monograph series 8 RX :3x/WEEK LAAM ALTERNATIVE TO METHADONE U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE • PUBLIC HEALTH SERVlCE • ALCOHOL, DRUG ABUSE, AND MENTAL HEALTH ADMINISTRATION PX : 3 X /WEEK LAAM ALTERNATIVE TO METHADONE EDITORS JACK D. BLAINE, M.D. PIERRE F. RENAULT, M.D. NIDA Research Monograph 8 The NIDA Research Monograph series is prepared by the Division of Research of the National Institute on Drug Abuse. Its primary objective is to provide critical reviews of research problem areas and techniques, the content of state-of-the-art conferences, integrative research reviews and significant original research. Its dual publication emphasis is rapid and targeted dissemination to the scientific and professional community. EDITORIAL ADVISORY BOARD Avram Goldstein, M.D. Addiction Research Foundation Palo Alto, California Jerome Jaffe, M.D. College of Physicians and Surgeons Columbia University. New York Reese T. Jones, M.D. Langly Porter Neuropsychiatric Institute Unversity of California San Francisco, California William McGlothlin, Ph.D. Department of Psychology, UCLA Los Angeles, California Jack Mendelson, M.D. Alchohol and Drug abuse Research Center Havard Medical School McLean Hospital Belmont, Massachusettts Helen Nowlis, Ph.D. Office of Drug Education, DHEW Washington, D.C. Lee Robins, Ph.D. Walhington University School, of Medicine St. Louis, Missouri NIDA RESEARCH MONOGRAPH series Robert DuPont, M.D. DIRECTOR, NIDA William Pollin, M.D. DIRECTOR, DIVISION OF RESEARCH, NIDA Robert C. Petersen, Ph.D. EDITOR-IN-CHIEF Eunice L. Corfman, M.A. EDITOR Rx :3 x/WEEK LAAM ALTERNATIVE TO METHADONE EDITORS JACK D. BLAINE, M.D. PIERRE F. RENAULT, M.D. Division of Research National Institute on Drug Abuse July 1976 NIDA Reseach Monograph 8 THE NATlONAL INSTlTUTE ON DRUG ABUSE 5600 Fishers Lane Rockville. Maryland 20857 U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE Public Health Service DHEW Publication No. (ADM)78-347 Formerly DHEW Publication No. (ADM)76-347 Printed 1976 Reprinted 1977 Library of Congress catalog number 76-20257 For sale by the National Technical Information Service Springfield, Va. 22161 Stock order #PB 253 763; Papercopy: $7.25; Microfiche: $3.00 iv FOREWORD This monograph is a biomedical review and assessment of LAAM (Levo-alpha acetylmethadol), a new treatment drug for heroin addiction now undergoing large scale clinical trials, following several years' intensive research and development under the auspices of the National Institute on Drug Abuse (NIDA) and its pre- decessor, the Special Action Office for Drug Abuse Prevention (SAODAP). LAAM was developed as an alternative to methadone. Over 800 methadone-related deaths per year are being reported by the Drug Abuse Warning Network (DAWN) from 24 major cities across the country. Moreover, heroin use has been increasing nationally since mid- 1973 and 15 percent of heroin-related deaths (from 1,440 in 1973 to over 2,000 in 1975) reported by DAWN also involve methadone. Many of these deaths are directly attributable to illicit methadone diversion from drug treatment pro- grams to street sale. Because methadone patients must take their dose daily while simultaneously try- ing to stabilize their work, school, training, family and personal lives, they have been allowed take-home doses to reduce the number of clinic visits they must make. But this practice has made methadone widely available, accounting for much illicit diversion and subsequent painful record of methadone overdose deaths. In contrast, LAAM dosage is three times a week, it does not yield a quick high and appears to provide a level, sustained effect. Animal toxicity studies and clinical research experience indicate that LAAM is a safe and effective opiate maintenance drug, under appropriate medical supervision. A wide spectrum of treatments is needed for various degrees of addiction and kinds of dependent persons. But LAAM seems promising for patients who may need opiate stabilization to ease the difficult switch from a drug-hustling street life to a less self- destructive one. LAAM provides one more choice in tailoring treatment to each individual's needs. Robert L. DuPont, M.D. Director National Institute on Drug Abuse v CONTENTS Foreword v Robert L. DuPont, M.D. Introduction 1 Jack Blaine, M.D. and Pierre Renault, M.D. The Chemistry of LAAM 10 Sydney Archer, Ph.D. PRECLINICAL STUDIES Pharmacology of LAAM 15 Sydney Archer, Ph.D. Toxicology of LAAM 29 Ms. Ann Wolven and Sydney Archer, Ph.D. CLINICAL STUDIES Phase I 39 Ralph M. Sollod, M.S., and Marcia G. Goldstein, M.A. Selected Clinical Studies Synopses 52 Sumnary of Veterans Administration Phase II Cooperative Study for LAAM and Methadone 94 Walter Ling, M.D. V. Charles Chamvastra, M.D. Samuel C. Kaim, M.D. C. James Klett, Ph.D. Summary of SAODAP Phase II Cooperative Study of LAAM vs. Methadone 103 Walter Ling, M.D. C. James Klett, Ph.D. Roderic D. Gillis Phase III Clinical Study of Levo-Alpha-Acetylmethadol 109 John A. Whysener, M.D., Ph.D. The Use of LAAM in Treatment 112 James Cooper, M.D. A Clinical Experience with LAAM 115 Avram Goldstein, M.D. A LAAM Bibliography Preclinical 118 Clinical 123 vii INTRODUCTION Jack Blaine, M.D. and Pierre Renault, MD. MEDICAL DETOXIFICATION problems arising from the need to administer the drug intravenously several times daily. For many years heroin addicted individuals were "treated" by abrupt or gradual discon- METHADONE DETOXIFICATION tinuation of heroin, leading to abstinence. Resulting withdrawal symptoms were either During World War II, German chemists at the untreated or treated palliatively with non- I.G. Farbenindustrie developed a synthetic opiate medications including sleeping pills, narcotic analgesic, 6-dimethylamino-4-4-diphen- tranquilizers, analgesics, antidiarrheals, y1-3-heptanone (methadone, dolorphine) as a sub- and/or antispasmodics. The failure of heroin stitute for morphine. After the war, American withdrawal alone as a treatment with the goal investigators (Isbell et al. 1948) found that of long-term continued abstinence has been methadone’s pharmacological pmfile was voluminously documented. similar to that of morphine and demonstrated that methadone could substitute for morphine At best, medically controlled detoxification in morphine-dependent subjects to relieve the has only inmediate and temporary value as a abstinence symptoms after discontinuation of first step in a comprehensive rehabilitation morphine. Furthermore, methadone could pre- program. Thus, regulated detoxification vent the appearance of withdrawal signs and reduces human suffering and frees the indi- symptoms when substituted for morphine in vidual from his compulsive search for and use equipotent doses. So methadone seemed a of the drug, permitting a shift in attention likely candidate to substitute for heroin when to other more constructive pursuits. Long detoxifying heroin addicts. periods of confinement in a hospital, thera- peutic commmity, or prison, even with tradi- Methadone has several advantages over morphine tional psychotherapeutic intervention have not for detoxification of heroin dependent persons. significantly altered subsequent relapse to Methadone is almost as effective orally as heroin abuse for the vast majority of addicts. parenterally, thus avoiding problems of intra- venous dosage. Also, methadone is metabolized Further, efforts at treatment by large scale to inactive substances more slowly than maintenance of heroin addicts on legally morphine. These two factors extend the dura- dispensed heroin appears to be an inadequate tion of action of methadone to 24 hours which treatment approach due to the practical permits once-a-day &sage and smooths the time-effect curve. Thus, an oral daily dose of 1 methadone can be substituted for several treatment experience, approved the New Drug times daily intravenous doses of morphine or Application for methadone maintenance treat- heroin. The dose of methadone can then be ment of heroin or morphine-like drug dependent lowered gradually until it is completely persons and published rules and regulations withdrawn, producing only a mild abstinence in the Federal Register controlling its use. syndrome. METHADONE DISADVANTAGE METHADONE MAINTENANCE While methadone maintenance had been shown In 1965, Dole and Nyswander (1965) extended repeatedly to be the most effective treatment the clinical use of methadone to a medical of opiate addiction available, several maintenance or stablization treatment, used investigators realized in the late sixties with a comprehensive program of rehabilitation. (Jaffe et al. 1970; Blachly 1971) that In a clinical research setting, they demon- significant problems related to the pharma- strated that heroin addicts could be cology of methadone existed. Methadone did "stabilized" for many months on a single daily not suppress the narcotic craving for a full oral dose of methadone (50-150 mg) achieved 24 hours in many addicts. Very large doses of by gradually increasing the dose over a methadone were necessary to provide sustained period of four weeks as tolerance developed relief of abstinence of symptoms for 24 hours to the dose which relieved the abstinence for these patients. These doses often produced syndrome. At the stabilization-maintenance unwanted sedation causing the patient to "nod" dose, the medication appears to relieve for the first several hours after consumption. narcotic “hunger” or craving, induce sufficient tolerance to prevent an abstinence Furthermore, the patient was required to syndrome and block