F

National Institutes of Health Consensus Development Statement on Effective Medical Treatment of Heroin Addiction

NIH Consensus Statements are prepared by a nonadvocate, non-Federal panel of experts, based on (1) presentations by investigators working in areas relevant to the consensus questions during a 2-day public session; (2) questions and statements from conference attendees during open discussion periods that are part of the public session; and (3) closed deliberations by the panel during the remainder of the second day and morning of the third. This statement is an independent report of the consensus panel and is not a policy statement of the NIH or the Federal Government.

ABSTRACT

Objective. To provide health care providers, patients, and the general public with a responsible assessment of the effective approaches for treating opiate dependence.

SOURCE: National Institutes of Health. 1997. NIH Consensus Development Statement: Effective Medical Treatment of Heroin Addiction. November 17-19, 1997 [WWW Document]. URL http://odp.od.nih.gov/consensus/statements/cdc/108/108_stmt.html (Accessed March 27, 1998).

This statement will be published as: Effective Medical Treatment of Opiate Addiction. NIH Consensus Statement 1997 November 17-19;15(6): in press. For making bibliographic reference to consensus statement No. 108 in the electronic form displayed here, it is recommended that the following format be used: NIH Consensus Statement Online 1997 November 17-19 [cited year, month, day]; 15(6): in press.



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F National Institutes of Health Consensus Development Statement on Effective Medical Treatment of Heroin Addiction NIH Consensus Statements are prepared by a nonadvocate, non-Federal panel of experts, based on (1) presentations by investigators working in areas relevant to the consensus questions during a 2-day public session; (2) questions and statements from conference attendees during open discussion periods that are part of the public session; and (3) closed deliberations by the panel during the remainder of the second day and morning of the third. This statement is an independent report of the consensus panel and is not a policy statement of the NIH or the Federal Government. ABSTRACT Objective. To provide health care providers, patients, and the general public with a responsible assessment of the effective approaches for treating opiate dependence. SOURCE: National Institutes of Health. 1997. NIH Consensus Development Statement: Effective Medical Treatment of Heroin Addiction. November 17-19, 1997 [WWW Document]. URL http://odp.od.nih.gov/consensus/statements/cdc/108/108_stmt.html (Accessed March 27, 1998). This statement will be published as: Effective Medical Treatment of Opiate Addiction. NIH Consensus Statement 1997 November 17-19;15(6): in press. For making bibliographic reference to consensus statement No. 108 in the electronic form displayed here, it is recommended that the following format be used: NIH Consensus Statement Online 1997 November 17-19 [cited year, month, day]; 15(6): in press.

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Participants. A non-Federal, nonadvocate, 12-member panel representing the fields of psychology, psychiatry, behavioral medicine, family medicine, drug abuse, epidemiology, and the public. In addition, 25 experts from these same fields presented data to the panel and a conference audience of 600. Evidence. The literature was searched through Medline and an extensive bibliography of references was provided to the panel and the conference audience. Experts prepared abstracts with relevant citations from the literature. Scientific evidence was given precedence over clinical anecdotal experience. Consensus Process. The panel, answering predefined questions, developed their conclusions based on the scientific evidence presented in open forum and the scientific literature. The panel composed a draft statement that was read in its entirety and circulated to the experts and the audience for comment. Thereafter, the panel resolved conflicting recommendations and released a revised statement at the end of the conference. The panel finalized the revisions within a few weeks after the conference. The draft statement was made available on the World Wide Web immediately following its release at the conference and was updated with the panel's final revisions. Conclusions. Opiate dependence is a brain-related medical disorder that can be effectively treated with significant benefits for the patient and society, and society must make a commitment to offer effective treatment for opiate dependence to all who need it. All opiate-dependent persons under legal supervision should have access to methadone maintenance therapy, and the U.S. Office of National Drug Control Policy and the U.S. Department of Justice should take the necessary steps to implement this recommendation. There is a need for improved training for physicians and other health care professionals and in medical schools in the diagnosis and treatment of opiate dependence. The unnecessary regulations of methadone maintenance therapy and other long-acting opiate agonist treatment programs should be reduced, and coverage for these programs should be a required benefit in public and private insurance programs. INTRODUCTION In the United States, prior to 1914, it was relatively common for private physicians to treat opiate-dependent patients in their practices by prescribing narcotic medications. While the passage of the Harrison Act did not prohibit the prescribing of a narcotic by a physician to treat an addicted patient, this practice was viewed as problematic by Treasury officials

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charged with enforcing the law. Physicians who continued to prescribe were indicted and prosecuted. Because of withdrawal of treatment by physicians, various local governments and communities established formal morphine clinics for treating opiate addiction. These clinics were eventually closed when the AMA, in 1920, stated that there was unanimity that prescribing opiates to addicts for self-administration (ambulatory treatment) was not an acceptable medical practice. For the next 50 years, opiate addiction was basically managed in this country by the criminal justice system and the two Federal Public Health Hospitals in Lexington, Kentucky, and Fort Worth, Texas. The relapse rate for opiate use from this approach was close to 100 percent. During the 1960s opiate use reached epidemic proportions in the United States, spawning significant increases in crime and in deaths from opiate overdose. The increasing number of younger people entering an addiction lifestyle indicated that a major societal problem was emerging. This stimulated a search for innovative and more effective methods to treat the growing number of individuals dependent upon opiates. This search resulted in the emergence of drug-free therapeutic communities and the use of the opiate agonist, methadone, to maintain those with opiate dependence. Furthermore, a multimodality treatment strategy was designed to meet the needs of the individual addict patient. These three approaches remain the main treatment strategies being used to treat opiate dependence in the United States today. Opiate dependence has long been associated with increased criminal activity. For example, in 1993 more than one-quarter of the inmates in State and Federal prisons were incarcerated for drug offenses (234,600), and prisoners serving drug sentences were the largest single group (60 percent) in Federal prisons. In the past 10 years, there has been a dramatic increase in the prevalence of human immunodeficiency virus (HIV), hepatitis B and C viruses, and tuberculosis among intravenous opiate users. From 1991 to 1995, in major metropolitan areas, the annual number of opiate related emergency room visits has increased from 36,000 to 76,000, and the annual number of opiate-related deaths has increased from 2,300 to 4,000. This associated morbidity and mortality further underscore the human, economic, and societal costs of opiate dependence. During the last two decades, evidence has accumulated on the neurobiology of opiate dependence. Whatever conditions that may lead to opiate exposure, opiate dependence is a brain-related disorder, with the requisite characteristics of a medical illness. Thus, opiate dependence as a medical illness will have varying causative mechanisms. There is a need to identify discrete subgroups of opiate-dependent people and the most relevant and effective treatments for each subgroup. The safety and efficacy of narcotic

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agonist (methadone) maintenance treatment has been unequivocally established. Although there are other medications (e.g., levo-alpha-acetylmethadol [LAAM] and naltrexone, an opiate antagonist, etc.) that are safe and effective in the treatment of opiate addicts, the focus of this consensus development conference was primarily on methadone maintenance treatment (MMT). MMT is effective in reducing illicit opiate drug use, in crime reduction, in enhancing social productivity, and in reducing the spread of viral diseases such as AIDS and hepatitis. Approximately 115,000 of the estimated 600,000 opiate-dependent persons in the United States are in MMT. Science has not yet overcome the stigma of addiction and the negative public perception about MMT. Some leaders in the Federal Government, public health officials, members of the medical community, and the public-at-large frequently conceive of opiate dependence as a self-inflicted disease of the will or a moral flaw. They also regard MMT as an ineffective narcotic substitution and believe that a drug-free state is the only valid treatment goal. Other obstacles to MMT include Federal and State government regulations that restrict the number of treatment providers and patient access. Some of these Federal and State regulations are driven by disproportionate concerns about methadone diversion, concern about premature (e.g., in 12-year-olds) initiation of maintenance treatment, and concern about provision of methadone without any other psychosocial services. Although a drug-free state represents an optimal treatment goal, research has demonstrated that this goal cannot be achieved or sustained by the majority of opiate-dependent people. However, other laudable treatment goals including decreased drug use, reduced crime, and gainful employment can be achieved in most MMT patients. To address the most important issues surrounding effective medical treatment of opiate dependence, the NIH organized this 2 1/2-day conference to present data on opiate agonist treatment for opiate dependence. The conference brought together national and international experts in the fields of the basic and clinical medical sciences, epidemiology, natural history, prevention and treatment of opiate dependence, and broad representation from the public. After 1-1/2 days of presentations and audience discussion, an independent, non-Federal consensus panel chaired by Lewis L. Judd, M.D., Mary Gilman Marston Professor, Chair of the Department of Psychiatry, University of California, San Diego School of Medicine, weighed the scientific evidence and wrote a draft statement that was presented to the audience on the third day. The consensus statement addressed the following key questions:

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What is the scientific evidence to support conceptualization of opiate addiction as a medical disorder including natural history, genetics and risk factors, pathophysiology, and how is diagnosis established? What are the consequences of untreated opiate addiction to individuals, families and society? What is the efficacy of current treatment modalities in the management of opiate addiction including detoxification alone, nonpharmacological/psychosocial treatment, treatment with opiate antagonists, and treatment with opiate agonists (short-term and long-term)? And, what is the scientific evidence for the most effective use of opiate agonists in the treatment of opiate addiction? What are the important barriers to effective use of opiate agonists in the treatment of opiate addiction in the U.S. including perceptions and adverse consequences of opiate agonist use, legal, regulatory, financial and programmatic barriers? What are the future research areas and recommendations for improving opiate agonist treatment and improving access? The primary sponsors of this meeting were the National Institute on Drug Abuse and the NIH Office of Medical Applications of Research. The conference was cosponsored by the NIH Office of Research on Women's Health. 1. What Is the Scientific Evidence to Support a Conceptualization of Opiate Dependence as a Medical Disorder Including Natural History, Genetics and Risk Factors, and Pathophysiology, and How Is Diagnosis Established? The Natural History of Opiate Dependence Individuals addicted to opiates often become dependent on these drugs by their early twenties and remain intermittently dependent for decades. Biological, psychological, sociological, and economic factors determine when an individual will start taking opiates. However, it is clear that when use begins, it often escalates to abuse (repeated use with adverse consequences) and then to dependence (opioid tolerance, withdrawal symptoms, compulsive drug taking). Once dependence is established there are usually repeated cycles of cessation and relapse extending over decades. This ''addiction career" is often accompanied by periods of imprisonment. Treatment can alter the natural history of opiate dependence, most commonly, by prolonging periods of abstinence from illicit opiate abuse. Of the various treatments available, MMT, combined with attention to

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medical, psychiatric, and socioeconomic issues, as well as drug counseling, has the highest probability of being effective. Addiction related deaths, including accidental overdose, drug-related accidents, and many illnesses directly attributable to chronic drug dependence explain one-fourth to one-third of the mortality in an opiate-addicted population. As a population of opiate addicts age, there is a decrease in the percentage who are still addicted. There is clearly a natural history of opiate dependence, but causative factors are poorly understood. It is especially unclear for a given individual whether repeated use begins as a medical disorder, (e.g., a genetic predisposition) or whether socioeconomic and psychological factors lead an individual to try and then later compulsively use opiates. However, there is no question that once the individual is dependent on opiates, such dependence constitutes a medical disorder. Molecular Neurobiology and Pathogenesis of Opiate Dependence: Genetic and Other Risk Factors for Opiate Dependence Twin, family, and adoption studies show that vulnerability to drug abuse may be a partially inherited condition with strong influences from environmental factors. Cross-fostering adoption studies have demonstrated that both inherited and environmental factors operate in the etiology of drug abuse. These cross-fostering adoption studies identified two distinct genetic pathways to drug abuse/dependence. The first is a direct effect of substance abuse in a biologic parent. The second pathway is an indirect effect from antisocial personality disorder in a biologic parent, leading to both antisocial personality disorder and drug abuse/dependence in the adoptee. Family studies report significantly increased relative risk for substance abuse (6.7-fold increased risk), alcoholism (3.5), antisocial personality (7.6), and unipolar depression (5.1) among the first-degree relatives of opiate-dependent patients compared with relatives of controls. The siblings of opiate-dependent patients have very high susceptibility to abuse and dependence after initial use of illicit opioids. Twin studies indicate substantial heritability for substance abuse and dependence, with half the risk attributable to additive genetic factors. Neurobiological Substrates of Opiate Dependence Dopaminergic pathways from the ventral tegmentum (VT) to the nucleus accumbens (NA) and medial frontal cortex (MFC) are activated during rewarding behaviors. Opiates exert their rewarding properties by binding to the "mu" opioid receptor (OPRM) at several distinct anatomical

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locations in the brain, including the VT, NA, MFC, and possibly the locus coeruleus (LC). Opiate agonist administration causes inhibition of the LC. Chronic administration of opioid agonists causes adaptation to the LC inhibition. Rapid discontinuation of opioid agonists (or administration of antagonists) results in excessive LC neuronal excitation and the appearance of withdrawal symptoms. Abnormal LC excitation is thought to underlie many of the physical symptoms of withdrawal, and this hypothesis is consistent with the ability of clonidine, an alpha 2 noradrenergic agonist, to ameliorate opiate withdrawal. Regional Cerebral Glucose Metabolism in Opiate Abusers Two independent human studies (using positron emission tomography) suggest that opiates reduce cerebral glucose metabolism in a global manner, with no regions showing increased glucose utilization. A third study demonstrates decreased D2 receptor availability in opiate-dependent patients compared with controls. Opiate antagonist administration produced an intense withdrawal experience but did not change D2 receptor availability. Diagnosis of Opioid Dependence Opioid dependence (addiction) is defined as a cluster of cognitive, behavioral, and physiological symptoms in which the individual continues use of opiates despite significant opiate-induced problems. Opioid dependence is characterized by repeated self-administration that usually results in opioid tolerance, withdrawal symptoms, and compulsive drug-taking. Dependence may occur with or without the physiological symptoms of tolerance and withdrawal. Usually, there is a long history of opioid self-administration, typically via intravenous injection in the arms or legs, although recently, the intranasal route or smoking also is used. Often there is a history of drug-related crimes, drug overdoses, and family, psychological, and employment problems. There may be a history of physical problems including skin infections, hepatitis, HIV infection, or irritation of the nasal and pulmonary mucosa. Physical examination usually reveals puncture marks along veins in the arms and legs and "tracks" secondary to sclerosis of veins. If the patient has not taken opiates recently, he/she may also demonstrate symptoms of withdrawal, including anxiety, restlessness, runny nose, tearing, nausea, and vomiting. Tests for opioids in saliva and urine can help support a diagnosis of dependence. However, by itself, neither a positive nor a negative test can rule dependence in or out. Further evidence for opioid dependence can be obtained by a naloxone (Narcan) challenge test to induce withdrawal symptoms.

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Evidence That Opioid Dependence Is a Medical Disorder For decades, opioid dependence was viewed as a problem of motivation, willpower, or strength of character. Through careful study of its natural history and through research at the genetic, molecular, neuronal, and epidemiological levels, it has been proven that opiate addiction is a medical disorder characterized by predictable signs and symptoms. Other arguments for classifying opioid dependence as a medical disorder include: Despite varying cultural, ethnic, and socioeconomic backgrounds, there is clear consistency in the medical history, signs, and symptoms exhibited by individuals who are opiate-dependent. There is a strong tendency to relapse after long periods of abstinence. The opioid-dependent person's craving for opiates induces continual self-administration even when there is an expressed and demonstrated strong motivation and powerful social consequences to stop. Continuous exposure to opioids induces pathophysiologic changes in brain. 2. What Are the Consequences of Untreated Opiate Dependence to Individuals, Families, and Society? Of the estimated total opiate-dependent population of 600,000, only 115,000 are known to be in methadone maintenance treatment (MMT) programs. Research surveys indicate that the untreated population of opiate-addicted people are younger than those in treatment. They are typically in their late teens and early to mid-twenties, during their formative, early occupational, and reproductive years. The financial costs of untreated opiate dependence to the individual, the family, and society are estimated to be approximately $20 billion per year. The costs in human suffering are incalculable. What is currently known about the consequences of untreated opiate dependence to individuals, families, and society? Mortality Prior to the introduction of MMT, annual death rates reported in four American studies of opiate dependence varied from 13 per 1,000 to 44 per 1,000, with a median of 21 per 1,000. Although it cannot be causally attributed, it is interesting that after the introduction of MMT, the death rates of opiate-dependent persons in four American studies had a narrower range, from 11 per 1,000 to 15 per 1,000, and a median of 13 per 1,000.

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The most striking evidence of the effectiveness of MMT on death rates are studies directly comparing these rates in opiate-dependent persons, on and off methadone. Every study showed that death rates were lower in opiate-dependent persons maintained on methadone compared with those who are not. The median death rate for opiate-dependent persons in MMT was 30 percent of the death rate of those not in treatment. A clear consequence of not treating opiate dependence, therefore, is a death rate that is more than three times greater than that experienced by those engaged in MMT. Illicit Drug Use Multiple studies conducted over several decades and in different countries demonstrate clearly that MMT results in a marked decrease in illicit opiate use. In addition, there is also a significant and consistent reduction in the use of other illicit drugs including cocaine and marijuana, and in the abuse of alcohol, benzodiazepines, barbiturates, and amphetamines. Criminal Activity Opiate dependence in the United States is unequivocally associated with high rates of criminal behavior. More than 95 percent of opiate-dependent persons report committing crimes during an 11-year at-risk interval. These crimes range in severity from homicides to other crimes against people and property. Stealing in order to purchase drugs is the most common criminal offense. Over the past two decades, clear and convincing evidence has been collected from multiple studies that effective treatment of opiate dependence markedly reduces the rates of criminal activity. Therefore, it is clear that significant amounts of crime perpetrated by opiate-dependent persons is a direct consequence of untreated opiate dependence. Health Care Costs Although the general health status of people with opiate dependence is substantially worse than that of their contemporaries, they do not routinely use medical services. Typically, they seek medical care in hospital emergency rooms only after their medical conditions are seriously advanced. The consequences of untreated opiate dependence include much higher incidence of bacterial infections, including endocarditis, thrombophlebitis, and skin and soft tissue infections; tuberculosis; hepatitis B and C; AIDS and sexually transmitted diseases; and alcohol abuse. Because those who are opiate-dependent present for medical care late in their diseases, medical care is generally more expensive. Health care costs related to opiate dependence have been estimated to be $1.2 billion per year.

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Joblessness Opiate dependence prevents many users from maintaining steady employment. Much of their time each day is spent in drug-seeking and drug-taking behavior. Therefore, many seek public assistance because they are unable to generate the income needed to support themselves and their families. Long-term outcome data show that opiate-dependent persons in MMT earn more than twice as much money annually as those not in treatment. Outcomes of Pregnancy A substantial number of pregnant women dependent upon opiates also have HIV/AIDS. Based on preliminary data, women who receive MMT are more likely to be treated with zidovudine. It has been well established that administration of zidovudine to HIV-positive pregnant women reduces by two-thirds the rate of HIV transmission to their babies. Comprehensive MMT, along with sound prenatal care, has been shown to decrease obstetrical and fetal complications as well. 3. What Is the Efficacy of Current Treatment Modalities in the Management of Opiate Dependence Including Detoxification Alone, Nonpharmacological/Psychosocial Treatment, Treatment with Opiate Antagonists, and Treatment with Opiate Agonists (Short-Term and Long-Term). And, What Is the Scientific Evidence for the Most Effective Use of Opiate Agonists in the Treatment of Opiate Dependence? The Pharmacology of Commonly Prescribed Opiate Agonists and Antagonists The most frequently used agent in medically supervised opiate withdrawal and maintenance treatment is methadone. Methadone's half-life is approximately 24 hours and leads to a long duration of action and once-a-day dosing. This feature, coupled with its slow onset of action, blunts its euphoric effect, making it unattractive as a principal drug of abuse. LAAM, a presently less commonly used opiate agonist, has a longer half-life and may prevent withdrawal symptoms for up to 96 hours. An emerging treatment option, buprenorphine, a partial opioid agonist, appears also to be effective for detoxification and maintenance. Naltrexone is a nonaddicting specific "mu" antagonist with a long half-life permitting once-a-day administration. It effectively blocks the cognitive and behavioral effects of opioids, and its prescription does not re-

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quire special registration. The opioid-dependent person considering treatment should be informed of the availability of naltrexone maintenance treatment. However, in actively using opiate addicts, it produces immediate withdrawal symptoms with potentially serious effects. Medically Supervised Withdrawal Methadone can also be used for detoxification. This can be accomplished over several weeks after a period of illicit opiate use or methadone maintenance. If methadone withdrawal is too rapid, abstinence symptoms are likely. They may lead the opiate-dependent person to illicit drug use and relapse into another cycle of abuse. Buprenorphine holds promise as an option for medically supervised withdrawal, because its prolonged occupation of "mu" receptors attenuates withdrawal symptoms. More rapid detoxification options include use of opiate antagonists alone; the alpha-2 agonist clonidine alone; or clonidine followed by naltrexone. Clonidine reduces many of the autonomic signs and symptoms of opioid withdrawal. These strategies may be used in both inpatient and outpatient settings and allow medically supervised withdrawal from opioids in as little as 3 days. Most patients successfully complete detoxification using these strategies, but information concerning relapse rates is not available. The Role of Psychosocial Treatments Nonpharmacologic supportive services are pivotal to successful MMT. The immediate introduction of these services as the opiate-dependent patient applies for MMT leads to significantly higher retention and more comprehensive and effective treatment. Comorbid psychiatric disorders require treatment. Other behavioral strategies have been successfully used in substance abuse treatment. Ongoing substance abuse counseling and other psychosocial therapies enhance program retention and positive outcome. Stable employment is an excellent predictor of clinical outcome. Therefore, vocational rehabilitation is a useful adjunct. Efficacy of Opiate Agonists It is now generally agreed that opiate dependence is a medical disorder and that pharmacologic agents are effective in its treatment. Evidence presented to the panel indicates that availability of these agents is severely limited and that large numbers of patients with this disorder have no access to treatment. The greatest experience with such agents has been with the opiate

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John S. Gustafson Executive Director National Association of State Alcohol and Drug Abuse Directors, Inc. Washington, DC Donald Hedeker, Ph.D. Associate Professor of Biostatistics Division of Epidemiology and Biostatistics School of Public Health University of Illinois, Chicago Chicago, Illinois Howard H. Hiatt, M.D. Professor of Medicine Harvard Medical School Senior Physician Division of General Medicine Brigham and Women's Hospital Boston, Massachusetts Radman Mostaghim, M.D., Ph.D. Greenbelt, Maryland Robert G. Petersdorf, M.D. Distinguished Professor of Medicine University of Washington Seattle, Washington SPEAKERS M. Douglas Anglin, Ph.D. "The Natural History of Opiate Addiction" Director UCLA Drug Abuse Research Center Los Angeles, California Donald C. Des Jarlais, Ph.D. "Transmission of Bloodborne Viruses Among Heroin Injectors" Director of Research Chemical Dependency Institute Beth Israel Medical Center and National Development and Research Institutes New York, New York David P. Desmond, M.S.W. "Deaths Among Heroin Users In and Out of Methadone Maintenance" Instructor Department of Psychiatry University of Texas Health Science Center San Antonio, Texas Rose Etheridge, Ph.D. "Factors Related to Retention and Posttreatment Outcomes in Methadone Treatment: Replicated Findings Across Two Eras of Treatment" Senior Research Psychologist National Development and Research Institutes, Inc. (NDRI, Inc.) Raleigh, North Carolina

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Igor I. Galynker, M.D., Ph.D. "Methadone Maintenance and Regional Cerebral Glucose Metabolism in Opiate Abusers: A Positron Emission Tomographic Study" Physician-in-Charge Division of Psychiatric Functional Brain Imaging Department of Psychiatry Beth Israel Medical Center New York, New York G. Thomas Gitchel "Diversion of Methadone: Expanding Access While Reducing Abuse" Chief Liaison and Policy Section Office of Diversion Control U.S. Drug Enforcement Administration Washington, DC Michael Gossop, Ph.D. "Methadone Substitution Treatment in the United Kingdom: Outcome Among Patients Treated in Drug Clinics and General Practice Settings" Head of Research, National Addiction Centre Institute of Psychiatry Maudsley Hospital London, United Kingdom John Grabowski, Ph.D. "Behavioral Therapies: A Treatment Element for Opiate Dependence" Director Substance Abuse Research Center Professor Department of Psychiatry Health Science Center University of Texas, Houston Houston, Texas Henrick J. Harwood "Societal Costs of Heroin Addiction" Senior Manager The Lewin Group Fairfax, Virginia Jerome H. Jaffe, M.D. "The History and Current Status of Opiate Agonist Treatment" Director Office for Scientific Analysis and Evaluation Center for Substance Abuse Treatment Substance Abuse and Mental Health Services Administration Rockville, Maryland Herbert D. Kleber, M.D. "Detoxification with or without Opiate Agonist Treatment" Professor of Psychiatry Division of Substance Abuse Department of Psychiatry Columbia University College of Physicians and Surgeons New York, New York

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Mary Jeanne Kreek, M.D. "Opiate Agonist Treatment, Molecular Pharmacology, and Physiology" Professor and Head Senior Physician Laboratory of the Biology of Addictive Diseases Rockefeller University New York, New York David C. Lewis, M.D. “Access to Narcotic Addiction Treatment and Medical Care” Director, Center for Alcohol and Addiction Studies Brown University Providence, Rhode Island Dennis McCarty, Ph.D “Narcotic Agonist Treatment as a Benefir Under Managed Care” Human Services Research Professor Institute for Health Policy Heller Graduate School Brandeis University Waltham, Massachusetts A. Thomas McLellan, Ph.D. “Problem-Service Matching in Methadone maintenance Treatment: Policy Suggestions From Two Prospective Studies” Scientific Director DeltaMetrics in Association with Treatment Research Institute Philadelphia, Pennsylvania Jeffrey Merrill, Ph.D. "Impact of Methadone Maintenance on HIV Seroconversion and Related Costs" Director Economic and Policy Research Treatment Research Institute University of Pennsylvania Philadelphia, Pennsylvania Eric J. Nestler, M.D., Ph.D. "Neurobiological Substrates for Opiate Addiction" Elizabeth Mears and House Jameson Professor of Psychiatry and Pharmacology Department of Psychiatry Connecticut Mental Health Center Yale University School of Medicine New Haven, Connecticut David N. Nurco, D.S.W. "Narcotic Drugs and Crime: Addict Behavior While Addicted Versus Nonaddicted' Research Professor Department of Psychiatry University of Maryland School of Medicine Baltimore, Maryland Mark W. Parrino, M.P.A. "Legal, Regulatory, and Funding Barriers to Good Practice and Associated Consequences" President American Methadone Treatment Association, Inc. New York, New York

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J. Thomas Payte, M.D. "Methadone Dose and Outcome" Medical Director Drug Dependence Associates San Antonio, Texas Roy W. Pickens, Ph.D. "Genetic and Other Risk Factors in Opiate Addiction" Senior Scientist Division of Intramural Research Addiction Research Center National Institute on Drug Abuse National Institutes of Health Baltimore, Maryland D. Dwayne Simpson, Ph.D. "Patient Engagement and Duration of Treatment" Director and S.B. Sells Professor of Psychology Institute of Behavioral Research Texas Christian University Fort Worth, Texas Barbara J. Turner, M.D. "Prenatal Care and Antiretroviral Use Associated with Methadone Treatment of HIV-Infected Pregnant Women" Professor of Medicine Director of Research in Health Care Thomas Jefferson University The Center for Research in Medical Education and Health Care Philadelphia, Pennsylvania George E. Woody, M.D. "Establishing a Diagnosis of Heroin Abuse and Addiction" Chief, Substance Abuse Treatment Unit Veterans Affairs Medical Center Clinical Professor Department of Psychiatry University of Pennsylvania Philadelphia, Pennsylvania Joan E. Zweben, Ph.D. "Community, Staff, and Patient Perceptions and Attitudes" Executive Director 14th Street Clinic and East Bay Community Recovery Project Clinical Professor of Psychiatry University of California, San Francisco Berkeley, California

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PLANNING COMMITTEE James R. Cooper, M.D. Planning Committee Chair Associate Director for Medical Affairs Division of Clinical and Services Research National Institute on Drug Abuse National Institutes of Health Rockville, Maryland Elsa A. Bray Program Analyst Office of Medical Applications of Research National Institutes of Health Bethesda, Maryland Mona Brown Press Officer National Institute on Drug Abuse National Institutes of Health Rockville, Maryland Kendall Bryant, Ph.D. Coordinator AIDS Behavioral Research National Institute on Alcohol Abuse and Alcoholism National Institutes of Health Rockville, Maryland Jerry Cott, Ph.D. Chief Pharmacologic Treatment Research Program National Institute of Mental Health National Institutes of Health Rockville, Maryland Donald C. Des Jarlais, Ph.D. Director of Research Chemical Dependency Institute Beth Israel Medical Center and National Development and Research Institutes New York, New York John H. Ferguson, M.D. Director Office of Medical Applications of Research National Institutes of Health Bethesda, Maryland Bennett Fletcher, Ph.D. Acting Chief Services Research Branch Division of Clinical and Services Research National Institute on Drug Abuse National Institutes of Health Rockville, Maryland Joseph Frascella, Ph.D. Chief Etiology and Clinical Neurobiology Branch Division of Clinical and Services Research National Institute on Drug Abuse National Institutes of Health Rockville, Maryland G. Thomas Gitchel Chief, Liaison and Policy Section Office of Diversion Control U.S. Drug Enforcement Agency Washington, DC

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William H. Hall Director of Communications Office of Medical Applications of Research National Institutes of Health Bethesda, Maryland Jerome H. Jaffe, M.D. Director, Office for Scientific Analysis and Evaluation Center for Substance Abuse Treatment Substance Abuse and Mental Health Services Administration Rockville, Maryland Lewis L. Judd, M.D. Panel and Conference Chair Mary Gilman Marston Professor Chair, Department of Psychiatry School of Medicine University of California, San Diego La Jolla, California Herbert D. Kleber, M.D. Professor of Psychiatry Division of Substance Abuse Department of Psychiatry Columbia University College of Physicians and Surgeons New York, New York Mitchell B. Max, M.D. Chief, Clinical Trials Unit Neurobiology and Anesthesiology Branch National Institute of Dental Research National Institutes of Health Bethesda, Maryland A. Thomas McLellan, Ph.D. Scientific Director DeltaMetrics in Association with Treatment Research Institute Philadelphia, Pennsylvania Eric J. Nestler, M.D., Ph.D. Elizabeth Mears and House Jameson Professor of Psychiatry and Pharmacology Department of Psychiatry Connecticut Mental Health Center Yale University School of Medicine New Haven, Connecticut Stuart Nightingale, M.D. Associate Commissioner for Health Affairs U.S. Food and Drug Administration Rockville, Maryland Roy W. Pickens, Ph.D. Senior Scientist, Division of Intramural Research Addiction Research Center National Institute on Drug Abuse National Institutes of Health Baltimore, Maryland Nick Reuter, M.P.H. Associate Director for Domestic and International Drug Control U.S. Food and Drug Administration Rockville, Maryland

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Charles R. Sherman, Ph.D. Deputy Director Office of Medical Applications of Research National Institutes of Health Bethesda, Maryland Alan Trachtenberg, M.D., M.P.H. Medical Officer Office of Science Policy and Communications National Institute on Drug Abuse National Institutes of Health Rockville, Maryland Frank Vocci, Ph.D. Acting Director Medications Development Division National Institute on Drug Abuse National Institutes of Health Rockville, Maryland Anne Willoughby, M.D., M.P.H. Chief Pediatric, Adolescent and Maternal AIDS Branch Center for Research for Mothers and Children National Institute of Child Health and Human Development National Institutes of Health Rockville, Maryland Stephen R. Zukin, M.D. Director Division of Clinical and Services Research National Institute on Drug Abuse National Institutes of Health Rockville, Maryland CONFERENCE SPONSORS Office of Medical Applications of Research, NIH John H. Ferguson, M.D., Director National Institute on Drug Abuse Alan I. Leshner, Ph.D. CONFERENCE COSPONSORS Office of Research on Women's Health, NIH Vivian W. Pinn, M.D., Director

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