits with the patient to monitor progress, whereas the prescription is provided by the physician who sees the patient at less frequent intervals. In such an arrangement, patients could be required to bring their medications to the visit for a pill count with the nurse practitioner.

PROGRAM COORDINATOR Unless the physician has the capacity to coordinate care for patients, as in a private practice that treats a limited number of patients, a clinical or administrative staff person can be used to help manage the flow of patients through the practice. Depending on the circumstances, a nurse, a social worker, a case manager, or an administrative staff member may be able to play this role, or these duties can be delegated to more than one individual. Ongoing training and regular feedback are imperative because the duties performed by the coordinator are critical to the operation of the practice. The coordinator might perform the following duties: • • • • •

Answer general questions about buprenorphine from patients, family members, or other providers seeking to refer a patient Manage the initial phone screening of potential patients for buprenorphine treatment Help organize the required forms and ensure that each patient chart contains the necessary documentation Manage and schedule office visits for inductions and follow-up visits Assume the role of primary contact person for patients, family members, and other providers.

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PSYCHOSOCIAL TREATMENT Ideally, psychosocial counseling is offered on-site as an integral component of treatment. Availability of psychosocial treatment on-site improves adherence to treatment as well as outcomes (McLellan et al. 1993). If psychosocial treatment is offered on-site, at least one clinician with experience treating substance use disorders needs to be identified. Individual counseling, group psychotherapy, family therapy, couples counseling, motivation enhancement therapy, relapse prevention, cognitive-behavioral therapy, and contingency management are examples of therapies that may be offered (Strain and Lofwall 2008). Additionally, group therapy is a method that is very effective, widely used, and popular among patients (Brook 2008). The support provided for and by peers is also an important element in recovery. Specialized groups, such as a women’s group, a young adults’ group, or a dual-diagnosis group, should be considered if appropriate (Brook 2008). (See Chapter 8, “Clinical Management II,” for more details on specific counseling approaches.) If psychosocial treatment is not offered on-site, it is recommended that appropriate therapists and counselors be identified before prescribing buprenorphine. A Web site maintained by SAMHSA at http://dasis3.samhsa.gov can be helpful in identifying such therapists at local substance abuse treatment facilities. A list of off-site providers and facilities should be developed and made available to patients. A collaborative approach and open communication about the clinical progress of patients helps improve patient care. For further discussion on this topic, see Chapter 8. Feedback from patients is also helpful in evaluating the quality of services provided by off-site clinicians. Over time, it will be easier to identify counselors, therapists, and facilities with experience working with buprenorphine patients. Ideally, these clinicians will also provide treatment in multiple modalities, so that treatment can be tailored to meet the needs of individual patients. Finally, all patients should be encouraged to attend and participate in 12step groups such as Alcoholics Anonymous (AA) or Narcotics Anonymous (NA) or other self-help groups. Evidence is clear that patients involved with 12-step and other self-help groups experience better outcomes (Moos and Timko 2008). Telephone directories in all areas of the United States usually list local AA and NA groups, and these groups’ local Central Service Offices (sometime referred to as intergroups) are able to direct patients to ongoing meetings. Information about finding a local AA or NA chapter can also be obtained on each group’s Web site: www.aa.org or www.na.org, respectively. Patients can also contact AA’s General Service Office directly at 1-212-870-3400 or NA directly at 1-818-773-9999, extension 771, to obtain information about local offices. (See Chapter 8 for details on effective techniques for working with patients in self-help programs.)

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GENERAL MEDICAL

OR

PSYCHIATRIC CARE

Because psychiatric diagnoses are common in patients with opioid dependence, general medical practitioners should have the ability to refer patients for psychiatric assessment and treatment when indicated (Kessler et al. 2005). Conversely, psychiatrists should have the ability to refer patients for medical care such as physical exams, baseline laboratory testing including liver function tests (LFTs), and treatment for HIV infection or hepatitis C. Moderate to severe hepatotoxicity has been reported in hepatitis C–positive patients prescribed buprenorphine (Berson et al. 2001). Psychiatrists should therefore have the capacity to obtain, on- or off-site, LFT results at baseline and periodically during maintenance therapy with buprenorphine.

TRAINING Mentoring and ongoing training for prescribing physicians as well as office staff are important considerations. Experienced buprenorphine prescribers in the local area can help navigate the various clinical and administrative issues that may arise during the course of treatment. A free SAMHSA-funded network of experts called the Physician Clinical Support System (PCSS) is available at www.pcssmentor.org. This mentoring system is composed of experts from across the United States and includes a variety of medical and psychiatric specialists who are available to act as individual resources and mentors for any enrolled physician. The PCSS Web site also contains helpful resources on clinical and logistical issues relevant to buprenorphine prescribers. Another resource for ongoing training for prescribers can be found at a National Institute on Drug Abuse–sponsored Web site called Buprenorphine (Suboxone) Training and Practice Tools, at www.buppractice.com. This site contains links to training guides and courses for clinical and administrative staff. Training for staff should include: • • • • •

Education on the disease concept of addiction and the rationale for longterm treatment The role of medication as well as psychosocial treatment in treating opioid dependence Rationale of policies outlined in the treatment agreement Maintaining patient confidentiality Professionalism.

For a more detailed discussion of issues related to staff training, see Chapter 7, “Clinical Management I.”

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COVERAGE Coverage for the prescriber during periods of absence needs to be arranged. The covering physician should be a prescriber himself or herself, so that buprenorphine can be provided in cases of emergency. Policies regarding early refills, lost medications, and benzodiazepine prescriptions, for example, should be agreed on in advance with the covering physicians. The coverage system should also be clearly communicated to the patient.

Office Needs The basic needs for the office are described here in further detail. Usually, incorporating buprenorphine treatment into an existing practice is quite simple. However, considerations should be given to the following areas.

PHYSICAL SPACE During the induction visit, patients may be required to wait in the waiting room for the duration of the visit, or they may be allowed to go off-site and return at a prearranged time. If the patient is going to remain on-site, comfortable seating, reading material such as magazines or educational materials, or a television with educational videos may help pass the time. A waiting room specifically reserved for patients undergoing induction may be created to provide privacy, but this is not required. If psychosocial treatment is offered on-site, rooms for individual and/or group therapy are needed. Efforts should be made to assure confidentiality, such as using noise machines to prevent conversations from being heard outside the room. If the prescriber is dispensing buprenorphine directly to patients for induction (see the next section), the medication must be kept in a secure location (i.e., stored on-site in a locked safe or within a locked room, with limited access). The DEA recommends installing an electronic alarm to provide further security.

BUPRENORPHINE INDUCTION: OFFICE OR PHARMACY If the prescriber chooses to dispense buprenorphine directly to patients for induction, the medication can be obtained from medical suppliers, or it can be purchased from the manufacturer by calling the Suboxone Help Line at 1-877-

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782-6966. For documentation requirements when buprenorphine is dispensed directly to patients from the office, see the section “Inventory of Any Controlled Substances Dispensed” later in this chapter. If the physician chooses not to dispense buprenorphine during the induction phase of treatment, it is important to identify a pharmacy that will provide the medication. Ideally, the pharmacy will be located close to the office, understand that patients may need to return frequently during induction, have a reliable supply of buprenorphine, and have business hours that are convenient for the purposes of induction. If prescriptions will be faxed to the pharmacy, the patient needs to sign a form allowing the release of information between the pharmacy and the physician’s office. The physician should decide before induction whether the patient will pick up the medications from the pharmacy before the visit or arrive at the office first. If the former, the physician should specify on the prescription that it should be filled only on the day of induction, or at most the day before induction. If patients are to arrive at the office first, physicians should be aware of the possibility that during busy hours pharmacies may require more time to fill the prescriptions, thus prolonging the distress and discomfort patients experience. Some pharmacies, however, allow for delivery, eliminating the need for prescriptions to be picked up.

TOXICOLOGY TESTING Assessing treatment efficacy through biological markers is an important component of successful substance abuse treatment (Moeller et al. 2008). Most commonly, urine toxicology testing is the preferred method due to its reliability, ease of administration, and low cost (Strain and Lofwall 2008). However, some practices may choose to incorporate oral fluid (saliva) or serum testing. Saliva testing in particular may be an attractive alternative due to its ease of sample collection, ability to provide prompt results, reliability, resistance to tampering, and acceptable cost, although the detection time is less than that of urine testing (Cone et al. 2007; DuPont and Selavka 2008). Sweat or hair testing should not be required as long as adequate urine or serum testing is conducted. If on-site urine collection is done, a suitable bathroom facility is needed. For the majority of buprenorphine practices, unobserved urine testing is sufficient. Various products intended for office-based testing with good reliability are available commercially at low cost. Observed urine sampling should not be a routine requirement unless there are reasons to believe that specimens are being tampered with or adulterated. If testing is done off-site, inquires should be made about how the specimen is obtained, tested, and reported. Additionally, the testing facility should have the ability to detect tampered or adulterated samples by testing for color, tem-

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perature, specific gravity, and creatinine (Moeller et al. 2008). Testing, whether on-site or off-site, should include testing for the presence of buprenorphine along with common classes of abused substances—opioids, amphetamines, cocaine, cannabis, benzodiazepines, and barbiturates. Breath, serum, or urine tests for alcohol should be available if indicated. Specific testing for semisynthetic opioids (e.g., oxycodone, hydrocodone) and synthetic opioids (e.g., methadone, fentanyl) should also be considered because routine toxicology testing assays do not identify them (Strain and Lofwall 2008). Ideally, urine specimens should be obtained both routinely and randomly because tests can only identify recent drug use. The exception is urine testing for cannabinoids, which can remain positive for 1–2 weeks in regular users and over 30 days in chronic heavy users (Moeller et al. 2008). Chapter 7 provides additional information on the technical aspects of urine drug screens and on the interpretation of test results. Finally, the physician and other clinical staff should have an agreement about how to respond to positive urine test results. The substance that tested positive, the phase of treatment, frequency of positive results, and status of other comorbid illnesses all should be included in determining the response to positive results.

FORMS Using standardized forms is very helpful in assuring full compliance with all documentation requirements. The following is a suggestion of forms that should be stocked and made available as needed: •

•

•

•

Telephone screening forms: Each practice needs to decide the appropriate criteria for entry into treatment. For practices without psychiatric expertise, for example, severe psychiatric illness may be an exclusion. Another reason for exclusion may be active co-occurring alcohol dependence or dependence on sedative-hypnotic drugs. To facilitate decisions on treatment eligibility, the initial telephone screen should be sufficiently structured so that all relevant information is obtained. Informed consent forms: Patients must provide written informed consent to enter treatment. If indicated, family members and significant others should be included in the discussion, with appropriate release of information. A sample informed consent form is included in Chapter 7. Treatment agreements: A clearly written treatment agreement should be reviewed with every patient. Suggestions for this agreement are described later in this chapter (see “Treatment Agreement” section), and a sample is provided in Chapter 7. Release of information forms: Signed consent must be obtained before disclosing any individually identifiable addiction treatment information to any

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•

•

third party. Patients should be advised that signed releases to communicate with previous and current providers as well as with the pharmacy are a requirement for entry into treatment. A sample release form is presented in Figure 13–1, in the “Confidentiality” section later in this chapter. DSM-IV-TR criteria for opioid dependence: A diagnosis of opioid dependence based on DSM-IV-TR criteria (American Psychiatric Association 2000) is a requirement for entry into office-based treatment with buprenorphine. Clinical Opiate Withdrawal Scale (COWS): A reliable and widely used clinician-administered scale to assess the severity of opioid withdrawal (Wesson and Ling 2003), COWS is helpful in assessing withdrawal symptoms during the induction phase of treatment.

INFORMATION

FOR

PATIENTS

Patient handouts should be made available in waiting rooms or be given directly to patients during office visits. Helpful patient materials are available online from Reckitt Benckiser at www.suboxone.com. As discussed earlier in the “Internet Listings” section of this chapter, another helpful Web site for patients provided by the manufacturer is www.heretohelpprogram.com. This Web site focuses on coaching and educating patients through the treatment process. The U.S. Food and Drug Administration also provides a sample patient handout, which can be found at www.fda.gov/downloads/Drugs/ DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ UCM191530.pdf. This handout includes information about the differences between Suboxone and Subutex that patients and families will understand. Suggested material for patient handouts includes: •

•

•

Information about buprenorphine: Patients may find information on the basic pharmacology of buprenorphine helpful. The ceiling effect and the blocking effect of buprenorphine should be described. Information on side effects, notably precipitated withdrawal, as well as the dangers of injection use of buprenorphine should also be included. Explanation of the induction visit: A written reminder should be provided, clearly explaining the procedure for the induction visit: the need to arrive in mild to moderate withdrawal, the need to arrive with a full bladder, the need to spend several hours at the office, and so forth. Psychosocial treatment resources in the local community: If patients are going to be referred to off-site psychosocial treatment, they should be given a list of local treatment providers and facilities, including information about AA and NA meetings.

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Privacy rights: Patients should be provided with a written summary of confidentiality provisions and a notice that federal regulations protect substance abuse treatment records from unnecessary disclosure.

CONFIDENTIALITY Patients entering substance abuse treatment are justifiably concerned about privacy issues. Federal privacy regulations have been enacted not just to protect patient privacy but also to provide reassurance to patients that their information will not be disclosed without their permission. The physician must adhere to the privacy requirements outlined by the confidentiality regulation of Title 42, Part 2 of the Code of Federal Regulations (42 C.F.R. Part 2), Confidentiality of Alcohol and Drug Abuse Patient Records. This regulation applies to office-based treatment of opioid dependence with buprenorphine and prohibits the prescriber from releasing individually identifiable addiction treatment information without a signed consent from the patient. Release of information for the pharmacy is required for buprenorphine prescriptions to be faxed. However, consent for disclosure is not required for medical emergencies and mandated reporting. The consent form authorizing the release of information must contain the following elements: • • • • • • • • •

Name of the patient Name of the provider or facility being authorized to provide identifying information Type and amount of information to be disclosed Name of the individual or facility to which disclosure is being made Purpose of the disclosure (be as specific as possible) Signature of patient and date Signature of parent, guardian, or authorized representative (if required) Expiration of the release 42 C.F.R. Part 2 Notice.

A sample format that satisfies the above requirements is shown in Figure 13–1.

BILLING Currently there are no special addiction medicine or addiction psychiatry codes for billing office-based opioid dependence treatment. Physicians should be aware that insurance reimbursements vary.

264 Handbook of Office-Based Buprenorphine Treatment of Opioid Dependence

•

I, ______________________________ (name of patient)

•

authorize ________________________ (name or general designation of program which is to make the disclosure)

•

to disclose _______________________ (kind and amount of information to be disclosed)

•

to ______________________________ (name or title of the person or organization to which disclosure is to be made)

•

for _____________________________ (purpose of disclosure, as specific as possible).

•

I understand that my records are protected under the federal regulations governing confidentiality of alcohol and drug abuse patient records, 42 CFR Part 2, and cannot be disclosed without my written consent unless otherwise provided for in the regulations.

•

I also understand that this consent is subject to revocation at any time except to the extent that the program which is to make the disclosure has already taken action in reliance on it. If not previously revoked, this consent will terminate upon _____________________________________ (specification of date, event, or condition).

•

Signature of patient __________________________________

•

Signature of parent, guardian, or authorized representative (where required) __________________________________

•

Date ___________________________ (date on which this consent is signed)

FIGURE 13–1. Sample release of information form. Source. Adapted from the Code of Federal Regulations, Title 42, Part 2, Confidentiality of Alcohol and Drug Abuse Patient Records, Section 2.31 (form of written consent); available at: http://edocket.access.gpo.gov/cfr_2002/octqtr/42cfr2.31.htm.

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Primary Care Primary care physicians should use Current Procedural Terminology evaluation and management (E/M) codes, based on either complexity of service or time. Coding based on time is used if counseling or coordination of care takes up more than half of the visit. Counseling is defined as face-to-face time spent with the patient, family members, or other caregiver discussing such topics as diagnostic results, impressions, prognosis, risks and benefits of treatment, and instructions for treatment. If billing as time-based treatment, the total time for the visit, total time spent counseling, and the content of the counseling must be included in the documentation. For the initial evaluation visit, use the following codes, either time based or complexity based: • •

99205 (Outpatient: New) 99215 (Outpatient: Established).

For the induction visit, the prolonged visit codes can be used in addition to the usual E/M codes. However, only face-to-face time with the patient, continuous or not, beyond the average time required for a visit can be billed. The codes are as follows: • •

99354 (Prolonged visit: up to 60 additional minutes) 99355 (Prolonged visit: each additional 30 minutes beyond 99354).

Psychiatry Psychiatrist should use Behavioral Health codes. These codes are time based, and do not involve any complexity-based requirements. There are no special codes for prolonged visits. The following are the codes psychiatrists should use: • • •

•

•

90801 (Outpatient: Initial assessment) 90862 (Outpatient: Medication management without psychotherapy) 90804, 90806, and 90808 (Outpatient: Psychotherapy without medication evaluation and management for 20–30 minutes, 45–50 minutes, and 75– 80 minutes, respectively) 90805, 90807, and 90809 (Outpatient: Psychotherapy with medication evaluation and management for 20–30 minutes, 45–50 minutes, and 75– 80 minutes, respectively) 90853 (Outpatient: Group psychotherapy).

Accepting cash for office-based treatment is an acceptable option. Due to privacy concerns, some patients may in fact seek providers who accept cash. Nevertheless, ethical billing practices should be followed when determining

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fees. It should be noted that if a physician has a contract with an insurer, the contract may prohibit the acceptance of cash for covered services, even if provided in a different practice setting. Physicians are advised to check with each insurer to confirm whether accepting cash is allowed and, if not, whether accepting cash is allowed if a specific waiver is signed by the patient.

Documentation The recommendations for documentation for office-based treatment of opioid dependence are outlined in the guidelines set by the Federation of State Medical Boards (2002). The documentation should remain current, and it should be easily accessible and available if there is a need for review by regulatory agencies. Specifically, the physician should include the components described below.

EVALUATION

OF THE

PATIENT

At the time of the initial evaluation, a medical history and physical examination should be completed and documented. Evaluation of the medical history should include the following components: • • • • •

Nature of the patient’s addiction(s) Underlying or comorbid medical conditions Physical and psychological dysfunction caused by the drug use History of substance use and prior treatments Suitability of patients for buprenorphine maintenance based on the diagnosis of opioid dependence using DSM-IV-TR criteria.

TREATMENT PLAN The treatment plan should include clear objectives that can be documented and monitored throughout the course of treatment. Objective measures for treatment may include abstinence from substances of abuse, attendance at psychosocial treatment, and improved psychological and physical functioning. Referral to psychosocial interventions and the involvement of family and significant others should be recommended and documented in the treatment plan. Finally, the treatment plan should include responses to treatment failure.

TREATMENT AGREEMENT The physician should negotiate a formal treatment agreement with each patient. The following issues need to be discussed and included in the signed treatment agreement:

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Risks and benefits of treatment with buprenorphine, including precipitated withdrawal and interactions with benzodiazepines Receiving buprenorphine from one prescriber and pharmacy Treatment options other than buprenorphine Policies regarding urine toxicology testing and pill counts Policies regarding the number and frequency of refills for buprenorphine Policies regarding the discontinuation of buprenorphine therapy Policies regarding no-shows and appointment cancellations Policies regarding the replacement of lost or stolen medication Responsibility for safe storage of medication Prohibition against diversion of prescriptions Expectations for psychosocial treatment Procedures for contacting the office off-hours Expectations regarding payment.

See Chapter 7 for an example of a model treatment agreement. Patients should be given a copy of the signed treatment agreement.

INFORMED CONSENT The signed informed consent provided by the patient should be a part of the medical record. A sample informed consent form is included in Chapter 7, Figure 7–1.

RELEASE

OF INFORMATION

Documentation of consent to release individually identifiable information should be included in the medical record. A sample release form is presented in Figure 13-1; see the section “Confidentiality” earlier in this chapter.

DIAGNOSTIC, THERAPEUTIC, AND LABORATORY TEST RESULTS The medical record should contain the results of any tests that were conducted as part of the evaluation or ongoing monitoring. Baseline laboratory evaluation such as a complete blood count, LFTs, electrolyte levels, urine toxicology, and assessments by mental health providers should all be documented.

CONSULTATIONS The medical record should include documentation of referrals to consultants for additional evaluation and treatment, if indicated. The results of such con-

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sultations should be included in the medical record. Before starting treatment, patients should be asked to sign HIPAA (Health Insurance Portability and Accountability Act)–compliant release of information forms to permit communication among all providers involved in their care. This should be a mandatory requirement for participation in treatment. A sample release of information form (Figure 13–1) is included in the earlier “Confidentiality” section of this chapter.

MEDICATIONS PRESCRIBED Documentation is required for all prescriptions provided to patients, which should include the date, patient’s name, dosage, quantity, and number of refills for each medication prescribed and/or dispensed. Including a photocopy of every prescription prescribed will satisfy this requirement.

INVENTORY OF ANY CONTROLLED SUBSTANCES DISPENSED If the prescriber chooses to dispense buprenorphine directly to patients from supplies kept in the office, a physical inventory must be kept. A written log of all doses dispensed must be maintained and kept up to date (Federation of State Medical Boards of the United States 2002). The log should track and document the date, patient’s name, dosage, and quantity of all medications dispensed. Clinicians must comply with any relevant state and federal regulations regarding the dispensing and storage of buprenorphine. For state regulations, physicians should ensure compliance by contacting their state substance abuse agencies. A listing of such agencies can be found through the SAMHSA Web site at http://buprenorphine.samhsa.gov/pls/bwns_locator/abusedirectors.

Models of Care Office-based treatment with buprenorphine can be provided in a variety of treatment settings and modified to match specific resource availability. For most community-based psychiatrists and primary care physicians, integrating office-based treatment into their current practice should not be difficult. Several models of care are presented below. Each of these models fulfills the basic clinical requirements and does so by utilizing very different physical and staffing resources. Each of these models can be further customized according to the particular needs of the practice.

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PRIVATE PRACTICE MODEL: PSYCHIATRY •

• •

• • •

• •

Overview: The private practice psychiatrist manages the treatment with support from off-site therapists; the focus is on integrating outpatient psychiatric care with substance abuse treatment. Setting: The private practice office of a psychiatrist. Primary referral source: Patient self-referral through Internet listings; referral from other psychiatrists; referral from community substance abuse treatment facilities (i.e., detoxification units, residential programs); patients with severe or uncontrolled psychiatric illness identified are referred to practices with higher levels of care. Staffing: Psychiatrist. Pharmacy: Local community pharmacy. Patient flow: Patients are screened over the phone and then scheduled for an initial evaluation visit. Patients are required to have a primary care physician. Patients are also required to meet with an individual therapist if not already engaged in individual therapy. On day 1 of induction, a prescription for a 1-week supply of buprenorphine is provided. The first dose is then given under direct observation. The patient returns 2 hours later for reassessment. The patient returns on day 2 or 3 for additional assessments, and the dosage is adjusted as needed. The patient returns weekly for the first month. If urine toxicology results are negative and the buprenorphine dosage is stable for a specific period of time, the visit interval is increased to every 2 weeks for 1–2 months before increasing monthly. Urine toxicology: Obtained at every visit initially, then randomly once a period of stability in test results is achieved. Psychosocial treatment: Mandatory counseling with an off-site therapist in the community.

PRIMARY CARE MODEL: COMMUNITY-BASED PRIMARY CARE CLINIC •

• •

Overview: The primary care physician manages the clinical care with the support of an on-site addiction counselor; the focus is on integrating primary care and substance abuse treatment. Setting: An urban neighborhood health clinic. Primary referral source: Patient self-referral through Internet listings; referrals from clinicians in other community health centers.

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• • •

• •

Staffing: Primary care physicians, counselors, nurses. Pharmacy: Local community pharmacy. Patient flow: After the initial telephone screening, the patient is evaluated face-to-face by a physician and separately by an addiction counselor. If appropriate, the patient is scheduled for the induction visit. The patient fills the prescription at the pharmacy before arriving for the induction, and the first dose is given while being directly observed. The patient returns 2 hours later to be reassessed. The patient is reassessed again in several days and returns to meet the prescriber weekly for the first month. If urine screening results are negative and the buprenorphine dosage is stable, the patient returns for visits every 2 weeks. If the patient continues to demonstrate a positive response to treatment, visits are scheduled monthly. Urine toxicology: Obtained at every visit. Psychosocial treatment: Mandatory weekly meetings with an on-site addiction counselor.

NURSE CARE MANAGER MODEL: HOSPITAL-BASED PRIMARY CARE CENTER •

• • • • •

Overview: A nurse care manager acts as the coordinator and is responsible for the day-to-day clinical care, including the induction and ongoing maintenance visits; the nurse undergoes 8 hours of training similar in content to the training required for physicians to obtain the waiver to prescribe buprenorphine; the focus is on providing coverage to a large number of patients, integrating primary care with substance abuse treatment. Setting: A large, urban, hospital-based primary care center. Primary referral source: Referral through a state-run hotline for substance abuse treatment. Staffing: Primary care physicians, nurse care manager, addiction counselors. Pharmacy: On-site hospital pharmacy for outpatients. Patient flow: After the initial telephone screening, the patient is scheduled to meet with the nurse for the initial evaluation visit. If appropriate, the patient returns for a second evaluation visit to meet the physician. The physician ultimately decides whether the patient will be allowed entry into treatment. If the patient is approved, a prescription for a 1-week supply of buprenorphine for induction is faxed to the pharmacy, to be picked up by the patient on the day of induction. The patient returns for the induction, which is supervised by the nurse. The patient remains at the clinic for several hours before being allowed to leave to complete the induction at home, but remains in contact with the nurse by telephone. The patient meets with the nurse frequently during the first week, then weekly for 1–2 months. If

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•

•

271

urine screening results are negative and the buprenorphine dosage is stable, the visit interval is gradually increased to every 2 weeks, then every 3 weeks, and then once a month. The patient meets with the prescriber at a minimum of every 6 months, and a monthly prescription is faxed to the pharmacy with up to five refills. If the patient is not adherent to treatment, the nurse cancels any unused refills on the prescription. Urine toxicology: Frequent on-site testing initially, then random urine testing and pill counts; for random testing, patients are given a call in the morning and are required to provide a urine sample that day, and to bring their medications for a pill count within 48–72 hours. Psychosocial treatment: Mandatory weekly on-site group counseling for a minimum of 6 months.

INTENSIVE OUTPATIENT MODEL: HOSPITAL-BASED DUAL-DIAGNOSIS CLINIC •

• •

• • •

•

Overview: Psychiatrists and therapists in an integrated dual-diagnosis treatment clinic manage the treatment; the focus is on treating patients with co-occurring psychiatric disorders and individuals who were not successful in a less structured program. Setting: A hospital-based dual-diagnosis clinic. Primary referral source: Referrals accepted only from patients with a primary care physician at the affiliated hospital and with a documented physical examination within 30 days of entry into treatment. Staffing: Psychiatrists, psychologists, nurses, social workers, case managers. Pharmacy: On-site hospital pharmacy for outpatients. Patient flow: After the initial telephone screening, the patient is scheduled to meet with a social worker for an initial evaluation visit. If appropriate, the patient returns for an evaluation with a physician. The physician ultimately decides whether the patient will be allowed entry into treatment. If the patient is approved, a 2- to 3-day supply of buprenorphine for induction is faxed to the pharmacy to be picked up by the patient on the day of induction. The patient is observed for the first induction dosing, then returns to the clinic every 2 hours as needed. The patient is reassessed within several days. The patient meets the physician weekly for at least 1–2 months. If urine screening results are negative and the buprenorphine dosage is stable, the visit interval is increased to every 2 weeks. After several months of stability, the interval may be increased to once a month. Urine toxicology: Frequent on-site testing initially, then randomly once a period of stability in test results is achieved; after receiving notice for random testing, the patient has 36 hours to provide a urine sample.

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•

Psychosocial treatment: Mandatory on-site intensive outpatient treatment for 4 weeks after completion of induction, and weekly on-site group therapy thereafter. The intensive outpatient treatment consists of 3 hours of group therapy per day, 3 days a week, for a total of 4 weeks. If appropriate, the patient is offered concurrent individual therapy. Additional group therapy may be offered depending on the patient’s need. After completion of the intensive outpatient phase, the patient is required to attend group therapy once a week for the duration of treatment.

OPIOID DEPENDENCE TREATMENT PROGRAM MODEL: METHADONE CLINIC •

• • • • •

•

•

Overview: A physician within a methadone clinic dispenses buprenorphine, utilizing the infrastructure already available; SAMHSA regulations do not require such a physician to obtain the DEA waiver, nor is he or she bound by the 30-patient limit; the focus is on providing comprehensive help to patients with a wide spectrum of severity of opioid dependence. Setting: A methadone clinic. Primary referral source: Patient self-referral; methadone clinic staff. Staffing: Internist, nurses, addiction counselors, case managers. Pharmacy: Medication is dispensed by the clinic, following the same takehome regulations that apply to methadone treatment. Patient flow: After the initial telephone screening, the patient is scheduled to meet with a counselor for an initial evaluation visit. If appropriate, the patient returns for an evaluation visit with a physician. The physician ultimately decides whether the patient will be allowed entry into treatment. The patient is observed for the first induction dosing, then returns to the clinic every 2 hours as needed. The patient is reassessed daily until a stable buprenorphine dosage is established. The patient meets the physician weekly initially, and the visit interval is increased gradually. Urine toxicology: Frequent on-site testing initially, then randomly once a period of stability in test results is achieved; after receiving notice for random testing, the patient has 36 hours to provide a urine sample. Psychosocial treatment: Mandatory weekly on-site group counseling.

Conclusion Office-based buprenorphine treatment is an effective method of helping opioid-dependent patients achieve abstinence from illicit drug use. This chapter reviews the logistical requirements for setting up a successful office-based

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buprenorphine treatment program. Flexibility exists in how the necessary elements can be incorporated into existing programs. As long as the basic components outlined in this chapter are present, office-based opioid dependence treatment programs can be tailored to meet the specific needs of each particular practice.

Clinical Pearls • Necessary elements for office-based treatment of opioid dependence are not difficult to integrate into existing clinical programs. • Prepare in advance for ancillary services, including on-site or off-site psychosocial treatments. • Ongoing participation in psychosocial counseling and self-help programs are critical to successful treatment and should be required of all patients. • Adequately train office staff regarding the treatment of patients with opioid dependence, including the importance of pharmacotherapy, long-term treatment, confidentiality, and office policies. • Ensure proper documentation. • Provide urine toxicology testing to monitor treatment progress.

References American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision. Washington, DC, American Psychiatric Association, 2000 Berson A, Gervais A, Cazals D, et al: Hepatitis after intravenous buprenorphine misuse in heroin addicts. J Hepatol 34: 346–350, 2001 Brook DW: Group therapy, in The American Psychiatric Publishing Textbook of Substance Abuse Treatment, 4th Edition. Edited by Galanter M, Kleber HD. Washington DC, American Psychiatric Publishing, 2008, pp 413–428 Center for Substance Abuse Treatment: Clinical Guidelines for the Use of Buprenorphine in the Treatment of Opioid Addiction. Treatment Improvement Protocol (TIP) Series 40. DHHS Publ No (SMA) 04-3939. Rockville, MD, Substance Abuse and Mental Health Services Administration, 2004. Available at: http:// www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=hssamhsatip&part=A72248. Accessed April 29, 2010. Cone EJ, Clarke J, Tsanaclis L: Prevalence and disposition of drugs of abuse and opioid treatment drugs in oral fluid. J Anal Toxicol 31:424–433, 2007

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DuPont RL, Selavka CM: Testing to identify recent drug use, in Textbook of Substance Abuse Treatment. Edited by Galanter M, Kleber HD. Washington DC, American Psychiatric Publishing, 2008, pp 655–664 Federation of State Medical Boards of the United States: Report of the Center for Substance Abuse Work Group: Model Policy Guidelines for Opioid Addiction Treatment in the Medical Office. April 2002. Available at: www.fsmb.org/pdf/ 2002_grpol_opioid_addiction_treatment.pdf. Accessed January 15, 2009. Kessler RC, Chiu WT, Demler O, et al: Prevalence, severity, and comorbidity of 12month DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry 62:617–627, 2005 McCance-Katz EF: Office-based buprenorphine treatment for opioid-dependent patients. Harv Rev Psychiatry 12:321–338, 2004 McLellan AT, Arndt IO, Metzger DS, et al: The effects of psychosocial services in substance abuse treatment. JAMA 269:1953–1959, 1993 Moeller KE, Lee KC, Kissack JC: Urine drug screening: practical guide for clinicians. Mayo Clin Proc 83:66–76, 2008 Moos RH, Timko C: Outcome research on 12-step and other self-help groups, in Textbook of Substance Abuse Treatment. Edited by Galanter M, Kleber HD. Washington DC, American Psychiatric Publishing, 2008, pp 511–521 Strain E, Lofwall MR: Buprenorphine maintenance, in The American Psychiatric Publishing Textbook of Substance Abuse Treatment, 4th Edition. Edited by Galanter M, Kleber HD. Washington DC, American Psychiatric Publishing, 2008, pp 309–324 Wesson DR, Ling W: The Clinical Opiate Withdrawal Scale (COWS). J Psychoactive Drugs 35:253–259, 2003

14 Comments on the Case Vignettes John A. Renner Jr., M.D. Gregory Acampora, M.D.

CASE 1 FROM CHAPTER 6, “CLINICAL USE

OF

BUPRENORPHINE”

Given that Sally is over 18 years old and meets 4 of the 7 criteria for opioid dependence (tolerance, withdrawal, failure to stop on her own, and continued use despite negative impact on her functioning; see Table 5–5, DSM-IV-TR criteria for substance dependence), she meets federal criteria for buprenorphine treatment. She would not be eligible for methadone maintenance since she has not been dependent for the required 12 months. According to DSM-IV-TR criteria (American Psychiatric Association 2000), she cannot be given the diagnosis of opioid abuse because she meets criteria for dependence for that class of drugs. Because there is no evidence of dependence on other drugs or alcohol or another psychiatric disorder and she has been doing well in college, she would likely be an excellent candidate for office-based treatment. Before starting treatment, she should be educated about buprenorphine and asked to sign an informed consent form for treatment. It would be important to stress that a) buprenorphine will cause a form of opioid dependence; b) withdrawal symptoms will occur if she stops taking the drug abruptly; and c) although the medication is safe when taken as directed, it can cause death if taken with benzodiazepines or other sedative-hypnotic drugs, including alcohol. A urine 275

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toxicology screen for opioids and other common drugs of abuse is a highly recommended element in the initial evaluation of potential buprenorphine patients. She should be asked to abstain from any opioid use for at least 24 hours before induction and plan to spend 4–6 hours in the office on the day of induction. It will be necessary that she experience some moderate withdrawal symptoms before her initial dose, but she should also be told that the symptoms can be easily controlled once buprenorphine therapy is started. Her history suggests that she will be reliable, so it would be appropriate to write an initial buprenorphine prescription to cover the first 2 or 3 days of induction. An initial sublingual dose of 4 mg buprenorphine/1 mg naloxone would be standard, once you have documented a moderate level of opioid withdrawal. If symptoms of precipitated withdrawal occur, additional buprenorphine doses of 2 mg to 4 mg (in combination with naloxone 0.5 mg to 1 mg) should be adequate to control the symptoms. In most circumstances, no more than 8 mg of buprenorphine would likely be required for the first 24 hours of induction. A target buprenorphine dose range of 8–16 mg/day is reasonable for most patients, particularly younger patients with shorter histories of dependence, as in this case. The initial goal of treatment should be stabilization, control of craving and withdrawal symptoms, and elimination of illicit drug use. Once stability is achieved, a gradual buprenorphine taper can be initiated. We recommend a minimum of 1 year of treatment before attempting detoxification, assuming the patient has invested in counseling and mutual support groups and has demonstrated a mature level of coping skills. Before attempting detoxification, the patient needs to be educated about the high risk of relapse and the value of long-term, if not indefinite, agonist therapy.

CASE 2 FROM CHAPTER 7, “CLINICAL MANAGEMENT I” Converting a patient from methadone to buprenorphine treatment is fairly straightforward. After obtaining a release from the patient, you should contact the methadone clinic to verify the patient’s status and negotiate a gradual methadone taper to 30 mg/day. After the patient has been stable on that dosage for at least a week, methadone should be discontinued and the patient should report to your office 24–36 hours after the last methadone dose, at a time when he is in mild to moderate opioid withdrawal. After you document his withdrawal symptoms with the Clinical Opiate Withdrawal Scale (COWS), induction can begin with a dose of 4 mg buprenorphine/1 mg naloxone, following standard induction recommendations. After the first dose of buprenorphine no further methadone should be taken. Any ongoing symptoms of withdrawal should be handled with additional doses of buprenorphine, up to a total firstday dose of 12 mg buprenorphine/3 mg naloxone.

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Any patient requesting transfer from another buprenorphine provider should be assessed carefully. It is important to verify the patient’s report by talking directly with his current physician. In some cases, patients may be trying to avoid participation in counseling or other important supportive services. You may choose to establish a minimum level of participation in ancillary treatment or recovery activities for your practice; if you decide to do so, make sure that patients understand your requirements before you accept them into treatment. Weekly group therapy with a skilled addiction counselor and/or regular involvement in Alcoholics Anonymous (AA) or Narcotics Anonymous is helpful to most—but not all—patients. Let your patient know that research data show the best treatment outcomes occur in those who commit to a comprehensive recovery program that includes behavioral treatment.

♦ ♦

♦

♦

♦ ♦

♦

It is often recommended that patients sign a treatment agreement that describes expectations regarding attendance, urine testing, participation in psychosocial treatment, and rules about the use of other medications as well as expectations for abstinence from all illicit drugs. The occurrence of cocaine abuse and a missed group therapy session indicate the need to review the patient’s status and may require an increase in counseling, a shortening of the time between medication visits, or more frequent urine tests. Although clear rules are important, the clinician should be flexible and approach problems from the perspective that rule violations indicate the need for more intensive treatment, not punishment. Patients should always be given the opportunity to correct problems before any decision is made to terminate care or to refer the patient to a more structured opioid treatment program.

CASE 3 FROM CHAPTER 8, “CLINICAL MANAGEMENT II” Clinicians treating patients with buprenorphine should have a working knowledge of drug testing and interpretation of test results. Most standard drug tests provide very accurate results within a nominal cost structure, and the availability of mass spectroscopy–gas chromatography assures valid confirmation of questionable results. Positive test results for illicit drugs require a meeting with the patient to review the results. If the patient continues to deny use (after confirmatory lab tests), we recommend gentle confrontation from the perspective of motivational interviewing—comment on the frequency of relapse, the ongoing struggle with the disease of addiction, the difficulty many individuals have admitting problems, and the patient’s likely ambivalence about complete sobri-

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ety. Be sure to emphasize your desire to work with him to establish a more successful recovery program. Clinicians can expect occasional relapses, even in the most motivated patients, and may use these episodes to educate the patient about the nature of the illness and identify weaknesses in the current recovery program. Transfer to a higher level of care should only be considered after clear evidence of recurrent failure in office-based treatment.

CASE 4 FROM CHAPTER 8, “CLINICAL MANAGEMENT II” Martha should be encouraged to seek out a new sponsor who is accepting of addiction pharmacotherapy. Make sure that she understands that taking buprenorphine as prescribed under medical supervision is not a form of addiction. Also let her know that patients who attempt recovery on their own are less likely to succeed. Her initial participation in AA was an important element of her success with buprenorphine treatment; having a sponsor and joining a “home group” are good indications that an individual is seriously committed to the AA program. Clinicians should encourage participation in mutual support groups, but patients need to be informed about both the benefits and risks of such programs. AA has no formal position on medication-assisted recovery, although it is supportive of medication taken under physician supervision and of psychotherapy. Unfortunately, some individual AA members strongly discourage any form of psychopharmacology, including methadone and buprenorphine. If Martha is not able to find a more supportive sponsor or AA group, she should be encouraged to explore alternative self-help programs or be referred for individual or group psychotherapy.

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CONTINUED FROM CHAPTER 11, “MANAGEMENT CHRONIC PAIN”

OF

A CUTE

AND

Perioperative pain control for a buprenorphine patient builds on the options described in the Case 10 discussion. For minor planned surgery, such as dental extractions, the patient may continue on his or her daily buprenorphine dose and be given supplemental low doses of sublingual buprenorphine (buprenorphine 2 mg/naloxone 0.5 mg) or a short-acting opioid (oxycodone, hydrocodone, or fentanyl) every 6–8 hours as needed for 1 or 2 days after surgery. For major surgery, the buprenorphine dosage may be stopped 2 days before the surgery (tapering the dose is not required); 10–20 mg of methadone may be given the day before surgery and then full opioid agonist analgesics may be used as required following the operation. Once acute postsurgical pain has resolved, buprenorphine therapy can be reinduced.

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279

If the patient is pregnant, then she should be switched from the combo buprenorphine-naloxone tablets to the mono buprenorphine tablets (without naloxone) with the same dose and dosing schedule. Naloxone may result in third-trimester pregnancy complications due to either a) the minute amounts of the drug that may be bioavailable through the sublingual route (if the woman takes the buprenorphine-naloxone medication as prescribed), or b) the acute precipitated withdrawal caused by naloxone (if the woman decides to crush and inject the buprenorphine-naloxone tablets). Alternatively, a pregnant patient may be switched to methadone for the treatment of her opioid dependence.

CASE 5 FROM CHAPTER 8, “CLINICAL MANAGEMENT II” Some buprenorphine patients may escalate their drinking once their opioid problem is under control or increase their use of other substances. Discuss with Henrietta that her drinking is beyond the limits of safe social consumption and that mixing buprenorphine and alcohol or other sedative-hypnotic drugs can be dangerous. It is likely that she will need treatment for alcohol dependence, including alcohol detoxification. Opioid addicts are at high risk for dependence on other classes of drugs. The safest recovery necessitates the elimination of all alcohol, tobacco, and illicit drug use; buprenorphine patients, in particular, need to carefully monitor their use of alcohol or prescribed medications with any abuse potential. In this case, Henrietta should be encouraged to join AA, and 12-step facilitation may be a useful therapy approach. If she requires alcohol detoxification, be sure to refer her to a facility that will permit her to continue taking buprenorphine during hospitalization.

♦ ♦ CONTINUED

FROM

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♦

CHAPTER 9, “PSYCHIATRIC COMORBIDITY”

It is helpful to have office policies regarding the management of intoxicated patients. In this case, the immediate issue is patient and staff safety. If the patient refuses detoxification treatment, she should not be permitted to drive home intoxicated. However, it is not safe to challenge uncooperative, intoxicated individuals; in rare circumstances, it may be necessary to seek assistance from law enforcement or security personnel to contain the situation. Although this problem is very rare with buprenorphine patients, staff should be educated about the management of belligerent or intoxicated patients. If patients are unable to control inappropriate behavior or cover the cost of treatment, they should be referred to a structured program, most typically a public opioid treatment program, which is better equipped to manage their care.

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CASE 6 FROM CHAPTER 9, “PSYCHIATRIC COMORBIDITY” These symptoms are suggestive of posttraumatic stress disorder (PTSD) or borderline personality disorder and indicate the need for a more thorough psychiatric evaluation. Should an Axis I or Axis II diagnosis be confirmed, more specialized psychiatric treatment is needed, although this is not a contraindication to buprenorphine treatment. A more structured intervention such as the Seeking Safety protocol is likely to be more effective than standard cognitivebehavioral therapy (CBT) or motivation enhancement therapy. This manualguided group therapy was specifically designed to treat women with co-occurring substance use disorders and a history of trauma or PTSD.

CASE 7 FROM CHAPTER 9, “PSYCHIATRIC COMORBIDITY” Co-occurring psychiatric disorders are common among opioid-dependent individuals. In this case, Karen’s symptoms of depression and anxiety had been well controlled with antidepressant treatment. Given her stability with buprenorphine, and the absence of any recent illicit drug use, it is unlikely that the recurrence of these symptoms is drug induced. Clarification of her psychiatric symptomatology before her opioid use and the presence of symptoms during extended periods of sobriety suggest that she has recurrent major depression with associated anxiety. Given the recent increase in her symptoms of depression and anxiety, it would be appropriate to review and adjust her antidepressant medications and consider referring her for psychotherapy. There is no evidence that any particular antidepressant is more effective in buprenorphine patients, or that there would be any significant drug-drug interactions between buprenorphine and any of the standard antidepressants. If she develops a panic disorder, she should be referred for CBT. If her panic symptoms do not respond to the combination of CBT and antidepressant treatment, the addition of a long-acting benzodiazepine such as clonazepam can be explored. This option should not be considered if she has a history of benzodiazepine abuse or dependence. She needs to be warned of the risk for overdose if buprenorphine is combined with highdose benzodiazepines, or any other sedative-hypnotic drug including alcohol.

CASE 8 FROM CHAPTER 9, “PSYCHIATRIC COMORBIDITY” During periods of illicit drug use, it is difficult to separate drug-induced depressive symptoms from those secondary to PTSD or to an independent de-

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pressive disorder. In this case, the patient’s suicidal ideation and homicidal comments necessitate immediate hospitalization, regardless of etiology. He will also require treatment to control opioid withdrawal symptoms and should be considered for long-term opioid agonist treatment. There is a very high risk for relapse following detoxification treatment, and individuals with serious PTSD are even less likely to remain drug free. Although this veteran meets DSM-IV-TR criteria for opioid dependence, he has only been using opioids for 4 months and thus does not meet criteria for methadone maintenance therapy. Buprenorphine would be a reasonable option. Once his opioid problem has stabilized with buprenorphine therapy, he will need to be reassessed to rule out the presence of an independent depressive disorder and referred to the Veterans Administration system to initiate treatment for PTSD. Given his short history of opioid dependence, a gradual buprenorphine taper could be considered, but should not be initiated until his other psychiatric symptoms are under good control and he has committed himself to a strong recovery program.

CASE 9 FROM CHAPTER 10, “MEDICAL MANAGEMENT” In this case, jaundice is most likely a systemic sign of underlying hepatic illness manifested by an increase in serum bilirubin levels. Cases of hepatitis that can be directly attributed to buprenorphine are rare. In the few cases where there seems to be a causal relationship, the acute dose of buprenorphine was very high and the drug had been administered intravenously. Anecdotal reports of jaundice and liver failure exist with sublingual buprenorphine use in combination with acetaminophen in patients with severe active liver disease. Research has documented the safety of sublingual buprenorphine treatment in individuals with acute hepatitis C infection and abnormal liver transaminase levels. It would be reasonable to continue buprenorphine treatment in this case, although her care should be coordinated with a gastrointestinal medicine specialist. She will also require additional counseling and other services to help her find housing and establish control over her drinking. Once her condition has stabilized, she could be considered for interferon-ribavirin combination therapy.

CASE 10 FROM CHAPTER 11, “MANAGEMENT

OF

ACUTE

AND

CHRONIC PAIN”

Prescribing buprenorphine can seem complicated in patients with either acute or chronic pain problems. The important consideration is to avoid an interaction between the partial agonist buprenorphine and any full opioid agonists. Options for addressing less severe acute pain include the use of the following:

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• • • •

Nonopioid analgesics such as nonsteroidal anti-inflammatory agents and acetaminophen Local anesthetics (lidocaine) Topical anesthetics (capsaicin, menthols) Nonpharmacological treatments (massage, relaxation, physical therapy).

For moderate to severe pain, opioid analgesia is indicated. Options include the following: • • •

Prescribing supplemental low doses of sublingual buprenorphine (buprenorphine 2 mg/naloxone 0.5 mg) every 6–8 hours as needed Adding a short-acting opioid (oxycodone, hydrocodone, or fentanyl) and titrating to effect Stopping the use of buprenorphine and titrating a short-acting opioid (oxycodone, hydrocodone, or fentanyl) to effect.

If the pain is prolonged, the patient’s buprenorphine therapy may be converted to methadone for the duration of the required treatment. Another alternative is to shift the buprenorphine treatment from once-a-day dosing to divided dosing administered three times a day or four times a day. In many cases, divided buprenorphine doses (sometimes at a slightly higher total dosage than the previous maintenance dosage) will adequately control the pain. Sublingual buprenorphine provides significant analgesia, but the duration of this effect is 6– 8 hours; thus divided doses are required. When combining buprenorphine with a full opioid agonist, it is important that the buprenorphine be administered first to avoid precipitating withdrawal. Adding supplemental full agonists following the buprenorphine dose will not precipitate withdrawal and these drugs can then be safely titrated to effect. Combining buprenorphine with mixed agonist-antagonists such as butorphanol, nalbuphine, or pentazocine should be avoided because the effect is unpredictable. Collaboration with other specialists should be obtained in unusually complicated cases or whenever the patient fails to respond to the standard treatment options described above.

CASE 11 FROM CHAPTER 12, “OPIOID USE

BY

ADOLESCENTS”

Although many clinicians avoid long-term opioid therapy in adolescents, the relapse rate is very high following detoxification treatment, except for those adolescents who complete an intensive residential program. Tommy has a 3-year history of opioid dependence with two prior detoxification treatments and is

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clearly a candidate for long-term buprenorphine therapy. His parents will need support and education to help them understand the benefits of buprenorphine and the high risks associated with drug-free treatment. At 16, Tommy is legally eligible for buprenorphine treatment although parental consent is required in most states. Family therapy would be beneficial in this case, and ongoing court supervision increases the likelihood that he will follow through with treatment. Treatment goals should include elimination of all illicit drug use. Treatment with buprenorphine for a minimum of 1–2 years is indicated, and a gradual buprenorphine taper should not be considered until Tommy is stable, is fully invested in a drug-free lifestyle, and has established a network of drug-free peers.

References American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision. Washington, DC, American Psychiatric Association, 2000

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Appendix 1 Useful Web Sites and Recommended Readings Federal Government Web Sites •

•

•

http://buprenorphine.samhsa.gov—The Center for Substance Abuse Treatment (CSAT) of the Substance Abuse and Mental Health Services Administration (SAMHSA), U.S. Department of Health and Human Services, maintains this site for patients and health care providers interested in buprenorphine as treatment for opioid addiction. Patients can find general information in English and Spanish regarding buprenorphine, including how it works, Medicare and Medicaid coverage, and locations of treatment centers. Physicians can find information about training and treatment protocols. Links specific to nurses, counselors, and pharmacists are being developed. http://dasis3.samhsa.gov—This SAMHSA site provides contact information for addiction treatment programs across the country and connects to the Buprenorphine Physician Locator, which provides contact information for programs and physicians authorized to prescribe buprenorphine in each state and U.S. territory. It is an invaluable resource for patients seeking treatment. www.drugabuse.gov/nidamed—The National Institute on Drug Abuse (NIDA), of the National Institutes of Health, created this site (NIDAMED) to provide primary care physicians with an effective tool for alcohol and drug screening; however, this approach is useful for all health professionals.

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•

•

•

It contains an online screening tool for alcohol, tobacco, and other drug use (NM ASSIST); resources on treatment and prevention; information on clinical trials; and resources that can be provided to patients, including youth (grade school through young adult ages). www.usdoj.gov/dea/pubs/abuse—The U.S. Drug Enforcement Administration (DEA) magazine on drugs of abuse is available at this site. The magazine presents photographs and straightforward scientific information about drugs of abuse geared for educating the general public and covers history, pharmacology, addiction, and treatment options. http://sbirt.samhsa.gov/index.htm—SAMHSA has created a resource manual for screening, brief intervention, and referral to treatment (SBIRT). It concentrates on early intervention and treatment services for persons with and at risk for abuse of substances, including alcohol, tobacco, and other drugs. The site provides various resources for screening instruments, health care provider and patient information for brief intervention, treatment center locators, reimbursement coding guidelines, and references for publications regarding screening and intervention. www.guideline.gov—This site is the home page for the National Guideline Clearinghouse, which provides a complete summary of clinical guidelines for the use of buprenorphine in the treatment of opiate dependence. www.niaaa.nih.gov—This excellent site, maintained by the National Institute on Alcohol Abuse and Alcoholism, is primarily focused on alcoholrelated diseases rather than opiate dependence or buprenorphine. Information is up to date and well maintained. Useful resources include research articles, specific links for information related to children and youth, and frequently asked questions directed to the general public.

Private Nonprofit Organization Web Sites •

•

www.drugstrategies.org—This site is for patients and families looking for treatment for drug or alcohol addiction. The site includes ways to contact counselors for help 24/7 via online chat or telephone, a locator for Alcoholics Anonymous and Narcotics Anonymous meetings and treatment centers around the country, and articles about various addictions. Drug Strategies is a nonprofit research foundation that promotes more effective ways of dealing with drug and alcohol problems. www.bubblemonkey.com—Drug Strategies maintains this high-graphic site specifically for teens. Here teens can anonymously find reliable information about drugs and alcohol, take a screening test to see if they may have a problem with substances, read true stories from other teens, ask questions, and get

Appendix 1: Useful Web Sites and Recommended Readings

•

•

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•

•

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information about where to seek help. Text is available in English and Spanish; sites are specific to cities in California, Colorado, and Massachusetts. www.reclaimingfutures.org—Reclaiming Futures is an organization that began with a donation from the Robert Wood Johnson Foundation and works to help young people in trouble with drugs, alcohol, and crime. The site describes a six-step model implemented in 10 pilot communities that focuses on coordinated substance abuse treatment for teens in the juvenile justice system. Treatment involves the courts, service providers, community groups, and individual volunteers. The very useful site includes results from these communities, names of new communities implementing the model, and resources for individuals interested in juvenile justice. www.fsmb.org/pdf/2002_grpol_opioid_addiction_treatment.pdf—The Federation of State Medical Boards of the United States prepared this document in conjunction with CSAT to provide model guidelines for state medical boards in regulating office-based treatment of opioid addiction. www.csam-asam.org/resources.vp.html—The California Society of Addiction Medicine (CSAM) provides practical information for physicians regarding buprenorphine treatment. This very useful site includes clinical tools, presentations, clinical guidelines, training information, and other resources. Clinical forms can be downloaded and edited for the specific requirements of any clinical practice. www.pcssbuprenorphine.org—SAMHSA funded the American Society of Addiction Medicine to create a national mentoring program, the Physician Clinical Support System—Buprenorphine (PCSS-B), for physicians prescribing buprenorphine. At this site, physicians can either find or become a mentor to other physicians prescribing buprenorphine. The site also includes a number of clinical “guidances” to aid in the management of patients taking buprenorphine and links to various other clinical resources and training materials. www.naabt.org—The National Alliance of Advocates for Buprenorphine Treatment (NAABT) is a nonprofit organization that serves to educate the public about opioid addiction and buprenorphine treatment and reduce stigma and discrimination against patients with substance dependence. In addition to information about buprenorphine, the site includes a patientphysician matching system, information for treatment providers, and online support communities for patients taking buprenorphine. www.amersa.org—The Association for Medical Education and Research in Substance Abuse (AMERSA) is a nonprofit multidisciplinary professional organization devoted to the development of curricula and teaching materials related to substance abuse services and professional education. Their site includes downloadable teaching materials and information on conferences and other educational resources.

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•

•

www.drugpolicy.org/docUploads/aboutmethadone.pdf—Drug Policy Alliance, a group dedicated to advancing policies and attitudes to reduce the harms of drug misuse and prohibition, created this document (“About Methadone and Buprenorphine,” Revised Second Edition) for patients to provide them with information about methadone and buprenorphine treatment for opioid addiction. The document is an easy read and covers essential information regarding reasons for treatment, drug interactions, treatment during pregnancy, overdose, detoxification, travel, and contact information for state substance abuse agencies. http://www2.aaap.org/buprenorphine—The American Academy of Addiction Psychiatry provides an online training and certification course for physicians interested in office-based opioid addiction treatment with buprenorphine at this site. www.casacolumbia.org—The National Center on Addiction and Substance Abuse (CASA) at Columbia University is the only nationwide organization that brings together all the professional disciplines needed to study and combat abuse of all substances—alcohol, nicotine, and illegal, prescription, and performance-enhancing drugs—in all sectors of society. This Web site provides information on various training activities, research reports prepared by CASA, and a range of resources about drug abuse prevention and drug information. http://jointogether.org—Join Together supports community-based efforts to advance effective alcohol and drug policy, prevention, and treatment. This organization provides assistance to help communities respond to the harms caused by excessive alcohol and drug use and provide free Internet services supporting their efforts. In addition to this Web site, Join Together operates a number of other sites, including www.AlcoholScreening.org, www.DrugScreening.org, and www.AddictionAction.org. Join Together recently merged with CASA at Columbia University. www.asam.org—This Web site, run by the American Society of Addiction Medicine (ASAM), provides information on various ASAM activities and public policy initiatives and links to a number of other organizations active in the addiction field.

Commercial Web Sites •

www.suboxone.com—This site, maintained by the Suboxone manufacturer, Reckitt Benckiser, contains useful information and resources for patients and physicians, including a zip code–based physician locator. A related site (www.heretohelpprogram.com) contains videos of successful patients and encourages patients to participate in counseling and supportive

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services. Upon request, a patient will be put in telephone contact, at no charge, with a professional “care coach” who will help support him or her through the treatment process. www.buppractice.com—This commercial site developed by ClinicalTools, Inc., under a contract with NIDA, contains links to training guides and courses specifically designed for clinical and administrative staff.

Recommended Readings Alford DP, Compton P, Samet JH: Acute pain management for patients receiving maintenance methadone or buprenorphine therapy. Ann Intern Med 144:127– 134, 2006 American Psychiatric Association: Practice guideline for the treatment of patients with substance use disorders, 2nd edition. Am J Psychiatry 164(4 Suppl):5–123, 2007. Available at: http://www.psychiatryonline.com/pracGuide/pracGuideTopic_5. aspx. Accessed April 23, 2010. Ball JC, Ross A: The Effectiveness of Methadone Maintenance Treatment: Patients, Programs, Services, and Outcome. New York, Springer-Verlag, 1991 Center for Substance Abuse Treatment: Clinical Guidelines for the Use of Buprenorphine in the Treatment of Opioid Addiction. Treatment Improvement Protocol (TIP) Series 40. DHHS Publ No (SMA) 04-3939. Rockville, MD, Substance Abuse and Mental Health Services Administration, 2004. Available at: http:// www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=hssamhsatip&part=A72248. Accessed April 29, 2010. Cowan A: Buprenorphine: the basic pharmacology revisited. J Addict Med 1:68–72, 2007 Dole VP, Nyswander M: A medical treatment for diacetylmorphine (heroin) addiction: a clinical trial with methadone hydrochloride. JAMA 193:646–650, 1965 Fiellin DA, Moore BA, Sullivan LE, et al: Long-term treatment with buprenorphine/ naloxone in primary care: results at 2–5 years. Am J Addict 17:116–120, 2008 Fudala PJ, Bridge TP, Herbert S, et al: Office-based treatment of opiate addiction with a sublingual-tablet formulation of buprenorphine and naloxone. N Engl J Med 349:949–958, 2003 Galanter M, Kleber HD: The American Psychiatric Publishing Textbook of Substance Abuse Treatment, 4th Edition. Washington, DC, American Psychiatric Publishing, 2008 Hser YI, Hoffman V, Grella CE, et al: A 33-year follow-up of narcotics addicts. Arch Gen Psychiatry 58:503–508, 2001 Kalivas PW, Volkow ND: The neural basis of addiction: a pathology of motivation and choice. Am J Psychiatry 162:1403–1413, 2005 Khantzian EJ: Treating Addiction as a Human Process. Northvale, NJ, Jason Aronson, 1999 Kosten TR, George TP: The neurobiology of opioid dependence: implications for treatment. Sci Pract Perspect 1:13–20, 2002. Available at: http://www.nida.nih. gov/pdf/perspectives/vol1no1/03perspectives-neurobio.pdf. Accessed July 8, 2010. Leschner AI: Science-based views of drug addiction and its treatment. JAMA 282: 1314–1316, 1999

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Levounis P, Arnaout B: Handbook of Motivation and Change: A Practical Guide for Clinicians. Washington, DC, American Psychiatric Publishing, 2010 Lowinson JH, Ruiz P, Millman RB, et al (eds): Substance Abuse: A Comprehensive Textbook, 4th Edition. New York, Lippincott Williams & Wilkins, 2005 Marlatt GA, Gordon JR: Relapse Prevention: Maintenance Strategies in the Treatment of Addictive Behaviors. New York, Guilford, 1985 McCance-Katz EF: Office-based buprenorphine treatment for opioid-dependent patients. Harv Rev Psychiatry 12:321–338, 2004 McLellan AT, Lewis DC, O’Brien CP, et al: Drug dependence, a chronic medical illness: implications for treatment, insurance, and outcomes evaluation. JAMA 284:1689–1695, 2000 Miller WR, Rollnick S: Motivational Interviewing: Preparing People for Change, 2nd Edition. New York, Guilford, 2002 Moeller KE, Lee KC, Kissack JC: Urine drug screening: practical guide for clinicians. Mayo Clin Proc 83:66–76, 2008 Musto DF: The American Disease: Origins of Narcotic Control, 3rd Edition. New York, Oxford University Press, 1999 Najavits LM: Seeking Safety: A Treatment Manual for PTSD and Substance Abuse. New York, Guilford, 2002 Nunes EV, Levin FR: Treatment of depression in patients with alcohol or other drug dependence: a meta-analysis. JAMA 291:1887–1896, 2004 Nunes EV, Selzer J, Levounis P, et al: Substance Dependence and Co-Occurring Psychiatric Disorders: Best Practices for Diagnosis and Clinical Treatment. New York, Civic Research Institute, 2010 Prochaska JO, DiClemente CC: Transtheoretical therapy: towards a more integrative model of change. Psychotherapy: Theory, Research and Practice 19:276–288, 1982 Ries RK, Fiellin DA, Miller SC, et al: Principles of Addiction Medicine, 4th Edition. Philadelphia, PA, Lippincott Williams & Wilkins, 2009 Substance Abuse and Mental Health Services Administration: The Determinations Report: A Report on the Physician Waiver Program Established by the Drug Addiction Treatment Act of 2000 (“DATA”), March 30, 2006. Available at: http:// www.buprenorphine.samhsa.gov/SAMHSA_Determinations_Report.pdf. Accessed April 29, 2010. Westreich LM: Helping the Addict You Love: The New Effective Program for Getting the Addict Into Treatment. New York, Fireside, 2007 Woody GE, Poole SA, Subramaniam G, et al: Extended vs short-term buprenorphinenaloxone for treatment of opioid-addicted youth: a randomized trial. JAMA 300:2003–2011, 2008

Appendix 2 Study Questions and Answer Guide Chapter 1 OPIOID DEPENDENCE 1.1

IN

AMERICA

Which of the following statements is accurate regarding opioid agonist therapy (OAT)? A. Was initially authorized by the Harrison Narcotics Act of 1914. B. Was common medical practice in the late nineteenth century in the United States. C. Was not supported by scientific research until 1985. D. Has never been authorized by federal legislation. Correct answer is B. OAT was common in the nineteenth century. It was prohibited by the Harrison Act in 1914 and was not authorized by federal legislation until methadone maintenance treatment was approved in 1972. Dole and Nyswander published their initial research demonstrating the efficacy of methadone treatment in 1965. Section: Opioid Dependence 1830–1995.

1.2

Hser’s 33-year follow-up of California heroin addicts documented that A. 10% of the subjects were dead at the time of the 33-year follow-up. B. 22% of the subjects were abstinent. C. 28% of the subjects were enrolled in methadone maintenance treatment. 291

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D. 2% of the subjects were in jail. E. Options A and C are both correct. Correct answer is B. At the time of the 33-year follow-up, 48% of the subjects were dead, 4% were in jail, and only 6% were in methadone treatment. Section: The Harrison Act and the Prohibition of Addiction Treatment. 1.3

The Drug Addiction Treatment Act of 2000 (DATA 2000) included all of the following provisions, except A. Approval of office-based treatment for opioid dependence. B. A limitation of OAT to 24 months duration. C. A requirement that physicians apply for a Drug Enforcement Administration (DEA) waiver to treat opioid dependence in an officebased setting. D. A limitation on qualifying physicians to treat no more than 30 patients in each individual or group practice. E. A requirement that qualifying physicians have the capacity to refer for ancillary services. Correct answer is B. There is no time limit for opioid agonist treatment under DATA 2000. This law authorized office-based practitioners to prescribe U.S. Food and Drug Administration (FDA)–approved narcotic drugs in Schedules III, IV, and V, or combinations of such drugs, for maintenance or detoxification treatment of opioid dependence; the buprenorphine waiver and X number were required for the prescription of buprenorphine in an outpatient setting. Practitioners had to be deemed qualifying physicians, which was defined as having the capacity to refer patients for appropriate counseling and ancillary services. Qualifying physicians were initially limited to no more than 30 patients at one time for an individual or group practice, which was intended to avoid the development of large buprenorphine practices. Section: Drug Addiction Treatment Act of 2000.

1.4

The evaluation of the impact of DATA 2000 showed all of the following, except A. Addicts treated with buprenorphine were more likely to be unemployed and less well educated than individuals treated in methadone maintenance programs.

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B. There was a significant increase in the number of opioid addicts in treatment. C. Both physicians and patients showed a high level of satisfaction with office-based treatment for opioid dependence. D. The majority of patients treated with buprenorphine had been addicted to prescription pain medications rather than heroin. E. There were minimal safety or diversion problems associated with buprenorphine. Correct answer is A. The 2006 formal report by the secretary of the U.S. Department of Health and Human Services (DHHS) indicated that the buprenorphine waiver program had expanded access to treatment and had produced effective treatment outcomes without producing negative public health issues. Both patients and waivered physicians reported a high level of satisfaction with office-based buprenorphine treatment. Regarding accessibility to treatment, DHHS determined that 31% of patients taking buprenorphine were new to any type of substance abuse treatment and 60% were new to medication-assisted treatment. Of equal importance was the finding that 60% of buprenorphine patients had been addicted to nonheroin opioids. Buprenorphine treatment populations have had higher percentages of women than methadone treatment populations have, as well as higher percentages of whites and employed individuals and more than three times as many individuals with some postsecondary education. Section: Evaluation of DATA 2000.

Chapter 2 EXPERIENCE W ITH BUPRENORPHINE IN THE UNITED STATES, 2002–2008 2.1

Buprenorphine and buprenorphine-naloxone are classified by the DEA in A. B. C. D. E.

Schedule I. Schedule II. Schedule III. Schedule IV. Schedule V.

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Correct answer is C. Since 2002, buprenorphine has been a Schedule III drug; methadone is Schedule II, and heroin is Schedule I. Section: Creating a New Treatment Paradigm. 2.2

DATA 2000 approved buprenorphine and buprenorphine-naloxone for the treatment of opioid dependence in office-based settings in order to A. B. C. D. E.

Improve access to treatment. Decrease methadone diversion. Encourage use of naloxone. Shift the treatment paradigm from psychotherapy to pharmacotherapy. All of the above.

Correct answer is A. While decreased methadone diversion and increased use of naloxone to treat opioid overdose may be important public policy goals, DATA 2000 approved office-based treatment of opioid dependence with a Schedule III drug in order to improve access. DATA 2000 shifts the treatment of opioid dependence from clinic-based to office-based settings; it does not discourage psychotherapy. Section: Creating a New Treatment Paradigm. 2.3

The primary use of diverted buprenorphine doses appears to be A. B. C. D. E.

By opioid-dependent people to avoid opioid withdrawal. By opioid-dependent people to get high. By non-opioid-dependent people to avoid opioid withdrawal. By non-opioid-dependent people to get high. By opioid-naive adolescents to enhance academic performance.

Correct answer is A. Opioid-dependent people use buprenorphine primarily to avoid or selfmedicate opioid withdrawal and rarely to achieve a drug high (which would likely require intravenous administration of the “mono” buprenorphine formulation). Non-opioid-dependent people do not experience opioid withdrawal and do not favor the use of buprenorphine, which has little value as a drug that produces euphoria. Adolescents use stimulants—not opioids—for academic performance enhancement. Section: Buprenorphine Diversion.

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The currently modified DATA 2000 regulations stipulate that the maximum number of patients that an individual physician can treat with buprenorphine at any one time is A. Thirty, if the physician is in solo practice; 100 if he or she is in a group practice of two or more physicians. B. Thirty, if the physician is in solo or group practice, 100 if he or she practices at a federally regulated opioid treatment program (OTP). C. Thirty for the first year; 100 after a year of practice. There is no numerical limit for patients treated at OTPs. D. One hundred for all treatment settings. E. There are no longer any numerical patient limits. Correct answer is C. The current regulations allow an individual physician who has a buprenorphine waiver to treat a maximum of 30 patients for the first year and to request approval to treat up to 100 after a year of practice. The regulations provide patient limits to individual physicians, not group practices. There are no numerical patient limits in OTPs (formerly known as methadone clinics). Section: Legislative Changes and Regulatory Concerns.

2.5

According to the Substance Abuse and Mental Health Services Administration/Center for Substance Abuse Treatment (SAMHSA/CSAT) patient survey, approximately how many patients who are treated with buprenorphine indicated that buprenorphine was “very helpful” or “extremely helpful”? A. B. C. D. E.

5%. 25%. 50%. 75%. 95%.

Correct answer is E. Ninety-five percent of patients surveyed felt that buprenorphine was very or extremely helpful, and 60% reported retention in treatment at 6 months. Section: Table 2–2: Major findings from SAMHSA CSAT surveys on DATA 2000.

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Chapter 3 GENERAL OPIOID PHARMACOLOGY 3.1

The abuse potential of opioids is generally related to factors that result in a more rapid onset of pharmacological effects. Which of the following is not relevant in determining the abuse potential of this class of drugs? A. Receptor affinity (the strength with which the drug binds to the receptor). B. A faster route of administration (drugs that are smoked or injected intravenously). C. A shorter drug half-life. D. Lipophilicity (the rate at which the drug passes the blood-brain barrier). Correct answer is A. The strength of receptor affinity does not have an impact on the abuse potential of drugs that bind the µ opioid receptor. There are three primary factors that result in a more rapid onset of opioid pharmacological effects: 1) a faster route of administration—that is, injecting and smoking a drug give it greater abuse potential than oral ingestion; 2) a shorter halflife has greater abuse potential, such as short-acting heroin versus longacting methadone; and 3) greater lipophilic properties. Section: Opioid Key Features.

3.2

Which of the following is not a characteristic symptom of opioid withdrawal? A. B. C. D. E. F. G.

Muscle cramps. Nausea or vomiting. Constipation. Lacrimation or rhinorrhea. Yawning. Pupillary dilation. Dysphoria/anxiety and insomnia.

Correct answer is C. Constipation is a common side effect of all opioids. Opioid withdrawal is typically associated with diarrhea. Section: Opioid Withdrawal Issues.

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Precipitated withdrawal occurs when a full agonist is displaced from the opioid receptor. All of the following statements are correct, except A. Naloxone will rapidly displace a full opioid agonist from the µ receptor. B. Buprenorphine will displace a full agonist from the µ receptor. C. If withdrawal is precipitated in an individual who is opioid dependent, it will likely produce a full opioid withdrawal syndrome of significant severity. D. Precipitated withdrawal is easily reversed by administering a full opioid agonist. Correct answer is D. Full opioid agonists will not reverse the effect of an antagonist or a partial agonist, since both have greater affinity for the µ receptor than any full agonist. Precipitated opioid withdrawal is best handled by administering additional doses of a partial agonist such as buprenorphine. Section: Opioid Withdrawal Issues. Please also see Managing Precipitated Withdrawal in Chapter 6, “Clinical Use of Buprenorphine.”

3.4

Which of the following statements is not accurate regarding the sublingual buprenorphine-naloxone “combo” tablet? A. The Suboxone combo tablet is formulated at the ratio of 4 mg buprenorphine for every 1 mg naloxone. B. Both drugs have excellent oral bioavailability. C. If the tablet is dissolved into solution and injected, naloxone will precipitate opioid withdrawal in any dependent individual. D. The primary reason for the presence of naloxone is to minimize the risk of diversion. Correct answer is B. Buprenorphine and naloxone both have poor oral bioavailability. Buprenorphine has good sublingual bioavailability, but there is no significant absorption of naloxone from the sublingual route—hence the only active drug effect when the combo tablet is taken sublingually, as directed, is that of buprenorphine. If the combo product is dissolved into solution and injected, then naloxone is clinically active and binds to the µ receptors and its antagonist effect predominates, blocking much of the opioid effect. The only reason naloxone is an added component of the combo tablet is to prevent dissolving and injecting the tablet for euphoric effect, thus minimizing the risk of diversion. Section: Clinical Use Issues.

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Chapter 4 EFFICACY 4.1

AND

SAFETY

OF

BUPRENORPHINE

Buprenorphine is A. B. C. D. E.

An agonist at the opioid receptor-like-1 (ORL-1) receptor. A partial agonist at the µ opioid receptor. An antagonist at the κ opioid receptor. A mixed agonist-antagonist. All of the above.

Correct answer is E. Buprenorphine is both a partial agonist at the µ opioid receptor and an antagonist at the κ opioid receptor, which renders it a mixed agonistantagonist. Recent data suggest that the descending limb of buprenorphine’s dose-response curve may be linked to an alternative pharmacological action at the ORL-1 receptor. Section: Pharmacological Features. 4.2

Compared with sublingual administration, crushing and intravenously injecting the combination buprenorphine-naloxone tablet will result in A. Initial withdrawal followed by intense euphoria. B. Initial euphoria followed by intense withdrawal. C. Precipitated withdrawal if the person is not physiologically opioid dependent. D. Precipitated withdrawal only if the person is physiologically opioid dependent. E. No effect, irrespective of physiological dependence status. Correct answer is D. Intravenous naloxone will precipitate an opioid withdrawal syndrome in people who are physiologically dependent on opioids, but will have no effect in people who are not physiologically dependent. Intravenous administration of the buprenorphine-naloxone combination may produce mild euphoria in nondependent individuals. Section: Pharmacological Features.

4.3

Comparing the efficacy of methadone with the efficacy of buprenorphine (typically in terms of treatment retention and illicit opioid use) all of the following conclusions are correct, except

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A. Dosages of about 8–24 mg/day of buprenorphine produce outcomes similar to those seen with moderate dosages of methadone (i.e., up to 60 mg/day). B. For dosages greater than 60 mg/day, methadone appears to have better outcomes than 8–24 mg/day of buprenorphine. C. Buprenorphine is not a good treatment option for patients with high levels of opioid dependence. D. Nonpharmacological aspects of treatment (e.g., counseling, patient motivation, access to treatment) impact efficacy and can often override pharmacological considerations. E. Both medications are effective, and a patient who is not responding well to one—when all aspects of treatment have been optimized— should be considered for treatment with the other. Correct answer is C. While findings from controlled clinical trials comparing sublingual buprenorphine to methadone suggest somewhat better outcomes at higher doses of methadone, there is considerable variability in patient response to medications. Both buprenorphine and methadone are good treatment options for patients with high levels of physiological dependence to opioids. Section: Buprenorphine Compared With Methadone. 4.4

Fatalities associated with buprenorphine use have been due to A. Liver failure with very high doses of buprenorphine. B. Respiratory failure with intravenous administration of a combination of buprenorphine and a benzodiazepine. C. Cardiac conduction abnormalities secondary to QTc interval prolongation and torsades de pointes. D. Severe precipitated withdrawal secondary to high levels of physiological dependence before induction. E. None of the above; there are no documented fatalities associated with buprenorphine use. Correct answer is B. In France, patient deaths have been associated with injection of the “mono” formulation of buprenorphine along with flunitrazepam. Although buprenorphine has been associated with serum transaminase increases, clinical experience has not supported a particular concern with liver function. QTc interval prolongation and torsades de pointes have been implicated in fatalities of patients taking L-α-acetylmethadol

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(LAAM) and methadone; there is no evidence that buprenorphine is associated with QTc interval prolongation. Opioid withdrawal, precipitated or spontaneous, is extremely distressing but not fatal. Section: Buprenorphine’s Safety and Side Effects. 4.5

According to the FDA-approved label for buprenorphine, in a 4-week study that compared buprenorphine with placebo, the most common side effect noted by patients treated with buprenorphine was A. B. C. D. E.

Constipation. Decrease in cognitive function and performance. Erectile dysfunction. Headache. Sweating.

Correct answer is D. The most commonly reported side effect was headache followed by constipation. Erectile dysfunction and sweating associated with buprenorphine have also been reported. Buprenorphine does not appear to produce impairment in cognitive function and performance. Section: Other Side Effects.

Chapter 5 PATIENT ASSESSMENT 5.1

An accurate drug use history is an important part of the initial assessment. Which of the following approaches will help provide accurate information and establish a good working relationship? A. Before your first meeting, ask the patient to fill out a detailed drug use questionnaire. B. A concerned, curious, but nonjudgmental approach works best. (“Can you help me understand what is going on here?”) C. Confrontation is the quickest and most successful approach. Assume the patient is probably withholding information. Act forcefully to break through their denial and evasions. (“Please don’t waste my time with any more of your baloney.”) D. A matter-of-fact, historical approach. (“What was the first drug you ever used?”) E. Options B and D are both recommended approaches.

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Correct answer is E. Either B or D is recommended. Confrontation is often counterproductive and should be avoided except in the most extreme cases. A written drug questionnaire may provide useful information, but the clinician can miss an opportunity to better understand their patient and solidify the doctor–patient relationship. Section: Establishing a Relationship; Taking a History of Drug Use. 5.2

Which of the following statements is accurate regarding the role of motivation in addiction treatment? A. It is impossible to treat unmotivated patients. B. Therapists can have little impact on a patient’s motivation. C. Ambivalence is a pathological aspect of the addictive process and predicts a poor outcome. D. If a patient relapses, it is safe to assume that their earlier efforts in treatment were insincere. E. Patients in denial about problems related to their substance use may respond positively to education provided by their physician. Correct answer is E. Minimal physician intervention may have a powerful effect on a patient’s drug and/or alcohol use. Research on the stages of change paradigm has shown that ambivalence is a normal part of the change process, that motivation fluctuates, and that a clinician’s behavior can have a significant effect on a patient’s motivation. Any physician working with addicted individuals should become familiar with the fundamentals of motivation enhancement therapy (MET). Section: Motivation for Change. Please also see Handling Resistance to Treatment: Motivation Enhancement Therapy in Chapter 8, “Clinical Management II.”

5.3

Which of the following regulatory requirements does not apply to methadone maintenance treatment? A. B. C. D.

Patients must meet DSM-IV-TR criteria for opioid dependence. Patients must document a minimum 1-year history of addiction. Patients must be at least 18 years of age. Patients may begin regular “take-home” dosing after the first week of treatment.

Correct answer is D.

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Federal regulations preclude take-home dosing during the first 90 days of methadone maintenance treatment. The requirements for daily methadone clinic attendance lead many patients to seek out office-based buprenorphine treatment. Although buprenorphine can be prescribed to anyone age 16 years and older who currently meets DSM-IV-TR criteria for opioid dependence, methadone treatment requires that patients be at least 18 years old, currently meet DSM-IV-TR criteria for opioid dependence, and have been addicted for at least 1 year before admission to treatment. Section: Buprenorphine Versus Methadone: Regulatory Criteria and Limitations. 5.4

All of the following patients would be likely candidates for office-based buprenorphine treatment, except A. A 16-year-old high school student who has been abusing oxycodone intermittently for 3 years and has relapsed again after a second inpatient detoxification admission. B. A 23-year-old unemployed waitress who has been addicted to heroin (intravenously) for 3 years. She has a history of alcohol and benzodiazepine abuse starting when she was 15. She stopped drinking when she began using heroin, but she continues to use 4–6 mg/day of alprazolam to “boost” her heroin high. C. An employed auto mechanic who became addicted 6 months ago after being treated with opioids following a back injury. He admits that he no longer has back pain but has been unable to stop using pain medications. D. A 35-year-old musician who has been snorting heroin intermittently for 10 years. About 6 months ago she started injecting heroin on a daily basis and she is now seeking treatment because she cannot stop. She smokes marijuana a few times a week, but denies problems with alcohol or other drugs. Correct answer is B. All of these patients—except the waitress with severe co-occurring benzodiazepine abuse problems—would be appropriate for office-based buprenorphine treatment. Because of the potential risk of fatal respiratory depression when buprenorphine is combined with high-potency benzodiazepines, patients who are heavy benzodiazepine users are not recommended for buprenorphine treatment. Section: Appropriateness for Office-Based Buprenorphine Treatment; Conclusion. Please also see Overdose in Chapter 4, “Efficacy and Safety of Buprenorphine.”

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Chapter 6 CLINICAL USE 6.1

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BUPRENORPHINE

Which one of the following is a commercially available formulation? A. B. C. D. E.

0.5 mg buprenorphine/2 mg naloxone. 2 mg buprenorphine/0.5 mg naloxone. 4 mg buprenorphine. 8 mg buprenorphine/0.5 mg naloxone. 16 mg buprenorphine/2 mg naloxone.

Correct answer is B. Buprenorphine is available in four sublingual formulations. The two “mono” products are: 2 mg buprenorphine and 8 mg buprenorphine. The two “combo” products come in a 4:1 buprenorphine-to-naloxone ratio: 2 mg buprenorphine/0.5 mg naloxone and 8 mg buprenorphine/2 mg naloxone. Section: Buprenorphine Formulations. 6.2

All of the following signs are included in the Clinical Opiate Withdrawal Scale (COWS), except A. B. C. D. E.

Facial erythema. Resting pulse rate. Sweating. Yawning. Pupil size.

Correct answer is A. The COWS assesses the following signs and symptoms: resting pulse rate, sweating, restlessness, pupil size, bone or joint aches, runny nose or tearing, gastrointestinal upset, tremor, yawning, anxiety or irritability, and gooseflesh skin. Facial erythema is characteristic of alcohol dependence. Section: Figure 6–5: Clinical Opiate Withdrawal Scale. 6.3

The most recommended strategy for the management of precipitated withdrawal during buprenorphine induction is to A. Do nothing other than observe, reassure, and wait for the precipitated withdrawal to run its course.

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B. Administer additional doses of buprenorphine. C. Administer naloxone intravenously. D. Abort the induction, administer supportive medications for withdrawal symptoms, and reschedule for another day. E. Transfer the patient to the intensive care unit (ICU). Correct answer is B. Aborting the induction, offering symptomatic relief, and scheduling a new date for induction are reasonable alternatives but run the risk of losing the patient, who may be too distressed and disappointed to come back for another trial. Pushing the dose of buprenorphine to achieve relief through its agonist effect is the recommended approach. Administering intravenous naloxone will either have no effect or worsen the withdrawal. Opioid withdrawal can be extremely distressing but is never life threatening and thus does not necessitate admission to the ICU. Section: Managing Precipitated Withdrawal. 6.4

The most common dose of buprenorphine maintenance is A. B. C. D. E.

1–2 mg/day. 2–4 mg/day. 4–8 mg/day. 8–16 mg/day. 16–32 mg/day.

Correct answer is D. While some patients will do well on just 1–2 mg/day of buprenorphine and others will need 24–32 mg/day for maintenance, the majority of patients fall in the 8–16 mg/day dosage range. Practically, this translates into one to two pills a day, which is a very convenient dosing schedule for the patient. Section: Buprenorphine Maintenance. 6.5

Clinically significant drug-drug interactions have been demonstrated between buprenorphine and A. B. C. D. E.

Antipsychotics. Antidepressants. Mood stabilizers. Anxiolytics. All of the above.

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Correct answer is D. Intravenous administration of benzodiazepines with intravenous use of the mono formulation of buprenorphine has resulted in fatal overdoses secondary to a synergistic depressant effect on the respiratory system. While the combination of buprenorphine with benzodiazepines and other central nervous system depressants is not contraindicated, both the patient and the physician should exercise caution because of the increased risk of respiratory depression. No clinically significant drugdrug interactions between buprenorphine and other classes of psychotropic medications have been reported. Section: Drug-Drug Interactions.

Chapter 7 CLINICAL MANAGEMENT I 7.1

Office staff should be educated about the nature of addiction and appropriate expectations for buprenorphine treatment. The prescribing physician should be prepared to handle questions from staff about which of the following issues? A. Addiction is a moral problem and not a medical or psychiatric disorder. B. OAT is just substitution of one drug for another. C. Drug-free treatment is more effective than buprenorphine and indeed is the only appropriate form of treatment. D. Self-help treatment is incompatible with buprenorphine treatment. E. Relapse is a sign of treatment failure and should lead to the termination of buprenorphine treatment. F. All of the above. Correct answer is F. All of these issues are common attitudes among the general public and should be covered in any staff education program. Nurses, office staff, and even many medical providers may hold deep-seated beliefs about the causes or treatment of addiction, many of which are not at all evidence based. Any investment made in educating staff about the natural history and treatment of opioid dependence will provide immediate value in the clinical setting. Section: Staff Education and Training. Please also see Staffing Needs in Chapter 13, “Logistics of Office-Based Buprenorphine Treatment.”

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7.2

Which of the following items is not required in an informed consent document? A. A statement that buprenorphine is an opioid medication and may cause withdrawal symptoms if it is stopped abruptly. B. Information on how to contact your office after hours or on weekends. C. The common side effects of buprenorphine. D. Disclosure of the risks of combining buprenorphine with alcohol, benzodiazepines, or other sedative-hypnotic medications. E. Disclosure of the risk for precipitated opioid withdrawal if buprenorphine is taken along with other opioid medications. F. A statement that buprenorphine will block the effects of other opioids including opioid pain medications and an outline of procedures for handling surgery or the need for pain medications. Correct answer is B. Information regarding office hours and services should be included in the treatment agreement. This information does not belong in the informed consent document. Section: Informed Consent; Figure 7–1: Sample informed consent form for buprenorphine treatment.

7.3

Which of the following items is not necessary in a treatment agreement? A. A review of standard treatment requirements in your practice, such as attendance at counseling or participation in self-help groups. B. Procedures for managing lost or stolen medication. C. Requirements for urine testing or call-backs for pill counts. D. Descriptions of services to be provided by the clinician. E. Procedures for referral to a higher level of treatment services. F. All of these items should be included. Correct answer is F. All of these issues are important and should be part of any treatment agreement. The agreement should cover expectations for both the patient and the clinician and office staff. It should not be a one-sided document that only places expectations on the patient. Section: Treatment Agreements; Figure 7–2: Sample buprenorphine treatment agreement with program statement.

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Which of the following management approaches would not be a standard part of office-based buprenorphine treatment? A. Each appointment should begin with a review of the medication record and dosing information. B. Broader treatment/recovery goals should be reviewed at each visit. C. Minor episodes of drug use should be ignored, so as not to discourage the patient. D. Any relapse should be framed as a learning opportunity or as a signal that the treatment plan needs to be reviewed or updated. E. Participation in nonpharmacological counseling services and other ancillary services should be reviewed at every visit. F. The clinician should always reinforce progress and motivation. Correct answer is C. No incidence of drug use should be ignored, no matter how small. They are always of concern and should be explored to help identify risks for relapse or weaknesses in the treatment plan. Section: Chronic Disease Management Principles.

7.5

Which of the following should be your first response to problem behavior such as a recurrence of drug use? A. Increase the frequency and intensity of current treatment services and increase the frequency of urine toxicology exams. B. Require participation in self-help programs or ancillary behavioral counseling. C. Eliminate prescriptions and see the patient on a daily basis. D. Terminate office-based treatment and transfer patient to a methadone program. Correct answer is A. The first response to problem behavior should be to increase the frequency and intensity of treatment services. If that fails to resolve the problem, the treatment plan should be revised to require participation in additional counseling and supportive services. Transfer to a methadone program should be the last option considered. Section: Managing Problem Behaviors.

7.6

The time frame for detecting drugs of abuse in standard urine screening examinations is limited. Which of the following examples is not correct?

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A. Opioid metabolites (morphine and heroin) can be detected for 2–3 days. B. Cocaine metabolites can be detected for 7 days. C. Marijuana can be detected for 3–30 days, depending on the amount of prior use. D. Amphetamines can be detected for 2 days. Correct answer is B. Cocaine metabolites can only be detected for 2–4 days after use. Section: Table 7–1: Federal workplace drug testing cutoff values and detection time in urine. Please also see Toxicology Testing in Chapter 13, “Logistics of Office-Based Buprenorphine Treatment.”

Chapter 8 CLINICAL MANAGEMENT II 8.1

Which one of the following comparisons of psychosocial treatments is best supported by the Project MATCH data? A. Cognitive-behavioral therapy (CBT) and MET are more effective than 12-step facilitation (TSF). B. MET is more effective than either CBT or TSF. C. TSF is more effective than either CBT or MET. D. All three interventions are effective but none is shown to be significantly better than the other two. E. None of the three interventions is effective. Correct answer is D. All three psychosocial treatments (CBT, MET, and TSF) were equally effective and subjects in all three treatment groups showed significant improvements. To this day, Project MATCH remains the largest and most scientifically rigorous trial comparing the effects of different types of psychosocial treatments in substance use disorders. Section: Professional Counseling Improves Outcome.

8.2

According to the American Society of Addiction Medicine Patient Placement Criteria, Second Edition Revised (ASAM PPC-2R), severity of illness is assessed in six dimensions, including all of the following except

Appendix 2: Study Questions and Answer Guide A. B. C. D. E.

309

Acute intoxication and withdrawal potential. Medical conditions. Psychiatric conditions. Spirituality. Recovery environment.

Correct answer is D. The six dimensions of the ASAM PPC-2R are 1. Acute intoxication/withdrawal potential. 2. Biomedical conditions and complications. 3. Emotional, behavioral, or cognitive conditions and complications. 4. Readiness to change. 5. Relapse, continued use, or continued problem potential. 6. Recovery/living environment. Spirituality, although critical for many people’s recovery, is not one of the dimensions of illness severity of the ASAM PPC-2R. Section: Assessment for Professional Treatment. 8.3

How many patients who enter therapeutic communities complete the full course of treatment? A. B. C. D. E.

Almost none. 15%–25%. 40%–60%. 75%–85%. Almost all.

Correct answer is B. Although most people who graduate from therapeutic community programs tend to do well in terms of substance use, employment, and rehabilitation outcomes, the attrition is high; only 15%–25% of people who start the program end up completing the full course of treatment. Section: Residential and Intensive Outpatient Programs. 8.4

MET strategies include all of the following, except A. B. C. D. E.

Discourage disagreement. Roll with resistance. Express empathy. Develop discrepancy. Support self-efficacy.

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Correct answer is A. Many clinicians mistakenly assume that a patient-centered approach to treatment, such as MET, is incompatible with argumentation and disagreement. On the contrary, MET encourages clinicians and patients to be upfront with their agendas, especially when they disagree with one another. In order to make sure that there is no confusion on this issue, the second edition of Motivational Interviewing has put aside the “A” of the “A-REDS” acronym, which stood for “Avoid argumentation.” The acronym now is simply “REDS,” which stands for “Roll with resistance,” “Express empathy,” “Develop discrepancy,” and “Support self-efficacy.” Section: Handling Resistance to Treatment: Motivation Enhancement Therapy. 8.5

What is the official position of Narcotics Anonymous (NA) and Alcoholics Anonymous (AA) towards buprenorphine? A. Patients receiving buprenorphine treatment are not sober and thus are not allowed to attend meetings. B. Patients receiving buprenorphine treatment may attend NA or AA and are allowed to listen—but not talk—during the meetings. C. Patients receiving buprenorphine detoxification treatment—but not buprenorphine maintenance—can be NA or AA members and fully attend meetings. D. Patients who take buprenorphine only as prescribed by a licensed physician can be NA or AA members and fully attend meetings. E. The only requirement for membership in NA or AA is a desire to stop using. Correct answer is E. The AA preamble states: “The only requirement for membership is a desire to stop drinking.” The NA preamble states: “There is only one requirement for membership, the desire to stop using.” Unfortunately, several AA and NA groups continue to frown upon people who receive OAT, sometimes accepting people on buprenorphine detoxification but not maintenance and sometimes asking people to remain silent during meetings if they take methadone or buprenorphine. Section: Facilitating Involvement in 12-Step Groups.

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Chapter 9 PSYCHIATRIC COMORBIDITY 9.1

All of the following psychiatric problems are considered contraindications to office-based buprenorphine treatment, except A. B. C. D. E.

Active psychosis. Active suicidal ideation. Active homicidal ideation. A recent history of arrests for drug possession or dealing. Cognitive impairment or dementia.

Correct answer is D. Histories of arrests for drug possession and dealing are not unusual in opioid-dependent individuals. Unless there is evidence of violence and severe antisocial behavior, such individuals may be considered for officebased buprenorphine treatment. Section: Table 9–2: Psychiatric contraindications to office-based treatment of opioid dependence. 9.2

It is important to differentiate independent psychiatric disorders from those disorders induced by substance use or dependence. Which of the following issues is not helpful in making this distinction? A. B. C. D.

Sequence of onset of psychiatric symptoms. A family history of a similar diagnosis. Psychiatric symptoms during prolonged periods of sobriety. Suicidal ideation during periods of depression.

Correct answer is D. Differentiating substance-induced psychiatric disorders from independent psychiatric disorders can be a challenge even for very experienced addiction psychiatrists. Important to this differentiation are the patient’s history, the patient’s family history, and the course of symptoms following cessation of substance abuse. Suicidal ideation can occur in either independent or substance-induced disorders. Section: How to Differentiate Substance-Induced From Independent Psychiatric Disorders.

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9.3

Which of the following statements best describes guidelines for the pharmacotherapy of co-occurring psychiatric disorders in the opioiddependent patient? A. Most forms of pharmacotherapy are contraindicated in buprenorphine patients. B. Research suggests that tricyclic antidepressants are the medications of choice for this population. C. While there is a small evidence base for the treatment of psychiatric disorders in these patients, there is also no evidence that standard treatments are not effective. D. Benzodiazepines are highly effective in managing most co-occurring disorders in these patients. Correct answer is C. Standard psychiatric medications appear to be effective for the treatment of co-occurring disorders in buprenorphine patients. However, abusable medications such as the benzodiazepines should be used with great caution. Section: Pharmacotherapy.

Chapter 10 MEDICAL MANAGEMENT 10.1 Effective vaccines exist for all of the following, except A. B. C. D. E.

Hepatitis A. Influenza. Hepatitis C. Tetanus. Pneumococcus.

Correct answer is C. Patients who suffer from opioid dependence should be tested (and treated) for hepatitis C, but no vaccine against hepatitis C is currently available. Vaccines against hepatitis A, hepatitis B, influenza, tetanus, and pneumococcus are available and can be offered to patients as indicated. Section: Routine Preventive Care.

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10.2 The hepatitis B vaccination schedule is A. B. C. D. E.

A series of five shots administered at 0, 1, 2, 3, and 6 months. A series of four shots administered at 0, 1, 3, and 6 months. A series of three shots administered at 0, 1, and 6 months. A series of two shots administered at 0 and 6 months. A single shot.

Correct answer is C. The Advisory Committee on Immunization Practices recommends a hepatitis B vaccination series of three shots administered at 0, 1, and 6 months. Section: Routine Preventive Care. 10.3 The least effective route of hepatitis C transmission is A. Sharing needles during intravenous drug use. B. Sharing “works” (tubing, syringe, wastewater, etc.) with an infected individual. C. Needlestick injuries. D. Receipt of blood transfusion before 1992. E. Unprotected sexual intercourse. Correct answer is E. The most common cause of hepatitis C seroconversion is injection drug use. While hepatitis C is known to be also transmitted through needlesticks and “works,” it is not readily transmissible through sexual contact. Blood banks started testing for hepatitis C in 1992. Section: Hepatitis C: Epidemiology. 10.4 Clinically significant drug-drug interactions of buprenorphine with medication(s) used in the treatment of HIV disease include A. Only atazanavir/ritonavir, a medication that tends to increase buprenorphine concentrations and cause sedation resulting in the need to decrease the buprenorphine dose. B. Only atazanavir/ritonavir, a medication that tends to decrease buprenorphine concentrations and cause cravings for opioids resulting in the need to increase the buprenorphine dose. C. Only atazanavir/ritonavir, a medication that tends to sometimes increase and sometimes decrease buprenorphine concentrations, neces-

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sitating close monitoring and frequent adjustments of the buprenorphine dose. D. All protease inhibitors. E. All highly active antiretroviral therapy (HAART) medications. Correct answer is A. The only clinically significant drug-drug interaction between buprenorphine and antiretroviral medications is the potential interaction of buprenorphine with the protease inhibitor atazanavir/ritonavir. Because atazanavir/ritonavir may increase buprenorphine concentrations and thus cause sedation, the dose of buprenorphine may need to be decreased. In contrast, several protease inhibitors induce the metabolism of methadone thus lowering its serum concentration; methadone patients who also take antiretroviral medications often require higher methadone doses. Section: HIV Infection and Opioid Agonist Treatment. 10.5 A positive purified protein derivative (PPD) skin test for exposure to latent tuberculosis infection (LTBI) consists of A. >20 mm induration (>10 mm if HIV positive) at 48–72 hours after skin testing. B. >15 mm induration (>10 mm if HIV positive) at 48–72 hours after skin testing. C. >10 mm induration (>5 mm if HIV positive) at 48–72 hours after skin testing. D. >5 mm induration (any induration, but not just redness, if HIV positive) at 48–72 hours after skin testing. E. Any detectable induration, but not just redness, at 48–72 hours after skin testing. Correct answer is C. A positive PPD skin test for exposure to LTBI consists of >10 mm induration (>5 mm if HIV positive) at 48–72 hours after skin testing. However, immunocompromised patients may be anergic (i.e., unable to mount a response to the protein derivative even if exposed to TB) and thus give a false-negative PPD skin test. Section: Tuberculosis.

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Chapter 11 MANAGEMENT

OF

ACUTE

AND

CHRONIC PAIN

11.1 Which of the following statements accurately describes the risks associated with pain management in patients receiving OAT? A. Providing opiates for the treatment of acute pain is likely to precipitate relapse in patients receiving methadone or buprenorphine maintenance treatment. B. Untreated pain in patients receiving OAT increases the risk of relapse. C. Patients receiving OAT do not require supplemental opiates to manage acute or chronic pain. D. Chronic severe pain syndromes in OAT patients are best managed without additional pharmacotherapy. Correct answer is B. There is no evidence that providing opiates to OAT patients for the management of either acute or chronic pain will increase the risk for relapse. The analgesic effect of a single daily dose of methadone or buprenorphine rarely lasts more than 6–8 hours, necessitating the use of supplemental pain medications when needed. Untreated pain is more likely to precipitate relapse. Section: Introduction. 11.2 All of the following statements accurately describe properties of buprenorphine, except A. Buprenorphine suppresses craving and opiate withdrawal for 24– 48 hours. B. Buprenorphine has a very high affinity for the µ opioid receptor and will displace or block the binding of most full opioid agonists. C. Buprenorphine acts as an antagonist at the κ opioid receptor, likely producing some degree of spinal analgesia and dysphoria. D. Buprenorphine provides analgesia at the µ opioid receptor for 24– 30 hours.

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E. Buprenorphine, like methadone, causes cross-tolerance to the effects of other opioids; for that reason, patients on OAT often require higher and more frequent doses of opioid analgesics for adequate pain control. Correct answer is D. The analgesic effect of buprenorphine lasts for 6–8 hours. All of the other statements are correct. Section: Buprenorphine Pharmacology. 11.3 Which of the following interventions is not appropriate for the management of acute pain in a patient receiving buprenorphine maintenance treatment? A. Mixed agonist-antagonists such as pentazocine (Talwin), nalbuphine (Nubain), or butorphanol (Stadol) can be added to the single daily buprenorphine dose. B. Aggressively implement nonpharmacological and nonopioid pain treatments. C. Because of cross-tolerance, control of severe pain will usually require higher opioid doses at shorter intervals than is customary in nonopioid-dependent patients. D. Continue the patient’s current buprenorphine dose and titrate a short-acting opioid analgesic to effect. E. Analgesic doses should be continuous or scheduled rather than on an as-needed basis. Correct answer is A. Mixed agonists-antagonists should be avoided because they are likely to displace the maintenance opioid from the µ receptor, thus precipitating acute opioid withdrawal. All of the other interventions would be appropriate for the management of acute pain in a patient receiving buprenorphine maintenance treatment. Section: Acute Pain Management. 11.4 Which of the following options should be considered first in the management of chronic pain in patients receiving buprenorphine? A. Aggressively treat any co-occurring psychiatric disorder. B. Treat with CBT, acupuncture, stress management, and behavior modification programs. C. Divide the daily buprenorphine dose to every 6–8 hour dosing.

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D. Treat with nonopioid medications (e.g., acetaminophen, nonsteroidal anti-inflammatory drugs, antidepressants, anticonvulsants). E. Transfer the patient to a methadone maintenance program. F. Options A, B, and D should be considered before any change in the maintenance medication program. Correct answer is F. Whenever possible, chronic pain syndromes should be managed without reliance on additional opioid medication. Nonpharmacological treatments should always be considered first. Section: Chronic Pain Management.

Chapter 12 OPIOID USE

BY

ADOLESCENTS

12.1 Since the year 2000, adolescent illicit use of prescription opioids like oxycodone and hydrocodone has increased by approximately A. B. C. D. E.

1%. 5%. 10%. 50%. 100%.

Correct answer is E. According to the Monitoring the Future study, use of “narcotics other than heroin” has doubled among high school students since 2000. The most commonly abused prescription opioids among adolescents are long-acting oxycodone and hydrocodone-acetaminophen tablets. Section: Epidemiology. 12.2 All of the following have been correlated robustly with adolescent opioid use, except A. B. C. D. E.

High parental income. Low parental monitoring. Inconsistent discipline. Conflicted parent-child relationships. Parental alcohol or drug use.

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Correct answer is A. Lower socioeconomic status—not higher—is a risk factor for adolescent substance use disorders. Conflicted parent-child relationships, parental ineffectiveness, insufficient parental monitoring, inconsistent discipline, and parental alcohol or drug use have also been robustly correlated with adolescent opioid use. Lower levels of parental education have been associated with heroin use among teenagers. Section: Risk and Protective Factors. 12.3 The CRAFFT screening questionnaire explicitly asks adolescents about use of all of the following substances, except A. B. C. D. E.

Alcohol. Cocaine. Marijuana or hashish. Over-the-counter and prescription drugs used to get high. Things that you sniff or “huff ” in order to get high.

Correct answer is B. The first part of the CRAFFT questionnaire consists of the following three-part question: “During the past 12 months, did you: 1) Drink any alcohol (more than a few sips)? 2) Smoke any marijuana or hashish? 3) Use anything else (illegal drugs, over-the-counter and prescription drugs, and things that you sniff or ‘huff ’) to get high?” A positive screen on any of these first three areas leads to the second part of the questionnaire, which consists of the six questions responsible for the name CRAFFT (Car, Relax, Alone, Forget, Family or Friends, Trouble). Section: Figure 12–1: CRAFFT screening questionnaire. 12.4 Primary prevention strategies for adolescents who require opioid medications for pain management include A. Advising parents to hold, dispense, and observe all medication doses. B. Insisting that the adolescent receive all opioid prescriptions from a single prescriber and fill prescriptions at a single pharmacy. C. Recommending that the family bring remaining medications for a pill count at every visit. D. Keeping the lines of communication open among all treating physicians. E. All of the above.

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Correct answer is E. While pain medications can be safe and effective when used as prescribed, they are also highly addictive. Physicians and other clinicians should provide anticipatory guidance to adolescents and their parents in order to minimize the risk of opioid misuse, abuse, and addiction. Section: Non-Opioid-Dependent Teens: Primary Prevention. 12.5 Which of the following statements regarding buprenorphine maintenance treatment in adolescents is correct? A. It has been shown to be significantly more effective than methadone maintenance treatment. B. It has been shown to be no more effective than opioid detoxification. C. It is approved for patients age 16 years and above. D. It is subject to state—but not federal—regulations. E. Documentation of a 1-year history of opioid dependence is required before initiation of treatment. Correct answer is C. Buprenorphine treatment is approved for patients age 16 years and older who meet DSM-IV-TR criteria for opioid dependence. Buprenorphine maintenance treatment has been shown to a) be as efficacious as methadone maintenance treatment and b) result in better substance use outcomes than opioid detoxification. Both methadone and buprenorphine are federally regulated, but only methadone treatment requires documentation of at least a 1-year history of opioid dependence. Section: Long-Term Pharmacotherapy: Buprenorphine.

Chapter 13 LOGISTICS OF OFFICE-BASED BUPRENORPHINE TREATMENT 13.1 Which statement correctly describes federal limitations on the number of buprenorphine patients that a practitioner can treat in an office-based setting? A. With documentation of extra office staff, a practitioner can treat up to 150 patients. B. All practitioners are limited to 30 patients at any one time.

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C. Practitioners who are board certified in addiction psychiatry can treat up to 75 patients at any one time. D. After 1 year of experience treating buprenorphine patients, any waivered physician can request authorization to increase his or her number of patients to 100. Correct answer is D. One year after a physician receives his or her original buprenorphine waiver, federal regulations permit that physician to request an increase in his or her patient limit to 100. The request can be submitted online at http://buprenorphine.samhsa.gov/bwns/federal.html, or by calling the CSAT Buprenorphine Information Center at 1-866-BUP-CSAT (1-866-287-2728). Section: Prescriber. Please also see Qualifying Physicians in Chapter 1, “Opioid Dependence in America.” 13.2 According to DATA 2000, all buprenorphine practitioners are required to have A. B. C. D. E.

Office staff skilled in the management of opiate dependence. The ability to provide on-site CBT or other forms of psychotherapy. On-site laboratory services for urine toxicology. The capacity to refer for counseling and ancillary services. Secure storage facilities for buprenorphine.

Correct answer is D. The only requirement for a waivered physician, beyond a valid medical license and DEA registration, is the capacity to refer for any needed ancillary services. Section: Drug Addiction Treatment Act of 2000 in Chapter 1, “Opioid Dependence in America.” 13.3 To maximize clinical outcome, practice guidelines strongly encourage all of the following, except A. Random urine toxicology screens for buprenorphine, opioids, and other drugs of abuse. B. Ongoing weekly prescriptions and physician visits to monitor patient progress throughout the course of buprenorphine treatment. C. Individual or group counseling provided by professionals skilled in work with drug-dependent patients.

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D. Participation in self-help groups such as Alcoholics Anonymous and/or Narcotics Anonymous. E. Couples counseling. Correct answer is B. While weekly physician visits are recommended during the first 1–2 months of treatment, stable patients receiving buprenorphine treatment do not require that level of physician monitoring, particularly if they are participating in individual or group counseling or are actively engaged in a self-help program. Section: Models of Care. Please also see Psychosocial Treatment. 13.4 DATA 2000 permits buprenorphine to be dispensed in an opioid treatment program (methadone clinic). In the methadone clinic setting, all of the following regulations apply, except A. The clinic may not treat more than 100 patients with buprenorphine. B. Clinic physicians are not required to obtain the DEA buprenorphine waiver. C. The same regulations that limit methadone take-home doses also apply to buprenorphine. D. On-site urine toxicology and ancillary counseling services are required. Correct answer is A. Under DATA 2000, there is no limit on the number of buprenorphine patients that may be followed in a methadone clinic. Section: Opioid Dependence Treatment Program Model: Methadone Clinic.

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Index Page numbers printed in boldface type refer to tables or figures. Age of onset abuse of pain relievers and, 11 for opioid dependence or abuse, 8, 11, 12, 229 Agonists, and pharmacology of opioids, 47, 48–49, 60, 112. See also Full agonists; Partial agonist AIDS. See HIV/AIDS Alanine aminotransferase (ALT), 53, 194, 200 Alcohol and alcohol abuse. See also Alcoholics Anonymous; National Institute on Alcohol Abuse and Alcoholism clinical management of problem behaviors and, 138 evaluation of patients with opioid abuse and, 169–170 Alcoholics Anonymous (AA), 151, 154– 155, 257, 310. See also Twelve-step groups Alprazolam, 54, 111 Alternative novel formulations, of buprenorphine, 74 American Academy of Addiction Psychiatry, 17, 30, 288 American Academy of Child and Adolescent Psychiatry, 242 American Academy of Pediatrics, 230 American Board of Psychiatry and Neurology, 16, 31 American Medical Association, 17 American Osteopathic Association (AOA), 17, 30, 31

Abstinence violation effect, 159 Access, to treatment for opioid abuse, 13 Acetaminophen, 213, 217, 218, 220, 281, 282 Action, and stages of change paradigm, 85 Acute residential treatment (ART) programs, for adolescents, 244 Addiction, use of term, 87, 89 Addiction Physician Survey, 33, 34 Adefovir, 196, 198 Adherence, to prescribed medications, 181–182. See also Compliance Adolescents behavioral treatments for, 241–242, 244–248 buprenorphine maintenance therapy for, 205, 319 case example of, 249, 282–283 epidemiology of opioid abuse in, 227–228, 317 guidelines for assessment and care of substance use disorders in, 243– 244 prevention of substance abuse in, 233–241 psychiatric comorbidity and opioid abuse in, 229 risk and protective factors for opioid abuse in, 228–229, 318 screening and assessment of opioid abuse in, 230–233 Affinity, and opioid receptor binding, 50–51

323

324 Handbook of Office-Based Buprenorphine Treatment of Opioid Dependence

American Psychiatric Association, 17, 30 American Society of Addiction Medicine (ASAM), 17, 30, 31, 149, 288, 309 Amphetamines, 141, 142. See also Stimulants Antagonists, of opioids, 49 Antiemetics, and withdrawal, 107 Antiretroviral medications, 53, 314 Antisocial behavior, 311 Antisocial personality disorder, 168 Anxiety medical management of pain and, 214 as symptom of opioid withdrawal, 166–167 Anxiety disorders, 184 AOD agencies, and survey on funding for buprenorphine treatment, 37 Appropriate pain relief-seeking behavior, 214 Aspartate aminotransferase (AST), 53, 194, 200 Assessment, for buprenorphine treatment. See also Diagnosis adolescents and, 230–233, 243–244 appropriateness of patient for, 90–91 of co-occurring psychiatric disorders in opioid-dependent patients, 170–173 drug use history and, 80–83 establishing relationship with patient and, 79–80 intensity of treatment services and, 149 laboratory examination and, 86–87 motivation for change and, 85–86 of pain, 217 patient history and, 84–85 physical examination and, 86 previous treatments and recovery efforts, 83–84

Association for Medical Education and Research in Substance Abuse (AMERSA), 287 Atazanavir, 112, 186, 203, 314 Atomoxetine, 184 Attention deficit/hyperactivity disorder (ADHD), 167–168, 184 Atypical antipsychotics, 185 Automation of Reports and Consolidated Orders System, 32 Behavior. See also Antisocial behavior; Behavioral treatment clinical management of problem forms of, 136–139, 307 pain management and, 214 Behavioral Health codes, 265 Behavioral treatment. See also Cognitivebehavioral therapy adolescent patients and, 241–242, 244–248 care management model and collaboration, 121 chronic disease management and, 134 Benzodiazepines clinical management of problem behaviors and, 138 drug-drug interactions with buprenorphine, 53, 72, 112– 113, 167, 186, 302, 305, 312 drug screening and, 142 evaluation of substance use disorders and, 169–170 Benzoylecgonine, 140 Billing, and office management, 263, 265–266 Bioavailability, of buprenorphine, 56, 61–62, 98, 297. See also Oral availability Blood-brain barrier, and abuse potential of drugs, 46–47 Borderline personality disorder, 91

Index Brain, changes in due to chronic abuse of opioids, 166 Brief interventions, for adolescents, 234, 246 Web site for screening, brief intervention, and referral to treatment (SBIRT), 286 Brief Pain Inventory, 217 Buprenorphine, and treatment of opioid dependence. See also Assessment; Clinical management; Dosages; Drug-drug interactions; Medical management; Office-based buprenorphine treatment; Opioid abuse and dependence; Overdose; Side effects adolescent patients and, 205, 236– 237, 319 appropriateness of patient for, 90–91 clinical trials assessing efficacy of, 63–69 clinical use issues for, 55–56 controlled trials assessing efficacy of for withdrawal, 69–70 creation of new treatment paradigm and, 27–28 detoxification with, 113–114 diversion of for abuse, 33, 35–36, 294 drug screening for, 143, 144 evaluation of impact of new paradigm for, 31–38 FDA approval of office-based treatment with, 15, 18–20, 27– 28, 89, 292 formulations of, 55, 95–96, 97, 99– 100, 303 future directions for, 74 geriatric patients and, 205–206 hepatitis infection and, 196, 199, 201 history and rationale for development of, 59–63 HIV infection and, 185–186, 203 implementation of new paradigm for, 28–31

325

improvements to new paradigm for, 38–40 induction phase in clinical use of, 98– 109, 239, 259–260, 262, 304 maintenance phase in clinical use of, 109–113 methadone maintenance treatment compared to, 21, 22–24, 67–70, 91, 299 pain management and, 218–221, 316 pharmacology of, 48–53, 60–62, 97– 98, 216–217, 297, 298 pregnancy and, 206, 239, 241 regulatory criteria for methadone maintenance compared to, 89–90 safety of, 70–74, 136 stabilization phase in clinical use of, 109 tapering dosage of, 115, 135 Buprenorphine Physician Locator (SAMHSA), 285 Buprenorphine (Suboxone) Training and Practice Tools, 258 Bupropion, 184 Butorphanol, 218 California Civil Addict Program, 5, 7 California Society of Addiction Medicine (CSAM), 287 Cancer patients, and pain management, 214 Carbamazepine, 54, 185 “Care coaches,” 254 Care management model, 121 Case examples of adolescent patients, 249, 282–283 of clinical management, 145, 161– 163, 275–279 of clinical use of buprenorphine, 116–117 of medical management, 207–208, 281 of pain management, 223, 281–282 of psychiatric comorbidity, 187–189, 280–281

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Centers for Disease Control and Prevention (CDC), 167, 193 Center for Substance Abuse Treatment (CSAT), 29, 33, 34–35, 37, 98, 285, 295, 320 Children, and buprenorphine overdoses, 136 China, immigration from and history of opioid abuse, 2–3 Chronic disease paradigm, and clinical management, 131–136 Chronic hepatitis infection, 195–196, 200–201 Chronic pain syndrome, 91, 220–221, 317. See also Pain and pain management Cigarette smoking, 156, 170 Cirrhosis, and hepatitis, 199 Civil War, and history of opioid abuse, 2 “Clinical Guidelines for the Use of Buprenorphine in the Treatment of Opioid Addiction” (TIP 40), 19 Clinical management case examples of, 145, 161–163, 275– 279 chronic disease paradigm and, 131– 136 counseling and improvement in treatment outcome, 148–50 establishment of therapeutic environment and, 123–131 facilitating outpatient treatment and/ or recovery group involvement, 152–159 management of problem behaviors and, 136–139, 307 organization of office for, 120–123 of residential and intensive outpatient programs, 150–152 screening for drugs of abuse and, 139–144 Clinical Opiate Withdrawal Scale (COWS), 101, 102–104, 107, 262, 303 Clinical Tools, 289

Clinical trials, on efficacy of buprenorphine treatment, 63–69 Clinical Trials Network (CTN), 114, 115 Clonidine, and opioid withdrawal, 69, 70, 107, 113, 235 Cocaine assessment of opioid-dependent patients and, 170 drug testing and, 140, 141, 308 Code of Federal Regulations Title 42 (66 Federal Register 4076–4102), 176, 263 Codeine, 46, 81, 86, 140, 143, 232 Cognitive-behavioral therapy for adolescents, 245 chronic pain and, 220 coping skills and, 157–159 relapse prevention and, 157 Cognitive functioning evaluation of patients for office-based buprenorphine treatment and, 171, 173 side effects of buprenorphine and, 73, 300 Cold turkey, 83 Collaborative models, of care management, 121 Columbia University, 288 Combo product, of buprenorphine and naloxone, 55, 96, 99–100, 297, 303 Communication, and coordination with other treatment providers, 122–123 Community-based primary care clinics, 269–270 Comorbidity, of opioid dependence with psychiatric disorders adolescents and, 229 assessment for professional treatment and, 149 case examples of, 187–189, 280–281 epidemiology of, 165–168 evaluation of, 168–177 frequency of in severe and persistent forms of addiction, 132

Index management of, 178–185 treatment goals and improvement in, 133–134 Compliance. See also Adherence clinical management of problem behaviors and, 137 psychotherapeutic interventions and, 182–183 Conduct disorder, 168 Confidentiality, and logistics of officebased buprenorphine treatment, 263 Constipation, as side effect of buprenorphine, 73, 296, 300 Consultations, documentation of, 267– 268 Contemplation, and stages of change, 85 Contingency management, 247 Contracts. See also Treatment agreements adolescent patients and, 238–239, 240–241 problem behaviors and, 137 Controlled Substances Act, 28 Controlled trials, on efficacy of buprenorphine for opioid withdrawal, 69–70 Coping skills, and cognitive-behavioral therapy, 157–159 Counseling comorbidity and, 178 improvement in outcome and, 148– 150 prevention of opioid abuse in adolescents and, 233–234 previous treatments and assessment, 83 for relapse prevention, 157, 158 Course specifiers, for substance dependence, 89 Coverage, for prescribers during periods of absence, 259 CRAFFT questionnaire, 230, 231, 318 Criminal behavior, and clinical management, 137. See also Homicidal ideation Cross-tolerance, among opioids, 216–217

327

CYP450 3A4 enzyme, and pharmacokinetics of buprenorphine, 52–53, 54, 111– 112, 185–186 Daytop Village, 150 Day treatment programs, for adolescents, 242 Dementia, and evaluation of opioiddependent patients, 171, 173 Department of Health and Human Services (DHHS), 17, 19, 20–21, 33, 236, 293 Department of Veterans Affairs (VA), 31 Dependence, use of term, 89, 230, 232. See also Opioid abuse and dependence; Physical dependence; Physiological dependence; Substance dependence Depression, and comorbidity with opioid abuse, 166, 184 Detoxification adolescent patients and, 205, 235 assessment and, 83 buprenorphine and, 113–114 relapse rates and efficacy of, 5 Diagnosis, of substance abuse, 87–89. See also Assessment; Differential diagnosis; Evaluation Diazepam, 54, 111, 112, 186 Dicyclomine, 107 Differential diagnosis assessment of adolescents and, 230 of substance-induced from independent psychiatric disorders, 174, 311 Diphenhydramine, 185 Dissociation, of opioids from receptors, 52 Diversion, of buprenorphine for abuse, 33, 35–36, 56, 98, 294 Documentation intoxicated patients and, 177 logistics of office-based buprenorphine treatment and, 266–268

328 Handbook of Office-Based Buprenorphine Treatment of Opioid Dependence

Dole, Vincent, 5, 291 Dopamine system, and comorbidity in opioid-dependent patients, 166 Dosages. See also Dose-related blockade; Dose-response curve; Overdose; Tapering buprenorphine induction and, 106, 107, 108, 109 buprenorphine maintenance and, 110–111, 304 buprenorphine stabilization and, 109 chronic disease paradigm and review of, 135 detoxification with buprenorphine and, 113–114 future directions in buprenorphine treatment and, 74 of methadone compared to buprenorphine, 67–68, 106 research on buprenorphine efficacy and, 65, 66, 68 Dose-related blockade, and laboratory studies of buprenorphine, 64–65 Dose-response curve, of buprenorphine, 60–61 Driving, and intoxicated patients, 176–177 Drug Abuse Warning Network, 35 Drug Addiction Treatment Act of 2000 (DATA 2000), 16–21, 28, 33, 34– 35, 36, 63, 236, 292, 294, 295, 321 Drug Enforcement Administration (DEA), 17–18, 20, 28, 32, 36, 89, 286, 320 Drug-drug interactions. See also CYP450 3A4 enzyme of benzodiazepines with buprenorphine, 53, 72, 112– 113, 167, 186, 302, 305, 312 buprenorphine maintenance and, 111–113 of methadone with antiretroviral medications, 203 Drug Policy Alliance, 288 Drug Strategies, 286–287

Drug testing. See Screening; Urine toxicology examinations Drug use history, and assessment, 80– 86, 172 DSM-IV-TR, 55, 87, 89, 149 ADHD and, 167 opioid abuse and, 232 opioid dependence and, 109, 262 opioid withdrawal disorder and, 50 substance abuse and, 87 substance dependence and, 88–89 Duration of treatment, and goals of treatment planning, 130–132 Duty to warn, and homicidal ideation, 181 Education, and training of staff, 120– 121, 305. See also Psychoeducation; Training E/M codes, 265 Emergency departments diversion of buprenorphine for abuse and, 35 heroin-related visits to by adolescents, 228 Emergency plans, and recovery groups, 158 Employment consequences, of drug use, 83 Entecavir, 196, 197 Entry inhibitors, and HIV infection, 204 Enzyme immunoassay testing, for HIV, 202 Epidemiology. See also Prevalence of adolescent opioid abuse, 227–228 of hepatitis B, 193–194, 199 of HIV/AIDS, 201–202 of pain in opioid-dependent patients, 215–216 of psychiatric comorbidity in opioid dependence, 165–168 Erectile dysfunction, as side effect of buprenorphine, 73 Euphoria, and buprenorphine, 56 Evaluation. See also Assessment; Diagnosis

Index buprenorphine treatment in adolescents and, 238 documentation of, 266 of psychiatric comorbidity with opioid abuse, 168–177 False-negative results, of drug tests, 140, 144, 202 False-positive results, of drug tests, 140, 142, 143, 232 Family. See also Family therapy; Parent(s) assessment and, 81, 84–85 drug use history and relationship with, 82 informed consent process and, 124 Family therapy, and adolescents, 246 Federation of State Medical Boards, 19, 266, 287 Fentanyl, 141, 143 Fibrosis, and hepatitis, 199 Financial consequences, of drug use, 83 Flunitrazepam, 72, 299 Fluvoxamine, 54, 111, 186 Food and Drug Administration (FDA) adolescents and buprenorphine therapy, 237 approval of LAAM, 62 approval of office-based buprenorphine therapy, 15, 18– 20, 27–28, 89, 220, 292 establishment of, 4 federal methadone regulations and, 5 formulations of buprenorphine approved by, 95 information for patients and, 262 labeling and side effects of buprenorphine, 71 naltrexone and naloxone for treatment of opioid abuse and, 49 Forms, use of standardized, 261–262 Formulations, of buprenorphine, 55, 95– 96, 97, 99–100, 303 Full agonists, and pharmacology of buprenorphine, 48, 51, 60, 112, 297

329

Gas chromatography-mass spectrometry (GC-MS), 139, 144 Geriatric patients, and buprenorphine treatment, 205–206 Goals adolescents and setting of for treatment, 238 of chronic disease management, 133 of treatment planning, 130–131 Government, and Web sites, 285–286. See also Policy; Regulation; States; specific agencies Group therapy adolescents and, 246 psychiatric comorbidity and, 178–179 Guidelines for assessment and care of substance use disorders in adolescents, 243–244 chronic disease management principles and, 133–135 intoxicated patients and, 176–177 for managing co-occurring psychiatric disorders, 178 for pain management during buprenorphine maintenance, 219 for treatment agreements, 267 Web site for, 286 Guilt, and relapse prevention, 159 Hair testing, 260 Harrison Narcotics Tax Act (1914), 4, 5, 21, 28, 291 Headaches, as side effect of buprenorphine, 73, 300 Health Insurance Portability and Accountability Act of 1996 (HIPAA), 122, 123, 268 “Here to Help Program,” 254 Hepatitis hepatitis B serology, 195 liver enzyme levels in buprenorphine patients and, 53, 71 medical management of, 193–201

330 Handbook of Office-Based Buprenorphine Treatment of Opioid Dependence

Hepatitis (continued) preventive care and vaccinations for, 193, 312, 313 Heroin, 86 abuse of compared to abuse of pain relievers, 13 addiction to as chronic lifetime disorder, 6 adolescents and, 228 blood-brain barrier and, 46–47 buprenorphine induction and, 104, 106 drug screening and, 140, 141, 143 history of opioid abuse and, 4, 6, 46 pain reliever abuse and secondary increase in abuse of, 13, 15 Highly active antiretroviral therapy (HAART), 203 History, of opioid abuse development of buprenorphine for treatment of, 59–63 early cultivation of opium poppy and, 45 Harrison Act and prohibition of addiction treatment, 4–6 heroin abuse in post-World War II era and, 6 new epidemic of abuse of pain relievers and, 8–11 patterns of during nineteenth century, 1–4, 45–46 HIV/AIDS drug interactions with buprenorphine and, 185–186 evaluation of opioid-dependent patients with, 171 medical management of, 201–203, 204 preventive care and testing for, 193 HIV/AIDS Bureau, of Health Resources and Services Administration, 30–31 Home buprenorphine induction, 100

Homicidal ideation evaluation of opioid-dependent patients and, 171, 172, 173, 176 psychiatric comorbidity and, 181 Hospital-based dual diagnosis clinics, and intensive outpatient model, 271–272 Hospital-based primary care centers, and nurse care managers, 270–271 Hospitalization. See also Emergency departments; Residential programs adolescents and, 242, 244 of intoxicated patients, 177 Hydrocodone adolescents and, 228, 317 buprenorphine induction and, 104, 106 drug testing and, 141, 143 Hydrocodone-acetaminophen compound, 9 Hydromorphone, 143 Hydroxyzine, 107 Ibuprofen, 107 Immunoassays, and drug screening, 140, 142 Immunosuppressants, and hepatitis, 197 Inappropriate drug-seeking behavior, and pain management, 214 Induction, of buprenorphine, 98–109, 239, 259–260, 262, 304 Influenza, 193 Information, for patients, 262–263. See also Web sites Informed consent documentation and, 267 sample form for, 125–127, 261 therapeutic environment and, 123– 124 Insomnia, 184–185 Integrase inhibitors, 204 Intensive outpatient model, and hospital-based dual-diagnosis clinics, 271–272 Interferon, and hepatitis, 196, 197, 200, 201

Index Internet listing, and office management, 254–255. See also Web sites Intoxication, and evaluation of opioiddependent patients, 175–177 Inventory, of controlled substances dispensed, 268 Involuntary hospitalization, of intoxicated patients, 177 Isoniazid, 205 Jaundice, and hepatitis, 194, 195 Join Together, 288 LAAM approval and use of, 15, 62–63 side effects of, 71, 206, 299–300 Laboratory examination assessment and, 86–87 documentation of, 267 hepatitis and, 194, 200 HIV/AIDS and, 202 Laboratory studies, on efficacy of buprenorphine treatment, 64–65 Lamivudine, 196, 197 Laudanum, 1–2 Legal consequences, of drug use, 83 Letters, to other treatment providers, 122 Liver function assessment and laboratory examination of, 86–87 disease of and buprenorphine treatment, 206 hepatitis and, 193, 199 side effects of buprenorphine and, 53, 70–71 tuberculosis and, 205 Lofexidine, 70, 107 Log, of controlled substances dispensed, 268 Loperamide, 107 Maine, and oxycodone abuse, 9 Maintenance. See also Methadone maintenance treatment

331

clinical use of buprenorphine and, 109–113 stages of change paradigm and, 85 Major depression, 184 Manual-driven protocols, for psychotherapeutic treatment, 242 Marijuana, 11, 141, 142 Massachusetts, and survey of physicians prescribing buprenorphine, 30 Maturation inhibitor combination, and HIV infection, 204 Medical conditions. See also Medical management buprenorphine maintenance and changes in, 110 evaluation of in opioid-dependent patients, 170 personal choices and development or course of, 132 Medical history, and assessment, 82, 84, 91, 192, 266 Medical management. See also Medical conditions; Physician(s) adequate treatment of pain and, 213 case examples of, 207–208, 281 of hepatitis, 193–201 of HIV/AIDS, 201–203 logistics of office-based buprenorphine treatment and, 258 referrals to primary care and, 192 routine preventive care and, 192–193 tuberculosis and, 203, 205 Medication(s). See also Pharmacotherapy; Prescription opioid abuse adherence to prescribed, 181–182 documentation of prescriptions for, 268 hepatitis B treatment and, 197–198 HIV treatment and, 201–203, 204 metabolized by CYP450 3A4, 54 “Medication-Assisted Treatment for Opioid Addiction in Opioid Treatment Programs” (TIP 43), 19

332 Handbook of Office-Based Buprenorphine Treatment of Opioid Dependence

Mental health history, 82, 172 Meperidine, 143 Methadone, as drug of abuse. See also Methadone maintenance treatment antiretroviral medications and, 203, 314 buprenorphine induction and, 106– 107 cardiac conduction and side effects of, 71 drug screening for, 141, 143 Methadone maintenance treatment adolescents and, 236 buprenorphine treatment compared to, 21, 22–24, 67–70, 91, 299 comorbidity and, 179–180 federal regulations and legalization of, 5 hepatitis and, 201 opioid dependence treatment program model and, 272 pain management and, 220 pregnancy and, 108, 206 regulatory criteria for buprenorphine treatment and, 89–90, 302 search for alternatives to, 15 tuberculosis tests and, 205 Methamphetamine, 170 Minnesota Model, for residential programs, 150 Misuse, and opioid abuse, 230, 232 Mixed agonist-antagonist, 61 Monitoring the Future study (NIDA), 227–228, 317 Mono product, of buprenorphine, 55, 96, 99–100, 303 Morphine, 86 drug screening and, 140, 143, 232 history of opioid abuse and, 2, 3, 45– 46 Morphine sulfate, 8 Motivation, and assessment, 85–86, 301 Motivation enhancement techniques (MET) adolescents and, 245

chronic disease management and, 134–135 resistance to treatment and, 152–154, 310 Multidimensional family therapy, 246 Multisystemic therapy, 247 Mu receptors, and pharmacology of buprenorphine, 47, 50–51, 60, 61, 112, 216, 296, 297, 298, 316 Nalbuphine, 218 Naloxone comorbidity and intensive outpatient programs, 180 formulation of in combination with buprenorphine, 55, 56, 96, 99– 100 µ receptor affinity of, 51 as opioid antagonist, 49 pain management and, 218–219 precipitated withdrawal and, 72, 298 pregnancy and, 206 sublingual bioavailability of, 62, 98, 297 Naltrexone adolescent patients and, 237 µ receptor affinity of, 51 as opioid antagonist, 49, 112 Narcotics Anonymous (NA), 151, 154– 155, 257, 310. See also Twelve-step groups National Alliance of Advocates for Buprenorphine Treatment (NAABT), 19, 254–255, 287 National Association of State Alcohol and Drug Abuse Directors, 37 National Center on Addiction and Substance Abuse (CASA), 288 National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), 6, 8 National Guideline Clearinghouse, 286 National Institute on Alcohol Abuse and Alcoholism (NIAAA), 148, 153, 154, 159, 286

Index National Institute on Drug Abuse (NIDA), 27, 38, 62, 73, 114, 121, 227, 258, 285–286 National Institutes of Health, 38, 200, 285 National Survey on Drug Use and Health (NSDUH), 6, 9, 11, 13 Nefazodone, 54, 186 Neolithic Period, and opium poppy cultivation, 45 Neonatal abstinence syndrome, 206, 239, 241 Neurobiology, of pain, 215–216 New York, and registration of physicians prescribing buprenorphine, 31 Nicotine dependence, 170. See also Cigarette smoking NIDA Clinical Trials Network, 38 Nonnucleoside reverse transcriptase inhibitors (NNRTIs), 111–112, 204 Nonsteroidal anti-inflammatory agents (NSAIDs), 107, 142, 213, 220, 282 Norbuprenorphine, 52, 144 Nucleoside analogues, and hepatitis, 197–198 Nucleoside reverse transcriptase inhibitors (NRTIs), 204 Nurse care manager model, and hospital-based primary care centers, 270–271 Nurses, and office staffing needs, 256 Nyswander, Marie, 5, 291 Office-based buprenorphine treatment, logistics of. See also Clinical management models of care and, 268–272 office needs and, 259–266 referral sources and, 253–255 staffing needs and, 255–259 Off-label uses, of buprenorphine, 18, 220 Opioid(s). See also Buprenorphine; Heroin; Hydrocodone; Methadone; Opioid abuse and dependence; Opioid treatment programs; Oxycodone

333

agonist effects of, 47 drug screening and, 141–143 key pharmacological features of, 46– 47, 296 ongoing use of during buprenorphine treatment, 137–138 receptors and, 47–50 withdrawal issues, 50–52 Opioid abuse and dependence. See also Adolescents; Buprenorphine; Comorbidity; Opioids abuse of pharmaceuticals as dominant form of, 9, 11 definition of in adolescents, 232 DSM-IV-TR criteria for, 109, 262 growth in abuse of prescription medications and, 169 history of, 1–6 Opioid agonist therapy (OAT). See Buprenorphine; Methadone maintenance treatment Opioid debt, and pain management, 217 Opioid dependence treatment program model, and methadone clinics, 272 Opioid misuse, 232 Opioid receptor-like-1 (ORL-1) receptor, 49, 61, 298 Opioid treatment programs (OTPs), 15, 91 buprenorphine dosing strategies and, 110–111 LAAM and, 62–63 methadone treatment and, 90, 221, 222 regulations on dispensing buprenorphine in, 19, 37 studies comparing efficacy of buprenorphine and methadone, 68, 70 Opium, 1–3, 45, 46, 81, 169 Oral availability, of sublingual buprenorphine, 55–56, 297. See also Bioavailability Outpatient clinical trials, of buprenorphine efficacy, 65–66

334 Handbook of Office-Based Buprenorphine Treatment of Opioid Dependence

Outpatient programs for adolescent patients, 242 clinical management and, 150–159 Overdose of buprenorphine, 72, 305 opioid agonists effects and, 47 Overmedication, and buprenorphine induction, 98 Oxycodone adolescents and, 228, 317 buprenorphine induction and, 104, 106–107, 116–117 development of, 8–9 drug testing and, 141, 143 Oxycodone-acetaminophen compound, 9 OxyContin, 9, 11, 35, 81, 81, 189 Pain and pain management. See also Chronic pain syndrome; Pain relievers adequate treatment of as essential dimension of medical care, 213 assessment of, 217 case examples of, 223, 281–282 epidemiology and neurobiology of, 215–216 injectable buprenorphine and, 96, 316 relapse and opiates for, 315 terminology and, 214–215 treatment of acute pain and, 217–220 Pain relievers. See also Hydrocodone; Oxycodone; Prescription opioid abuse heroin abuse compared to, 13 new epidemic of abuse of, 8–11, 13, 24 prevalence of dependence or abuse of, 8 sources of, 14 Papaver somniferum (opium poppy), 45 Parent(s), and adolescent patients, 205, 228, 239, 318. See also Family

Parenteral buprenorphine hydrochloride (HCL), 55 Partial agonist, buprenorphine as, 48– 49, 60, 216, 297, 298 Partial hospitalization programs, for adolescents, 242 Patent medicines, and history of opioid abuse, 2, 4 Patients, buprenorphine induction and instructions to, 100–101. See also Assessment; Evaluation; Information Pentazocine, 8, 218 Percocet, 9, 81, 218 Personal history. See Psychosocial history Pharmacies buprenorphine induction and, 99 compounded products containing buprenorphine and, 37 confidentiality issues and, 263 Pharmacokinetics, of buprenorphine, 52–53 Pharmacology key features of opioids, 46–47, 296 opioid receptors and, 47–51, 60, 112, 216, 296, 297, 298 opioid withdrawal issues and, 50–52 primary features of buprenorphine, 60–62, 97–98, 216–217, 297, 298 Pharmacotherapy. See also Medications; Prescription opioid abuse assessment and patient history of, 83 for co-occurring opioid dependence and psychiatric disorders, 183– 185 opioid-dependent adolescents and, 234–237 Phencyclidine, 141, 142 Phoenix Academy, 150, 247 Physical dependence, and pain management, 214–215 Physical examination, and assessment, 86, 233

Index Physician(s). See also Medical management buprenorphine induction and, 99– 100 DATA 2000 and qualification of, 16– 18, 292, 295 logistics of office-based buprenorphine treatment and, 265 prescribing behavior of, 32–33 registration of for office-based buprenorphine treatment, 31 staffing needs and, 255–256 training of for office-based buprenorphine treatment, 28– 31 Physician assistants, 256 Physician Clinical Support System (PCSS), 19–20, 30–31, 258, 287 Physiological dependence, and opioid dependence, 88, 89, 108–109 Placebo, and studies on efficacy of buprenorphine, 64–65, 66–67 Pneumococcal vaccine, 193 Police, and safety issues with intoxicated patients, 176–177 Policy, and topics for future research, 40 Posttraumatic stress disorder (PTSD), 167 Precipitated withdrawal. See also Withdrawal buprenorphine induction and management of, 107, 297 side effects of buprenorphine and, 50, 52, 71–72 Precontemplation, and stages of change, 85 Pregnancy buprenorphine treatment and, 206, 239, 241 methadone and, 108 naloxone and, 98, 108 Preparation, and stages of change paradigm, 85

335

Prescription opioid abuse, 169. See also Hydrocodone; Oxycodone; Pain relievers Prevalence. See also Epidemiology of pain reliever abuse, 13 of substance use disorders, 6, 8 Prevention, of opioid abuse in adolescents, 233–241 Primary care model, and communitybased clinics, 269–270 Privacy rights, and information for patients, 263 Private practice model, and psychiatry, 268 Problematic opioid use, 232 Problem behaviors, and clinical management, 136–139, 307 Program coordinators, 256 Project MATCH, 148, 153, 154, 159, 308 Propoxyphene, 143 Protease inhibitors, 204, 314 Protective factors, and opioid abuse by adolescents, 228–229 Psychiatric care, and logistics of officebased buprenorphine treatment, 258, 265, 269 Psychiatric history, and assessment, 82, 172 Psychoeducation adolescents and, 245 continued substance abuse and, 183 Psychosis, and evaluation of patients, 171, 173 Psychosocial history, and assessment, 82, 85 Psychosocial interventions. See also Counseling for adolescents, 245–247 buprenorphine maintenance and, 110 buprenorphine stabilization and, 109 information for patients on, 262 logistics of office management and, 257 Project MATCH and, 148, 153, 154, 159, 308

336 Handbook of Office-Based Buprenorphine Treatment of Opioid Dependence

Psychotherapy, compliance with, 182– 183. See also Cognitive-behavioral therapy; Group therapy; Psychosocial interventions Purdue Pharma, 9 Pure Food and Drug Act (1906), 4 Purified protein derivative (PPD) skin test, for tuberculosis, 203, 314 Quetiapine, 185 Ramelteon, 185 Rapid testing, for HIV, 202 Rational Recovery, 156 Receptors, and pharmacological characteristics of opioids, 47–51, 60, 112, 216, 296, 297, 298, 316 Reckitt Benckiser (pharmaceutical manufacturer), 254, 262, 288–289 Reclaiming Futures, 287 Recovery environment, 149 Reevaluation, of opioid-dependent patients after stabilization with buprenorphine, 175 Referrals comorbidity and, 180 evaluation of opioid-dependent patients and, 173 management of inquiries and, 120, 253–255 medical illness in opioid-dependent patients and, 171 Regulation. See also Government; Policy; States changes in since DATA 2000, 36–37 criteria and limitations for buprenorphine versus methadone, 89–90, 302 FDA approval of office-based buprenorphine treatment and, 15, 18–20, 27–28 history of opioid abuse and, 3–4 Rehabilitation, and previous medical treatments for substance abuse, 83

Relapse chronic disease management and, 134 counseling for prevention of, 157, 158, 159 opiates for pain management and, 214, 315 stages of change and, 85–86 triggers for, 83–84 Release of information forms, 123, 261– 262, 264, 267 Residential programs. See also Hospitalization adolescents and, 244 clinical management and, 150–152 Resistance, to treatment, 152–154, 156, 310 Ribavirin, 200, 201 Risk factors, for opioid abuse by adolescents, 228–229, 318 Ritonavir, 54, 111, 112, 186, 203, 314 Robert Wood Johnson Foundation, 287 Safety. See also Homicidal ideation; Suicide and suicidal ideation of buprenorphine, 70–74, 136 intoxicated patients and, 176–177 Saliva testing, 140, 260 Screening, for drugs of abuse. See also Urine toxicology examinations adolescents and, 230–233 clinical management and, 139–144 logistics of office management and, 260–261 Screening, brief intervention, and referral to treatment (SBIRT), Web site for, 286 Sedative-hypnotics, 53. See also Benzodiazepines Seeking Safety protocol, 179 Selective norepinephrine reuptake inhibitors, 184 Selective serotonin reuptake inhibitors (SSRIs), 184

Index Self-help groups, and assessment, 83. See also Twelve-step groups Self-medication buprenorphine diversion and, 294 pain management and, 215 psychiatric comorbidity and, 166 Self-reports, and assessment of pain, 217 Semisynthetic opioids, 46 Sertraline, 54, 111, 142 Setting, for buprenorphine induction, 100 Side effects, of buprenorphine, 53, 70– 74, 239, 296, 300 6-monoacetylmorphine (6-MAM), 86 Slipping, and twelve-step groups, 157 Social relationships. See also Family cognitive-behavioral therapy and, 158–159 drug use history and, 82 Sociopathy, substance-induced, 168 Soldier’s disease, 2 Spirituality, and twelve-step programs, 156 Sponsors, and twelve-step programs, 155 Spontaneous withdrawal, 50, 52 Stabilization, and clinical use of buprenorphine, 109 Staff education and training of, 120–121, 305 logistics of office-based treatment and need for, 255–259 Stages of change paradigm, 85, 86, 152, 301 States, and support for office-based treatment with buprenorphine, 31, 37. See also Regulation Stimulants, and ADHD, 184. See also Amphetamines Subjective Opiate Withdrawal Scale (SOWS), 101, 105 Sublingual forms, of buprenorphine, 55– 56 Suboxone Help Line, 259–260

337

Substance abuse. See also Screening; Substance dependence; Substance abuse disorders comorbidity and continued forms of, 183 comorbidity and evaluation of opioid-dependent patients, 169–170 diagnosis of, 87–89 DSM-IV-TR criteria for, 87 Substance Abuse and Mental Health Services Administration (SAMHSA), 17, 18, 19–20, 120, 151, 254, 257, 268, 285, 286, 295. See also Center for Substance Abuse Treatment Substance Abuse Prevention and Treatment (SAPT) Block Grants, 37 Substance Abuse Treatment Facility Locator, 151 “Substance Abuse Treatment for Persons With Co-Occurring Disorders” (TIP 42), 19 Substance addiction, use of term, 87, 89 Substance dependence. See also Dependence DSM-IV-TR criteria for, 88–89 use of term, 87, 89 Substance use disorders (SUDs). See also Alcohol and alcohol abuse differentiation of substance-induced from independent psychiatric disorders, 174, 311 guidelines for assessment and care of in adolescents, 243–244 prevalence of, 6, 8 Substance Use Disorders Quality Enhancement Research Initiative (VA), 31 Suicide and suicidal ideation evaluation of opioid-dependent patients and, 171, 172, 173, 176 psychiatric comorbidity and, 180– 181, 311

338 Handbook of Office-Based Buprenorphine Treatment of Opioid Dependence

Sumerian civilization, and opium poppy cultivation, 45 Sustained virologic response (SVR), and hepatitis, 200–201 Sweat testing, 260 Synthetic opioids, 46 Take-home medication privileges, and use of buprenorphine in OTPs, 19 Tapering, of buprenorphine dosage, 115, 135 Telbivudine, 196, 197 Telephone lists, and twelve-step programs, 155 Telephone screening forms, 261 Temperance Movement, 3 Tenofovir, 196, 198 Termination, of office-based buprenorphine treatment, 138–139 Tetanus-diphtheria-pertussis vaccine, 193 Therapeutic community programs adolescents and, 244, 248 attrition rate for, 309 efficacy of, 5 as model for long-term residential programs, 150 Therapeutic environment, clinical management and establishment of, 123–131 Tolerance. See also Cross-tolerance drug use history and, 82 opioid withdrawal and, 50 pain management and, 214–215 substance dependence and, 88 Training of physicians for office-based buprenorphine treatment, 28– 31, 258 of staff, 120–121, 258 Transitions, off of buprenorphine treatment, 74 Transtheoretical Model of Change, 85 TRAPPED (acronym), 84 Trazodone, 107, 185

Treatment, of opioid abuse. See also Behavioral treatment; Brief interventions; Buprenorphine; Counseling; Medical management; Methadone maintenance treatment; Psychosocial interventions; Psychotherapy; Treatment planning assessment and history of previous, 83–84, 172 current statistics on, 13 opioid-dependent adolescents and, 234–241 resistance to, 152–154, 156, 310 Treatment agreements. See also Contracts clinical management and, 124, 306 documentation and, 266–267 sample forms for, 128–129, 261 Treatment Episode Data Set (TEDS), 23, 24 Treatment Improvement Protocol (TIP), 19 Treatment planning documentation of, 266 goals of, 130–131 Tricyclic antidepressants, 184 Triggers, and relapse, 83–84 Tuberculosis, 203, 205, 314 Twelve-step groups. See also Alcoholics Anonymous; Narcotics Anonymous adolescents and, 246 assessment and, 83 buprenorphine stabilization and, 109 clinical management of problem behaviors and, 138 comorbidity and referrals to, 179 coordination of professional treatment with, 150, 154–156 psychosocial treatment and, 257 Undermedication, and buprenorphine induction, 98–99 Urine toxicology examinations (UTs). See also Screening adolescents and, 232

Index assessment and, 86–87 clinical management and, 140, 141, 143 logistics of office-based buprenorphine treatment and, 260–261, 269, 270, 271, 272 Vaccinations, and preventive medical care, 193, 312, 313 Valproate, 186 Vicodin, 9, 81, 218 Virginia, and oxycodone abuse, 9 Waiting room, 259 Waivered Physician Survey, 33, 34 Waiver Notification Form, 17, 18, 29 Web sites, 18, 19, 121, 151, 254, 257, 258, 262, 268, 285–289, 320. See also Internet listings Western blot analysis, and HIV infection, 202

339

Window period, for HIV testing, 202 Withdrawal. See also Precipitated withdrawal anxiety as symptom of, 166–167 buprenorphine induction and level of, 101, 102–105, 304 characteristic symptoms of, 296 controlled trials assessing efficacy of buprenorphine for treatment of, 69–70 management of patients with acute, 177 naloxone and, 72, 298 pharmacological characteristics of opioids and, 50–52 substance dependence and, 88 Women, and PTSD, 167 Wood, Alexander, 46 Wright, C.R., 46 X number, 17–18, 292