Rx :3 X /Week Laam Alternative to Methadone

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 programs to street sale. Because methadone patients must take their dose daily while simultaneously trying 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

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, therapeutic 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 intravenous 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 the euphoric effect of attend a methadone dispensing clinic daily to intravenous heroin. The maintenance dose is consume his medication under staff supervision. not intoxicating itself. Thus methadone This inconvenient and burdensome time and stabilization produces a normal steady func- travel demand was often draining physically tional state rather than the wave-like fluctu- and emotionally. When the patient was assuming ating feeling states of euphoric intoxication responsibility and trying to engage in work, ("high"), normality ("straight"), and rehabilitation or education programs, or abstinence ("sick") commonly experienced in responsible homemaking, this requirement was the street heroin addict life style. This considered by some to be antitherapeutic. A stabilization on methadone appears to free compromise solution was reached. the patient from heroin-oriented hustling, allowing participation in the treatment and After demonstrating satisfactory adher- rehabilitation program and development of ence to the program regulations for at less destructive interests and activities. least 3 months, and showing substantial progress in rehabilitation by partici- In the ensuing several years, many other pating actively in the programs’ clinical researchers, some with support from activities and/or participating in the Division of Narcotic Addiction and Drug educational, vocational and homemaking Abuse, National Institute for Mental Health activities, those patients whose (DNADA, NIMH) NIDA’s precursor, intensively employment, education, or homemaking evaluated the use of methadone as a maintenance responsibilities would be hindered by drug for the treatment and rehabilitation of daily attendance may be permitted to heroin addicts. (Jaffe 1972; Goldstein 1971, reduce to three times weekly the times 1972; Blachly 1972; Zaks and Feldman 1972). when they must ingest the drug under By 1970 a rapid proliferation of methadone observation. maintenance programs had occurred across the (Federal Register, Vol. 37, country, and almost 9,000 heroin addicts were No. 242 page 26790, Dec. 15, in treatment (Dole, 3rd Methadone Maintenance 1972). Conference, November 1970). Data from these patients indicated safety and efficacy of this Take-home doses were dispensed for the form of treatment under good medical super- other four days. vision. Unfortunately, the practice of permitting The concept of methadone maintenance, with take home supplies of methadone for unsuper- several variations from the original prototype vised self-administration away from the clinic of Dole and Nyswander, achieved widespread contributed to new problems (Jaffe et al. acceptance. Programs and number of patients 1970; Fink 1973). Accidental ingestion of in treatment continued to expand. On December methadone by non-tolerant persons, especially 15, 1972 the Food and Drug Administration, children, led to an alarming increase in after an extensive review of the methadone methadone toxic reactions and overdose

2 fatalities. Also, a market developed for months) toxicity studies in several animal illicit sale and redistribution of methadone species. to heroin addict peers suffering from with- (3) A detailed protocol of the planned drawal or to non-addict drug users seeking a investigation. new euphorient. More recently, the phenomenon of primary methadone abuse without prior Following preclinical animal studies indicating heroin addiction surfaced. That is the treat- the drugs presumptive safety for humans, the ment agent was becoming a new source of clinical investigation, consisting of three addiction. Finally, the patient might skip phases, accumulates substantial scientific or delay a dose of methadone in order to evidence of safety and effectiveness in man. "shoot up" with heroin after the blockade has This is needed to approve or disapprove the diminished. Thus, the take-home privileges drug for marketing. The Phase I clinical inadvertently negated much of the usefulness investigation involves a small number of healthy of random urine monitoring for illicit heroin patients to establish baseline data. Pharma- use. Furthermore, an adversary system or cological studies are used to determine drug game was created in which the patient might action, toxicity, metabolism, absorption, attempt to deceive the staff in order to gain elimination, preferred route of administration or retain take-home privileges (Goldstein and safe dosage range. Phase II clinical trials and Judson 1974). are conducted on a limited number of diseased patients to determine safety and effectiveness Thus, a longer lasting medication would have of the drug. If Phase II studies indicate that many practical therapeutic advantages over the drug may be useful and safe in treating methadone and partially resolve some of these a disease and the long-term animal testing problems encountered in clinical treatment performed concomitantly indicates no unwarranted programs. Fortunately, chemical and pharma- toxicity, Phase III studies may commence. The cological data were already available on Phase III investigation involves extensive, optical and structural isomers of methadone careful controlled and monitored clinical as well as several derivatives (Pohland et trials assessing the drug’s safety, effective- al. 1949; Chen 1948; Eddy et al. 1950,1952; ness and most desirable dosage in treating a Speeter et al. 1949; Sung and Way 1954). specific disease in a large number of patients. This data suggested potential clinical useful- Phase III study approximates general clinical ness for L-alpha-acetyl-methadol (LAAM, l- use. methadyl-acetate) because of its high oral effectiveness, long duration of action, and Once Phase III is completed and claims of low toxicity. safety and effectiveness of the drug arc supported, a New Drug Application (NDA) is NEW DRUG DEVELOPMENT submitted to FDA requesting approval to market the drug. The NDA contains all the information The development of a new drug product is a available about the drug which has accumulated long and complex process. The 1962 Kefauver from studies in animals and several hundred Harris Amendments to the Federal Food, Drug, to several thousands patients. The FDA reviews and Comestic Act established investigative the NDA to determine whether the benefits of procedures to supply substantial scientific the drug when used properly outweigh the risks. evidence that a drug is safe and effective. Once an NDA is approved, the drug can be Before a new drug can be marketed to the marketed to the general public. However, the general public, thorough testing must occur manufacturer is still required to report both in animals and humans under carefully regularly to FDA on any adverse reactions or controlled circumstances. toxicity which occurs. At any stage in this entire process the FDA may prohibit further Before a new drug may be tested clinically on testing or marketing based on unacceptable humans, the sponsor, usually a pharmaceutical toxicity or ineffectiveness. company, must provide FDA with information as specified as a “Notice of Claimed Investi- LEVO-ALPHA ACETYL METHADOL (LAAM) gational Exemption for a New Drug" known as an IND. Among the requirements are: The early clinical work on LAAM focused on morphine-like analgesic properties (Keats and (1) Complete composition of the drug, its Beecher 1952; David et al. 1956; David and source and manufacturing data. Semler 1952). However, at the Addiction (2) Results of all preclinical investigations Research Center, NIDA, Fraser, Isbell and demonstrating that there will not be coworkers (1952, 1954) demonstrated LAAM’s unreasonable hazard in initiating studies ability to relieve and prevent opiate within humans. The minimmum data required are drawal symptoms in addicts for long periods of the pharmacological profile, acute toxi- time, up to 72 hours. They also noted that city and short term (two weeks to three abrupt withdrawal from LAAM resulted in a mild but prolonged abstinence syndrome. 3 Merck Company in the early and mid-sixties that LAAM is less likely to be a reinforcer investigated LAAM’s usefulness as an analgesic. of daily drug taking behavior than methadone. However, the delayed onset of action and pro- The three times weekly dosage schedule frees longed time course limited its clinical useful- the patient from the daily necessity of ness for analgesia. Thus, Merck did not pro- engaging in drug seeking and drug taking ceed with LAAM beyond the early Investigational behavior. This represents an important thera- New Drug stage. peutic step forward because the destructive, habitual pattern of behavior associated with Jaffe and co-workers first utilized alpha- the heroin addict daily life style is broken. acetyl-methadol in a clinical narcotic treat- The individual feels less psychologically and ment program (Jaffe et al. 1969, 1970). They physically dependent when not involved with substituted D, L-alpha-acetylmethadl (DLAAM) daily drug taking. This strengthens the three times weekly for methadone daily in addict’s identification with the drug free a small group of methadone maintenance population and breaks association with the patients in 1968. TIhe results of that initial drug taking culture. pilot study corroborated the findings of Fraser and Isbell that D-LAAM could suppress opiate These factors are consistent with the treat- withdrawal symptoms for up to 72 hours and ment program goal of de-emphasizing of the might be a useful agent for the treatment of mystique of drugs and drug taking while empha heroin addicts. sizing human relationship and alternate pursuits as sources of gratification. In the Eased on the positive results of this pilot context of treatment, LAAM allows a reduction study, Dr. Sidney Cohen, Director, Division of emphasis on chemicals, since the life style of Narcotic Addiction and Drug Abuse, NIMH, no longer pivots around the consuming contracted with Merck Company for production preoccupations associated with taking drugs of four kilograms of LAAM in 1969. DNADA several times a day or even once a day at the encouraged further clinical investigation by treatment clinic. So there can be less talk- DNADA funded clinical research centers in the ing, seeking, taking and relating around early seventies. Research by this group sub- chemicals. More energy is available for stantiated the comparable usefulness and achievement of psychological, social, educa- safety of LAAM as a maintenance treatment of tional and vocational goals rather than biolog- heroin addiction (Jaffe et al. 1971, 1972; ical stabilization (Senay and diMenza 1972; Blachly et al. 1972; Zaks et al. 1972; Senay Jaffe et al. 1970). et al. 1974). Also, LAAM offers a practical answer to the LAAM ADVANTAGES problems related to take-home methadone. Illicit redistribution can be lessened because These researchers found that LAAM offers the three times weekly LAAM reduces the amount of patient, clinician and treatment program take-home medication a clinic must provide several advantages over methadone. Due to patients for out of clinic administration. If LAAM’s long duration of action, the frequency necessary, a no-take-home policy can be estab- of visits to clinic can be reduced from daily lished by a clinic or program where redistri- to three times weekly even for patients just bution and accidental overdose is especially entering treatment (Levine et al. 1973). prevalent (Jaffe et al. 1970; Fink 1973). Addicts find participation in treatment more acceptable and return more regularly, Further, several pharmacological properties especially those trying to engage in work, make LAAM less prone than methadone to abuse. education or rehabilitation activities outside LAAM itself is one-tenth as active as its of the clinic, because travel time and effort metabolites (Smits 1974; Nickander et al. 1974). is greatly reduced. Because metabolism requires time, several hours pass between taking LAAM and the onset Some investigators found that LAAM offers the of psychoactivity (Billings et al. 1974). patient a smoother, sustained drug effect. The Therefore, LAAM is less likely to be a rein- patients appeared more alert and more emotion- forcer of drug taking because substances with ally level. Oral consumption even during the a rapid, immediate onset of euphoric effects period of escalating doses did not produce are much more desired by drug users. LAAM has excessive sedation or subjective euphoria, i.e. another unique characteristic which makes it the patients do not report being "loaded" or less desired. Unlike other narcotics? LAAM "nodding" (Blachly 1971). This effect is is more rapidly effective orally than intra- consistent with phanmacokinetic data on LAAM venously, the preferred route of heroin addicts and its active metabolites (Goldstein 1975; (Blachly 1971; Fraser 1952). Billings et al. 1974; Henderson 1974, 1975) LAAM may offer treatment programs advantages Jaffe et al. (1970), Goldstein and Judson over methadone by improving the logistics of (1974). and Senay and diMenza (1972) emphasized 4 drug distribution. Three times weekly dosage Facilities were not available in the industry allows for more controlled drug delivery to for preclinical narcotic testing nor was there increasingly large numbers of patients. By an existing structure to perform the carefully reducing the required number of clinic visits, monitored clinical studies required. efficiency of treatment may be increased due to savings of staff dispensing and pharmacy Thus, SAODAP recognized that LAAM was not services (Senay et al. 1972; Blachly 1971). proceeding because the pharmaceutical industry Thus, conversion from methadone to LAAM can did not want to develop and promote it. potentially either reduce the cost of treat- Therefore SAODAP set a high priority on creat- ment or increase the number of available ing and coordinating a governmental mechanism treatment slots. for developing this type of drug using LAAM as the prototype. Therapeutic drug development SAODAP UNDERTAKES COORDINATION OF LAAM had previously been the function of the DEVELOPMENT pharmaceutical industry and not a practic of government. In fact, the recognized function In June 1971, the Special Action Office for of the Federal Government was to regulate the Drug Abuse Prevention (SAODAP) was established pharmaceutical industry. This led to the by Executive Order "to focus the comprehensive interesting and potentially anomolous situation resources of the Federal Government.... and of the government attempting to develop and to develop a comprehensive, coordinated, long- also regulate the same compound, the former term federal strategy to combat drug abuse." at SAODAP and DNADA and the latter at FDA. The Drug Abuse Office and Treatment Act of 1972 (Public Law 92-255, Sec. 224, 86 stat. Although LAAM was to be developed as rapidly 72, March 21, 1972) mandated the expansion of as possible, it was imperative to avoid the research on "long-lasting, non-addictive, many problems encountered by methadone due blocking and antagonist drugs or other pharma- to inadequate and incomplete study. Federal cological substances for the treatment of Agencies had the assigned responsiblity to heroin addiciton." Based on the potential be certain that LAAM was a safe and effective advantages of LAAM over methadone, Dr. Jerome drug before marketing. Therefore, SAODAP Jaffe, SAODAP's first director, initiated in organized and promoted interagency cooperation the summer of 1971 a comprehensive review of in LAAM development, with DNADA and FDA the status of LAAM and other long-lasting playing the leading roles. SAODAP effectively blocking drugs utilizing experts from the utilized the expertise in academic and various government agencies and the private phamaceutical communities for advice and sector. monitoring the process. A LAAM Medical Advisory Panel served this latter purpose. The conclusion of the review was that LAAM was the most promising compound available at the The amount of LAAM available severely limited time, but that the pharmacological development the progress of both animal and clinical of LAAM was not proceeding rapidly enough. investigation. A larger supply of LAAM was Several problems were found to be delaying obtained through the cooperation of the LAAM development. There was little general Penick Pharmaceutical Company in 1972 and interest in or knowledge about LAAM in the arrangements were made for an additional treatment, research or pharmaceutical fields. supply when needed. The recognition that No one in Federal Agencies or industry was further animal studies were needed to establish promoting the drug. LAAM investigation was intermediate and long-term nontoxicity of limited to a few research centers. Large LAAM prompted an agreement between DNADA and quantities of LAAM necessary for use in treat- Department of Army’s research facilities at ment were not available from any source, and Edgewcod Arsenal to perform the necessary only a few kilograms remained from the LAAM studies in December 1971. In the Spring of produced for DNADA several years previously. 1972 an interagency Pharmacology Task Force was formed of representatives from SAODAP, Furthermore, unlike methadone, which was the Veterans Administration, Department of the marketed as an analgesic prior to its use in Army, Food and Drug Administration, FM, narcotic addiction treatment, LAAM was not National Academy of Sciences. and the Division patented or marketed for any indication. LAAM of Narcotic Addiction and Drug Abuse, National was not patentable because it had been in the Institute of Mental Health DNADA,(NIMH). This public domain for many years. Thus, the group reviewed previous and ongoing work on pharmaceutical companies were not interested LAAM and planned and coordinated the subse- in spending research and development funds for quent development toward the New Drug Appli- a drug without exclusivity and with a limited cation stage. market. Also, the pharmaceutical industry drew attention to the special precautions and Through this coordinated effort, the necessary regulatory controls pertaining to development animal toxicological and teratological studies of controlled, Schedule I, narcotic substances. could be phased with the subsequent clinical 5 studies of humans. The animal toxicology period, terminating in the Spring of 1975. studies done previously by Merck and Company Four hundred thirty (430) male heroin addicts were utilized for the clinical Phase I were studied. Of these, 142 received LAAM and Investigational New Drug studies begun in the remainder were equally divided between June 1972 by DNADA. DNADA initiated extensive high and low dose methadone. chronic animal studies including a one year study in dogs and rats to provide required Because of technical inadequacies in the Edge- toxicological data to support safe, prolonged wood Arsenal Study, DNADA initiated additional administration in man. acute and chronic rat and dog studies of LAAM in 1973. At approximately this time, SAODAP began planning and organizing another larger The existence of these animal and early cooperative clinical study of LAAM to provide clinical studies stimulated clinical interest more patient data. The study was designed in LAAM. Planning began early in 1972 for to complement the VA study. larger scale cooperative clinical studies to test LAAM safety and efficacy which could Interested patients were selected from those follow by 6 to 8 months the chronic animal already in methadone maintenance programs. studies required to support long term admini- In the major part of the new clinical study, stration to humans. Dr. Samuel Kaim, Director patients were randomly assigned to the LAAM of the Alcohol and Drug Dependence Service of study group or the methadone control group. the Veterans Administration expressed V.A.‘s The study was open rather than double-blind. interest to SAODAP. The VA had vast experience Take-home methadone was permitted according with large scale clinical cooperative studies to clinic policy, while all LAAM patients of other psychotropic drugs. The administra- attended the clinic three times a week. Cross- tive mechanism including the data gathering over dose from methadone to LAAM was fixed, and analysis section and pharmacy was already but subsequent dose levels were flexible at the functional at V.A. Hospital, Perry Point, discretion of the clinic physician. In addi- Maryland, under the direction of James Klett, tion, sub-study was performed to examine Ph.D. Also, the VA had recently established further the use of LAAM on Friday only in a network of Drug Dependence Treatment Centers place of weekend methadone. for returning addicted soldiers. The SAODAP cooperative study was initiated The planning and initiation of further clinical in February 1974 when the safety data from studies proceeded cautiously. To protect the the second animal toxicity study and the well-being of potential subjects, the Advisory clinical data from the VA Cooperative Study Committee and Pharmacology Task Force wanted was adequate to support an additional 40 week some data from the long-term animal studies human safety and efficacy study. Sixteen (16) available before long-term clinical studies outpatient drug treatment clinics throughout were initiated. By the Spring of 1973 the country were chosen for participation in sufficient animal toxicity data was available order to provide widespread experience with from the Edgewood Arsenal study to support the LAAM in local treatment programs in a cautious initiation of Phase II clinical controlled, carefully monitored and coordinated studies. These studies were to proceed in manner. Seven hundred sixty seven (767) male successive stages contingent upon continued patients, of whom 383 received LAAM, partici- evidence of lack of toxicity in animals pated in this study. Of these, 136 patients, indicating probable safety in man. of whom 65 received LAAM, participated in the LAAM Friday only substudy. In April 1973, pilot studies were initiated in three VA Hospitals to evaluate the safety and COORDINATION OF LAAM DEVELOPMENT TRANSFERRED efficacy of LAAM maintenance (80 mg three times TO NIDA weekly) compared to high (100 mg daily) and When SAODAP began to phase out in the Fall low (50 mg daily) dose methadone maintenance. of 1974, the coordination and direction of The study was conducted double-blind and the LAAM project, including the Pharmacology utilized a common protocol for random selection Task Force and Cooperative Studies were of subjects, induction of street heroin addicts officially transferred to the recently onto the study drugs, maintenance dosage, and established Division of Research, National for evaluating safety and efficacy. In the Institute on Drug Abuse, (NIDA), successor summer of 1973 based on the up&ted animal to DNADA,(NIMH). Shortly thereafter, based on data, the existing data from the pilot studies the available results of the animal and and other available clinical data, the decision clinical studies, the Food and Drug Adminis- was made to continue tentatively the study for tration permitted the use of LAAM for up to a total of 40 weeks and to proceed with the 80 weeks to provide longer comparative toxi- addition of nine more Veterans Administration city data. Also, the inclusion of women with Hospitals in the Cooperative Study. The no child-bearing potential was permitted. clinical study was carried out over a 2 year Accordingly, NIDA extended the SAODAP clinical 6 studies until the Spring of 1976 to perform common protocol for medical monitoring and additional studies of LAAM. evaluation of clinical efficacy will be utilized to produce uniform data. The study will Thus, by the Fall of 1974 all of the basic require approxmiately two years to complete work necessary to initiate Phase III large after which the New Drug Application for LAAM scale clinical study of LAAM had been completed can be submitted to FDA to permit its marketing or was in the process of completion. LAAM to interested chronic opioid dependence treat- appeared to be a safe and efficacious drug ment programs. for use in the treatment and rehabilitation of chronic opioid dependent persons. The staffs Pending successful completion of this Phase III of the Clinical-Behavorial Branch, Division of large scale clinical trial, the project has Research, NIDA and the Drug Abuse Section, accomplished the formidable task of developing Division of Neuroharmacology, FDA, began to at an accelerated pace a drug which offers plan the Phase III clinical study of LAAM considerable potential benefit to heroin addicts through the Pharmacology Task Force. A Phase and treatment programs. The task of developing III clinical study is a full scale clinical a drug the private sector was unwilling or trial of the drug under the conditions of the unable to undertake has been carried out, and use in the general population. Thus, those in accordance with stringently applied Federal groups of heroin addicts excluded from parti- Regulations designed both to ensure the kind cipation in a Phase II study can be included of scientific baseline data establishing in Phase III. These Phase III studies can LAAM safety and efficacy and to provide a include subjects with medical and/or mechanism that can be a model for future drug psychiatric illnesses, subjects concurrently development in the narcotic dependence treatment taking other medication and women of child- field. Conjointly the task has entailed creat- bearing potential. ing the means for cooperation between the many agencies and individuals involved in a far-flung In the Spring of 1975, NIDA advertised a RFP and large scale project. This also, is a to perform the Phase III study under a cost legacy for future drug development. sharing contract. In return for the cost- sharing NIDA provides patent-like protection REFERENCES for the contractor to protect his investment in LAAM and to assure the marketing of the Billings, R. E., McMhahon, R. E., Blake, D.A. drurg in the public’s interest. NIDA agreed 1-acetylmethadol (LAM) treatment of opiate to give the contractor the right to exclusive dependence: plasma and urine levels of two possession and use of all data generated in pharmacologically active metabolites. Life the performance of this contract which would Sciences 14:1437-1446, 1974a. be necessary to prepare and file a New Drug Application on LAAM for eight years pending Blachly, Paul., Recent developments in the satisfactory performance of the contract. Therapy of Addictions. Current Psychiatric Therapies 12:98-103, 1972. Despite the investment and commitment already made by Federal Agencies the pharmaceutical Billings, R. E., McMahon, R. E., Blake, D.A. industry did not respond. However, other 1-acetylmethadol treatment of opiate dependence: competitive bids were received. In July 1975, the crucial role of active metabolites. a medical consulting firm, Whysner Associates, Federation Proceedings 33(3):473, 1974b. was contracted by NIDA to conduct Phase III Clinical Evaluation of LAAM for the treatment Blachly, P. H. L-alpha acetylmethadol in the of chronic opioid dependence and to make treatment of opiate addiction: Progress Report, appropriate arrangements for the eventual 1971. Methadone, 1971 Workshop Proceedings, filing of the New Drug Application and P. H. Blachly, ed., ACEB Books, Corvallis, marketing of LAAM. Oregon, 1971. p. 23-25. The contract is currently ongoing and arrange- Blachly, P. H., David, N. A., Irwin, S. Alpha- ments are made to formulate and distribute acetylmethadol (LAM) : comparison of laboratory LAAM The Phase III Investigational New Drug findings, electmencephalograms, and Cornell Application has been submitted and clinics are Medical Index of patients stabilized on LAM being enlisted to carry out the clinical study. with those on methadone. Proc. of Fourth Natl. An estimated 6000 patients, including those Conf. on Methadone Treatment, San Francisco, already maintained on methadone and heroin Jan. 1972, pp. 203-205. addicts entering treatment, will be asked to participate in a 40 week study of safety and Chen, K. K. Pharmacology of methadone and efficacy of LAAM. The open study will be related compounds. Annals of the New York performed in approximately 50 cooperating Academy of Sciences 51:83-97, 1948. methadone maintenance programs nationwide. A

7 David, N. A., Semler, H. J., Clinical trial of 1975. (Unpublished) alpha acetylmethadol (dl-6-dimethylamino-4, 4-diphenyl-3-acetoxy-heptane) as an analgesic. Henderson, G. L. Two-year pharmacokinetic Journal of Phamcology and Experimental study of LAAM.. Seventh quarter progress Therapeutics 106:380, 1952. report. 1975b. (Unpublished) David, N. A., Semler, H. J., Burgner, P. R. Isbell, H., Wickler, A., Eisenman, A. J., Control of chronic pain by dl-alpha-acetyl- Daingerfield, M., Frank, E. Liability of methadol. Journal of the American Medical addiction to 6-dimethlamino-4-4-diphenyl-3- Association 161(7):599-603, 1956. hepatone in man. Archives of Internal Medicine 82:362-392, 1948. Dole, U. P., Nyswander, M. A. A medical treatment for diacetylmorphine (heroin) addiction. Jaffe, J. H. The maintenance approach to the Journal of the American Association 193:646- management of opiod dependence. In: Zarafo- 650, 1965. netis, Chris J. D., ed. Drug Abuse: Proceed- ings of the International Conference. Phila- Eddy, N. B., May, E. L., Mosettig, E. Chemistry delphia: Lea and Febiger, 1972, pp.161-170. and pharmacology of the methadols and acetylmethadols. Journal of Organic Chemistry 17(2): Jaffe, J. H., Schuster, C. R., Smith, B. B., 321-326, 1952. Blachly, P. H. Comparison of acetylmethadol and methadone in the treatment of long-term Eddy, N. B., Touchberry, C. F., Lieberman, heroin users: A pilot study. Journal of the J. E., Khazan, N. Synthetic analgesics; metha- American Medical Association 211:1834-1836, done isomers and derivatives. Journal of 1970. Pharmacology and Experimental Therapeutics 98:121-137, 1950. Jaffe, J. H., Schuster, C. R., Smith, B. B., Blachly, P. Comparison of dl alpha-acetyl Fraser, H. F., Isbell, H. Actions and addic- methadol and methadone in the treatment of tion liabilities of alpha-acetylmethadols in narcotics addicts. Phamacologist 11(2):256, man. Journal of Pharmacology and Experimental 1969. Therapeutics 105(4):458-465, 1952. Jaffe, J. H., Senay, E. C. Methadone and Fraser, H. F., Nash, T. L., Vanhorn, G. D., and 1-methadyl acetate. Use in managment of Isbell, H. Use of miotic effect in evaluating narcotics addicts. Journal of the American anagesic drugs in man. Archives Internationales Medical Association 216:1303-1305, 1971. de Phamacodynamie et de therapie 98:443-451, 1954. Jaffe, J. H., Senay, E. C., Rehault, P. F. A six-month preliminary report of the rehabil- Goldstein, A. Blind controlled dosage compari- itative efficacy of 1-methadyl acetate compared sons in Two hundred patients. Proceedings of to methadone. Proc. of Fourth National Confer- the Third National Conference on Methadone ence on Methadone Treatment, San Francisco, Treatment. p. 31. Washington, D.C.: U.S. Jan. 1972, pp. 199-201. Government Printing Office 1971. Jaffe, J. H., Senay, E. C., Schuster, C. R., Goldstein, A. Heroin Addiction and the role Renault, P. F., Smith B., diMenza, S. Methadyl of methadone in its treatment. Archives of acetate vs methadone. A double-blind study in General Psychiatry 26:291-297, 1972. heroin users. Journal of the American Medical Association 222(4):437-442, 1972. Goldstein, A. LAAM and LAAM metabolites: plasma levels in patients. Summary progress report. Levine, R., Zaks, A., Fink, M., Freedman, A. M. 1975 (Unpublished) Levomethadyl acetate. Prolonged duration of opiod effects, including cross tolerance to Goldstein, A., and Judson, B. Three critical heroin, in man. Journal of the American issues in the management of methadone programs: Medical Association 226(3):316-318, 1973. Critical Issue 3: Can the community be protected against the hazards of take-home metha- Moreton, J. E., Roehrs, T., Khazan, N. Sleep- done. Addiction. Peter G. Bourne, ed. awake activity and self-injection pattern of Academic Press, New York, p. 140-148, 1974. rats dependent on morphine, methadone, or L-alpha-acetyl-methadol (LAAM). Federation Henderson, G. L., A two-year pharmacokinetic Proceedings 33(3):516, 1974. study of LAAM. Fourth quarter progress report. 1974. (Unpublished) Nickander, R., Booher, R., Miles, H. a-l-acetylmethadol and its N-demethylated metabolites Henderson, G. L., Two-year pharmacokinetic have potent opiate action in the guinea pig study of LAAM. Sixth quarter progress report. 8 isolated ileum. Life Sciences 14:2011-2017, Smits, S. E. The analgesic activity of a-l- acetylmethadol and two of its metabolites in mice. Research Communications in Chemical Pohland, A., Marshall, F. J., Carney, T. P. Pathology and Pharmacology 8(3): 575-578, 1974. Optically active compounds related to methadon Journal of the American Chemical Society 71: Speeter, M. E., Byrd, W. M., Cheney, L. C., 460-462, 1949. Binkley, S. B. Analgesic carbinols and esters related to amidone (methadon). Journal of American Chemistry Society 71:57-60, 1949. Senay, E. C. and diMenza, S. Methadyl acetate in the treatment of heroin addiction: A review, Sung, C. Y., Way, E. L. The fate of the 34th Annual Scientific Meeting of the Committee optical isomers of alpha-acetyl-methadol. on Problems of Drug Dependence, 1972, Ann Journal of Pharmacology and Experimental Thera- Arbor, Michigan. peutics 110:260-270, 1954. Zaks, A., Feldman, Martin. Private methadone maintenance: analysis of a program after one Senay, E. C., Jaffe, J. H., diMenza, S., and year. Journal of the American Medical Associa- Renault, P. F. A 48-week study of methadone, tion 222(10):1279-1280, 1972. methadyl acetate, and minimal services. Chapter in Fisher, S. and Freedman, A. M., eds., Opiate Zaks, A., Fink, M., Freedman, A. M. 1-alpha- Addiction: Origins and Treatment, V. H. Winston acetylmethadol in maintenance treatment of Sons, 1974. opiate dependence. Proc. of Fourth National Conference on Methadone Treatment, San Senay, E. C., Renault, P. F., diMenza, S., Francisco, Jan. 1972, pp. 207-210. Collier! W. E., Daniels, S. J., and Dorus, W. Three times a week LAAM equals seven times a Zaks, A., Fink, M., Freedman, A. M. Levo- week methadone: A preliminary report of a methadyl in maintenance treatment of opiate control study. Proceedings of the First dependence. Journal of the American Medical National Drug Abuse Conference, 1974. (In Press) Association 220(6):811-813, 1972.

9 THE CHEMISTRY OF LAAM

Sydney Archer, Ph. D.

CHEMICAL S’TRUCTURAL. FORMULA AND DESCRIPTION and has a specific rotation of -59.0 to -61.3°. 25 D (c=1 in water). Infrared Levo-alpha-acetylmethadol (LAAM) is levo- absorption conforms to structure in CHCl3 alpha-6-dimethylamino-4, 4-diphenyl-3-heptyl solution and KBr Pellet. acetate and is used as its hydrochloride salt. The chemical structure of LAAM is as follows: RELATIONSHIP TO OTHER RELATED DRUGS The compound was first reported by Pohland, Marshall and Carney (1949)l as a water-soluble substance with a melting point of 201-202°C and an observed rotation of 25 D = -59° (c=0.2 in water). It was prepared by catalytic reduction of d- methadone (II) to afford 1-alpha-methadol (III) which on acetylation with acetic an- hydride in pyridine furnished LAAM (I).

1 References cited my be found at the conclu- It is a white crystalline compound with a sion of the monograph in the LAAM Preclinical melting point of 215-218°C. It is levorotary Bibliography. 10 Pohland, Marshall and Carney (1949) also per- pairs of isomers are possible. However, cata- formed the same sequence of reactions on 1- lytic hydrogenation gave only the alpha-series methadone. This yielded d-alpha-acetylmethadol as reported by Pohland et al. May and Mosettig whose hydrochloride was also water-soluble and (1948) showed that catalytic hydrogenation of melted at 200-303°C. The optical rotation was dl-methadone furnished the alpha-series exclu- 25 D = +57° (c=0.2 in water). sively and Speeter, Byrd, Cheney and Binkley (1949) found that lithium aluminun hydride It will be noted that the dextrorotary form of reduction of dl-methadone furnished dl- methadone gave levorotatory acetylmethadol, methadol exclusively also. whereas the analgetically more active l-methadone gave the dextrorotatory isomer. On the other hand Eddy, May, Mosettig (1952) found that sodium propanol reduction of either It will also be noted that whereas methadone racemic or optically active methadone gave the (II) has only one chiral center (starred car- beta-methadols, as the major but not exclusive bon) the acetylmethadols have two chiral cen- products. These results are summarized in ters (starred carbons). Two diastereomeric Chart I.

11 These authors converted the isomers to the DESCRIPTION OF DOSAGE FORM AND corresponding acetates. Thus, all four poss- QUANTITATIVE COMPOSITION ible isometric acetates were synthesized. In the course of studying the metabolism of The dosage form of 1-alpha-acetylmethadol is LAAM, two new matabolites were discovered. a colorless, clear liquid with the odor of These are 1-alpha-6-methylamino-4, 4-diphenyl- parabens. One ml of concentrate contains: 3-heptyl acetate (V), (Nor-LAAM), and 1-alpha- 6-amino-4, 4-diphenyl-3-heptyl acetate (VII), 1-alpha-acetylmethadol 10 mg (DiNor-LAAM). Their synthesis was reported methyl paraben 0-18 percent by Booher and Pohland (1975) and is outlined propyl paraben 0.02 percent in Chart II. in distilled water. LAAM (I) was treated with trichlororthyl chloroformate to give the amide (IV), which was reduced with zinc in formic acid to give Nor-LAAM (V) in 44 percent overall yield from ASSAY OF LAAM FOR STABILITY I. Oxidation with potassium permanganate gave the nitro ester VI in 24 percent yield. Re- The following procedures were developed by duction using Raney nickel gave DiNor-LAAM the United States Public Health Service HSHMA (VII) in 72 percent yield. Supply Service Center, Perry Point, Maryland (January, 1974), for the assay of samples of Chatterjie and Inturissi (1975) were able to LAAM packaged in 16-ounce amber, polyethylene prepare Nor-LAAM from LAAM in one step using bottles and stored at 25°C and 45°C. The a mercuric acetate demethylation procedure. titrimetric procedure which follows is a The yield was 50 percent and is shorter than modification of the USP XVIII procedure for the method of Booher and Pohland (1975). Methadone Hydrochloride Injection:

12 Transfer a volume of concentrate equivalent to about 50 mg. of LAAM to a separatory funnel and wash with 25 Ml. of either. Transfer the aqueous layer quantitatively to the Watkins Continuous Extraction Apparatus set up for use with ether. Make alkaline with NaOH T.S. and charge the apparatus with ether. Reflux for 6 hours. Remove the receiving flask, add 20.0 ml. of 0.02 N sulfuric acid, and evaporate the ether. Cool, add methyl red T.S., and titrate the excess acid with 0.02 N sodium hydroxide. Each

ml. of 0.02 n sulfuric acid is equivalent to 7.799 mg. of C23H31NO2 HCl.

Recovery with this method was as follows:

Because of the need for a "stability indicating" assay method a gas chromatographic method was developed and is as follows:

Standand Solutions: Prepare two (2) standard solutions of LAAM-HCl in water such that standard solution #1 contains 11.0 mg. of LAAM-HCL per ml. and standard solution #2 contains 9.0 mg. LAAH-HCl per ml.

Internal Standard: Prepare a solution of Diphenhy dramine Hydrochloride in water at a concentration of 10.0 mg. per ml.

Sample: Dilute a portion of sample with water to a theoretical concentration of about 10.0 mg. / 10 ml.

Procedure: Treat the sample and each of the standard solutions as follows:

Transfer 10.0 ml. to a 100.0 ml. volumetric flask. Add 5.0 ml. of internal standard, dilute to volume with water, and mix. Inject 1 microliter of each solution into the apparatus. Run at least 3 injections of each standard and the sample. From the chromatograms obtained calculate the ratio of the peak area of LAAM-CHCl to the peak area of Diphenhydramine HCl. Plot the peak area ratios of the two standard solutions versus the weight ratios. Read the weight ratio of the sample and calculate the wt. of LAAM- HCl in the sample.

Recoveries with this method were as follows:

PRECLINICAL STUDIES

PHARMACOLOGY OF LAAM Sydney Archer, Ph.D.

The synthesis of levo-alpha-acetylmethadol Five areas of LAAM animal pharmacology (LAAM) and early preclinical investigations research findings are discussed below: into toxic and analgesic properties were carried out in 1948. The delayed onset and long duration of action of this compound was Analgesic Activity of LAAM suggestive of the activity of metabolites, and Related compounds and further studies showed that two metabolites, noracetylmethadol (N-LAAM) and dinoracetylmethadol (DN-LAAM), were responsi- K. K. Chen (1948)1 first reported on the ble for the unique time-response character- analgesic activity of 1-alpha-acetylmethadol istics of 1-alpha-acetylmethadol. Currently, (LAAM) and d-alpha-acetylmethadol (DAAM) research is being carried out into the LAAM was prepared from d-methadone which is pharmacokinetics of 1-alpha-acetylmethadol, less active as an analgesic than l-methadone. as well as long-term toxicity studies and The latter is the precursor of DAAM. Chen studies of the effects of the drugs upon found that in rats l-methadone is seven times reproduction. as potent as d-methadone but in higher animals the difference in potency is even This chapter is devoted to an account of greater. The l-isomer is 25 times as active LAAM preclinical animal studies and provides in dogs and 50 times as active in man. Thus, a summary of all pharmacological studies of it may be expected that the analgesic activ- LAAM. The following chapter offers an ity of DAAM will be greater than LAAM. This account of the preclinical toxicology of proved to be the case. It was found that in LAAM. rats using the Haffner technique for determining analgesic activity (F. Haffner, PHARMACOLOGICAL SUMMARY OF FINDINGS Deutsch, Med. Wochenschrift 55: 731, 1929) DAAM was 5.4 times as active as LAAM by the The following summary of LAAM preclinical subcutaneous (s. c.) route of injection and studies presents a comprehensive overview of the pharmacological research which had been References cited my be found at the con- conducted with LAAM in animals, through clusion of the Monograph in the LAAM Pre- summer of 1975. clinical Biography. 15 twice as active as dl-methadone. It was 0.67 (0.53-0.86) times as potent as morphine noted that LAAM had a delayed onset but a sulfate but at peak activity, which occurred long duration of activity as compared with three and one-half hours after drug admin- the d-isomer. istration, it was six times as potent as morphine. The onset of analgesic action was Smith and Lehman (1953) found that the considerably later than that of morphine or analgesic effects of methadone and LAAM in methadone. rats were additive when both were injected subcutaneously using the D'Armour-Smith test. Leimbach and Eddy (1954) determined the analgesic activity in mice (s.c.) of all Using the pinch test with rats, McCarthy four of the stereoisomers as well as the (1974) found that at 30 minutes after sub- LD50 values. Their analgesic results are cutaneous administration, LAAM was about summarized in Table I and Table II.

In agreement with K. K. Chen, these authors doses, the onset, and duration were almost found that d-a-acetylmethadol (DAAM) is identical. When compared with dl-methadone, about six times as active as an analgesic LAAM was more active orally (ED50 =1.1 vs than 1-a-acetylmethadol (LAAM). They also 9.2) and had a greater duration of action. noted a delay in onset and a longer duration for LAAM as compared with DAAM. However, these differences tended to disappear when the durgs were administered orally (Table The LD50 data for these compounds is II). When the oral route was used, the ED50 summarized in Table III. 16 LAAM turned out to be the least toxic effects of DAAM and LAAM as compared with stereoisomer whether given orally or sub- l-methadone and d-methadone. The ED values cutaneously and was less toxic than dl- were obtained by intraventricular injection. methadone also. It must be emphasized that Because of the long duration of action of these acute toxicities were determined in LAAM and the relative short duration of nondependent mice and caution must be action of nalorphine, the latter (50/mg/kg) observed in extrapolation of these results. was administered 40 minutes after the dose of LAAM and doses of the antagonist were given every hour thereafter for a total of Veatch, Alder, and Way (1964) studied the six hours. The results are summarized in nalorphine reversibility of the analgesic Table IV.

It is surprising that no nalorphine Analgesic Activity of LAAM Metabolites reversibility was noted after administration of LAAM or d-methadone. The results are self-consistent in the sense that d-methadone is the precursor of LAAM and l-methadone is the precursor of DAAM. When it became known that LAAM was metabolically converted to 1-alpha-noracetylmethadol Nevertheless, it would be expected that (N-LAAM) and 1-alpha-dinoracetylmethadol nalorphine would reverse these morphine-like (DN-LAAM), Nickander, Booher, and Miles effects of all the compounds. In contrast, (1973) compared the analgesic activity of Killam (1974) found that in monkeys the these three compounds on the guinea pig ileum respiratory depressant effects of LAAM were preparation. The results are summarized in nalorphine and naloxone reversible. Table V. 17 Smits (1974 studied these drugs for analge- 1-alpha-noracetylmethadol (N-LAAM) is more sic activity in the acetic acid-induced active than LAAM. The slow onset of the writhing test in mice. The results are sum- latter coupled with the high activity of the marized in Table VI. metabolite, N-LAAM, is highly suggestive that LAAM is metabolically transformed to an active drug which is probably N-LAAM. The studies of Way using SKF-525A strongly It was noted that LAAM had a slower onset of support this proposition. action than its metabolites. Addiction Potential of LAAM and Its Cogeners Billings, Booher, Smits, Pohland, and McMahon (1973) found that ED50 of l-alpha- dinoracetylmethadol (DN-LAAM) in the acetic Deneau and Seevers (1960, 1955) determined acid-induced mouse writhing test for analge- the physical dependence capacity (PDC) of sia was 1.5 mg/kg S.C. and 5.6 mg/kg peroral some compounds related to LAAM although LAAM itself was not run. The usual single dose (p.o.) suppression technique, using morphine-depend- It is clear that in both the in vitro and ent monkeys was employed. The results are in vivo tests for analgesic activity that summarized in Table VII. TABLE VII: PHYSICAL DEPENDENCE CAPACITY (PDC) OF CONGENERS OF LAAM

18 Although no studies were reported on LAAM it- injection. Upon methadone substitution, self, the racemic mixture of its primary me- the sleep-awake distribution within the tabolite (dl-alpha-noracetylmethadol) was run interinjection intervals was qualitatively as was the d-isomer of alpha-noracetylmetha- similar. In the case of LAAM self-admini- dol. The former had an equivalent dose of stration, EEG slow bursts usually occurred 0.75 mg/kg and the latter required a dose of several minutes after injection and were 3.5 mg/kg to suppress signs of morphine ab- followed by brief episodes of sleep and REM stinence. Thus, it may be concluded that the sleep. These few sleep and REM sleep epi- l-isomer is more active than the d-isomer in sodes were terminated by the appearance of suppressing abstinence in morphine-dependent wakefulness with EEG slow bursts and then monkeys. Since the 1-isomer is a metabolite behavioral arousal which lasted for two to of LAAM it may be concluded that LAAM will three hours. The arousal state, as in the have a high PDC. case of morphine and methadone, was followed by alternating episodes of sleep, REM sleep, During the development of tolerance to and wakefulness prior to the next injection. morphine in rabbits, the hyperglycemia produced by regularly spaced injections of the Under these experimental conditions of free drug gradually diminished and even turned to access to the drug, morphine (10 mg/kg/ a hypoglycemia as tolerance developed. injection) was self-administered as a single Phatak and David (1953) noted that LAAM or multiple injection at intervals of produced a hyperglycemia on initial injec- 2.5±0.1 hours. When methadone (2 mg/kg/ tion in rabbits which gradually diminished injection) was substituted for the morphine, as tolerance developed. Abrupt withdrawal the injection intervals were 1.4±0.1 hours. of the drug produced a hypoglycemic effect. With LAAM, the interinjection interval was 8.8±0.8 hours. Moreton, Roehrs, and Khazan (1974) studied the pattern of self-administration of mor- LAAM possessed a relatively slow onset and phine, methadone, and LAAM in rats. Adult long duration of action in dependent rats female albino rats weighing 250-300 g were having free access to the drug. When low made physically dependent on morphine and doses of naloxone were administered intra- intravenous (i.v.) cannulated to permit venously, there was an immediate precipita- self-administration of morphine (10 mg/kg/ tion of abstinence signs. injection). EEG and EMG activity was recorded continuously. Killam (1974) studied the effects of LAAM on the morphine uptake of morphine-dependent Morphine was available 24 hours per day. monkeys. At 2.0 mg/kg intramuscular (i.m.) Methadone (2 mg/kg/injection) was substi- three morphine-dependent monkeys exhibited tuted for morphine and LAAM (1 mg/kg/injec- a slight decrease (2-16 percent) in morphine tion) was then substituted for methadone. uptake, but a fourth showed a significant increase (40-50 percent). The next day all In the naive rat, administration of morphine monkeys showed a significant increase which at 10 mg/kg intraperitoneal (i.p.) was dropped on the second day and returned to followed by a biphasic pattern of behavioral baseline on the third day. At 4.0 mg/kg stupor and subsequent stimulation. The there was a 30.6 percent decrease in morphine depressed phase lasted 60-90 minutes and the uptake followed by an increase of 50-87 per- EEG tracings showed the occurrence of high- cent on the second day. On the third day, voltage slow bursts. During the phase of the intake returned to baseline values. At stimulation, lasting 60-90 minutes, the EEG 6.0 mg/kg, both monkeys were depressed and revealed desynchronized awake tracings. ataxic. This lasted for 8-16 hours during Only a few short episodes of behavioral which time there was no uptake of morphine. stupor with EEG slow bursts intervened in There was a rebound effect on the second this period. This phase was characterized day and morphine uptake varied for the by increased locomotor activity, stereotyped following three days. behavior, and episodes of startle reactions. In the dependent rat, the duration of the Other Pharmacological Effects biphasic response after self-injection of morphine was reduced by about 50 percent. Henderson (1974a) found that a dose-dependent The behavioral stuporous phase, concomitant acute necrosis of the kidney of rats occurred with EEG slow bursts, appeared within a few following administration of LAAM (2 mg/kg minutes and lasted for only 15 to 30 minutes. (0 percent), 5 mg/kg (65 percent), 10 mg/kg The behavioral stimulation and EEG activation (73 percent)). This effect was also noted lasted for only 30-60 minutes. Sleep and after administration of 50 mg/kg of morphine REM sleep predominated before the next sulfate (83 percent). Complete reversal 19 occurred after 32 hours. The fact that nal- toneal (i.p.) administration of LAAM oxone prevented this phenomenon indicated (0.1-2.0 mg/kg); they had prolonged post- that it was the result of the pharmacological ictal recovery. At 0.21-0.5 mg/kg, the action of the analgesics rather than an prolongation was followed by a decrease in intrinsic effect of LAAM. post-ictal recovery. Maickel (1974) found that at 0-10 minutes postadministration, LAAM caused a decrease Gary Henderson has studied the behavioral in spontaneous activity of mice. At doses effects of LAAM in beagle dogs. One mg/kg of 50 to 100 mg/kg s.c., the activity of the dose was administered intravenously and two mice was about 50 percent of that of the mg/kg doses were administered both intra- control group and at 200 mg/kg the spontan- venously and orally. enous activity decreased to only 60 percent of control. In comparison, methadone at One Mg/Kg Intravenously--Immediately after 15 mg/kg S.C. increased spontaneous activity dosing, dogs started to pant, become to about 200 percent of control. There was quiet, and lay down. By 30 minutes, three a marked decrease (<50 percent of control) of four dogs defecated. The females were at 45 mg/kg s.c. coordinated but moved slowly. The males were slightly ataxic. By one to one and Killam (1974) studied the effects of LAAM one-half hours after drug administration, in the monkey. Using doses of 1 to 8 mg/kg all dogs were quiet and unwilling to move. i.m. and 2-6 mg/kg p.o., it was noted that One male had vomited. At two to two and the drug produced an initial decrease in one-half hours postinjection, all dogs hostility and increase in salivation follow- were laterally recumbent but alert. At ed by a markedly depressed state with low the fourth hours, they were alert and muscle tone. Respiratory arrest occurred fairly well-coordinated. At the eighth which was reversible by nalorphine or nalox- hours, they had recovered. one. The EEG changes paralleled the behavioral changes. There was a delayed onset The body temperature fell from 98 degrees of action which occurred about 10-12 hours F to 94 degrees F, leveling at two hours after oral administration and lasted 38 and returning to normal after six hours. hours. Drug effects were noticed 40-50 Heart rates decreased from about 65 to minutes after intramuscular injection and 55 and started to return to normal after lasted about 24 hours. six hours. Respiration rose initially due to panting, but became normal after The interaction of LAAM with other drugs was two hours. The males seemed to be more also examined in the monkey (Killam, 1974). affected with respect to changes in tem- These were secobarbital, diazepam, ethanol, perature, respiration and heart rate, amphetamine, and diphenylhydantoin. The whereas the females showed greater degrees effects of amphetamine and secobarbital were of ataxia, vocalization, and shivering. slightly enhanced; those of ethanol and Owing to the small number of animals diazepam were slightly obtunded, and there involved, no firm conclusions about sex were no effects on diphenylhydantoin. differences can be drawn. Inwang et al., (1975) showed that LAAM was Two Mg/Kg Intravenously--Stimulation or qualitatively similar but differed quanti- excitement appeared immediately after drug tatively from methadone in its effect on administration. There was salivation, the rabbit cortex. New Zealand rabbits increased motor activity (circling), uri- which had chronically implanted electrodes in nation, and defecation. Respiration the optic and posterior sensory motor cortex increased but temperature and pulse were treated by intracortical administration decreased. This was followed by prolonged with 0.5 mg/kg and 1.25 mg/kg of LAAM. At hind limb ataxia, decreased motor the lower dose, an initial, facilitatory activity, and a sleep-like state. Respi- effect occurred four minutes postinjection ration was only mildly depressed but body and lasted 52 minutes. The onset of peak temperature dropped from 101.5 degrees F amplitude of the slow negative wave (SNW) to 95 degrees F and returned to normal in was delayed, followed by a depression of the 24 hours. The pulse was low and irregular amplitude of the SNW with no recovery in during the first 24 hours. delay of the SNW. At the higher dose, complete abolition of the SNW occurred without Two Mg/Kg Orally--The beagles which recovery. received 2 mg/kg i.v. also received 2 mg/kg perorally (p.o.) after a suitable Mice were electroshocked with 140 mV of D.C. recovery period. After 30-45 minutes, the by contacting their eyes with electrical dogs licked their lips, panted, and sali- terminals 10 or 20 minutes after intraperi- vated. One male vomited. The males were 20 depressed and were in a state of lateral minutes, reached a maximum in one hour, and recumbency, eyes partly closed and pupils lasted about 12 hours. By the end of the constricted. At one to one and one-half first hour, the animals were sedated and hours, one female was also depressed. showed signs of muscle twitching and shiver- One male could only be aroused by shaking ing. They were alert to external stimuli. and did not respond to audio or visual Rectal temperature fell from 100 degrees F stimuli. At two hours, the other female to 96 degrees F and stayed below normal for was depressed and showed hindquarter eight hours. Two monkeys were anorexic. weakness. By the third to fourth hours, the males dragged their hindquarters and were ataxic. The ataxia in the males lasted for two hours and about four hours in the female. Absorption, Distribution, Excretion, and Metabolism In both the i.v. and p.o. studies, the males seemed to be more affected than the females. The only major difference The first metabolic study on LAAM was carried between the two routes of administration out by Sung and Way in 1954. The compound is that, as expected, the onset of action was determined in tissues by a modification by i.v. injection was more rapid. of Brodie's methyl orange technique. The sensitivity of this procedure is very poor Behavioral effects of LAAM in monkeys were when compared to modern methods. also studied by Henderson (1975). Four naive and one morephine-depent monkey After subcutaneous injection in rats, about received 2 mg/kg (i.v.) H3 -LAAM. Drug 70 percent of the dose (20 mg/kg) was effects were noted within five minutes post- absorbed from the injection site after one injection and lasted about one hour. Eye- hour. About 7 percent was recoverable after lids drooped or closed completely, pupils 13 hours. The rate of disappearance was were dilated, and the frequency of eye much slower after oral administration; about blinking was decreased. Some catalepsy, 80 percent of the dose was recovered from the muscle twitching, and shivering were stomach after one hour and 50 percent of the observed. dose was recovered after 24 hours. There was some experimental evidence adduced to sug- There were little change in respiratory rate. gest that the drug was being secreted into The heart rate decreased slightly in the the stomach, because appreciable amounts of first three hours. The body temperature LAAM were found in the stomach after intra- fell from 100 degrees F to 96 degrees F. venous and subcutaneous administration. The pupils and body temperature returned to normal within four hours. The tissue levels of LAAM in Long-Evans rats were compared after administration of 20 In one morphine-dependent monkey, 2 mg/kg mg/kg of the drug. Except for the gastro- i.v. of LAAM had little effect. Papillary intestinal tract, levels in all other organs size did not change but there was a slight were higher after subcutaneous than oral decrease in heart rate from 150 b.p.m. to administration. The highest concentrations 120 b.p.m. Heart rate was normal in two and were found in the lung. The kidney, spleen, one-half hours. liver, and fat contained appreciable levels, whereas very low levels were present in the One naive male monkey was given 5 mg/kg p.o. heart, blood, and brain. As noted above, of H3 -LAAM. After three and one-half hours high concentrations were found in the stomach he was sedated and cataleptic. After six after oral and even subcutaneous and intra- hours there was marked sedation, shallow venous administration. A large proportion breathing, and a rapid heart rate. He of the drug was accounted for in the carcass expired one hour after drug administration. (chiefly muscle and bone). Tissue levels of The levels of radioactivity were high in the the drug persisted for at least 24 hours. lung and liver but very high in the bile which indicated that biliary excretion was Despite the rapid uptake and high tissue the major pathway of disposal of the drug. levels noticed after parenteral administration, the morphine-like effects did not H3 -LAAN (2 mg/kg p.o.) was given to four become manifest until four-six hours after naive monkeys and one morphine-dependent the injection. The effects lasted as long monkey. In the naive monkey, there was a as 24 hours. Following oral administration, decrease in heart rate and a slight decrease the tissue levels were lower, but the onset in respiratory rate beginning about one hour of action occurred about one hour later. In after drug ingestion which lasted about four view of these results, the authors concluded hours. The pupils began to dilate in 30 that LAAM was being converted to an active 21 metabolite, a process which occurs more hot-plate test for analgesia, the ED50 of rapidly after oral than parenteral LAAM is 3.25 mg/kg with an onset of 135 administration. minutes, a peak effect at 210 minutes, and a duration of greater than six hours. The Very little (less than 3 percent) of the ED90 dose was 21 mg/kg. At this dose the original dose was found in the feces and onset time was reduced to 15 minutes and urine of rats after subcutaneous administra- the peak was 110 minutes, after injection tion. Bile taken continuously from cannu- of the drug into the right thigh. 50 mg/kg lated bile ducts yielded very small amounts of SKF-525A was given 20 minutes before the of LAAM. The low recovery of LAAM supported ED90 dose of LAAM and the mean analgesic the view that the drug was being metabolized. response was recorded as the percentage of the control dose. After the first hour, the Sung and Way found that in mice 40-50 per- SKF-525A treated animals responded at 92 percent of the drug was still present after cent of the controls, after two hours at 12 hours. Appreciable amounts were detected 72 percent, after three hours at 67 percent, after 24 hours, but by 48-72 hours, LAAM was after four hours at 59 percent, and after barely detectable. In rats, the decline in the fifth and sixth hours at about 28 percent tissue levels was more rapid, but the of controls. Thus, it was clear that SKF- pharmacological effects were more sustained. 525A did decrease the analgesic response of LAAM. Veatch, Adler, and Way (1964) studied the effect of prior administration of the metabolic inhibitor SKF-525A. If microsomal McMahon, Culp, and Marshall (1965) succeeded biotransformation is converting LAAM to an in identifying the major metabolites of active metabolite, then SKF-525A ought to dl-alpha-acetylmethadol "sing radio-labeled interfere with the analgesic effectiveness drug. They labeled the N-methyl group and of the drug. In preliminary experiments, the O-acetyl group, using the synthetic they determined that in the Eddy-Leimbach methods shown in the following equations.

Note: The starred carbon atoms in equation (1) and (2) are C14-labeled.

22 The C14-labeled dl-alpha noracetylmethadols were prepared according to equation (3) and (4).

showing that a second N-methyl group was For in vivo studies, 150 g male albino rats coming off. The half-life for the removal of (Harlan Industries) were used. Since this strain was sensitive to the drug, the dose one N-methyl group was about two hours. of dl-alpha-acetylmethadol used was 2.5 mg/ kg. The identity of the metabolites was Orally, the initial rate of N-demethylation secured by the isotope dilution technique. was slower, but after 16 hours, it was When C14 -labeled N-methyl was used, the almost as great as that following intravenous 14 injection. rate and extent of expired C O2 was measured. Urine samples were assayed C14 -acetyl labeled dl-alpha-acetylmethadol directly in a scintillation counter and feces was administered to rats. By following loss were treated by the Schoniger method before of the acetyl label (due to ester hydrolysis) assay. it was found that this occurred to the extent of 30 percent following intravenous The in vitro metabolism of dl-alpha-acetyl- (i.v.) injection. About 15 percent of methadol studied using rat liver homoge- dl-alpha-noracetylmethadol hydrolyzed in the nates. It was found that the drug was deme- first 18 hours. thylated by microsomal N-demethylase to give dl-alpha-noracetylmethadol. The latter was The tissue levels of radioactivity were also a substrate for this enzyme and fur- measured following administration of N-methyl nished dl-alpha-dinoracetylmethadol but at C14 -labeled dl-alpha-acetylmethadol and a considerably slower rate. dl-alpha-noracetylmethadol. Following intravenous injection, peak levels of radioactiv- The N-demethylation was studied in vivo by ity were found in lung, muscle, and brain 14 using N-C CH3 dl-alpha-acetylmethadol and one to five minutes after injection. Peak following the respiration of C14O . On levels in the liver and kidney occurred 14 2 intravenous injection, C O2 formed rapidly. later. Plasma levels were low, tended to In five hours, 50 percent of the dose corre- drop, and then reached a new maximum at sponding to complete removal of one N-methyl about eight hours. Orally, much lower tissue group was recovered in the respired air. Ex- levels were found except for the liver. Peak cretion continued until nearly 80 percent of levels were observed to occur 0.5 to 1.0 14 the administered dose was recovered as C O2 hours postadministration of the drug. 23 At 0.5 hour postinjection, dl-alpha-acetyl- liver, and brain at eight hours following methadol predominates over the nor-analog by intravenous injection. The drug persisted a ratio of 2:1 in lung and liver and 6:1 in in the lung and liver for 24 hours. Radio- the brain. After two hours, the ratios activity was detected for 14 days after decreased and at four hours, dl-alpha-nor- administration, but this long-lasting effect acetylmethadol predominated in the liver and could be due to the fact that some of the 14 14 the radio was about 1:1 in the lung. In the C O2 from the N-C methyl. group was being brain, the isomer ratio shifted from 6:1 to incorporated into the body pool. 2:1 in this period of time. No quantitative studies were carried out because of the low level radioactivity. The radioactivity in the urine and feces foIlowing administration of C14 labeled With NC14 methyl dl-alpha-noracetylmethadol, dl-alpha-noracetylmethadol is shown in unmetabolized drug was found in the lung, Table VIII.

The metabolites from the N-methyl labeled It will be recalled that these authors drug can be either unchanged dl-alpha-nor- looked for unchanged LAAM whereas the acetylmethadol or dl-alpha-normethadol. The material secreted in the bile are metabolites metabolites from the acetyl-labeled drug can of the drug. be unchanged drug, dl-alpha-denoracetylmethadol or a derivative of the latter. Billings, Booher, Smits, Pohland, and Inspection of the column on urinary excre- McMahon (1973) developed a gas-chromato- tion shows that the percentages for N-methyl graphic method for the determination of and adetyl-labeled drug are almost the same. alpha-noracetylmethadol and alpha-dinor- Thus, unchanged drug is the primary excre- acetylmethadol. They formed the trichlor- tion product accompanied by some bisnor- acetyl derivatives of these metabolites. acetylmethadol. However, the differences These were separated on a two-foot silicon- in the fecal excretion patterns are very ized glass colunm containing 3 percent OV 1 on 100-200 mesh Gas Chrom Q at 205 degrees. large. The major product in the feces is 63 dl-alpha-dinoracetylmethadol or some conju- A Ni Ec-detector was used. Under these gate thereof. conditions, alpha-noracetylmethadol had a retention time of 3.4 minutes and alpha- Biliary excretion studies show that the dinoracetylmethadol had a retention time of major metabolic pathway involves retention 2.4 minutes. The identity of the metabolites of the C14 -acetyl group and loss of the was confirmed by mass spectrographic analy- C14 -N-methyl group. About 60 percent of sis. the administered drug is excreted via the bile in 24 hours. These authors determined the tissue levels Thus, the conclusion of Sung and Way that of dl-alpha-noracetylmethadol after i.p. biliary excretion is a minor pathway for the administration. The results are summarized disposition of LAAM requires modification. in Table IX. 24 From these data, it is clear that the tissue was excreted in free form. The metabo- build-up of dl-alpha-noracetylmethadol is a lites were separated on thin-layer chroma- relatively slow process and confirms the tography (TLC) and quantitated. A suspicions voiced by Sung and Way (1954) summary of the findings is given in about twenty years earlier. Table X.

Gary Henderson (1975b) is studying the metabolism and pharmacokinetics of LAAM in Preliminary experiments showed that the rats, dogs, and monkeys. These studies are recovery of l-alpha-acetylmethadol (LAAM not yet complete. The current Status of was 91 percent, l-alpha-noracetylmethadol this work is reviewed below. (N-LAAM) was 91 percent, alpha-methadol (MOL) was about 88 percent, nor-alpha- Rats (Excretion Patterns)--Four male methadol (N-MOL) was 90 percent, and Sprague-Dawley rats weighing between 204 l-alpha-dinoracetylmethadol (DN-LAAM) was and 273 g were given 2 mg/kg of H3 -LAAM 96 percent. The pH had to be kept at 9.5 orally. The rats were constipated for because at pH 13 acetyl migration about 12 hours. About 8 percent of the occurred rapidly. radioactivity was recovered from the urine in 96 hours and about 85 percent was It is clear that N-LAAM and DN-LAAM were found in the feces. Most of the urinary the major metabolites excreted in radioactivity was excreted in the first unbound form and that most of the urinary 48 hours and little (about 16 percent) metabolites were excreted as conjugates.

25 Higher doses of LAAM were also studied. feces. The females excreted 13.55 per- Two male and four female Sprague-Dawley cent in the urine and 59.86 percent in rats weighting between 212 and 371 g were the feces. given 5 mg/kg of H3 -LAAM by gavage. Food was supplied ad lib and urine and Rats (Tissue Distribution)--Four of the feces were collected every 24 hours up male rats which received 2 mg/kc H3 -LAAM through 96 hours. At this dose, the p.o. were sacrificed after 96 hours and males exhibited hematuria. At the end of selected tissues were assayed for radio- 96 hours, the males had excreted 6.66 activity. No attempt was made to iden- percent of the administered radioactivity tify the compounds in the tissues. The in the urine and 87.32 percent in the results are summerized in Table XI.

In contrast to Sung and Way’s results metabolites were DN-LAAM and N-acetyl-N- (1954), very little material was found in MOL. Following enzymic hydrolysis, the stomach. This discrepancy can be N-acetyl-N-MOL and DN-LAAM proved to be explained by the difference in time the major metabolites. In addition, interval between the initial medication LAAM, N-LAAM, MOL, and N-MOL were detect- and the subsequent sacrificing. In ed. It is difficult to see what sort of Henderson’s case, the sacrificing took conjugate LAAM itself can form. place much later than the original dosing. Despite the fact that tissues The experiment was repeated with a modi- were examined 96 hours post-dosing, it is fication which consisted of medication interesting to note that the only organ inmediately after the animals recovered which contained more than trace amounts from the surgery. The rats were given 5 of LAAM and/or its metabolites was the mg/kg of H3 -LAAM p.o. Bile was col- liver. lected every 30-60 minutes up to 96 hours. This experiment is incomplete; however, Kinetics of H3 -LAAM Elimination In Rat initial results have been reported and Bile--In the initial experiments, the are summarized below. interval between cannulation and dosing was so long that several rats were too Biliary excretion appears to follow zero- sick to be used. The remaining animals order kinetics until 72-96 hours when it were used to determine the nature of the then apparently follows first-order biliary excretion patterns. Free meta- kinetics. In two male rats, 80-85 per- bolites were determined and then the cent of the administered radioactivity remaining bile was treated with -gluc- was recovered from the bile after 96 uronidase (Sigma) to deconjugate the hours. The radioactivity appears in the water-soluble fraction. Hydrolysis was bile five minutes after dosing and less incomplete even after 36 hours incubation than 10 percent of the dose appears in at pH 5.0 at 37 degrees. Thirty percent the feces of bile-cannulated rats. Thus, of the radioactivity was excreted in the greater than 90 percent of LAAM is bile as unbound drug and metabolites. Of absorbed by the oral route. After 96 the remaining 70 percent, about 81 per- hours, about 96 percent of the adminis- cent underwent deconjugation. After tered radioactivity is eliminated in the six hours the bile contained detectable male rats and about 74 percent in the levels of free LAAM, N-LAAM, DN-LAAM, females. The nature and abundance of MOL, and N-acetyl-N-Mol. The major LAAM and its metabolites was the same as 26 in the previous experiment. In rat urine accounted for in the urine and feces after DN-LAAM was the major metabolite followed 96 hours. After 2 mg/kg i.v., 89 percent by N-LAAM, LAAM, and MOL. was accounted for in this time period. Urinary excretion peaked in the first 24 Dogs (Blood Levels)--Blood levels peaked hours, whereas in the feces, peak excre- in 30 seconds following a dose of 2 mg/kg tion occurred at 24-48 hours. After 2 i.v. and about the same time after 1 mg/kg p.o., 81 percent of the dose was mg/kg i.v. The levels drowned in 15 excreted in 96 hours by the males and minutes and were negligible after 96 somewhat less by the females. hours. After 2 mg/kg p.o., blood levels peaked one hour postadministration. The urinary recovery of LAAM and its Dogs (Excretion)--In dogs given 1 mg/kg metabolites after 2 mg/kg p.o. is shown i.v., 79 percent of the radioactivity was in Table XII.

Monkeys (Blood Levels)--After some pre- The blood levels of radioactivity appear- liminary dosing, four naive and one mor- ed in 30 minutes, peaked four to eight phine-dependent monkey were given 2 mg/kg hours after drug administration, and were (i.v.) of H3 -LAAM. These same animals still detectable after 96 hours. were used for the oral studies. The highest level of radioactivity was noted one minute after injection. This cor- responded to a blood level of LAAM equal to 0.47 ug/ml. There was a rapid Monkeys (Excretion)--The urines of three decrease in 15 minutes followed by a new female monkeys which were given 2 mg/kg peak one hour after injection which cor- of H3 -LAAM i.v. were examined. A total responded to a drug blood level of 0.35 of 21.55 percent of the radioactivitv ug/ml. This was followed by a steady was excreted over a 96-hour period. O f decline in radioactivity which was neg- this, 19.11 percent was in the conjugated ligible after 72 hours. form, and 2.44 percent was free. The distribution of the radioactivity is H3 -LAAM (2 mg/kg p.o.) was given to four summarized in Table XIII. The morphine- naive monkeys and one morphine-dependent dependent monkeys excreted 13.7 percent monkey. of the radioactivity in 96 hours.

27 Approximately 20 percent or less of the A better recovery of the drug was noted admininistered dose is excreted in the when 2 mg/kg p.o. was given in an apple urine of rat, dog, and monkey. Of this rather than by stomach tube. About 92 amount, most is excreted as conjugates percent of the radioactivity could be rather than free drug or metabolites. accounted for in 96 hours. Most of this In the male monkey, about 65 percent of was in the feces. The distribution of the drug is excreted in the feces and H3 -LAAM and its metabolites in monkey about 55 percent for the female. urine is summarized in Table XIV.

As usual, the amount of free LAAM and its metabolites in the urine was very low. The bulk of the metabolites were excreted as conjugates. Sullivan, Due, and McMahon (1973) reported The bile had only one major component which some preliminary results on the metabolism appeared to be a conjugate of 1-alpha-6-acet- of a l-alpha-methadol. They used the 2-C14 amido-4, 4-diphenyl-3-heptanol. These labeled derivative having a specific activity results suggest that the major biliary excre- of 14.1 µCi/mg. Bile-cannulated Wistar rats tion product of LAAM itself may be a conju- were given 40 mg/kg s.c. and the urine and gate of 1-alpha-6-acetamido-4, 4-diphenyl-3- bile were collected for 24 hours. Unconju- heptyl acetate. However, Henderson (1975b) gated drug and metabolites were extracted found that DN-LAAM readily undergoes OtN with butyl chloride at pH 9.5. The pH of acetyl migration so that the actual metabo- the body fluids was adjusted to 3.5 and the lite my be DN-LAAM rather than the N-acetyl materials were incubated with gluselase to derivative. deconjugate metabolites and these were then taken up in butyl chloride. Kochhar (1975) isolated and identified After 24 hours, 10 percent of the adminis- metabolites of LAAM after incubation of the tered radioactivity was found in the urine drug with a microsomal supernatant fraction and 36 percent was found in the bile. The obtained from liver homogenates of Sprague- following were identified in the urine: Dawley rats and also from the urine of rats which were given the drug intraperitoneally. Unaltered 1-alpha-methadol He identified methadol (MOL), nonnethadol 1-alpha-nonethadol (N-MOL) (N-MOL) 2-ethyl, 1, 5-dimethyl-3, 3-diphe- 1-alpha-bisnormethadol (DN-MOL) nylpyrroline, noracetylmethadol (N-LAAM), and l-alpha-6-acetamido-4,4-diphenyl-3- dinoracetylmethadol (DN-LAAM). The pyrroline heptanol may be an artifact derived from DN-LAAM.

AUTHOR Sydney Archer, Ph.D., is Research Professor of Medicinal Chemistry, Chemistry Department, Rensselaer Polytechnic Institute, Troy, N.Y., 12181. 28 TOXICOLOGY OF LAAM

Ms. Ann Wolven and Sydney Archer, Ph.D.

INTRODUCTION Before a new drug can be tested in humans, aging, the effects of the drug, or both. pre-clinical toxicity studies must be carried out to demonstrate that there will not be an The Food and Drug Administration (FDA) guide- unreasonable hazard to subjects to whom the lines suggest that at least one rodent and drug will be administered. Acute and chronic one non-rodent species undergo toxicity tests. toxicity studies can also demonstrate whether In this case, rats and beagle dogs were util- the observed toxic effects are such as to ized. Fats are often used in toxicity stud- preclude administration of the drug to man ies for their test convenience and in addition and also to alert the clinician to those because of their metabolic closeness to humans. effects which would require particular atten- Rabbits and rats are used in reproduction tion. For these reasons the doses which are studies because of their reproductive capacity used in toxicity studies are selected so that and because of their sensitivity to terato- some toxic effects will be produced. genic agents. Toxicity studies are so designed that informa- For these chronic toxicity studies, animals tion will be obtained about the relationship of a given species were divided into four of toxic to effective doses. It must be kept groups: a control group, and low, medium and in mind that such studies are not directly high dosage groups. Hematological and clini- translatable to presumed effects in humans. cal chemistry evaluations on the four groups The doses used in animals are much higher than were done periodically: e.g.,13 weeks, 26 weeks, the expected clinical dose. The life spans of 52 weeks, 79 weeks. At the end of each man and the test animals are not comparable so period, some portion of each group was sacri- that an 18 month chronic study in rats means ficed for gross and microscopic pathologic that the drug is administered for at least examination to determine possible effects of half the life span of that species. There is the drug. Postmortem examinations were also usually a rapid increase in rodent mortality performed on animals which died during the after 12 months so that deaths that occur in experiment. the second year of medication may be due to

29 An additional complication occurs when the CHRONIC TOXICITY STUDIES test drug is one in which drug tolerance occurs. In such a case tolerance is induced in One Year Chronic Oral Toxicity the medium and high dosage groups by gradually in Rats (Edgewood Arsenal) increasing the dosage to the predetermined medim and high dosage level, in order to reach In this study Sprague-Dawley albino rats were truly toxic levels while avoiding lethal depres- used. The drug was administered by gavage at sant reactions that would occur if such doses dose levels of 5.0, 10.0 and 15.0 mg/kg five were given to naive animals. days a week for 52 weeks. No induction schedule was employed. After the first 10 weeks The initial chronic toxicity study on LAAM was all the rats that died during that time period carried out for one year in rats and dogs at were replaced by fresh rats in order to have Edgewood Arsenal. Because LAAM was adminis- a sufficient number of animals for terminal tered for 5 days per week, further studies sacrifice and pathological examination. The were carried out by Industrial Biotest wherein mortality data is summarized in Table 1. the drug was given daily to the test animals Several rats that died after the first dose of for a longer period of time. LAAM were found to have intracellular calcification in the heart, liver and kidney. This ACUTE ORAL TOXICITY OF LAAM phenomenon was not observed in any of the IN RATS (Industrial Biotest) animals which died later or in any of the rats in the replacement groups. This effect was The acute oral toxicity of LAAM was determined not observed in a later Industrial Biotest study. in naive albino Charles River male and female A special study was carried out in an addi- rats. The LD50 of LAAM in the males was 28.6 tional group of rats to assess the signifi- mg/kg and in the females it was 35.0 mg/kg. cance of the intracellular calcification of The acute toxicity was determined in tolerant the heart, liver and kidney observed in the rats also. Rats were made tolerant by start- rats dying after the first dose of LAAM in the ing with a 2.0 mg/kg dose which was increased original study. To this end 75 rats were at two-week intervals until they were receiv- given 15.0 mg/kg of the drug for 5 days and at ing 12.0 mg/kg/day. This dose level was main- the end of that time were sacrificed and exam- tained for a 13 week period of medication and ined. None of the animals in this group then the LD50 values were determined. The showed signs of calcification in the previous- LD50 in males was 93.0 mg/kg and in females ly affected organs. As a result it was con- it was 220.0 mg/kg. Thus prior exposure to cluded that this phenomenon which was noted the drug had a considerable effect on the once was not drug related. acute toxicity of LAAM.

TABLE 1

Mortality of Rats Medicated With LAAM 5 days/week

Original Group Dose Levels Control 5.0 mg/kg 10.0 mg/kg 15.0 mg/kg # deaths/treated 4/80 3/40 17/40 52/80 Week of last death 36 4 39 47

Replacement Group

# deaths at 2 days/treated 0/12 0/24 14/74 # deaths at 38 weeks/treated 0/3 4/12 6/33 TOTAL 0/12 4/24 21/74 30 All of the test animals on the chronic tox- became tolerant to and dependent on the drug, icity study were observed for behavioral re- because when medication was omitted over the actions and general physical appearance after weekend the animals showed withdrawal signs. each daily dosing and prior to the next dos- The most prominent such sign in dependent ing. Body weights, food and water consump- rats upon abrupt withdrawal of an opiate-like tian and several clinical parameters, includ- drug is a rapid loss in body weight. Usually ing hematology and blood chemistry were this body weight loss can be reversed by measured at specific intervals. A special renewed administration of the drug. study was carried out to determine the effect of hepatic N-demethylase on LAAM in vitro. One Year Chronic Oral Toxicity- In the latter study it was noted that like in Dogs (Edgewood Arsenal) meperidine and 1,1-dimethylhydrazine, the two positive controls used in the experiment, Beagle dogs were medicated by capsule 5 days hepatic microsomes did demethylate LAAM as a week for 52 weeks at dose levels of 2.0, evidenced by the production of formaldehyde 6.0 and 11.0 mg/kg. Dosing was started at in the incubation media. 2.0 mg/kg in all test groups and was then gradually raised in the medium and high level Food and water consumption in all three groups groups until by the end of the sixth week the on LAAM was decreased when compared to the desired dose levels were achieved. Fourteen control rats but only the decreased food con- dogs served as controls. There were 12 dogs sumption was felt to be dose related. Bloody at the low and medium levels and 14 at the eyes, and analgesia, as evidenced by a high dose. decreased response to pinching of the tail, were observed during the first two weeks of All of the test animals were examined daily dosing. After that time sensitivity to tail for clinical signs of systemic toxicity. Body pinching appeared to increase. Piloerection, weights, food consumption and clinical para- exophthalmos and the Straub tail phenomenon meters including hematology and blood chemistry were present during the entire period of medi- were measured at specific intervals during the cation. Hematological and blood chemistry course of the medication. Complete physical values were all within normal limits for both examinations were performed monthly including the test and control groups, with the excep- electrocardiograms and ophthalmologic exams. tion of plasma lactic dehydrogenase (LDH) which was higher in the 10.0 mg/kg and 15.0 Body weight, food and water consumption decrea- mg/kg groups than in the controls at both the sed for all three test groups. Behavioral re- 6 month period of sacrifice and at the end of actions were observed at all dose levels and the year. After 12 months the LDH values consisted of depression, hind limb weakness, were: 1072 (controls), 1688 (10.0 mg/kg) and emesis, salivation and prostration. The fre- 1833 (15.0 mg/kg). quency and intensity of some of these signs decreased as the study progressed. Three dogs Gross examination of tissues at necropsy and died at the high dose level, none at lower levels. organ weights showed that with one exception Hematology and blood chemistry values in the there were no significant differences between test groups were comparable to those of the the treated and control groups. Only the controls. Physical examination revealed the liver/body weight ratios in the female rats presence of tachycardia, slower reflexes and at all doses were higher than the controls decreased respiration rates but these did after completion of medication. Histopatha- not appear to be dose related. The medicated logical examination of the tissues failed to dogs had rough coats, appeared to be thin and reveal any incidence of dose related lesions. presented a generally unkempt appearance as The most frequent finding was inflammation or if they did not do any grooming. Electro- congestion of the respiratory tract. cardiogram (EKG) recordings taken immediately after dosing showed an increase in duration During the first two weeks of exposure to of the S-T segment usually accompanied by LAAM there was little if any gain in weight bradycardia. Seventy-two hours after dosing by the medicated rats. During the course of the EKG tracings were normal. Reversibility the study the rate of gain in weight in the can be determined since the dogs were not treated groups was greatly retarded and ap- medicated on the weekend. Other than a large peared to be dose related. After the first absolute liver weight in the high dose dogs two weeks the dosed rats began to show a when compared to controls, no other signifi- weekly cyclic patter” of a large increase in cant differences in organ weights were appar- body weight on the first two or three days of ant. Histopathological examination of tissues the week followed by a loss in weight during disclosed no drug related abnormalities. This the remainder of the week. It is believed was true also for the three dogs which died that this pattern was related to the fact that spontaneously during the course of the medi- after the first weeks of medication the rats cations.

31 tion period all values were in the normal 79-Week Chronic Oral Toxicity range. Blood chemistry values were essen- in Rats (Industrial Biotest) tially normal for the test animals except for some scattered slightly elevated serum Charles River albino rats were used in this alkaline phosphatase (SAP) readings in medi- study. The final doses used were 2.0, 6.0 cated males. The females were comparable to and 12.0 mg/kg administered daily by gavage untreated controls. The serum glutamic- throughtout the 79 week period of medication. pyruvic transaminase (SGPT) values were essen- The dose schedule is shown in Table 2. tially normal but the serum glutamic-oxalo- acetic transaminase (SCOT) values were slightly The middle group (T-11) did not reach the 6.0 elevated in the high dose male and female rats. mg/kg daily dose until the 9th week and the The albmin/globulin ratios of both male and high dose (12.0 mg/kg) was not reached until female animals in the 6.0 and 12.0 mg/kg the 21st week. groups showed a moderate decrease at 52 and 78 weeks. All test females showed a moderate All of the test animals were examined daily decrease at 52 and 78 weeks. All test females for behavioral reactions and general physical showed a moderate increase in total protein at appearance including tumor palpation. Body week 52 but this parameter normalized by the weights, food consumption and clinical param- 78th week. The remaining blood chemistry aters were determined at specific intervals. studies were normal.

TABLE 2

Schedule for Administration of LAAM

Group No. of Animals Dose Level mg/kg/day Male Female Week: 1-4 5-8 9-12 13-16 17-20 21-79 Control 110 110 0 0 0 0 0 0 T-I 110 110 2 2 2 2 2 2 T-II 110 110 2 4 6 6 6 6 T-III 110 110 2 4 6 8 10 12 The Body weight gain of all test animals was The rat mortalities which occurred in this reduced significantly with the males showing study are shown in Table 3 Also included a greater initial reduction, but at the end are the animals which were deliberately sacri- of the 79th week body weight gain depressions ficed at 13, 26 and 52 weeks. There was an for both sexes were about the same. During the excessive mortality rate in the control ani- period of recovery the surviving animals at mals between weeks 23 and 26. Mortality in the 6.0 and 12.0 mg/kg dose levels exhibited all test groups at the end of week 52 was body weight gains comparable to the controls. moderate, but increased markedly from week The test females consumed less food during 52 to week 79. Mortality was high in the the first 27 weeks of the medication period control group throughout the test period. In but thereafter their food consumption was the both control and treated groups mortality was same as the controls. higher in the male rats. The vast majority (if not all) of the deaths was attributed to Observations for phammcological and behavior- naturally occurring disease characterized by al reactions during the 79-week treatment bronchoneumonia associated with metastatic period showed that the rats displayed hyper- infections and polyserositis. None of the irritability and hyperactivity gradually deaths was attributed to the medication but shifting to hypoactivity. The males in all mortality did appear to be related to the test groups showed greater hyperirritability length of exposure to LAAM. than the females. Alopecia and excretion of loosely formed stools were noted in the medicated groups. Hematological parameters for the test and control animals were comparable There was a significant reduction of absolute except for slight varlatlons in total leuko- organ weights of the livers of the 6.0 mg/kg male rats and of the kidneys of the 6.0 mg/kg cyte and erythrocyte counts in all groups of test animals. At the end of the medica- and 12.0 mg/kg tiles but the organ to body 32 TABLE 3

Rat Mortality in the 79-Week Study Dose Level Sex Treatment Time Period (wks) Total Mortality mg/kg Accumulated Deaths Recovery Number Tested 0-52 53-79 80-87 Control M 37 54 4 58/110 F 18 34 5 39/110 2.0 M 24 69 2 71/110 F 10 31 3 34/110 6.0 M 16 73 3 76/110 F 14 35 0 35/110 12.0 M 35 78 0 78/110 F 27 54 2 56/110

and organ to brain weight ratios were normal 52-Week Chronic Oral Toxicity and in most instances comparable to the con- in Dogs (Industrial Biotest) trols. Histopathological changes in the tissue, except for the liver, were judged to LAAM was administered orally, via gelatin be caused by spontaneous disease and were not capsule at final dose levels of 2.0, 4.0 and unusual for the strain and age of the rats. 8.0 mg/kg seven days a week for one year A fourth group served as controls. The medi- Treatment related changes were observed in cation schedule is shown in Table 4. the livers of most of the test animals at all dose levels of LAAM. These changes were characterized by hypertrophy of hepatocytes due An initial dose of 4.0 mg/kg produced severe primarily to an increase in cytoplasmic mass. reactions, particularly sedation. Gradually The relative extent of the changes could be increasing the dose from 0.5 mg/kg to 4.0 correlated with the dose of the drug and dur- ng/kg over a twelve week period resulted in ation of treatment. These changes were con- the production of only slight reactions to sidered to be an adaptive response of the the drug, i.e. tolerance developed. Increased hepatocytes to the metabolism of LAAM. A tolerance to the drug developed at all dose separate study demonstrated that there was an levels. Only one high (8.0 mg/kg) and one increase of microsomal enzyme activity in low (2.0 mg/kg) dose level male died at 26 rats receiving LAAM. (A similar observation and 49 weeks respectively. Neither death was was made in the Edgewood Arsenal study). considered to be drug related. During the recovery period surviving rats were sacrificed the first and second months All of the test animals were examined daily after cessation of medication. Marked but not for clinical signs of systemic toxicity, par- complete regression of the hepatocyte hyper- ticularly after dosing. Body weight, food trophy was noted. consuption and clinical parameters were measured at specific intervals during the med- The remaining organ changes observed at each ication period. Opthalmological examinations sacrifice interval were judged to be related and EKG recordings were made. to naturally occurring diseases or associated with the age of the animals at autopsy. These Food consumption during the first six months changes were present in the control as well was similar for both treated and control as medicated groups, The types of tumors groups. In the latter half of the study there present in all groups were not unusual was a noticeable increase in food intake in for a random population of the strain the treated groups which was not reflected in of rats used and there were no significant a corresponding increase in body weight. When differences in numbers between test and con- the dogs became tolerant to LAAM their weights trol groups. were comparable to that of the controls. 33 TABLE 4

Medication Schedule For LAAM in Dogs

Group Dose Weeks (mg/kg/day) at dose level T-I 0.5 1-4 1.0 5-20 2.0 21-52 T-II 0.5 1-4 1.0 5-8 2.0 9-12 4.0 13-52

T-III 0.5 l-4 1.0 5-8 2.0 9-12 4.0 13-16 6.0 17-20 8.0 21-52

REPRODUCTIVE STUDIES WITH LAAM Behavioral reactions were observed in the ani- (Industrial Biotest) mals at the 4.0 and 8.0 mg/kg doses. These consisted of salivation, hyperactivity, vomit- Teratogenic Studies ing and sedation. Increased tolerance to the drug occurred at all dose levels. The hemat- 1. Non-tolerant Rabbits ological parameters remained normal throughout the study. The only change in blood chemistry LAAM was administered orally via gelatin cap- was a slight elevation of the serum alkaline sules to non-tolerant, pregnant, New Zealand phosphatase (SAP) levels at the 4.0 mg/kg and rabbits at doses of 0.2, 0.6 and 2.0 mg/kg 8.0 mg/kg dose levels. These returned to from day 6 through day 18 of gestation. A normal during the 4 week recovery period. slight weight loss occurred during the treatment period but it was comparable to the un- Electrocardiogram tracings during the early treated and thalidomide-treated control groups. stages of the study showed some T-wave and S-T No deaths or unusual reactions occurred. All changes, some tachycardia at the 4.0 mg/kg dams were sacrificed on day 29 of the gesta- dose level. At 8.0 mg/kg QRS complex irregu- tion period. Fetal examination revealed no larities were observed and significant S-T external, internal or skeletal teratogenic and T wave changes as well as significant rate abnormalities among the fetuses of the LAAM- and rhythm disturbances were noted. These treated rabbits and untreated controls. The changes were present on later tracings but no thalidomide controls yielded the expected anom- further deterioration occurred. The tracings alies. The numbers of resorption sites and live made during the 4-week recovery period were young per 100 implantation sites was similar considered to be within normal limits. Histo- for LAAM and unmedicated controls. Body weights pathological examination of cardiac tissue at of fetuses from treated and untreated dams necropsy showed no significant abnormalities. were comparable also. Gross and histopathological examination of other organs and organ weights disclosed no 2. Tolerant Rabbits significant differences between treated and Rabbits were made tolerant to LAAM by adminis- control groups. tering the drug over a twelve week period 34 starting with 2.0 mg/kg/day and incrementally Reproduction and Progeny Cross-over Studies increasing the dose until the desired levels in Tolerant Rats were reached. Then doses of 6.0, 8.0 and 10.0 mg/kg/day of LAAM were given to three Using the same dosing schedule described in groups of tolerant animals from day 6 to day Section A-3 above it was noted that body 18 of gestation. A decrease in body weight weight reductions and hyperirritability occur was noted at the two higher dose levels and red in a dose related manner in both sexes. some non-dose related deaths occurred. It Mating experiments showed that there was no is concluded that pre-natal exposure to LAAM difference in reproductive performance among did not alter fetal skeletal development as treated animals as compared to controls. compared to unmedicated controls. The number of implantation sites, resorption sites and Female rats exposed to LAAM showed an increas- live young were not adversely affected by ed number of stillbirths. Following delivery LAAM. litters from drug treated rats were exchanged for litters from control rats and the progeny 3. Tolerant Rats remained with the foster mothers tnrougnout the lactation period. Concurrent groups of Rats were made tolerant to LAAM by gradually progeny delivered by treated and control rats escalating the doses from 2 mg/kg/day to 12.0 were retained by their natural mothers. Sur- mg/kg/day over a period of 90 days. The dose vival of each group of progeny exposed to levels of LAAM were 2.0, 6.0 and 12.0 mg/kg/ LAAM was reduced during lactation. Progeny day administered to day 20 of gestation. The fostered by LAAN-treated rats did not exhibit drug had no effect on the numbers of corpora as great a reduction in survival as those lutea, implantation sites, resorption sites pups; exposed to the drug in utero and then and viable fetuses. There was no effect on fostered by non-treated rats or those deliv- external and internal development but there ered and retained by LAAM-treated mothers. was an increased incidence of angulated ribs among fetuses obtained from dams exposed to The body weights of progeny exposed to LAAM 6.0 and 12.0 mg/kg/day. No other skeletal in utero and then fostered by unmedicated abnormalities were found. mothers were similar to drug-free controls. Those not exposed in utero but fostered by Perinatal and Lactation Performance treated mothers showed reductions in body in Albino Rats weight. Progeny delivered and retained by drug-treated rats showed body weight reductions only on day 1 and 4 of lactation. By 0.06, 0.20 and 0.60 mp/kg to non-tolerant day 12 of lactation only 1 litter was viable pregnant rats from day 15 of gestation and at weaning these 4 pups displayed weights throughout the period of lactation. A total equal to that of the untreated controls. of 28 or 29 doses were used. All dams were allowed to deliver their litters and carry DISCUSSION: them through weaning. In the cross-over portion of the study litters from the 0.6 mg/kg/ Methadone and LAAM were developed in the day test group were exchanged with a control 1940’s as analgesics. Although acute toxico- group with both dams carrying their litters logical studies had been performed, relatively through weaning. little animal toxicological data is available on subacute or chronic toxicity in the toler- In the first phase of this study no deaths ant animal. Therefore, these current studies occurred and no unusual behavior was observed. were performed because the drugs are now be- Only the dams at the 0.60 mg/kd/day dose showing utilized or proposed for long term, high ed a reduction in body weight from day 15 of dose maintenance in man. Because LAAM is gestation through day 4 of lactation. This being developed as an alternative to metha- dose group retained fewer pups than the con- done, it is appropriate to compare the toxic- trols but the difference did not appear to be ological effects of both drugs in the same statistically significant. The high dose species. group did show a statistically significant reduction in survival of the pups and re- Only one previous study reported toxicologic- duction in body weight as lactation progressed. al data for LAAM. (A.S. Keats and N.K. Beacher, During the cross-over study both groups of Analgesic activity-and toxic effects of acetyl- dams exhibited a reduction in the number of methadol isomers in man, Journal of Pharma- pups surviving to weaning. The groups of pups cology and Experimental Therapeutics, 105:210- exposed to LAAM in utero and reared by control 215. 1952). The authors report that Merck and dams revealed slightly meduced body weights Company studies found that racemic-levo- and through day 21. Pups untreated in utero but dextro-forms of acetylmethadol have a subcu- reared by treated dams also showed slightly taneous LD50 in mice of about 40 mg/kg. The reduced body weights. levo- form exhibited delayed onset of toxicity. 35 In comparison, the subcutaneous LD50 of race- the dosage regimen may have influenced the mic methadone (the form used clinically) in toxicity findings, and in view of the non- mice is 33-48 mg/kg. (National Research reproducible organ calcifications which appear- Council Handbook of Toxicology, 1956, pp. ed after the initial dosing in rats, it was 186-187). Although previous data is not avail- considered advisable to perform other chronic able for LAAM in other animals or by other toxicity studies, using a seven day dosage routes of administration, several studies have regimen. been performed for methadone. In the mouse, the following LD50’s have been noted: oral 93.8 mg/kg, i.v., 17.3-9 mg/kg. In the rat, A Toxicity panel consisting of outside con- the following LD50’s are reported: oral 90-95 mg/kg, subcutaneous, 45-48 mg/kg, and sultants was constituted to act as advisors to intravenous 9.2-14.6 mg /kg In the monkey NIDA, review data and generally oversee the subcutaneous LD50 of 10-20 mg/kg was reported progress of the new chronic toxicity studies No studies previously reported evaluated the of LAAM and methadone, run simultaneously in LD50 or chronic toxicity for methadone or LAAM the same laboratory (Industrial Bio-Test). in animals dosed chronically. In the studies supported by NIDA, Industrial Biotest carried out similar studies using similar protocols An 80-week chronic toxicity study in rats was in the same laboratory simultaneously with carried out using gradually increasing doses methadone and LAAM. These studies utilized of methadone to reach the final doses of 5, the oral route of administration which is used 10 and 15 mg/kg/day of methadone, 7 days a clinically in man. week. The protocol and design of the study resembled the LAAM experiment. The mortality ata for methadone is summarized in Table 5. The LD50 of methadone in non-tolerant male rats was 94.0 mg/kg and 102-0 mg/kg in females. The corresponding values for LAAM were 28.6 mg/kg for males and 35.0 mg/kg for females. In The above mortality also includes animals tolerant male rats the methadone LD50 was 102 which were deliberately sacrificed and thus mg/kg in males and 114 mg/kg for females. The is comparable with Table 3. The dosages in LAAM values in tolerant rats were 93.0 mg/kg both protocols are approximately the same, for males and 220.0 mg/kg for females. there was a greater mortality in males in both studies and a great number of animals died In the case of methadone there was no sex after the first year of treatment. In both difference in toxicity in either naive or tol- studies a large number of animals died and the erant rats nor were there significant differ- cause of death for LAAM, methadone and control ences between naive and tolerant rats. In the animals was attributed to naturally occurring case of LAAM there was a slight difference be- respiratory infections and are not drug tween sexes in the non-tolerant animals but a related. much larger difference in the tolerant ones. Of even greater interest is the fact that tol- On the basis of mortality figures alone, in erant animals of both sexes were less sensi- tolerant rats LAAM does not appear to be more tive to the acute toxic effects of LAAM given toxic than methadone. In both studies the orally than naive rats, whereas no such dif- drugs were administered daily whereas it is ference occurred with methadone. An explana- anticipated that in man LAAM will be given tion for this finding requires further study. three times a week with an average weekly intake of 180 to 240 mg. The average weekly Although LAAM and methadone are structurally intake of methadone is about 350 mg. similar there are major differences in their metabolism and pharmacokinetic behavior. The Hepatic changes were noted in both the LAAM major metabolites of LAAM are two N-demethyl- and methadone studies. Separate experiments ated derivatives, nor-LAAM and bisnor-LAAM showed that administration of either drug which persist in the animal for long periods induced an increase in N-demethylase activity. of time and are almost certainly responsible Such a phenomenon is commonly encountered on for the long duration of the pharmacological chronic administration of many drugs such as effects of LAAM. In contrast the metabolic phenobarbital and diazepam which are subject products of methadone do not persist and prob- to hepatic metabolism. In the case of metha- ably contribute little to its pharmacological done hepatic changes reverted to normal with- action. in one month of cessation of treatment. Recovery was not complete two months after In the Edgewood Arsenal rat and dog chronic LAAM treatment was stopped, but definite toxicity studies, the animals were medicated signs of normalization were apparent. The for five rather than seven days a week and the difference in metabolic behavior of the two duration of each study was 52 weeks. Because drugs may account for this difference. 36 TABLE 5

Frequency and Distribution of Deaths in Rats Treated With Methadone Group Sex Accumulated Deaths Total Mortality and Dose Level in Treatment Period Total Treated 52 weeks 80 weeks Recovery Control M 33 62 6 68/110 F 12 29 5 34/110

5 mg/kg/day M 39 65 4 69/110 F 15 37 1 38/110 10 mg/kg/day M 37 68 2 70/110 F 15 30 5 35/110 15 mg/kg/day M 58 77 1 78/110 F 48 JO 0 70/110

Changes in the electrocardiogrm tracings of In the studies with tolerant rats the drug dogs on the middle and high dose levels of treated group evidenced an increased number LAAM were noted in the Edgewood Arsenal and of stillbirths, a decrease in progeny during Industrial Bio-Test Studies. Owing to the lactation, and lower body weight of the pro- medication schedule in the former study the geny, although the weights were within the reversibility of these changes could be ob- normal range. The cross-over studies indi- served. This could not be seen in the latter cated that in utero exposure to LAAM was the study, but four weeks after medication the main cause for the decreased progeny survival. EKG tracings in the Industrial Bio-Test These findings would appear to be consistent experiment were essentially normal. Histo- with the effects of large, repeated doses of pathological examination of cardiac tissue a narcotic drug, resulting in fetal LAAM ex- revealed no drug related abnormalities. How- posure and neonatal dependence via placental ever. in view of these findings careful atten- transer. The decrease in progeny survival tion was paid to the possibility of cardio- could be related to narcotic withdrawal dur- toxic effects of LAAM in the Phase I and ing the neonatal period. The increase in Phase II clinical trials. No evidence of number of stillbirths was also found in sin- cardiotoxicity in man has been found to date. ilar studies with methadone. The decrease in progeny survival and lowered birth weight is consistent with clinical observations for infants born to heroin and methadone Teratogenic studies were carried out in dependent women. naive and tolerant rabbits and in tolerant rats. The highest dose used in naive rabbits was 2.0 mg/kg/day but it was possible to go On the basis of the toxicological studies to 10 mg/kg/day in tolerant rabbits. In both carried out thus far it can be concluded that experiments no embryotoxic or teratogenic eff- when the human dose regimens are taken into fects were observed. In tolerant rats the account the toxicity of LAAM and methadone only abnormality noted was an increased inci- are comparable in tolerant animals. The dence of angulated ribs at the middle and hepatic changes that were found are in all high dose levels. probability an adaptive response of the hepatocytes to the metabolism of both drugs. Reproduction, perinatal and lactation performance studies with progeny cross-over were The major difference between the two drugs is carried out in LAAM nontolerant and tolerant the greater sensitivity of non-tolerant ani- rats. The effects seen in the nontolerant mals to the toxicological and pharmacological animals were similar to but of lesser magni- effects of LAAM by the oral route. The dif- tude than those observed in the tolerant ference should be kept in mind when LAAM is rats. to be administered to humans. 37 REFERENCES AUTHORS

Farrand, R. L., McNamara, B.P., Christensen, Ms. Ann Wolven is associated with the Shell M.K., Toxicological Testing of l-Alpha- Chemical Company, 2401 Crow Canyon Road, Acetylmethodol, 1974. (Unpublished). San Ramon, Calif., 94022. Prepared at Edgewood Arsenal, Aberdeen Proving Grounds, Maryland. Sydney Archer, Ph.D. is Research Professor of Medicinal Chemistry, Chemistry Department. Industrial Bio-Test Laboratories, Inc. Rensselaer Polytechnic Institute, Troy, N.Y., One Year Chronic Feeding Study with LAAM 12181. in Beagle Dogs, 1975. (Unpublished). Prepared under Contract HSM-42-73-178 at Northbrook, Illinois. Industrial Bio-Test laboratories, Inc. Chronic Oral Toxicity Study with LAAM in Albino Rats for 79 Weeks, 1975. (Unpublished). Prepared under Contract HSM-42-73-178 at Northbrook, Illinois. Industrial Bio-Test Laboratories, Inc. Teratogenic Study with LAAM in Albino Rats, 1973. (Unpublished). Prepared under Contract HSM-42-72-171 at North- brook, Illinois. Industrial Bio-Test Laboratories, Inc. Perinatal and Lactation Performance Study with LAAM in Albino Rats, 1973. (Unpublished). Prepared under Contract HSM-42-72-171 at Northbrook, Illinois.

38 CLINICAL STUDIES PHASE I

Ralph M. Sollod, M.S. Marcia G. Goldstein, M.A.

Clinical studies on LAAM were conducted as tabolism are methadol (MOL) and normethadol early as 1952. Most investigations with the (NMOL) which are the result of deacetylation. drug in the 1950’s tested the use of LAAM as an analgesic. However, in the late 1960's LAAM has two methyl groups attached to nitro- and early 1970's, an interest developed in gen, These are N-demethylated by this drug as an alternative to methadone in N-demethylating enzymes in vivo to 1-alpha- the treatment of heroin addiction. These noracetylmethadol by the removal of one me- studies preceded the Phase II clinical trials thyl group and its replacement by hydrogen. on LAAM initiated by SAODAP in 1973. Here This, in turn, may be converted to a di-nor they are grouped as Phase I studies. Table form by the enzymatic removal of the second XVII, provides a list of LAAM Preclinical, methyl group and its replacement by hydrogen Phase I, and Phase II clinical investigators. (Billings 1974a). The demethylating enzymes are located in the liver and, hence, account PHASE I S’IUDIES--CROSS S’IUDY SUMMARY OF for the more rapid onset of action of LAAM FINDINGS when orally administered , and also explain the delayed onset of effect when LAAM is This section provides a comprehensive sum- administered intravenously, intramuscular- mary of clinical studies on LAAM exclusive ly, and subcutaneously (Fraser 1952). of the current VA/SAODAP Phase II clinical trials. The summary has been organized into Techniques for identifying and quantitating the following sections: plasma and urine levels of acetylmethadol and its metabolites in human biofluids have Pharmacokinetics been developed by Kaiko and Inturrisi (1973). Clinical Pharmacology Plasma and urine samples were obtained from Controlled Clinical Studies patients receiving maintenance dose of LAAM Other Clinical Studies (level unspecified) for treatment of heroin Summary of Toxicity-Safety Findings addiction. Peak plasma levels of acetylme- and Observations thadol were found to occur at four hours postadministration and had nearly disappear- The sumnary of toxicity-safety findings and ed at 24 hours. N-LAAM plasma levels peaked observations covers all clinical studies in four-eight hours and declined slowly over prior to Phase II (1952-1974). the next 40 hours. DN-LAAM levels remained constant during the dosing interval. The Pharmcokinetics time cource of pupillary effect was found to be related to the plasma levels of the The delayed onset and long duration of ac- active metabolites. (Kaiko and Inturrisi tion of 1-alpha-acetylmethadol has been at- 1975, in press). Henderson (1974, 1975) has tributed to its biotransformation to two found the time course of peak plasma levels active metabolites, noracetylmethadol (N- of LAAM and its metabolites (N-LAAM and DN- LAAM) and dinoracetylmethadol (DN-LAAM) (Bil- LAAM) following acute administration of 60 lings et al. 1974a). Other products of me- mg LAAM to be similar to those for racemic

acetylmethadol: LAAM, 6 hours; N-LAAM, 2-6 (1) Analgesic Activity--Early interest in hours; DN-LAAM 2-48 hours. After 90 days, a the acetylmethadols centered around their dose level of 85 mg of LAAM three times appropriateness for use as analgesics. Cli- weekly was attained. LAAM plasma levels nical trials were undertaken to evaluate the were only slightly higher than initially potential of these compounds as substitutes while N-LAAM and DN-LAAM levels were 5-10 for morphine. times higher. Billings et al. (1974) found that DN-LAAM levels were substantially high- David et al. (1952) found that 20-30 mg of er after repeated doses of LAAM, while LAAM racemic alpha-acetylmethadol, administered and N-LAAM levels tended to remain the same. orally and subcutaneously, relieved chronic pain for four to five hours and bad a cumu- Goldstein (1975 unpublished) found that lative effectiveness which enabled patients plasma levels of LAAM were very low at 72 to skip doses in some instances. hours postadministration in patients maintained on LAAM; the plasma levels of N-LAAM Keats and Beecher (1952) in clinical trials and DN-LAAM, on the other hand, increased with the levo isomer (LAAM) administered from 24 to 48 hours and were almost as high subcutaneously found it to be less effective at 72 hours as at 48 hours. This is con- as an analgesic than morphine. LAAM admini- sistent with the proposition that it is the stered subcutaneously in a dose of 20 mg/70 active metabolites which are responsible kg produced analgesia within 90 minutes, but for the long duration of action of LAAM: the the analgesia was less than that produced dosage was "holding" at 72 hours when LAAM by 10 mg of morphine. By extrapolation they plasma levels were practically nonexistent estimated that 50 mg of LAAM would be needed and N-LAAM and DN-LAAM plasma levels were to equal 10 mg of morphine in efffectiveness. still high. They did not find the duration of action of LAAM to be longer than that of morphine. The active metabolites of LAAM play a cen- Cumulative toxic effects were noted after tral role in the profile of action of this administration of LAAM, and coma occurred compound. An appreciation of their role is in four patients at dose levels below the helpful in understanding the slow onset, estimated equivalent effective dose. They long duration of action, and cumulative concluded that the margin of safety of this effects which have been observed. drug was too small to encourage its use as an analgesic. In addition, individual variations in the rates of formation and elimination of these There were subsequent interest in the anal- compounds have been noted (Billings et al. gesic potential of noracetylmethadol. Gru- 1974 a; Kaiko and Inturrisi 1975, in press). ber and Baptisti (1962) found that oral Goldstein (1975 unpublished) has also found doses of noracymethadol were three and one- a great deal of variation among individuals fourth times as potent as morphine and also in LAAM plasma levels (from 15 to 170 ng/ml had fewer undesirable side effects. at 24 hours postadministration). DN-LAAM levels also varied considerably among pa- Houde et al. (1962) found that noracetylme- tients from undetectable (<30 ng/ml) to 278 thadol subcutaneously administered was equi- ng/ml at 72 hours postadministration. valent to morphine in 8 and 16 mg doses and had a similar duration of action. These individual variations with respect to the metabolism of LAAM may help to explain The analgesic potential of the acetylmetha- the differences in response which have been dols has not been of interest currently and observed among LAAM patients in therapy. the results of the early studies, while of The extent of individual variability in the historical interest do not have particular metabolism of this compound appears to be relevance to the consideration of LAAM as a an important factor which should be taken substitute for methadone in the treatment into consideration in the formulation of of heroin addiction. Adverse experiences dosage levels and intervals. Several phar- and side effects noted in the course of these macokinetic studies are currently investi- clinical investigations will be of interest gating these clinical issues. in a consideration of the evidence pertinent to the safety of the drug to follow later Clinical Pharmacology in this summary. LAAM investigational studies on clinical (2) Relief Of Abstinence Syndrome (With- pharmacology have been summarized below un- drawal)--The early clinical investigations der four areas: (1) analgesic activity, (2) of Fraser and Isbell (1952) with alpha-ace- relief of abstinence syndrome (withdrawal), tylmethadol included the racemic form of the (3) opiate effects, and (4) cross tolerance. compound, as well as both optical isomers.

42 While only dl- and 1-alpha-acetylmethadol nence syndrome completely for 72 hours. have been of clinical interest as substitutes for methadone in the treatment of heroin ad- Subsequent clinical research has confirmed diction, some findings on the dextro isomer the ability of LAAM to prevent the develop- are discussed herein to provide a perspec- ment of withdrawal syndrome for long periods. tive of the background of the development of interest in LAAM. (3) Opiate Effects--Several investigators have established data on the onset, peak, Fraser and Isbell (1952) investigated the and duration of opiate effects following ad- potential of dl-, l-, and d-acetylmethadol ministration of the acetylmethadols. to relieve withdrawal symptoms after abstinence from morphine. They found that 15- Fraser and Isbell (1952) used subjects who 50 mg doses of dl-acetylmethadol adminis- were formerly addicted to morphine and with- tered subcutaneously between the 28th and drawn ("post-addicts") to evaluate the ef- 34th hours of abstinence from morphine fects of single doses of racemic acetylmeth- brought relief from the abstinence syndrome ado1 and both isomers. within two hours and that relief of symptoms was complete after a second dose. d-acetyl- dl-alpha-acetylmethadadol produced morphine- methadol, on the other hand, was less effec- like effects which included increased psy- tive than methadone in relieving abstinence chomotor activity, somnolence, garrulous- syndrome. Fifteen-twenty mg doses of d-ace- ness, pupillay constriction, itching, tylmethadol administered subcutaneously scratching, nausea, and insomnia. Fifteen- at the 28th and 32nd hours of abstinence forty mg of dl-acetylmethadol administered brought little relief; with 30-40 mg doses, subcutaneously produced morphine-like effects relief was marked. Oral administration of in 30 minutes which persisted for 24 hours. the d-isomer resulted in a less rapid onset of action and less pronounced effects. Do- The d-isomer produced morphine-like effects ses of d-alpha-acetylmethadol sufficient to which were subjectively pleasing to the pa- suppress all signs of abstinence resulted tients in 15 minutes following subcutaneous in the development of toxic symptoms. administration of single 5-20 mg doses. The duration of action was 24 hours. Twenty mg 1-alpha-acetylmetbadol, on the other hand, doses of d-alpha-acetylmethadol administered was more effective than the parent compound, orally bad no effects on any patients tested. d-methadone, in relieving abstinence. One mg of LAAM was equivalent to 6-8 mg of meth- Single ten-thirty mg subcutaneous doses of adone. Thirty mg of LAAM administered sub- 1-alpha-acetylmetbadol bad a delay in onset cutaneously bad inconsistent results with of action of four-six hours. Effects were respect to relief of abstinence; however, slow to appear (14 hours in some cases) and 30-60 mg administered orally completely were always evident at 24 hours, usually abolished all signs of abstinence. evident at 48 hours, and occasionally evident at 72 hours postadministration. Thirty mg Fraser and Isbell (1952) also found that of 1-alpha-acetylmethl administered intra- withdrawal from LAAM resulted in a mild but venously bad effects which were the same as definite abstinence syndrome, similar in those following subcutaneous administration. course and intensity to that following with- Thirty-forty mg of 1-alpha-acetylmethadol drawal from methadone. There appeared to administered orally had a more rapid onset be no significant difference in abstinence of action than that following subcutaneous syndrome following either abrupt or gradual or intravenous administration, effects being withdrawal from LAAM. evident in one and one-half hours and persisting in all cases for 24 hours and in Suppression of abstinence syndrome with LAAM some cases for 72 hours. was of long duration. Sixty mg of LAAM administered orally was shown to be sufficient The time course of miotic effects (decrease to prevent abstinence syndrome for 72 hours. in pupillary diameter) was shown to parallel Mild but definite abstinence symptoms did that of other drug effects. Following oral not appear until 84 hours postadministration. administration of the levo isomer, pupillary Significant withdrawal symptomes were not miosis began in 2 hours and was maximal in manifested until the interval was extended 4 hours with a return to baseline measures to 96 hours. at 24 hours. Following subcutaneous and intravenous administration of the levo isomer, Levine et al. (1973) found that 20-50 mg do- pupillary constriction appeared more slowly, ses of LAAM resulted in discomfort 48-72 was more intense, and lasted longer (48 hours), hours posttreatment, 70 mg doses produced mild abstinence syndrome 60-72 hours post- Fraser et al. (1954) confined earlier find- treatment. and 80 mg doses prevented absti- 43 ings of more rapid onset of action following cross tolerance to 30 mg morphine sulfate oral rather than subcutaneous administration in LAAM-maintenance subjects. It was found of LAAM. Miotic effects were observed to that most subjects experienced a slight rush last 72 hours and the time course of these after administration of morphine and could effects were related to patient subjective distinguish morphine from placebo. Res- reports of "euphoria." Oral administration ponses were unrelated to levels of LAAM doses. of LAAM produced an earlier, more intense One subject receiving 20 mg of LAAM showed euphoria which diminished more rapidly than a marked response to morphine injections, that following subcutaneous administration. while subjects receiving 30, 85, and 140 mg Miosis correlated with the delay of absti- doses all showed slight euphoric responses. nence until three days postadministration, Occasionally, a slight "high" was reported, but did not correlate well with analgesic usually either during the earlier (3-8 hours) actions of the drug. or later (52-54 hours) intervals postadministration. LAAM was usually, but not always, In an unpublished study using nonaddicted effective in suppressing the effects of mor- subjects, Irwin, Blachly, Marks and Carter phine. administered .2 mg/kg of LAAM and methadone orally and observed that the profile of Levine et al. (1973) undertook a study to action following acute administration was determine the dosage of LAAM which is re- the same for both drugs. Peak effects, mea- quired to provide blockade to 25 mg heroin sured by the Irwin Comprehensive Humans As- using heroin-addicted subjects who were sessment Procedures, occurred in four hours detoxified and drug free at least seven days and the duration of action of LAAM was not before the experiment. Patients were start- significantly longer than that of methadone. ed on 10 mg of LAAM three times a week and The period of observation was 10 hours. The dosages were increased by 10 mg per week up only significant difference in effects were to 100 mg. Heroin challenges were performed reductions in wakefulness and attentiveness at 72 hours after administration of varying following administration of LAAM. doses of LAAM. At dose levels of 30 mg LAAM, four of six subjects reported some effects In another unpublished study, Irwin, Kinohi, of heroin and two felt none. At dose levels Cooler and Bottomly (1973) administered .8 of 50 mg, no effect of heroin was perceived mg/kg and .16 mg/kg oral doses of LAAM and and at dose levels of 70 and 100 mg LAAM .1 mg/kg and .2 mg/kg oral doses of metha- blockade was complete. done to nonaddicted subjects. Peak effects occurred three hours posttreatment with both Zaks et al. (1972) found that three of four drugs. The duration of action of LAAM was subjects receiving 30-40 mg doses of LAAM over 24 hours; that of methadone was 12 responded to challenge with 50 mg heroin 24 hours. The higher dose of LAAM produced hours after administration of LAAM with effects similar to but less intense than mile, transient euphoria, while blockade was those produced by the lower dose of metha- complete in the fourth subject. All subjects done. LAAM and methadone produced bi-phasic receiving 80 mg of LAAM demonstrated complete effects which were: early activation, ele- blockade to 50 mg of heroin at 24 hours: one vation of mood, and liking for the drug fol- subject was challenged at 48 hours postad- lowed by later depressant effect and dis- ministration and demonstrated complete like of the drug. The effects of LAAM were blockade to heroin. primarily activating while those of methadone were generally depressant. Controlled Clinical Studies Levine et al. (1973) administered 100 mg Clinical trials prior to Phase I have pro- doses of LAAM to heroin-addicted subjects vided some evidence as to the safety and and evaluated the effects on pupillary effectiveness of LAAM as a substitute for diameter. Twenty mg of LAAM produced maxi- methadone in the treatment of heroin addic- mum miosis in 24 hours. Greater doses of tion. A review of the studies undertaken LAAM produced no further constriction; 30- and their results pertinent to the effective- 50 mg doses sustained maximum constriction ness of LAAM as a substitute for methadone for 48 hours, and 80-90 mg doses sustained will be presented here. Discussion of data maximun constriction for 72 hours. from these studies pertinent to the safety of LAAM will be presented in the section (4) Cross Tolerance--The ability of LAAM titled Summary of Toxicity-Safety Findings to provide blockade to the effects of heroin and Observations. A summary of all control- and the dose levels necessary for complete led clinical studies prior to Phase II is blockade have been studied by several inves- presented in table XVIII, which follows this tigators. Irwin, Blachly, Marks, and Carter page (unpublished) studied the development of

44 The term "controlled clinical studies" as A double-blind, controlled study was carried used here refers to all studies in which a out with 10 patients to determine if LAAM control group, i.e., a group of patients could be effectively substituted for metha- who are taking methadone, is used to provide done on weekends (Jaffe and Senay 1971). a basis for comparison of outcomes with the The duration of the study was three weekends LAAM-treated group. The study design may and no differences were found between the be open, where the patients are aware of experimental and control groups with respect the medication they are receiving; blind, to morphine-positive urines, clinic atten- where the patients are unaware of the medi- dance, interviewer observations, self-reports cation they are receiving and are given of symptoms, or requests for change in medi- placebo in place of active medication on cation. It was found that LAAM in doses nondrug days; or double-blind, where the equivalent to the patient’s usual dose of identity of the medications which patients methadone were sufficient to prevent absti- receive is not known to patients or the nence symptoms for 48 hours. Abstinence staff who administer the medication and ev- syndrome was prevented for 72 hours by doses aluate the results. of a mean of 1.3 mg of LAAM for every 1 mg of daily methadone. Mean dose levels were The following section will discuss other cli- 60 mg of LAAM and 68 mg of methadone. LAAM nical studies which likewise may be open or was found to be similar in potency to the blind, but in which no control group is used. racemic compound, not higher as anticipated. The first clinical trial (Jaffe et al. 1970) Senay, Jaffe, diMenza and Renault (1974) in was a double blind study of the effective- a 48-week, double-blind study started 157 ness of dl-alpha-acetylmethadadol as a sub- patients on mean doses of 57.8 mg of LAAM stitute for methadone in the treatment of three times weekly, with placebo on alter- 21 patients. Doses were administered in nate days, 40.6 mg of methadone daily (Full the ratio of 1.2 mg of dl-alpha-acetyl- Service Group), or 41.3 mg of methadone daily methadol to 1 mg of methadone. At 24 and (Dispensary Group). Few significant differ- 48 hours postadministration, there was no ences were found between the LAAM Full Ser- change from baseline measures on the Addic- vice group, the Methadone Full Service group, tion Research Center Inventory (ARCI) and and a third treatment group (Dispensary) re- a withdrawal symptom checklist. At 72 hours, ceiving methadone only and no counseling or there was a slight rise in the opiate with- other services. There were no significant drawal subscale of the ARCI; however, there differences in total number of weeks accumu- were no complaints on the checklist or in lated by patients in their original treatment interviews with experimenters. Ninety-six groups. At the end of 48 weeks, 49 percent hours postadministration there was a sharp of the Dispensary group, 50 percent of the rise in withdrawal symptoms and complaints. LAAM Full Service group, and 29 percent of No differences were found between groups the Methadone Full Service group had dropped with respect to relief of withdrawal symp- out. There were no significant differences toms, illicit drug use or other indicators between treatment groups with respect to use of social adjustment. One-third of the of illicit drugs and employment and arrest LAAM patients and 11 Percent of methadone rates. Requests for dose-level changes were patients dropped out of the study. significantly less in the Dispensary group. In a subsequent double-blind experiment Zaks, Fink and Freedman (1972) compared 40 comparing dl-alpha-acetylmethadol and metha- LAAM (30-80mg/three times a week) and methadone, 34 patients were studied for 15 weeks done (100 mg/day) patients in an open study (Jaffe et al. 1972). The withdrawal symp- of six months duration and found the groups toms of patients taking a mean dose of 36- to be equivalent with respect to patient 80 mg of dl-alpha-acetylmethadol/active acceptance, withdrawal symptoms, response dose three times weekly did not differ from to heroin challenges, and number of positive those of patients taking a mean of 30-90 mg urines tested for morphine. Patients taking of methadone daily. There were no signifi- 40-50 mg doses of LAAM evidenced withdrawal cant differences between the two groups for symptoms 40-48 hours posttreatment and 80 the following outcome measures: dropout mg of LAAM completely prevented abstinence rate, employment, arrests, percentage of syndrome for 72 hours. Twenty percent of urines negative for illicit drugs, clinic methadone patients and 11 percent of LAAM attendance and requests for dose level patients dropped out. changes. Twenty-six percent of the dl-alpha- acetylmethadol patients and 13 percent of In a controlled study with both double-blind methadone patients dropped out. The dif- and open comparisons, Lehmann (unpublished) ference was not significant. studied 42 16-21 year olds on LAAM every 72 hours. Some camplaints of mild discomfort 45 after 60 hours were made by patients in the to 14 patients receiving 75 mg of LAAM three open group (who knew they were taking LAAM); times weekly on a double-blind basis and 16 however, complaints were not severe enough patients taking 75 mg of LAAM three times to warrant change in dosages or inter-emo- weekly on an open basis. No significant tional reactions, performance in jobs, differences were noted in dropout rates, at- school, athletics, and therapy. Withdrawal tendance records, and jailings. Urine tests was accomplished from both drugs at the end for opiate use indicated the LAAM groups of 16 weeks with equal ease. were superior to the methadone group in having less illicit use of narcotics. Metha- Savage, Karp and Curran (unpublished) car- done group members were superior in reduc- ried out a six-month double-blind crossover tion of amphetamine and barbiturate use. comparison between 99 patients on LAAM (1.3 Goldstein also investigated the question of times their usual methadone dose) and metha- whether complaints of medication not holding done. Treatment groups did not differ in over the weekend were psychological or phar- frequency of positive urines, clinic atten- macological in nature. He increased the dance, and social and emotional adjustment. Friday dose of LAAM from 75 mg to 100 mg on Those patients who were induced on LAAM ini- three successive weekends on a limited ba- tially dropped out at a significantly high- sis with the expectation that complaints er rate than those who started on methadone would decrease if their origin was pharmaco- and transferred to LAAM (x2 5.49, p=0.2). logical rather than psychological. The ef- The dropout rate was also higher for LAAM fects of this dosage increase were inconsis- patients in the second half of the study, tent, indicating that complaints of withdraw- after the crossover, but the difference was al may well arise out of patients' concern not significant. Fifty-three percent of all that their medication will not hold than, patients taking LAAM dropped out and 35 per- rather than being pharmacological in origin. cent of all patients taking methadone dropped out. The overall results of all controlled clinical studies prior to Phase II reveal few Irwin, Blachly, Marks, Carlson, Loewen and differences between LAAM and methadone pa- Reade (1973) in an eight-month open study tients on outcome measures such as use of of 109 LAAM patients (mean dose 55 mg/day, illicit drugs, illegal activity and arrests, group one; mean dose 57 mg/day, group two), employment, clinic attendance and dose-level methadone patients (mean dose 50 mg/day), changes. A large number of studies have and nonaddict controls found that dropouts confirmed the initial findings of Fraser from the study were disproportionately males and Isbell that LAAM is capable of suppres- and tended to occur in the first two months sing the development of abstinence syndrome of the study. There was a higher percentage for 72 hours. The dose levels necessary to of dropouts in the LAAM group (42 percent) achieve this have been shown to vary great- than in the methadone group (23 percent) or ly, and the patient’s attitudes and concerns among the nonaddict controls (20 percent). about the ability of the medication to hold There were no differences between treatment him for this period of time are important. groups in social adjustment indicators. The main differences between treatment groups appear to be in the percentage of patients In an open study comparing 65 patients on who drop out of the studies. With one ex- LAAM and methadone, Senay, Renault, diMenza, ception (Zaks et al. 1972), all studies re- Collier, Daniels and Dorus (1974, unpub- ported a greater percentage of LAAM patients lished) found that patients can be main- dropping out than methadone patients, al- tained on a mean dosage of 44.4 mg of LAAM though the differences between groups were three times weekly in comparison with pa- often not significant. tients maintained on 36.5 mg of methadone daily. Mean initial dose levels were 44.7 Dropouts among LAAM patients tended to occur mg of LAAM and 33.5 mg of methadone. No early in the studies. Goldstein and Judson significant differences in illicit drug use (1974) noted a greater number of dropouts and employment and arrest records were no- among LAAM patients than among methadone ted at 14 weeks. LAAM patients tended to patients during the stabilization phase. drop out earlier than methadone patients. Savage et al. (unpublished) noted a signifi- The difference was significant at five weeks cantly greater number of dropouts among LAAM but was no longer significant by 14 weeks. patients in the first half of their cross- The dropout rate was 32 percent for LAAM over study. Dropouts were also greater among patients and 22 percent for methadone pa- LAAM patients after medications were switched, tients. but not significantly so. Goldstein and Judson (1974) compared 44 pa- Senay et al. (1974 unpublished) noted that tients receiving 50 mg of methadone daily the significant difference in percentage of 46 dropouts among LAAM and methadone patients of LAAM on Monday and Wednesday and 80- at the 5th week of their study had disap- 85 mg of LAAM on Friday after having peared by the end of the 14th week when the been maintained on methadone for three rate of dropouts for methadone patients in- months creased to a level similar to that of LAAM patients. Five patients induced directly on LAAM (60-65 mg Monday and Wednesday and 80- Jaffe et al. (1970) noted that the four pa- 85 mg on Friday) who had never taken tients taking dl-alpha-acetylmethadol who methadone dropped out of his study did so on the first day. Jaffe et al. (1972) found that the Six patients who received methadone average stay of patients on dl-alpha-acetyl- Monday through Thursday, and 80-85 mg methadol was 5.8 weeks compared to 10 weeks of LAAM on Friday for methadone patients. The dropout rate was identical in both groups In summary, investigators have found that taking only LAMM (40 percent). The group on most outcome measures, LAAM compares fa- who had never taken methadone stabilized on vorably with methadone as a substitute drug LAAM with less distress and fewer complaints in the treatment of heroin addiction. The than the group who had been transferred from dropout rate among LAAM patients has been methadone maintenance. The group of patients shown to be generally higher than that for taking methadone during the week and LAAM methadone patients, although differences on the weekends all experienced withdrawal are often not significant. Dropouts among on the third day after the Friday dose. Two- LAAM patients often occur during the early, thirds of them dropped out of the study after stabilization phase and may be related to five weekend doses; this part of the study physiological problems in inducing patients was discontinued after two months. onto a new drug or to psychological concerns about the taking of an "experimental" drug. Summary Of Toxicity-Safety Findings And Ob- If, as is suspected, the metabolite N-LAAM servations is the active agent, there is a lag in buildup of pharmacologically active blood When all the research which has been done levels. During the period when patients with LAAM prior to Phase II is taken into are off methadone and just starting on LAAM, consideration, it appears that there have the blood levels of the desired agent may been few unusual reports of toxicity; such be too low and initial discomfort may occur. adverse experiences as did occur resembled those of methadone, and particularly occurred Other Clinical Studies after excessive dosage. The cumulative nature of the drug effects and the variability Other clinical investigations have been among individuals in the rate at which LAAM carried out with LAAM where a methadone or is metabolized necessitate close attention other control group was not employed and to dosage levels and intervals. Following have produced findings pertinent to the ef- is a summary of clinical experience which fectiveness of LAAM in the treatment of has accumulated as a result of investigations heroin addiction. prior to Phase II and which has relevance to the safety of the drug. This summary is Blachly (1971) reported starting 74 patients organized in the following categories: re- on LAAM in an open study. The initial con- sults of laboratory tests, adverse expe- version factor of one-sixth the patient’s riences, and side effects usual dose of methadone proved to be inadequate, and all patients suffered withdrawa1. Results Of Laboratory Tests Twenty-two out of twenty-three patients started at those dose levels returned to Laboratory tests have revealed few diffe- methadone within a week. Twenty-four of rences between LAAM and methadone patients 51 other patients continued on dose levels and most results have been within normal li- equal to their methadone dose. Doses of mits, or unchanged from pretreatment values LAAM equivalent to the patient’s usual metha- where pretreatment values were not normal. done dose were sufficient to prevent absti- Following is a description of those results nence in 18 patients for 48 hours and in which are unusual in any respect. 6 for 24 hours. Blachly et al. (1972) canpared 21 LAAM Pa- Wilson, in an unpublished open study, ob- tients to a matched sample of 19 methadone served three treatment groups for 85 days: patients on laboratory findings (results of SMA 12 and SMA 6 screen and automated reagin Five patients transferred to 60-65 mg tests) and electroencephalograms. The only 48 statistically significant finding (p.025) (31 percent upon entry to 40 percent at for LAAM patients was hyperglycemia (mean eight months). There was a statistically blood glucose 117 percent for LAAM patients significant increase in incidence of EEG 103 percent for methadone patients where abnormalities for 24-hour LAAM patients (34 110 is defined as the upper limit of normal). percent upon entry to 100 percent at eight Sixty-three percent of the methadone pa- months) . There was no significant altera- tients and 38.5 percent of the LAAM patients tion of cognitive performance for LAAM or had EEG abnormalities but the difference was methadone patients and EEG abnormalities not significant (p 0.1-0.2, chi square=2.44). did not seem to be reflected in performance on cognitive tests. Irwin, Blachly, Marks and Carter (unpublished) in another discussion of the same study Blood chemistry analysis revealed that both also noted a higher incidence of abnor- LAAM and methadone produced elevations in malities in SGOT, albumin, and alkaline SGOT determinations and that methadone pro- phosphatese determinations in both the LAAM duced a greater incidence of lowered abnor- and the methadone groups, suggesting a mal T-3 value. Incidence of abnormalities slight impairment in liver function. ‘Ihir- was sustained for methadone patients and ty-five and 29 percent of methadone and LAAM decreased for LAAM patients over the eight- subjects, respectively, also had abnormally month study period. Urine analysis revealed high white blood counts. LAAM subjects’ no abnormalities. performance on cognitive tasks involving memory, learning, speed, and accuracy was Savage et al. (1974, unpublished) found no significantly better than was methadone differences in LAAM patients pre- and post- subject’s performance. treatment in EEG, blood chemistry analysis, or hematology. Methadone patients evidenced Jaffe, Senay, Schuster, Renault, Smith and significant changes on three of seven hema- diMenza (1972) in a study of dl-alpha-acetyl- tology measures; the mean values of neutro- methadol noted that only 7 of 66 patients philes decreased and the mean values of bad normal results on liver-function tests lymphocytes and basophiles increased. All upon entry and that profiles remained un- values were still within normal range, how- changed at the end of the study. With re- ever. spect to hematology, most subjects were normal initially and at the end of the study. Adverse Experiences In one subject, the hematocrit dropped from 48 percent to 39 percent but hemoglobin There have been several reports of adverse level, RBC, and WBC remained normal. White experiences in the course of investigations blood cell counts decreased in two patients with LAAM prior to Phase II. and increased in one; no symptoms were associated with any of these changes. Thir- Keats and Beecher (1950) noted four inci- teen subjects had positive results for VDRL dents of coma among 81 patients receiving and PTA tests initially, which were unchanged subcutaneous doses of LAAM for relief of at the end of the study, except for one sub- chronic pain. The patients bad received 16 ject whose values reverted to negative. 40 mg LAAM twice in 24-34 hours with one to three 6-10 mg doses of morphine in the same Wilson (unpublished) noted elevated SGOT interval. Coma occurred 12-24 hours after determinations and slightly decreased hemo- the last dose of LAAM and lasted an average globin, hematocrit, and white blood count of 20 hours. in five of six LAAM patients. Blachly (1971) noted four cases of toxicity Zaks et al. (1972) reported elevated trans- to LAAM at dose levels above 100 mg among aminase levels which were sporadic and not 74 patients taking LAAM. Two patients had dose-related for both the LAAM and the metha- seizures while on 180 mg and 120 mg LAAM done groups. Results of all other labora- every 24 hours. A female patient on 110 mg tory tests (fasting, blood glucose, blood LAAM every 24 hours lost consciosness, suf- urea nitrogen, uric acid, blood cell count, fered cardiac arrest, and showed EEG ab- and urinalysis) were normal. normalities, and a patient on 220 mg LAAM per day complained of feeling as though he Irwin, Blachly, Marks, Carlson, Leowen and were going to have a fit and was returned Reade (1973) found the incidence of EBG ab- to methadone. A fifth patient bad a manic normalities among methadone patients was 43 attack when his dosage was reduced to 35 mg/ percent upon entry into the study and had 48 hours from 55 mg/48 hours during voluntary increased to 53 percent at eight months. withdrawal. He was returned to methadone Incidence of EEG abnormalities increased (55 mg/day), treated with lithium and thora- less markedly for 48-hour LAAM patients zine, and subsequently completed withdrawal 49 while on LAAM. in the total sample complained of dizziness, thirteen reported feeling lethargic, and two Side Effects experienced severe depression attributable to intolerance to LAAM. The response of patients on LAAM has been shown to vary considerably among individuals. Fraser and Isbell (1952) found that repeated Some patients evidence no side effects or doses of dl-alpha-acetylmethadol and LAAM complaints, while others experience distress resulted in cumulative toxic effects in from either withdrawal or side effects. four patients: depression, approaching coma, nausea, respiratory depression, and mental Billings et al. (1974) observed different confusion. responses in three LAAM subjects studied. The subject with the highest plasma levels Reports of loss of sexual desire, constipa- NAM and NNAM reported only mild sweating tion, drowsiness, and loss of energy were and constipation. The two other subjects, received from patients in both LAAM and meth- whose plasma levels of the metabolites were adone groups. The mean number of complaints similar to each other, reported more severe was the same for each group, 2.6 (Irwin, side effects. One reported anxiety, sweat- Blachly, Marks, Carlson, Loewen and Reade, ing, and gooseflesh in the early weeks of 1973). the study which disappeared later; the other reported considerable dysphoria, irritabi- Gruber and Baptisti (1962) found that nausea, lity, muscle weakness, tremors, and paranoia. dizziness, and drowsiness increased in proportion to the dose level of nor-acetylmetha- Zaks et al. (1972) received no complaints dol; constipation, headache, nervousness, of side effects from methadone patients ex- and abdominal discomfort were reported as cept constipation (4 out of 10 patients). side effects but were not dose-related. Of the nine LAAM patients, three complained Itching was volunteered as a complaint often of irritability, one of anxiety, and two enough to be added to the list. of involuntary, jerky movements of the extremities before falling asleep. Houde et al. (1962) observed that nausea and drowsiness occurred in some patients at Jaffe, Senay, Schuster, Renault, Smith and higher doses of noracetylmethadol (8 and diMenza (1972) noted few complaints of side 16 mg) administered subcutaneously, and burn- effects in the 66 subjects in their study, ing at the site of injection occurred after and no toxic reactions. Two patients com- 25 percent of the 16 mg doses. plained of impotence and two complained of jerking and twitching of arms and legs when Jaffe et al. (1970) reported that four of at rest. twelve patients taking dl-alpha-acetylmethadol dropped out on the first day because Withdrawal, irritability, restlessness, gas- of complaints of anxiety and nervousness. trointestinal upset, and anxiety were com- The d-isomer has been suspected of producing plained of by methadone patients who were anxiety and nervousness (Fraser and Isbell taking LAAM on weekends (Wilson, unpub- 1952) and may be responsible for the side lished). All five patients in the treatment effects noted in this instance. groups who were transferred to LAAM from methadone all complained of amphetamine- In an open study with LAAM, Levine (1973) like effects, irritability, anorexia, con- noted that three of seven patients reported stipation, and diminished libido in the loss of appetite and abdominal discomfort early weeks of the study. Other complaints at doses greater than 50 mg; all patients were appetite and weight loss. The five reported constipation. patients in the treatment group who were induced directly on to LAAM stabilized with Senay et al. (1974) found no instances of fewer side effects than the group which was confusion, psychotic symptoms, or unpleasant transferred from methadone. subjective states among 157 patients studied. Anxiety was observed in all treatment groups. David and Semler (1956) found that side There were two deaths during the course of effects were minimal among patients receiv- the study: a methadone patient committed ing small doses of LAAN orally and subcut- suicide and a LAAM patient died of lung can- aneously for relief of chronic pain. Twen- cer . ty-five of seventy-six patients were nau- seated or vomited at some time while receiv- Senay et al. (1974, in press) reported that ing LAAM. Ten of thirty-one patients treat- 5 of 34 patients taking LAAM experienced ed for longer than 31 days complained of side effects; four suffered from anxiety and moderately severe constipation. Six patients nightmares early in treatment and one patient 5 0 exhibited bizarre behavior of which he had no recollection. One LAAM patient died as a result of heroin overdose 48 hours after his second dose of LAAM. * * * * * * * *

This chapter has summerized the clinical trials with LAAM which have been conducted pri- or to Phase II. A sampling of selected ab- stracts follows.

AUTHORS

Ralph M. Sallod and Marcia G. Goldstein are associated with Macro Systems, Inc., 1110 Fidler Lane, Silver Spring, Md., 20910.

51 The following synopses were prepared to a standard format by Macro System, Inc., from a review of LAAM research, published and unpublished, up to July, 1975.

SELECTED CLINICAL STUDIES SYNOPSES

INDEX

1 Billings, R. E., McMahon, R. E., Blake, D. A. 8 Henderson, G. L. 1-Acetylmethadol (LAM) Treatment Of Opiate Pharmacodynamics Of LAAM In Man: Plasma Dependence: Plasma And Urine Levels Of Two Levels Of LAAM And Its Metabolites Following Phamacologically Active Metabolites. 1974 Acute And Chronic Administration In Man (Fourth And Sixth Quarter Progress Reports). 2 Blachly, P. H. 1974-75 1-Alpha-Acetylmethadol In The Treatment Of 9 Irwin. S., Blachly, P. H., Marks, J., Opiate Addiction: Progress Report, 1971 Carlson, E., Loewen, J., Reade, N. The Behavioral, Cognitive, And Physiologic 3 Blachly, P. H., David, N. A., Irwin, S. Effects Of Long-Term Methadone And Methadyl 1-Alpha-Acetylmethadol (LAM): Comparison Treatment. 1973 Of Laboratory Findings, Electmencephalo- grams, And Cornell Medical Index Of Patients 10 Irwin, S., Blachly, P., Marks, J., Stabilized On LAM With Those On Methadone. Carter, C. C. 1972 Preliminary Observations With Acute And Chronic Methadone And I-Alpha-Acetylmethadol 4 Fraser, H. F., Isbell, H. Administration In Humans. Unpublished Actions And Addiction Liabilities Of Alpha- Acetylmethadols In Man. 1952 11 Irwin, S., Kinohi, R. G., Cooler, P. M., Bottomly, D. R. 5 Fraser, H. F., Nash, T. L., Vanhorn, G. D., Acute Time-Dose-Response Effects Of Cyclaz- Isbell, H. ocine, Methadone, And Methadyl In Man. Use Of Miotic Effect In Evaluating Analgesic April, 1973 (Unpublished Report) Drugs In Man. 1954 12 Jaffe, J. H., Schuster, C. R., Smith, B. B., 6 Goldstein, A. Blachly, P. H. LAAM And LAAM Metabolites: Plasma Levels In Comparison Of Acetylmethadol And Methadone Patients. Summary Progress Report. 1975 In The Treatment Of Long-Term Heroin Users: (Unpublished) A Pilot Study. 1970

7 Goldstein, A., Judson, B. A. 13 Jaffe, J. H., Senay, E. C. Can The Community Be Protected Against The Methadone And 1-Methadyl Acetate: Use In Hazards Of Take-Home Methadone? 1974 Management Of Narcotic Addicts. 1971 52 14 Jaffe, J. H., Senay, E. C., Schuster, C. R., 19 Savage, C., Karp, E., Curran, S. Renault, P. F., Smith, B., diMenza, S. A Methadone/l-Alpha-Acetylmethadol (LAAM) Methadyl Acetate vs Methadone: A Double- Maintenance Study. Unpublished Blind Study In Heroin Users. 1972 15 Kaiko. R. F., Chatterjie, N., 20 Senay, E. C., Jaffe, J. H., diMenza, S., Inturrisi, C. E. Renault, P. F. Simultaneous Determination Of Acetylmethadol A 48-Week Study Of Methadone, Methadyl And Its Active Biotransformation Products Acetate, And Minimal Services. 1974 (In In Human Biofluids. 1975 (In Press) Press) 16 Kaiko, R. F., Inturrisi, C. E. 21 Senay, E. C., Renault, P. F., diMenza, S., Disposition Of Acetylmethadol In Relation Collier, W. E., Daniels, S. J., Dorus, W. To Pharmacological Activity. 1975 (In Press) Three Times A Week LAAM Equals Seven Times A Week Methadone: A Preliminary Report Of 17 Lehmann, W. X. A Control Study. 1974 (In Press) The Use Of 1-Alpha-Acetyl-Methadol (LAAM) As Compared To Methadone In The Maintenance 22 Zaks, A., Fink, M., Freedman, A. M. And Detoxification Of Young Heroin Addicts. Levomethadyl In Maintenance Treatment Of 1973 Opiate Dependence. 1972 18 Levine. R.. Zaks. A.. Fink. M., Freedman, A. M. Levomethadyl Acetate: Prolonged duration Of Opioid Effects, Including Cross Tolerance To Heroin, In Man. 1973

53 Methodology One hundred mg of LAAM was taken orally on Mondays, Wednesdays, and Fridays. Blood samples (5-10 ml.) were taken at intervals in the succeeding 48 hours; total urine voided was collected for two days. Electron capture gas chromatography was used to determine the content of NAM and NNAM.

1 RESULTS Plasma Levels 1-ACETYLMETHADOL (LAM) TREATMENT OF Plasma levels of both metabolites were OPIATE DEPENDENCE: PLASMA AND URINE established soon after dosing. During the first day, the levels of NAM were higher LEVELS OF TWO PHARMACOLOGICALLY than those of NNAM. As time went on, NAM levels declined steadily while NNAM levels ACTIVE METABOLITES. 1974 remained at peak levels (50-75 ng/ml) up to the time of the second dose. NHAM levels were higher after a repeat dose of LAAM than after the initial dose (100-300 ng/ml). NAM levels varied in all three subjects. RUTH E. BILLINGS, ROBERT E. MCMAHON, Urine Levels DAVID A. BLAKE Less unmetabolized LAM was excreted than NAM or NNAM. Excretion levels of all three were much greater (six to eight times greater) after repeat dose than after the initial dose. This is felt to be due to LAAM, NAM, and NNAM becoming tissue bound easily and not being excreted until subsequent doses have saturated the abilitv of the tissues INTRODUCTION to bind amines, at which point the rate of excretion will increase. Two active metabolites of LAAM, 1-noracetylmethadol (NAM) and 1-denoracetylmethadol Adverse Reactions (NNAM) have been identified and are thought to explain the characteristic pharmacological The three subjects varied in the side effects effects of LAAM. (Sung and Way, 1954; they experienced. Billings et al., 1973). The determination of NAMl and NNAM levels in blood and urine of One subject reported only mild excessive patients receiving LAAM for treatment of sweating and constipation during the first opiate addiction was undertaken in order to week. He had higher plasma and urine support the proposition that the activity of levels of NAM and NNAM than the other two LAAM is due to its conversion to NAM and subjects. NNAM. The second subject had difficulty with amphetamine-like stimulation, anxiety, EXPERIMENTAL DESIGN sweating, and goose flesh for six weeks. Subjects The third subject evidenced dysphoria, irritability, muscle weakness, tremors, Three white male ex-heroin addicts, ages 25, and paranoia which decreased during the 28, and 37, previously stabilized on 80 mg/ first four weeks. He asked to be switch- day methadone for two to six years, were ed back to methadone at the seventh week taking 100 mg LAAM three times a week as because of discomfort. Significant volunteers in an experiment comparing LAAM plasma levels of NAM and NHAM were still to methadone and were asked to provide sam- present seven days after his last dose ples of blood and urine. of LAM. 54 2 EXPERIMENTAL DESIGN 1-ALPHA-ACETYLMETHADOL IN THE TREATMENT Subjects OF OPIATE ADDICTION: PROGRESS REPORT, Seventy-four patients were started on LAAM. 1971 They were told it was an experimental drug, that they might return to methadone if they wished, and there would be a transitional period during which dosages would be adjusted. Methodology P.H. BLACHLY Induction--Conversion from methadone was initially one-sixth the usual dose of methadone but was revised to doses of LAAM equal to the regular methadone dose. Dose Levels--The mean dose was 89.1 mg (range 25-140 mg).

Frequency Of Administration--Six patients received their dose of LAAM every 24 hours; 18 received theirs every 48 hours. INTRODUCTION RESULTS Jaffe et al. (1970), demonstrated that dl Dropout Rate alpha-acetylmethadol could be substituted for methadone and that it suppressed absti- Of the 23 patients started on doses of LAAM nence symptoms for 72-96 hours confirming equal to one-sixth their methadone dose, the earlier findings of Fraser and Isbell all but one returned to methadone within a (1952). In an unreported pilot study by week because of withdrawal symptoms. this investigator using higher doses (mean 106 mg), dl-alpha-acetylmethadol produced Of the 51 patients induced on LAAM in dose oversedation and gradually increasing tox- levels equal to their methadone dose, 24 icity. Further studies have been limited continued on LAAM. to the levo isomer which has two features of interest: The mean number of days on LAAM of those who prefer it is 132 (range 18-300). It is more effective orally than parentera11y. Reasons For Preference Of LAAM It is not psychologically addictive. The following reasons were given for pre- ferring LAAM by the number of persons indicated:

55 Methadone did not hold them (19) Male patient increased from 85 to 120 mg LAAM is cheaper (4) LAAM had an undocumented "seizure" but did They nodded too much on methadone (3) not lose consciousness. Symptoms disappear- LAAM is more convenient (2) ed when dose was lowered below 100 mg. They are more emotionally level (3) Sex life is improved (1) A fifth patient had a manic attack during withdrawal from LAAM (at 35 mg from pre- Reasons For Discontinuing LAAM vious stabilization dose of 55 mg). He was placed on regular dose of methadone, The following reasons were given for return- treated with lithium and thorazine. In a ing to methadone by the number of persons few days when the manic attack disappeared indicated: he returned to LAAM, and accomplished withdrawal without further difficulty while Somnolence and agitation (2) on lithium. Amphetamine-like effects (2) "Didn’t feel anything" (1) Decreased sex life (1) Nausea and vomiting (1) "Effects lasted only 30 hours" (1) Constipation (1) Stomach cramps (1) Irritability (1) Sluggish, overly sedated (2) Diffuse aches and pains (1) Heartburn (1) Insonmia (2) Sweating (1) Nine others could give no good reasons for wanting to return to methadone Toxicity There were four cases of toxicity to LAAM, all occurring in patients for whom high dose methadone would not prevent abstinence craving for a full 24 hours; all were receiving daily doses of LAAM in excess of 100 mg. In all cases toxicity developed between the 8th and 14th day. Female patient switched to 180 mg LAAM daily developed panic and “seizures” on the 14th day which disappeared when dose was lowered to 110 mg every 48 hours; she also was a Ritalin addict. EEG was normal. Female patient switched to 110 mg of LAAM every 24 hours experienced episodes of de- personalization and loss of contact with environment on the 9th day. She lost consciousness, suffered cardiac arrest, and showed EEG abnormalities; she had been a Doriden abuser with withdrawal seizures in the past. Male patient started on 200 mg LAAM every 24 hours from 235 mg methadone. Dose was not holding him and was raised to 220 mg. On the 8th day he complained of feeling as though he were going to have a fit and was returned to methadone.

56 Methadone--Mean age 31.4, seven females, two blacks, mean 10 years opiate use, mean 17 months on methadone program, mea” dose 3 95 mg (range 35-190 mg) LAAM--Mean age 32.2, seven females, one 1-ALPHA-ACETYLMETHADOL (LAM): black, one oriental, mean 10 years opiate COMPARISON OF LABORATORY FINDINGS, use, mean 15 months in methadone program, mean 7 months on LAAM, mean dose 75 mg ELECTROENCEPHALOGRAMS, AND CORNELL (range 60-100) MEDICAL INDEX OF PATIENTS STABILIZED Methodology ON LAM WITH THOSE ON METHADONE. 1972 LAAM dosages were adjusted to patient's preference. Seven patients consumed their doses at 24-hour intervals because it would not "hold" them 48 hours. P.H. BLACHLY, N.A. DAVID, SAMUEL IRWIN Fourteen consumed theirs at 48-hour intervals.

Blood and urine samples were collected in the fasting state and before administration INTRODUCTION of regular dose of LAAM and methadone. Blood analysis was by SMA 12 and SMA 6 screen and LAAM, an effective alternative to methadone automated reagin tests. (Jaffe et al., 1970; Jaffe and Senay, 1971), has several advantages over methadone: Eight channel EEG's were obtained at one or six hours after drug administration by a Suppression of abstinence syndrome two "blind" experimenter. times longer than methadone (Fraser and Isbell, 1952)

"Smoother" action RESULTS Less “nodding” The results are as follows: Oral effectiveness Urine And Blood Values Less subjective euphoria The only statistically significant finding (p <.025) for LAAM patients is hyperglycemia. Several disadvantages are: Mean blood glucose was 117 percent for LAAM patients, 103 percent for methadone patients Amphetamine-like effect and dysphoria in where 110 percent is given as the upper limit some patients of normal. Occasional complaints of feeling less EEG "mellow" Fifty-three percent of all patients had EEG Occasional complaints of abdominal cramps abnormalities: 63 percent of those on methadone and 38.5 percent of those on LAAM. This paper reports on clinical laboratory The difference was not statistically sig- studies in patients maintained on LAAM com- nificant. pared to those on methadone. Cornell Medical Index EXPERIMENTAL DESIGN Those patients with normal EEG's differed Subjects significantly (p <.001) from those with abnormal EEG's on their total Cornell Twenty--one patients were matched to 19 Medical Index score. The mean score for methadone patients on age, sex, race and those with normal EEG's was 35.0, for years of opiate use. abnormal EEG's, 69.3. 57 4

Subjects in the single-dose studies were ACTIONS AND ADDICTION LIABILITIES OF "post-addicts," previously addicted to morphine but withdrawn and no longer ALPHA-ACETYLMETHADOLS IN MAN 1952 tolerant. Subjects in the abstinence-alleviation studies were addicted to morphine at the time of the study. Methodology Single-Dose Studies (Post-Addict)-- l-alpha-acetylmethadol was administered: H.F. FRASER AND HARRIS ISBELL Subcutaneously (10-30 mgm) to 14 post- addicts Intravenously (30 mgm) to 5 post-addicts Orally (30-40 mgm) to 7 post-addicts Pupillary diameters were measured before and at intervals after oral, subcutaneous, and intravenous administration of 30 mgm 1-alpha-acetylmethadol. INTRODUCTION Subcutaneous (15 mgm) doses were admin- The pharmacology and analgesic effects of the istered twice daily for several days to acetylmethadols have been studied in animals six patients. (Chen, 1948; Specter, Byrd, Cheney and Binkley, 1949; Eddy, Touchberry and Relief Of Abstinence From Morphine-- Lieberman, 1950; Eddy, May and Mosettig, 1-alpha-acetylmethadol was administered to 1952); this paper reports on some of the currently addicted subjects: actions and addiction liabilities of dl-, d-, and 1-alpha-acetylmethadol in man. The Subcutaneously (30 mgm) at the 28th and findings with respect to l-alpha-acetylmeth- 36th hour of abstinence to two subjects adol will be of primary interest in this summary. Orally (30-60 mgm) at the 28th hour of abstinence to three subjects EXPERIMENTAL DESIGN Substitution Of 1-Alpha-Acetylmethadol For Subjects Morphine--Seventeen addicts received oral or subcutaneous doses of l-alpha-acetyl- Subjects were adult white male volunteers. methadol; the administration of morphine

58 was then discontinued. Ten subjects who Oral administration of the drug abolished received the drug orally remained on it all signs of abstinence. for fourteen days; the five who received it subcutaneously and two who received Substitution Of 1-Alpha-Acetylmethadol For it orally returned to morphine after two Morphine days on the drug. 1-alpha-acetylmethadol was substituted for The 10 orally dosed subjects were with- morphine effectively at a ratio of 1 mgm to drawn abruptly from the drug. Four each 6-8 mgm of the subject’s usual dose of additional subjects were withdrawn grad- morphine. ually over five to seven days. Abrupt withdrawal from 1-alpha-acetylmetha- Prolonged Suppression Of Abstinence By do1 produced an abstinence syndrome which 1-Alpha-Acetylmethadol--Five addicted was mild and similar to that from methadone. subjects received 40 mgm orally on a Gradual withdrawal from the drug produce an daily basis for 10 days after which the abstinence syndrome that did not differ in dosage was increased to 60 mgm and the course and intensity from that observed after interval was lengthened to 48 hours for abrupt withdrawal. a week, 72 hours-for two weeks, and 96 hours for two weeks. Prolonged Suppression Of Abstinence By 1-Alpha-Acetylmethadol RESULTS Sixty mgm oral doses of 1-alpha-acetylmetha- Single Dose Studies do1 successfully prevented development of significant withdrawal symptoms for 72 hours Single doses of 1-alpha-acetylmethadol pro- in subjects stabilized on 240 mgm morphine duced the following results: daily. Symptoms of euphoria did not develop until 4-6 hours after subcutaneous administration and persisted 48 and sometimes 72 hours. Intravenous administration of the drug produced results similar to subcutaneous administration. Following oral administration, morphine- like effects were observed within one and one-half hours and persisted 24 and sometimes 72 hours. Pupillary constriction following oral administration was observed in two hours, peaked in four hours, and disappeared in 24 hours. The onset of pupillary constriction was slower and less intense following subcutaneous or intravenous administration but persisted for 48 hours. Repeated doses of 1-alpha-acetylmethadol resulted in the development of cumulative toxic effects which were depression, approaching coma; respiratory depression; severe nausea and vomiting; mental confusion. Relief Of Abstinence From Morphine Subcutaneous administration 1-alpha-acetylmethadol had inconsistent effects with respect to abstinence relief.

59 Methodology Predrug measures and observations provided baseline data; each individual served as his own control. An individual was studied on placebo and four to ten analgesics (one per week) and observed at intervals up to 72 hours. The following observations were made: Pulse and respiratory rates Blood pressures Temperature Pupillary size Respiratory minute volume Behavioral changes ("euphoria") 5 Adverse side reactions USE OF MIOTIC EFFECT IN EVALUATING ANALGESIC DRUGS IN MAN 1954 RESULTS Route Of Administration 1-alpha-acetylmethadol induced effects more rapidly when given orally than subcutaneously. This difference was statistically significant. Duration Of Action H.F. FRASER, T.L. NASH, G.D. VANHORN, H. ISBELL Miotic effects of 1-alpha-acetylmethadol lasted as long as 72 hours. Correlation Of Miosis With Fuphoria The time-course of morphine-like "euphoria" relates to miotic measurements. l-alpha- acetylmethadol administered orally produced an earlier and more intense euphoria which diminished more rapidly than that produced by subcutaneous administration. Correlation Of Miosis With Relief Of Abstinence Syndrome

INTRODUCTION 1-alpha-acetylmethadol produced a long- lasting papillary constriction which The purpose of this report is to show the correlates with the delay of abstinence extent to which miotic effects of opiate- symptoms until three days after withdrawal. like drugs correlate with analgesic effects, side effects, and addiction liability as an Correlation Of Miosis With Toxic Effects aid to clinical evaluation of these drugs. Only the results with respect to l-alpha- The curves of miotic effect indicate that acetylmethadol will be summarized here. toxic effects would persist for long periods and too short an interval between doses EXPERIMENTAL DESIGN would result in cumulative toxicity. Subjects Correlation Of Miosis With Relief From Pain Former opiate addicts were used as subjects; Pupillay miosis does not correlate well they were hospitalized and observed under with analgesic properties. 1-alpha- “basal” conditions. Eight to ten men were acetylmethadol is a potent pupillary con- used in each experiment. strictor hut a poor analgesic. 60 6

LAAM AND LAAM METABOLITES: PLASMA RESULTS LEVELS IN PATIENTS. Plasma Levels SUMMARY PROGRESS REPORT. 1975 As with methadone plasma levels, the LAAM plasma levels at any given LAAM dosage are extremely variable from patient to patient; at 24 hours, for example, the levels ranged from 15 to 170 ng/ml. The same is true of the metabolites, which are considered to be the active compounds pharmacologically. At 72 hours, NNAM levels varied from undetectable (<30 ng/ml) to 278 ng/ml). AVRAM GOLDSTEIN Time Course Of Plasma Levels And Drug Effects LAAM itself was virtually absent from plasma 72 hours after a dose, but the dose seemed to "hold" quite well over that period. This is consistent with the view that the metabolites are primarily responsible for the LAAM effect, and also with the plasma levels of the metabolites, which were approximately as high as 72 hours as at 48 hours, and higher than at 24 hours. EXPERIMENTAL DESIGN Plasma levels were determined on 14 patients being maintained on LAAM. In a few of these patients, it was possible to obtain blood at 24, 48, and 72 hours after a LAAM dose. In most patients, a blood sample could only be obtained at one or two occasions. Determinations were carried out by GLC, using a modification of the customary method for determining methadone levels in plasma. The LAAM and its two N-demethylated metabolites-- norxetylmethadol (NAM) and dinoracetylmetha- do1 (NNAM)--were identified by retention time on the column, as verified by standards obtained from Eli Lilly Co. Quantitation is most accurate for LAAM, less so for NAM and NNAM, because of their broader peak shapes. Peak areas rather than heights were used for this reason.

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CAN THE COMMUNITY BE PROTECTED AGAINST EXPERIMENTAL DESIGN THE HAZARDS OF TAKE-HOME METHADONE? Subjects 1974 Patients were randomly assigned to one of five groups of 20 patients each. Females were subsequently excluded, hence, groups had fewer than 20 patients. Methodology Control Groups--Three groups (M-l, M-2, M-3) were stabilized on 50 mg of methadone AVRAM GOLDSTEIN AND BARBARA JUDSON daily and maintained at that level. Experimental Groups--LAAM subjects were started on 30 mg LAAM and increased by 10 mg increments to 75 mg LAAM three times a week. One group (L) was "open" and had knowledge that they were on LAAM; they came to clinic only Mondays, Wednesdays, and Fridays. INTRODUCTION The other group (L-P) was "blind", came to clinic six days a week but received It is desirable to have methadone patients quinine placebo on Tuesdays, Thursdays, consume all medication under observation Saturdays, and Sundays. Take-home to eliminate: privileges were given on Sundays and other placebo days. (Comments by Accidental poisonings patients about taste differences have raised doubts in the minds of the Diversion of methadone as a drug of abuse investigator about the validity of the “blind” nature of the experiment.) Adversary nature of routine urine checks An additional experiment was carried out However, seven day a week clinic attendance to determine whether Monday morning is a demand which may interfere with employ- sickness was psychological or phannaco- ment . LAAM is a long-acting substitute for logical. The Friday LAAM dose was methadone which has shown clinical promise increased from 75 mg to 100 mg on three (Jaffe et al., 1972; Zaks et al., 1972; alternate Fridays for both LAAM groups Senay et al., 1973). This report covers the on a "blind" basis. first three months of a clinical trial of LAAM.

62 Criteria For Effectiveness--The groups Urine Testing were compared on the following criteria of effectiveness: Three-quarters of all patients discontinued heroin use by week 13, and at week 13, no Weekly urinalysis for opiates, bar- consistent difference is evident between biturates and amphetamines LAAM and methadone groups (see table, preceding this page). A running average of Dropout rates (after a two-week incidence of clean urines for opiates for stabilization phase) the entire quarter was computed which showed both LAAM groups to be superior to Attendance records the methadone groups. Suspensions for absences Jailing "Feeling Sick" Monday morning questionnaire concerning withdrawal symptoms (“feeling sick”) Methadone groups had large differences experienced on Sunday morning, Sunday initially in percentage of patients with evening, and Monday morning complaints; the differences tended to decrease toward the end of the quarter. RESULTS The "open" LAAM group (L) showed an increase The results for all five groups at three in percentage of patients with complaints months are reproduced in the following from Sunday morning through Sunday evening table. to Monday morning. The "blind" LAAM group (L-P), however, did not show an increase Dropout Rates in percent feeling sick between Sunday morning and Monday morning. During the stabilization phase, dropouts were as follows: Increasing the Friday dose has inconsistent effects in reducing the percent of complaints M-1, (0) in the LAAM groups. Complaints may be more M-2, (0) psychological than pharmacological in origin. M-3, (2) L,(3) L-P, (1)

Survivorship was slightly lower in the LAAM Adverse Experiences groups but not significantly so. During induction to LAAM when tolerance was Attendance Records, Suspensions, And not established, delayed sedative actions of Jailings LAAM were noted (four to six hours). A problem of additive toxicity could develop Differences among groups in these dimensions if a patient were to take another drug in were variable with neither LAAN nor metha- this interval on the assumption that the LAAM done groups favored. dose was not effective.

63 8 respiration, blood pressure, and pupil size PHARMACODYNAMICS OF LAAM IN MAN: PLASMA were recorded prior to administration of daily dose of methadone. Group 2 patients LEVELS OF LAAM AND ITS METABOLITES were started directly on 20 mg LAAM. Blood and urine were collected at six intervals FOLLOWING ACUTE AND CHRONIC ADMINISTRA- after administration of methadone or LAAM. The following laboratory tests were done: TION IN MAN CBC, urinalysis, SGOT, alkaline phosphatase, bilirubin, BUN, blood sugar, LDH, HAA, VDRL, (FOURTH AND SIXTH QUARTER PROGRESS and chest X-ray.

REPORTS). 1974-75 Day 2 A blood sample was taken 24 hours after GARY L. HENDERSON hospitalization just prior to administration of 60 mg LAAM (1.2 times the usual methadone dose). Urine and blood were collected and the symptom checklist completed at six intervals on Day 2 and every 12 hours afterward until discharge from the hospital. Day 3

Patients were discharged after final blood and urine sampling and the second dose of LAAM Weekly blood and urine samples were INTRODUCTION collected on an outpatient basis. Groups 1 and 2 received LAAM every three days for The purpose of this study was to investigate 90 days at which point they were rehospital- the pharmacokinetics of LAAM in man. ized, and laboratory and physical examinations were repeated. EXPERIMENTAL DESIGN Urinalysis Subjects Urine was analyzed for pH, protein, glucose, Five male patients maintained on methadone ketones, bilirubin, and blood. Drug con- for at least 90 days comprised Group 1. centrations were calculated, and recovery Addicts with no previous experience with studies for drug and metabolites were con- methadone comprised Group 2. ducted at the beginning and end of the experiment. Methodology Plasma Day 1, Group 1 Plasma was analyzed by standard GLC proce- Patients were hospitalized. A symptom dures checklist was completed, blood and urine were collected, and temperature, pulse,

64 RESULTS Plasma kinetics of methadone appeared to be altered by subsequent administration Urine (Group 1) of LAAM; a slight increase in methadone plasma levels occurred 4-12 hours after Urine excretion patterns for LAAM and N-LAAM LAAM administration. (noracetylmethadol) did not vary much among patients. Less than 2 percent of the drug Three patients completed 90 days on LAAM. dose was excreted as LAAM and N-LAAM at the After 90 days on LAAM, the LAAM plasma end of the 72 hours. levels were only slightly higher than after the acute dose, but N-LAAM and Plasma DN-LAAM levels were 5-10 times higher than after the acute dose. The levels Group 1--Peak plasma levels of LAAM and of DN-LAAM were highest followed by its metabolites following acute admin- N-LAAM and LAAM. LAAM and N-LAAM de- istration were: creased with time, while DN-LAAM levels remained at a constant high level for LAAM, 135 ng/ml at 6 hours 72 hours. N-LAAM, 50 ng/ml at 2-6 hours N-MOL (normethadol) could not be detected in plasma after the first or the last dose DN-LAAM (dinoracetylmethadol), 20 ng/ml of LAAM. at 2-48 or more hours Group-2--After the initial dose of 20 mg LAAM, plasma levels of the drug were too low to quantitate. After 90 days (dose, Plasma levels of LAAM decreased rapidly 85 mg), the peak LAAM plasma levels were after 12 hours; N-LAAM and DN-LAAM reached two and four hours after the last levels remained fairly constant over dose of LAAM, but the concentration was a 48-hour period. the same as that of Group 1.

65 9 Methodology THE BEHAVIORAL, COGNITIVE, AND Dosages--Three treatment groups were PHYSIOLOGIC EFFECTS OF LONG-TERM established. METHADONE AND METHADYL TREATMENT Daily methadone (mean stabilization dose, 50 mg; range 25-115 mg) 1973 Daily LAAM (mean stabilization dose 55 mg; range 30-90 mg) Forty-eight hour LAAM (mean stabilization dose 57 mg; range 20-80 mg) SAMUEL IRWIN, PAUL H. BLACHLY, JOHN MARKS, Assessments--Subjects were assessed just prior to receiving medication and at ELAINE CARLSON, JAMES LOEWEN, NANCY READE four hours afterward (time of peak drug action) 11-14 days after entry with the program (0 time) and at l-, 2-, 4-, 8-, and 16-month intervals by EEG, blood and urine analysis, Irwin Comprehensive Human Assessment Procedure, Subjective State Questionnaire, Adverse Symptom Checklist, Special Performance tests, social adjustment questionnaire, and oral interview. Urine was monitored weekly for the presence of illicit drugs. INTRODUCTION RESULTS 1-alpha-acetylmethadol (LAAM) has been shown to be an effective, longer-acting Dropouts substitute for methadone in maintenance therapy (Chen, 1948; Fraser and Isbell, 1952; Dropouts occurred most in the first two Jaffe et al., 1970; Jaffe and Senay, 1971). months of treatment and were disproportion- The purpose of this study was to establish ately males, fairly equally divided between the basic data on the pharmacology, potential the races and much higher with LAAM (42 per- toxicity, and comparative safety of methadone cent) than methadone (23 percent) or controls and LAAM. The study will last 16 months; 29 percent). this report is based on 8 months’ data. The 16 LAAM patients who dropped out were EXPERIMENTAL DESIGN distributed as follows:

Subjects Non-LAAM related hospitalization, (3) Imprisonment, (4) Subjects were 54 male and 31 female heroin Switch to methadone, (6) addicts and 15 male and 9 female nonaddicted Withdrawal by request, (1) controls of similar socioeconomic status. Disappeared from study, (2)

66 The 11 methadone patients who dropped out Cognitive Performance Testing were distributed as follows: Data analysis thus far has revealed little or Nonmethadone related hospitalization, (1) no depressant effects or neurologic impair- Imprisonment, (2) ment. There was slightly less overall Withddrawal by request, (2) impairment of cognitive performance and Suicide, (1) functioning with LAAM than with methadone. Disappeared from study, (2) Overall data, however, show very little alteration of cognitive performance with The dropout rate was higher among those either drug and levels of cognitive per- receiving 24-hour LAAM than among those formance do not seem to be affected by the receiving 48-hour LAAM. increased incidence of EEG abnormalities. Dose Level Changes Subjective State Mean daily methadone doses were 50 mg LAAM patients indicated they felt a slightly (range 25-115 mg) after stabilization and greater intensity of drug effects than did had increased to 90 mg (range 50-170 mg) at methadone patients, and tolerance to drug eight months. effects did not develop during the study. Both drug treatment groups demonstrated Mean daily LAAM doses were 55 mg (range 30- improved affect relative to controls; the 90 mg) after stabilization and increased to Change was greater for methadone than for 63 mg (range 35-90) at eight months. LAAM patients hut not significantly so. Mean 48-hour LAAM doses were 57 mg (range Social Adjustment 20-80 mg) after stabilization and decreased to 56 mg (10-100 mg) at eight months. No major changes were seen in areas of social adjustment and only minor differences were Blood Chemistry Abnormalities evident between the two groups. Subjects had a high incidence of abnormal- Conformity to law and work adjustment were ities consisting of lowered T-3 and elevated increased for both treatment groups; and SGOT determinations upon entry into the sexual performance, and illegal activities study. The incidence of abnomality was and earnings diminished. A slight but sig- sustained over time for methadone patients nificant decrease in marihuana use was but decreased to almost normal values for reported by LAAM patients. LAAM patients by the eighth month. Illicit Drug Use EEG Abnormalities There were no significant differences in the incidence of use of illicit narcotic and There was an increased incidence of EEG non-narcotic drugs between treatment groups. abnormalities over time for all treatment groups, characterized primarily by diffuse Side Effects or focal slowing. Most frequent complaints for both drugs The incidence of abnormalities for 48-hour were loss of sexual desire, constipation, LAAM patients was not statistically signif- drowsiness, loss of energy, headache, in- icant and changed from 31 percent at 0 time creased or decreased appetite, and nausea. to 29 percent at four months to 40 percent There were no significant differences at eight months. betweem treatment groups in either the nature of complaints or mean number of complaints. The increase in abnormalities for methadone patients was significant (p<0.01) and changed from 43 percent at 0 time to 41 percent at four months to 53 percent at eight months. The incidence of EEG abnormalities for 24- hour LAAM patients was statistically significant (p<0.01) and illustrated the cumulative effects of chronic administration. The incidence of abnormalities was 34 percent at 0 time, 75 percent at four months, and 100 percent at eight months.

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PRELIMINARY OBSERVATIONS WITH ACUTE EXPERIMENTAL DESIGN AND CHRONIC METHADONE AND 1-ALPHA- Time-Course Of Action ACETYLMETHADOL ADMINISTRATION Five nonaddicted male subjects received .2 mg/kg oral doses of LAAM and methadone in a IN HUMANS cross-over study with one week between tests. The Irwin Comprehensive Human Assessment procedure was used to quantify the time- course of action and effects of the drugs on the psychosocial, physiologic, and cognitive state of the subjects. Cross-Tolerance Of LAAM-Treated Subjects To SAMUEL IRWIN, PAUL BLACHLY, JOHN MARKS Intravenous Morphine C.CONRAD CARTER Nine subjects maintained on LAAM were tested for cross-tolerance to 30 mg morphine sulfate, administered intravenously 3-54 hours after their LAAM dose. They were assessed for cross-tolerance with the procedure of Dole et al. (1966). Clinical Laboratory Studies Twenty methadone maintenance subjects (mean dose 93.5 mg, range 35-190 mg) were matched INTRODUCTION by age, sex, race, and years of opiate use with 21 LAAM maintenance subjects (mean dose This paper reports the results of studies to 79.6 mg, range 12-140 mg). LAAM subjects determine: were on methadone therapy an average of 13.9 months followed by an average of 8 months on Peak time effects for LAAM and methadone LAAM. Methadone subjects were on methadone over 10 hours an average of 17.9 months. Development of cross-tolerance to mor- They were assessed for electroencephalo- phine in LAAM-treated subjects graphic findings, blood chemistry, thyroid and urinary function, and cognitive perform- Possible adverse effects of LAAM and ance. methadone on: RESULTS EEG Blood chemistry Time Course Of Action Hematology Thyroid function Peak effects with LAAM and methadone occurred Urinary function four hours post-treatment and durations of Cognitive performance action were similar with subjects reporting

68 an earlier peak and greater intensity and Liver Function Abnormalities--The SGOT, duration of effects with LAAM than with albumin, and alkaline phosphatase deter- methadone. The only significant differences minations in both groups showed a higher were greater reduction of wakefulness and incidence of abnormalities, suggesting attentiveness, and a higher incidence of slight impairment in liver function. nausea and vomiting with LAAM than with methadone. Hematology--Abnormally high white blood counts occurred in 35 percent of metha- The duration of action of LAAM was not sig- done and 29 percent of LAAM subjects. nificantly longer for LAAM than methadone. Thyroid Function And Urine Analysis--No significant abnormalities were found in these areas. Cross-Tolerance Of LAAM-Treated Subjects To Intravenous Morphine Subjects experienced a slight rush and could Effects On Cognitive Performance distinguish morphine from placebo. A slight "high" was reported, usually soon LAAM maintenance subjects' performance on (3-8 hours) or long (52-54 hours) after cognitive tasks was significantly better treatment with LAAM. Responses were not than methadone maintenance subjects’ on completely dose related and LAAM was not tests involving memory, learning, speed, and invariably effective in suppressing the accuracy, and did not differ significantly effects of morphine. from the past performance of a control group of college students. Clinical Laboratory Studies Electroencephalograph Findings--Sixty- five percent of methadone and 33 percent of LAAM subjects had abnormal EEG findings (p < .10, two-tailed test), consisting of diffuse slowing (usually in temporal and occipital regions), low level of paroxysmal activity and bursts.

All methadone subjects with high Cornell Medical Index scores on admission had significant EEG abnormalities (8/8); none of the LAAM subjects with high C.M. I. scores did (0/5). The increase in slow wave activity which usually follows hyperventilation was suppressed in both groups with only 19-29 percent showing the expected response. The "driving" of the EEG which generally occurs with photic stimulation was likewise suppressed in LAAM and methadone subjects occurring in only 35 percent and 5 percent. Hyperglycemic Response--Both drugs produced a significant hyperglycemic response; the difference between mean blood glucose levels for methadone (103 mg percent) and LAAM (117 mg percent) was significant (p.<0.05). There was also a significant difference (p.<0.05) between the number of subjects with abnormally high blood glucose levels with LAAM (14) and with methadone (5).

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ACUTE TIME-DOSE-RESPONSE EFFECTS OF Methodology CYCLAZOCINE, METHADONE, AND METHADYL Subjects received two doses of drug orally at least one week apart on a randomized, IN MAN. 1973 coded, double-blind basis. Fourteen subjects received placebo. Seven subjects were used per dose level of drug. Dosages were .l and .2 mg/kg methadone hydrochloride and 0.8 and .16 mg/kg l-alpha-acetylmethadol. Trained observers assessed the subjects on a scale of 0.8 at -60, 20, 80, 160, 220, and 280 minutes before and after treatment using SAMUEL IRWIN, ROBERTA G. KINOHI, the Irwin Comprehensive human Assessment Procedures. A subjective state question- PAUL M. COOLER, DOUGLAS R. BOTTOMLY naire (SSQ) and adverse symptom checklist (ASC) were completed by the subject at 12 and 24 hours posttreatment. A variety of special performance tests were also used. Placebo effects were subtracted from the scores in reporting data. RESULTS Peak, Duration, And Intensity INTRODUCTION Peak time effects for all drugs tested occurred about three hours posttreatment. This study proposed to investigate the acute time-dose-response effects of cyclazocine, The duration of effects with the high dose methadone, and 1-alpha-acetylmethadol with of 1-alpha-acetylmethadol was over 24 hours; respect to psychosocial, cognitive, and for methadone it was 12 hours or less. physiologic functions. The profiles and durations of action were of particular inter- With respect to the intensity of drug est, as were the nature of the differences effects, the higher dose of 1-alpha-acetyl- between the three drugs. The investigations methadol produces effects similar to hut and findings with respect to cyclazocine somewhat less in intensity than the lower will not he reported in this summary. dose of methadone. EXPERIMENTAL DESIGN The two modes of assessment, observer rating and subject's self-reporting, correlate Subjects highly with each other. Twenty-eight male, nonaddicted volunteers 21-35 years of age were paid to participate in the experiment and were screened for mental and physical health.

70 Profiles Of Action All drugs produced biphasic effects, most On several measures, however, 1-alpha-acetyl- often an early activation, elevation of methadol produced effects similar to the mood, and liking for the drug followed by a effects of methadone in reducing: later depressant effect and dislike for the drug. The effects of 1-alpha-acetylmethadol were primarily activating and included: Impulse control Memory Slightly increased capacity for func- Respiratory rate tioning Pupil size Facial skin color Increased arousal, drives, energy, speed and durations of movement and expressive- and in promoting: ness Ataxia Slightly improved mood and emotions Unusual body sensations Distorted senses Methadone, on the other hand was generally Light headaches depressant and its effects were: Itching Impairing arousal, focusing, and psycho- mator activity As these effects are characteristic of the effects of narcotics in general, it would Distorted perceptions seem that methadone and 1-alpha-acetylmethadol are similar in potency but differ in Worsened moods and emotions their qualitative effects.

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COMPARISON OF ACETYLMETHADOL AND Methodology METHADONE IN THE TREATMENT OF LONG- Study design TERM HEROIN USERS: A PILOT STUDY. 1970 The study was a double-blind, controlled study lasting seven weeks. Patients reported to the clinic three days per week. Dosages--experimental group Dosages were computed initially at 1.2 times the usual methadone dose and JEROME H. JAFFE, CHARLES R. SCHUSTER, increased slightly in two cases. Subjects received dl-alpha-acetylmetha- BETH B. SMITH, PAUL H. BUCHLY dol on Mondays, Wednesdays, and Fridays, and placebo (dextromethorphan hydrobromide added to the usual vehicle) on alternate days. The average dose of dl-alpha-acetylmethadol was 50 mg three times weekly (range 24-66 mg). Dosages--control groups INTRODUCTION The control group received their usual dl-alpha-acetylmethadol has been shown to daily dose of methadone hydrochloride. prevent withdrawal symptoms for more than 72 hours (Fraser and Isbell, 1952). Its The average dose was 37 mg/day (range effectiveness as a substitute for methadone 20-55 mg). in maintenance treatment of narcotic addicts was the subject of this study. Criteria for effectiveness EXPERIMENTAL DESIGN Urines were checked for illicit opiate use at each clinic visit (three times/ Subjects week). Twentyy-one participants in a methadone The opiate withdrawal subscale of the maintenance clinic stabilized on 20-90 mg Addiction Research Center Inventory (ARCI) of methadone per day served as subjects. and a symptom checklist measuring Twelve were randomly assigned to the experi- intensity of withdrawal were filled out mental group and nine to the control group. three times weekly.

72 Open-ended interviews were held with the Control group staff three times weekly. No change was evidenced from baseline Baseline measures were obtained for two with a 24-hour interval between doses. weeks before the new drug was introduced. of the six patients who experienced a Intensity of withdrawal from methadone 48-hour interval with placebo, two took and dl-alpha-acetylmethadol was studied their emergency doses of methadone at by administering placebo in place of 36 hours and the remaining four active medication in six control and six experienced intense withdrawal distress experimental patients. This was done on at 48 hours. Monday of the seventh week, 48 hours after the last dose of methadone, and Experimental group 96 hours after the last dose of dl-alpha- acetylmethadol. All patients were pro- No change was evidenced from baseline vided with a dose of methadone to take at 24- and 48-hour intervals between in case of emergency. doses. At 72 hours there was a slight rise in the opiate withdrawal subscale of the ARCI, but no change in the symptom checklist or during the interview.

RESULTS At 96 hours there was a marked rise in intensity of withdrawal Symptoms as Dropout Rate measured by the test and interviews. Measures Of General Functioning Four patients in the experimental group dropped out on the first day complaining of Urine analysis showed no difference between abdominal pain. the two groups in illicit drug use. There were eight patients in each group at The two groups also did not differ with the end of the study. respect to numbers employed, arrest rate, or admissions of illegal activity. Withdrawal Symptom Reports Adverse Experiences There were no significant differences between the experimental and control groups Side effects of anxiety and nervousness were on the opiate withdrawal subscale of the perceived as sufficiently troublesome to 4 ARCI and the withdrawal symptoms checklist out of 12 subjects in the experimental group during the two week baseline period. to cause them to drop out of the study.

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METHADONE AND 1-METHADYL ACETATE: USE EXPERIMENTAL DESIGN A controlled clinical study was carried out IN MANAGEMENT OF NARCOTIC ADDICTS, 1971 to determine if 1-alpha-acetylmethadol could be effectively substituted for methadone on weekends. Subjects The subjects were volunteers participating in a methadone maintenance program, stabilized on a 30-100 mg. dose of methadone per day for three weeks prior to the experiment. JEROME H. JAFFE AND EDWARD C. SENAY Experimental Group--The experimental group consisted of five male patients taking a mean daily dose of 50 mg. (range, 40-60 mg/day) of methadone. Control Group--The control group consisted of five male patients taking a mean daily dose of 68 mg (range, 30-100 mg/day) of methadone. Methodology INTRODUCTION Study Desire Racemic methadyl acetate (dl-alpha-acetyl- nethadol) has been shown to be effective in The groups were studied for three suppressing narcotic withdrawal syndrome weekends. for periods up to three days (Jaffe, 1970). There are substantial differences between Patients were randomly assigned to drug the d- and l-isomers in effectiveness in or control groups; clinical observers suppressing the withdrawal syndrome (Fraser were blind to who was in which group. and Isbell, 1952). In view of the limited clinical experience with either isomer, the The experimental group received 1.2 mg purposes of this study were: of 1-alpha-acetylmethadol for every 1 mg of methadone in his daily dose (a three- To gain further clinical experience with day dose); they were given two 30 mg 1-alpha-acetylmethadol doses of dextromethorphan hydrobromide to take home as placebos. To determine if 1-alpha-acetylmethadol could be used interchangeably with The control group received their usual methadone dose of methadone at the clinic and two doses of methadone to take at home.

74 Criteria For Effectiveness Urine was collected and tested for the "Blind" experimenters found nothing in the presence of narcotics. behavior or reports of subjects to indicate which medication they had received. Clinical interviews were held on Fridays and Mondays. Patients in both groups complained of sweating; all had reported problems with Symptom checklists were filled out by sweating prior to the study. the subjects on Fridays and Mondays prior to receiving their medication. No side effects were reported by either group. Clinic attendance was noted. The rates of clinic attendance did not Requests for increase in medication was differ. noted. Subjects in both groups complained of their RESULTS medication not holding; the conversion factor was increased in the experimental The frequency of urine specimens positive group to 1.2 - 1.5 mg (mean 1.3 mg) 1-alpha. for morphine was the same in both groups acetylmethadol to 1 mg methadone hydrochlo- (one in each group). ride.

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METHADYL ACETATE VS METHADONE: A Methodology The study was carried out under double- DOUBLE-BLIND STUDY IN HEROIN USERS.1972 blind conditions and lasted 15 weeks. Subjects were randomly assigned to one of four groups in the study design. Experimental group receiving DLAAM three times a week and dextromethorphan placebo on alternate days (19 subjects) Control group receiving methadone daily JEROME H. JAFFE, EDWARD C. SENAY, (15 subjects) CHARLES R. SCHUSTER, PIERRE F. RENAULT, Waiting list detoxified with methadone receiving no further medication (16 BETH SMITH, SALVATORE DIMENZA subjects) Treatment group of the patient’s choice exclusive of the experimental and control groups in the study (16 subjects) Adjustments were made in dosage of medication by patients' requests to the weekly visiting physician. The program physician was blind to medications and levels. INTRODUCTION All medication was initially taken at the A pilot study using dl-alpha-acetylmethadol clinic under observation; take-home doses of (DLAAM) interchangeably with methadone in a methadone and placebo were later allowed. maintenance program (Jaffe et al., 1970), confirmed earlier findings of the ability Criteria For Effectiveness of this drug to prevent development of abstinence syndrome for 72 hours (Fraser and The following measures were used to determine Isbell, 1952). The purpose of this study the relative effectiveness of the drugs: was to gain further experience with the drug in more extensive trials. Frequency of illicit drug use as determined by urinalysis EXPERIMENTAL DESIGN Twice weekly completion of the morphine Subjects and opiate withdrawal subscales of the Addition Research Center Inventory (ARCI) Subjects were 66 male heroin addicts, age 20 and a withdrawal symptom checklist through 50, screened by physical and laboratory examination.

76 Weekly self-report of illicit drug use, Illicit Drug Use criminal activity, and legitimate employ ment Seventy-one and one-tenth percent of the treatment weeks were characterized by Clinic participation defined as keeping "clean" urines for the control group and 49 clinic appointments and group therapy; a percent for the experimental group. The dropout was defined as a person who did difference was not statistically significant. not attend for two consecutive weeks and was discontinued in the study Clinic And Group Therapy Attendance Adverse Experiences Looked For Clinic attendance was high for both groups and quite similar (93.3 percent, experi- The following tests were taken initially and mental; 91.8 percent, control). Group at the end of the study as indicators of the therapy attendance was lower for both groups safety of the drug: (60.5 percent, experimental; 61 percent, control) and the difference between them was CBC not significant. Urinalysis Liver-function tests Clinical Observations BUN Serrum uric acid determinations There were no differences in the subjective reports of patients; the "blind" physician RESULTS could not distinguish between DLAAM and methadone groups. Data for those subjects in the group assigned to clinics of their choice will not be Dose Level Changes reported; 12 of 16 of these patients did not report to clinics assigned to them. Dosages were 30-80 mg methadone hydrochloride/day and 36-80 mg DLAAM/active dose. Statistical analysis of data was based upon All patients requested increases in the patients who completed at least eight weeks initial two weeks; an equal number from of treatment: 15 subjects in the experi- each group requested increases thereafter. mental and 15 in the control group. Most patients required a higher dose of DLAAM for the 72-hour (Friday to Monday) Dropout Rate interval than the 48-hour intervals. Five (26.3 percent) subjects left the DLAAM Withdrawal Scales group; two (13.3 percent) left the methadone control group. This difference was not There was no significant difference between statistically significant. the two groups on any withdrawal scale. The average length of stay for the dropouts Medical Data And Adverse Experiences was 5.8 weeks in the experimental group and 10 weeks in the control group. Liver Function--Only seven of the 66 patients had normal results on liver- Employment function tests upon initial examination; profiles remained unchanged at the end Both groups evidenced increases in employ- of the study ment. The experimental group had 12 (80 percent) employed at the end of the study Hematology--Most subjects were normal and 4 (26.7 percent) employed at the begin initially and at the end of the study. ning; 10 (66.7 percent) of the methadone control group were employed at the end, 4 Four reverted to normal (26.7 percent) at the beginning. These tie remained the same changes were statistically significant. Two did not return for reevaluation Arrests In one subject, the hematocrit dropped from 48 percent to 39 percent but hemo- Decreases were observed in arrest rates for globin level, RBC, and WBC remained both groups compared to arrest rates in the normal. two years prior, however, the sample size was too small for a determination of statis- White Blood Cell Counts--All were stable tical significance either between groups or except in three subjects. as a result of treatment.

77 In one subject, the initial count was tive results for VDRL and FTA tests 12,800/cu mm and the count at reevalua- initially; these values were unchanged at tion was 3,400/cu mm; he had been reevaluation except in one subject whose treated with trifluoperazine hydrochlo- results reverted to negative. ride prior to reevaluation. Side Effects--There were few complaints Changes from 8,500 to 4,000/cu mm and of side effects and no toxic reactions. 7,100 to 41,000 cu mm were observed in Complaints of decreased libido came out two other patients. No symptoms were in conversations; two patients com- associated with any of these changes. plained of impotence. Jerking and twitching of arms and legs when at rest VDRL And Fluorescent Treponemal Antibody was complained of by two subjects. Tests (FTA)--Thirteen subjects had posi-

78 15 quantitation procedures are beyond the SIMULTANEOUS DETERMINATION OF ACETYL- scope of this summary; results will be METHADOL AND ITS ACTIVE BIOTRANSFORMA- reported. TION PRODUCTS IN HUMAN BIOFLUIDS. 1975 RESULTS Plasma

Most plasma samples contained AM, NAM, and NNAM in concentrations above 0.020 ug/ml. Concentrations of MOL and NMOL above this were not observed in any samples obtained. Urine ROBERT F. KAIKI, NITHIANANDA CHATTERJIE, A mean of 20 percent of the administered CHARLES E. INTURRISI dose was recovered as AM and biotransfomrma- tion products in total urine collected 48 hours after dosing; approximately 2 percent was recovered as AM, 8 percent as NAM, 5 percent as MOL, and 13 percent as NNAM. The pattern of excretion is the same regardless of dosage. Summary

Other routes of elimination (the gastroin- INTRODUCTION testinal tract) and other biotransformation products are likely. Biotransformation is The long duration of acetylmethadol (AM) a prerequisite for the elimination of AM suggests the biotransformation of AM to and N-demethylation is quantitatively more active metabolites. important than deacetylation in the human. AM, noracetylmethadol (NAM), methadol (MOL) normethadol (NMOL) have been identified in the urine of AM maintenance subjects (Kaiko and Inturrisi, 1973). Dinoracetylmethadol (NNAM) was identified by Billings (1973) in the biofluids of rats given AM and has been found in plasma and urine of AM maintenance subjects (Kaiko and Inturrisi, Fed. Proc., 1974). This report describes a specific and sensitive method for quantifying AM, NAM, and NNAM in human plasma and urine. The details of the extraction, identification, and

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DISPOSITION OF ACETYLMETHADOL IN EXPERIMENTAL DESIGN RELATION TO PHARMACOLOGICAL ACTIVITY. Subjects 1975 Subjects were 12 adult males; eight were maintained on a mean dose of 50 mg (range 40-60) acetylmethadol three times weekly for 4-25 weeks. Four others were inpatients, dosages and history not stated. Methodology Plasma--Venous blood samples were ROBERT F. KAIKI AND CHARLES INTURRISI collected just prior to dosing (i.e., 72 hours after last dose) and at 4, 8, 24 and 48 hours from all patients. Urine--The eight maintenance subjects provided urine specimens at 0, 24 and 48 hours after administration of acetylmethadol; urine was collected at 0, 4, 8, 24 and 48 hours from the hospitalized patients. Extraction And Estimation--A multistep INTRODUCTION solvent extraction procedure (Kaiko et al, in press) was employed; noractylmethadol Acetylmethadol has been shown to have a and dinoracetylmethadol were converted to 72-hour duration of action (Fraser and corresponding amides and measured as Isbell, 1952) which has been attributed to equivalents. Qantitation was achieved the biotransformation of acetylmethadol to by the addition of an internal standard, active metabolites (McMahon et al., 1965; SKF 525-A, prior to extraction. Sung and Way, 1954; Veatch et al., 1964). Acetylmethadol, noractylmethadol and dinor- Measurement Of Pupil Size--Miotic effect acetylmethadol have been identified in human was calculated by subtracting the size Plasma (Kaiko et al., in press; Kaiko and of the pupil (determined photograph- Inturrisi, 1973; Billings and McMahon, 1974). ically) at each blood sampling time from the baseline (0-hour) size. This report describes the disposition of acetylmethadol in maintenance subjects with Apparent Half-Life, Renal Clearance And particular emphasis on the relationship Urinary pH--Regression analysis program between the time course of acetylmethadol was used to calculate the apparent half- and its biotransformation products in plasma life for elimination of the compounds and the timeaction of pupillary miosis. from plasma. Renal clearance values were

80 calculated using the average rate of The effect of dinoracetylmethadol could urinary excretion of each compound for not be ascertained since plasma levels the four to eight hour collection period did not decline. and the corresponding plasma concentration at the midpoint of the collection Apparent Half-Life for elimination of period (6 hours). Urinary ph was mea- compounds from Plasma sured with a Metrohm E-512 pH meter. Acetylmethadol had an apparent half- RESULTS life of 7 hours (range 2-12 hours). Time Course, Mean Plasma Levels and Mean Noracetylmethadol had an apparent half- Pupillary Constriction in the Eight Main- life of 48 hours (range 13-78 hours). tenance Subjects Dinoracetylmethadol levels did not Acetylmethadol decline, therefore, no calculation of half-life value was possible. None present at 0 hour Peak level 0.060 µg/ml at 4 hours Renal Clearance and Urinary pH--The sub- Rapid decline to 0.013 µg/ml at 24 hours ject with the lowest urinary pH exhibited Undetectable at 48 hours the highest renal clearance of all three compounds; the subject with the highest Noracetylmethadol urinary pH exhibited the lowest renal clearance values. 0.042 ug/ml at 0 hour Peak level 0.114 µg/ml at 4 and 8 hours Correlation Between Plasma Levels and Slow decline to 0.068 µg/ml at 48 hours Drug Effect--Miotic effect is more closely associated with noracetylmetha- Dinoracetylmethadol dol plasma levels (p <0.10) than with the acetylmethadol dose (p <0.10). 0.052 µg/ml at 0 hour Spearman's correlation coefficient was Peak levels ranged from 0.057-0.123 used to determine the relationship µg/ml at 4 hours between noracetylmethadol plasma levels Levels did not decline during sampling and parameters which might influence its magnitude. High plasma levels of Pupillary Constriction any one of the compounds tend to be associated with high levels of the Pupillary constriction was greatest at others. 8 hours, 1.8 mm. Noracetylmethadol plasma level is a Return to predose value was slower than more reliable correlate of the effect rate of disappearance of acetylmethadol of acetylmethadol than is the acetyl- but faster than rate of disappearance methadol dose. of noracetylmethadol. Noracetylmethadol plasma level is more Time-action of miotic effect corres- a function of other factors relating ponds most closely with noracetylmetha- to its disposition than the acetyl- dol in plasma. methadol dose.

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the heroin detoxification program at Vitam THE USE OF 1-ALPHA-ACETYL-METHADOL Center, Norwalk, Connecticut, served as subjects. (LAAM) AS COMPARED TO METHADONE IN THE Methodology MAINTENANCE AND DETOXIFICATION OF Study Design--The study had two forms: YOUNG HEROIN ADDICTS, 1973 A double-blind comparison of LAAM and methadone Fourteen patients received 10 mg doses of LAAM every 72 hours and placebo on intervening days WALTER X. LEHMANN Twenty-one patients received methadone daily in doses sufficient to maintain a comfortable state An open study in which the drug and dosage were know to the patients Seven patients received LAAM every third day No placebo was given on intervening INTRODUCTION days The purposes of the study were to: The duration of the study was 16 weeks after which patients were detoxified; they were Compare LAAM with methadone for effective- followed up as long as they remained in the ness in a short-term, low-dose mainten- program. Withdrawal was accomplished on an ance program inpatient basis by lengthening the interval between doses for a week then stopping the Determine whether LAAM has potential as a drug completely. medication of choice for heroin addicts Criteria For Effectiveness--Patients were Compare LAAM with methadone with respect observed daily with respect to the to ease of withdrawal and note any clin- following: ical problems which might arise Physical and emotional reaction EXPERIMENTAL DESIGN Performance of job functions in the center Subjects Performance in group and individual therapy Forty-two male and female heroin addicts Atheletic involvement between the ages of 16 and 21, enrolled in

82 High school and special education Athletic Involvement involvement Community and home involvement Athletic involvement was the same for all Toxic reaction patients; there was no interference with coordination or ability to perform. Urines were collected and analyzed three times a week during the first two weeks; High School And Special Education Involvement they were collected three times a week but only analyzed weekly thereafter. These activities did not start until the 8th and 12th weeks, respectively; there RESULTS appeared to be no differences in performance. Physical And Emotional Reactions Community And Home Improvement There were no differences in the physical condition of the three groups. No side This applied only to those living in; no effects such as nausea, vomiting, constipa- differences were noted between groups and tion, weakness, or fatigue were reported. there was improvement after the fourth week. Half the patients in the open study complained of mild discomfort 60 hours after Toxic Reactions medication which disappeared during the third week. No toxic reactions were noted; it was not necessary to terminate treatment in any cases Emotional reactions were similar for all patients with some tension, depression, and hostility noted initially which dissipated Urinalysis by the third week. There were no urines positive for nonpre- Performance Of Job Functions scribed drugs in either group. There was no difference between groups; performance improved in all groups during the third week.

Performance In Groups And Individual Therapy Withdrawal There was no difference between grows in Withdrawal from LAAM and methadone was either type of therapy; performance &proved accomplished with equal ease; no clinical during the fourth week. problems were manifested during withdrawal

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EXPERIMENTAL DESIGN LEVOMETHADYL ACETATE: PROLONGED DURATION OF OPIOID EFFECTS, INCLUDING Subjects Seven male volunteers ranging in age from CROSS TOLERANCE TO HEROIN, IN MAN. 21-50 years with at least two years of narcotic abuse and two previous treatment 1973 failures were used as subjects. They were detoxified and drug free at least seven days before the experiment. Methodology Oral doses of LAAM were administered three ROBERT LEVINE, ARTHUR ZAKS, MAX FINK, times a week beginning with 10 mg and increasing 10 mg/week until doses of 100 mg ALFRED M. FREEDMAN were reached. Pupillary diameter was measured prior to the experiment and at 24, 48, and 72 hours after the third dose each week. The mean predrug diameter was 6.7 nun. A symptom checklist was completed at these times also. Heroin challenge of 25 mg was performed at 72 hours following various doses of LAAM. INTRODUCTION RESULTS Levomethadyl acetate (LAAM)has been determined to have an onset of action which is Adverse Experiences delayed by four to six hours post-administration and has been demonstrated to have Three of the seven patients withdrew after the ability to prevent the development of five weeks. Dose levels of 50 mg had been abstinence syndrome in methadone tolerant obtained by that time. patients for 72 hours (Jaffe and Senay, 1971; Zaks et al., 1972), the purpose of this study All patients reported constipation through- was to determine the dosage of LAAM which is out their participation in the study. required to provide blockade to 25 mg of heroin, to prevent opiate withdrawal symp- Three of the seven patients reported loss of toms, and to provide maximal opiate effect appetite and abdominal discomforts which for a minimum of 72 hours. later disappeared at dose levels greater than 40 mg.

84 Abstinence Syndrome At dose levels of 50 mg LAAM, no effect of heroin was perceived. The mean pupillary At doses of 20-50 mg, six Out of seven diameter was 0.1 mm greater following the patients reported discomfort, yawning, lac- heroin challenges. rimation, and uneasiness, occurring 48-72 hours post-treatment. At dose levels of 70 and 100 mg LAAM, block- At doses under 70 mg, three out of four ade was complete. remaining patients reported yawning and uneasiness 60-72 hours post-treatment. Symptoms were milder and of shorter duration than at lower doses. Sustained Opiate Effects At doses greater than 80 mg, there were no reports of discomfort. Twentymg of LAAM produced maximum miosis for 24 hours. Heroin Challenges Doses greater than 20 mg produced no further One patient refused to receive heroin. At decrease in pupillary diameter; maximum con- dose levels of 30 mg LAAM, four patients striction was sustained for 48 hours at dose reported feeling some effects of heroin, two levels of 30-50 mg LAAM and 80-90 mg LAAM felt none. The mean change in pupillary sustained a pupillary diameter of 5.0-5.2 mm diameter was 0.8 mm. for 72 hours.

85 19

Prior to treatment the following data were A METHADONE/1-ALPHA-ACETYLMETHADOL collected: (LAAM) MAINTENANCE STUDY. Background characteristics Medical and psychiatric history Physical examination and chest X-ray Laboratory examination: EEG, urinalysis, blood chemistry (BUN, glucose, bilirubin, total protein, albumin, alkaline phosphatase, and SGOT), hematology (white CHARLES SAVAGE, ELAINE KARP, STEPHEN CURRABN blood count, hematocrit and differential) Cornell Medical Index Psychological tests: Minnesota Multi- phasic Personality Inventory (MMPA), Personal Orientation Inventory (POI), Benton Visual Retention Test, Psycholog- ical Evaluation Profile (PEP), Wechsler Adult Intelligence Scale (WAIS) Methodology INTRODUCTION Treatment Groups--Assignment to treatment LAAM has had clinical success as a substitute groups was random and there were no sig- for methadone (Levine et al., 1973; Jaffe and nificant differences between groups in Senay, 1971; Jaffe et al., 1972). The pur- background characteristics, EEG results, pose of this study was to validate past clin- blood chemistry and hematology measures, ical research, to determine the relative and personality measures. Patients and safety and effectiveness of LAAM and metha- staff were blind to the medications. done, and to identify factors associated with treatment success and failure. Group 1, 52 patients, received methadone daily for three months and then were EXPERIMENTAL DESIGN switched to LAAM three times a week with dextromethorphan placebo on other Subjects days. Subjects were 99 male heroin addicts; they Group 2, 47 patients started on LAAM were, on the average, 28 years old with 11th and were switched to methadone at three grade education! seven years narcotic addic- months. tion, four to five arrests, and two treatment failures. Half were employed when they Dosages--All Medication was mixed with entered the study. Tang and dextromethorphan. Dosage was

86 flexible. LAAM patients received doses Dose levels equal to 1.3 times their usual dose of methadone There was no difference in the dose levels of those who completed LAAM treatment and Assessments--At the end of three and six those who dropped out. months, the EEG, physical examination, blood chemistry and hematology tests, Lower dosage methadone patients dropped out and MMPI were repeated. more frequently than higher dosage patients. Urine was checked one to three times a Physiological Assessments week for quinine, morphine, amphetamines, and barbiturates. There were no differences between dropouts and completers in EEG, hematology and blood Clinic attendance and changes in social and chemistry results except for bilirubin occupational status were monitored through- which was, nonetheless, within normal limits out the study. for both groups. RESULTS Personality Dropout Rates Dropouts differed from completers in several personality characteristics being: Sixty percent of the methadone group (Group 1) completed three months; 31 percent More suspicious and distrustful (MMPI, of the LAAM group (Group 2) completed. This Pa Scale) difference was significant (X2 5.49, p=0.2). More impulsive (POI Spontaneity Scale) In the crossover phase of the study, 66 percent of the LAAM patients (Group 1) com- Less self-accepting (POI, Self-Acceptance pleted the three subsequent months on Scale) methadone; 81 percent of the methadone patients (Group 2) completed the three sub- More grandiose (PEP, Great Cause Scale) sequent months on LAAM. This difference was not statistically significant. More easily fatigued, more frequently feeling ill, and more incapacitated due With both phases combined, 65 percent of the to illness (Cornell Fatigue and Frequency patients completed treatment with methadone of Illness Scale) and 47 percent with LAAM. Safety Analysis Of Reasons For termination No deaths or serious illness occurred in Side effects were given as the most frequent patients on either drug. reason for withdrawal regardless of which drug the patients were on by 31 percent of Methadone patients LAAN patients and 23 percent of methadone patients. The difference was not signifi- EEG measures did not differ pre- and cant. post-treatment The specific symptoms reported were the same Three hematology measures showed sig- for both medications: experiencing with- nificant changes, however, all were drawal or feeling over medicated. within normal range Urinalysis Mean value of neutrophiles decreased The mean percentages of urines positive for Mean values of lumphocytes and illicit drugs were 5 and 8 percent for the basophiles increased methadone and LAAM groups, respectively. The difference was not significant. LAAM patients--there were no differences in EEG, blood chemistry or hematology Clinic Attendance measures pre- and post-treatment. The mean absentee rates were 2 percent and 4 percent for the methadone and LAAM groups, respectively. The difference was not significant. 87 20

A 48-WEEK STUDY OF METHADONE, METHADYL ACETATE, AND MINIMAL SERVICES. 1974

EDWARD C. SENAY, JEROME H. JAFFE, SALVATORE DIMENZA, PIERRE F. RENAULT

INTRODUCTION There were no significant differences in the background characteristics of the groups dl- and 1-alpha-acetylmethadol have been with respect to race, education, employment, shown to be capable of suppressing narcotic arrests, family stability, and drug use withdrawal symptoms for long periods of time influences. The Dispensary group was sig- (Fraser and Isbell, 1952). These findings nificantly younger than the Methadone Full have been confirmed in pilot comparisons with Service group but not the LAAM group; the methadone (Jaffe et al., 1970; Jaffe and Methadone Full Service group had used heroin Senay, 1971; Jaffe et al., 1972). This study longer than the LAAM group or the Dispensary reports investigations into the clinical group. The correlation of age with years of acceptability and safety of the levo isomer, heroin addiction was .81; the difference in 1-alpha-acetylmethadol, (LAAM), and an age is thought to account for the difference evaluation of the role of auxiliary services in mean number years of addiction. in the treatment of heroin addiction. Methodology EXPERIMENTAL DESIGN Study Design--The study was a double- blind, controlled study. The LAAM group Subjects received active medication three times a week and a 30 mg dextromethorphan placebo The subjects were male narcotic addicts on alternate days; attendance at group between the ages of 20 and 50, randomly therapy sessions was requested weekly, and assigned to one of three groups: other counseling, vocational, legal and recreational services were provided. The Thirty to methadone with full services Methadone Full Service group received Thirty-one to LAAN with full services methadone daily and services as above. Ninety-six to methadone with no other The Dispensary group received methadone services daily for four weeks and then three times 88 weekly with take home doses on alternate days. No counseling or services were Illicit Drug Use offered. Dosage modifications were made during the study. The mean initial admin- There was an increase in numbers of urines istered doses were 57.8 for the LAAM negative for morphine in the Dispensary, LAAM, group, 40.6 mg methadone for the Methadone and Methadone Full Service groups whether Full Service group, and 41.3 mg for the based on percentages of remaining sample Dispensary group. (72.7 percent, 90.9 percent, and 60.0 percent, respectively), or percentages of the total Criteria For Effectiveness--The groups sample (33.3 percent, 33.3 percent, and 38.7 were compared with respect to the follow- percent, respectively). Differences between ing variables: the groups were not significant. Dropout rate Dosage Changes Changes in medication dosages Use of illicit drugs (as evidenced in Dispensary patients requested significantly biweekly urine checks) fewer changes (p<0.01) than did patients in Employment rate the full services groups (Dispensary: 3 Self-reports of illegal activity and changes/100 ma” weeks of treatment; LAAM: 7 arrests changes/100 man weeks of treatment, Metha- done Full Service: 8 changes/100 weeks of treatment). The mean LAAM dose at 48 weeks (93.9 mg) was significantly higher than the mean dose of the Dispensary group (p<0.01; 51.7 mg), or the Methadone Full Service RESULTS group (p<0.05; 70.9 mg), but total weekly dosage was less than that of patients on Failure Of Research Design With Respect To methadone. Dispensary Employment Rates Inpractice, counseling services, and support could not be withheld from the Dispensary There were no differences in employment patients by the clinic staff, so the com- rates among the three treatment groups. parison made by the study was between full and minimal services rather than between full Arrests And Illegal Activity and no services as intended. Self-reported illegal activity decreased in Methadone with full services appeared to be proportion to length of time in treatment superior to LAAM with full services and to for all groups. There was no significant methadone with minimal services. difference among groups in self-reports of arrests (Dispensary: 2.1 arrests/100 man Dropout Rate weeks in treatment; LAAM, 2.3 arrests/100 man weeks; Methadone Full Service, 3.0 Forty-nine percent of the Dispensary group, arrests/100 man weeks. 50 percent of the LAAM group, and 29 percent of the Methadone Full Service group had Clinical Observations dropped out by week 48. There were no significant differences among treatment groups There were no observations of confusion, in total number of weeks of participation in psychotic symptoms, or unpleasant subjective originally assigned group (Dispensary, 30.5 states in any subjects. Anxiety was ob- weeks; LAAM, 29.7 weeks; Methadone Full served but was not associated with any Service, 35.3 weeks). Methadone with or treatment group in particular. Two deaths without services had more holding power than occurred, one from suicide and one from lung LAAM. cancer.

89 21

THREE TIMES A WEEK LAAM EQUALS SEVEN EXPERIMENTAL DESIGN TIMES A WEEK METHADONE: A PRELIMINARY Subjects REPORT OF A CONTROL STUDY. 1974 Subjects were randomly assigned to one of two groups. Experimental (LAAM) Group--Thirty-four male patients were included in this group with the following characteristics: Average age, 31.1 years Average education, 11.2 years EDWARD C. SENAY, PIERRE F. RENAULT, Average years narcotic use, 11.7 SALVATORE DIMENZA, WESLEY E. COLLIER, 32.3 percent married STEPHEN J. DANIELS, WALTER DORUS 20.6 percent employed 73.3 percent arrested at least once in two years prior to entrance in study 100 percent black At least 14 weeks in treatment INTRODUCTION Control (Methadone) Group--Thirty-one male patients were included in this LAAM has been shown to be an effective sub- group with the following characteristics: stitute for methadone in the treatment of heroin addiction (Jaffe and Senay, 1971; Average age, 29.0 years Jaffe et al., 1970, 1972; Senay et al., 1973). Medication is only one part of therapy, how- Average education, 11.5 years ever; and the decreased frequency with which LAAM patients need to visit the clinic may Average years narcotic use, 9.7 weaken the influence of the rest of the program, i.e., therapy, vocational rehabilita- 30 percent married tion, and legal services. This paper reports an extension of previous studies to determine 25.8 percent employed whether new LAAM patients attend clinic less 70 percent arrested at least once in frequently than new methadone patients and two years prior to entrance in study if treatment outcome is influenced by attendance. 90 percent black, 6.4 percent white, 3.2 percent Spanish origin At least 14 weeks in treatment 90 Methodology The average initial daily methadone dose was 33.5 mg and was 36.5 mg at 14 weeks. Two clinics were established; one dispense LAAM and offered group therapy and individual Dose levels were very stable throughout the counseling three times weekly, remaining open duration of the study. with support staff and recreational facilities Monday through Friday. The other dispensed methadone and was open six days a week with Sunday medication taken home. The two groups were compared on the following criteria: Employment And Arrests

Dropout. rate Employment and arrest measures were identi- Clinic attendance cal in both groups: Urine negative for illegal drugs Dosage changes Two subjects in each group were arrested. Employment Arrest Five of the six patients who had jobs Side effects initially still had them at 14 weeks. Dose levels were 10 mg higher on Friday for One of the 17 unemployed in each group LAAM patients and dosage in both groups could found a job. be adjusted weekly. No other medications were prescribed. RESULTS Side Effects Retention Rate And Clinic Attendance No side effects attributable to methadone were reported. LAAM patients dropped out earlier in treatment; the difference was significant at five No medical complications developed in either weeks. By the end of the fourteenth week, group. ‘however, there was no significant difference between the two groups. The LAAM clinic One LAAM patient died due to heroin overdose retained 23 of 34 subjects. The methadone 48 hours after his second dose of LAAM. clinic retained 23 of 31 subjects. Five patients experienced side effects in LAAM patients attended the clinic on 57.6 the LAAM group. percent of the days it was open and 94.2 percent of the days on which medication was Four patients had anxiety and nightmares, dispensed. three in the first month of treatment and the fourth in the second month. Methadone patients attended the clinic on 90.3 percent of the days it was open, medica- Dose levels were 30 mg (2) and 50 mg tion being dispensed every day. (2). Urine Negative For Morphine Dose levels were lowered 10 mg in two subjects, one on 30 mg and one on 50 mg. The two groups were similar in extent of use Symptoms did not persist nor did they of unauthorized drugs. LAAM patients had return when dose levels were increased urines negative for morphine a” average of again. 10 out of 14 weeks; methadone patients, 9.8 out of 14 weeks. The early tendency for the Dose levels were maintained for the methadone group to have more urines negative other two patients and symptoms did not for morphine was reversed after the eighth persist more than one week. week when the LAAM group began to use drugs less. One patient on 50 mg LAAM exhibited bizarre behavior of which he had no Dosage Changes recollection. Medication was reduced to 40 mg and symptoms persisted. He was The initial average LAAM dose was 44.7 mg; transferred to a methadone clinic. He doses were 10 mg higher on Fridays than on subsequently reported having been hos- Mondays and Wednesdays. At 14 weeks, the pitalized in a mental institution seven average LAAM dose was 44.4 mg. years before the study. 91 22

group and ten to the control (methadone) LEVOMETHADYL IN MAINTENANCE TREATMENT group. The two groups did not differ from each other in age, years of drug abuse, or OF OPIATE DEPENDENCE, 1972 social class. They were detoxified and drug free at least one week before the study. Methodology The duration of the study was six months. Subjects in the experimental group received medication on Mondays, Wednesdays, and Fridays. Dose levels were built up as inpatients; the subjects were discharged when ARTHUR ZAKS, MAX. FINK, ALFRED M. FREEDMAN dose levels were attained. Two dose levels of LAAM were established: Four patients at low dose, 30-40 mg twice weekly and 50 mg on Fridays Five patients at high dose, 80 mg three times a week One subject was discontinued because of of a prior seizure disorder INTRODUCTION Subjects in the control group were built up to 100 mg methadone hydrochloride daily in The 72-hour duration of action of methadyl the hospital and discharged. After the first acetate has been established in single dose month, they attended the clinic twice weekly and controlled clinical studies (Fraser and and received take-home medication. Isbell, 1952; Jaffe et al., 1970 and 1971). The purpose of this study was to investigate Criteria For Effectiveness the potential of levomethadyl acetate (LAAM) in a maintenance program for narcotic addicts Subjects were evaluated for changes in voca- and to define dose levels. duration of tional and social rehabilitation on a scale action, secondary effects; and degree of from 0 (no change) to 2 (marked improvement). blockade to heroin. Substance abuse was monitored by twice weekly EXPERIMENTAL DESIGN urine testing for the presence of morphine, heroin, barbiturates, and amphetamines. Subjects Cross-tolerance to 25 mg heroin was estab- Subjects were 20 male narcotic addicts age lished while drug free and to 25 and 50 mg 21 or over with at least a two-year addiction heroin after induction at 24 hours after history and one treatment failure. Ten were treatment for all subjects and 48 hours after randomly assigned to the experimental (LAAM) for one high-dose LAAM subject. The quality

92 of the euphoria, voice change, and pupillary All five high-dose LAAM subjects demonstrated constriction were observed; subjects were complete blockade to 50 mg heroin. interviewed and completed an Addiction Research Center Inventory (ARCI) question- The high-dose subject challenged at 48 hours naire. demonstrated complete blockade to heroin. Adverse Experiences Look For All 10 100 mg methadone subjects demonstrated complete blockade to 50 mg heroin. Laboratory studies of liver function, fasting blood glucose, blood urea nitrogen, uric Urine Tests acid, blood cell caunt, and urinalysis were made prior to and weekly during the study. The LAAM group had 8.9 percent positive tests for morphine compared to 2.0 percent for the RESULTS methadone group. High- and low-dose LAAM subjects had 2.8 percent and 18.9 percent, Dropouts respectively.

One of the nine LAAM subjects dropped out at The LAAM group had 2.0 percent positive three months; two of the ten methadone tests for barbiturates and amphetamines com- patients dropped out, one at two months and pared to 7.9 percent for the methadone one at four months. Eight LAMM and eight group. methadone patients remained in the study at six months. Behavioral Change Ratings Adverse Experiences And Side Effects Ratings of change in vocational and social The methadone group did not complain of side functioning were similar in the two groups; effects; constipation at the beginning of 1.4 for the LAAM group and 1.2 for the metha- treatment was acknowledged by four subjects done group. when asked. Dose Levels Three of nine LAAM subjects complained of irritability; one of these also complained Withdrawal symptoms were experienced by of anxiety. Tranquilizers were prescribed three of the four low-dose LAAM group, 40-48 to two patients. hours following their last dose. Two of the LAAM subjects complained of in- At the 80 mg LAAM dose level, no withdrawal voluntary, jerky movements of the extremi- symptoms or craving for heroin were reported. ties preceding sleep, persisting inter- mittently throughout the study. Cross-Tolerance To Heroin Results of all laboratory tests were normal Three low-dose LAAM subjects responded to for both groups except liver function tests. challenge with 50 mg heroin with mild, trans- All subjects manifested intermittent ele- ient euphoria; blockade was complete in the vated transaminase levels which were fourth subject. sporadic and not dose related.

93 This chapter and the following present summaries of the Phase II clinical studies of LAAM. A8 discussed in the introductory chapter, both of these studies were initiated by SAODAP to detenmine safety and effectiveness of LAAM. The clinical trials in each of the Phase II studies were carried out simultaneously in multiple participating clinics utilizing a common protocol. This procedure ensured attainment of adequate sample sizes within a reasonable time and of a more geographically representative sample of addicts than possible in a single clinic. Also, this procedure permits analysie of variation in outcome between different clinics. Organization, execution, monitoring of both studies and data compilation, analysis, interpretation and reporting were performed by C. James Klett, Chief VA Central Neuropsychiatric Research Laboratory and Cooperative Studies Program Support Center. The following summaries of the VA and SAODAP Cooperative Studies of LAAM and Methadone were prepared from progress reports submitted by Dr. Klett to FDA as sponsor of the Phase II IWD. SUMMARY OF VETERANS ADMINISTRATION PHASE II COOPERATIVE STUDY FOR LAAM AND METHADONE Waltor Ling , M.D. V. Charles Charuvartra, M. D. Samuel C. Kaim, M.D. C. James Klett, Ph.D.

Although early studies tend to substantiate (80-120 mg) dosage. Garbutt and Goldstein the observation of the clinical usefulness of (2), for instance, have found an average of acetylmethadol, the number of patients 50 mg to be just as effective as 100 mg studied was quite small. The present study with respect to survivorship in the program attempted to maximize subject availability by and cessation of heroin use. means of multihospital participation in a common double blind protocol. The goals of METHOD the study were to evaluate the safety and toxicity of a fixed dose of acetylmethadol Patients (80 mg TIW) and to compare its relative efficacy with two doses of methadone, a high Patients were eligible for the study if they (100 mg) and a low (50 mg) daily dose. met all of the criteria for admission to Safety and toxicity were evaluated by a multi- methadone maintenance programs as defined by layer clinical and laboratory monitoring the FDA and were males between the ages of system. Relative efficacy was measured in 18 and 60. Patients were excluded for terms of a number of outcome variables, incapacitating or life-threatening condi- including positive urines, clinic attendance, tions, disease requiring regular repeated employment, and social rehabilitation. A medication, frankly psychotic states, secondary goal of the study was to compare epilepsy, current severe alcoholism, and the two methadone doses with regard to pending criminal charges. It was further these same outcome variables, since the specified that any addicted spouse or rela- desirability of high dose versus low dose tive in the same household must be under methadone maintenance remains an issue of treatment and that there be a reasonable controversy. Originally, Dole and Nyswander expectation that the patient would continue (1) had advocated a rather high methadone to reside in the vicinity of the clinic and dose. It was felt that this would produce a be able to attend for the full duration of physiological "blockade" against the effect the trial. Eligible patients who signed an of heroin and would thus discourage further informed consent for voluntary participation experimentation with illicit drugs. Others in the study were then given a general physi- have questioned the need for this high cal examination with neurologic and

94 psychiatric evaluation and including chest adherence to the clinic schedule of visits x-ray, electrocardiogram, urinalysis, and and details of medication dispensed. Urine blood studies. Patients began treatment on samples were collected weekly following a the following Monday. random testing sequence supplied centrally. Specimens were sent to the clinical labora- Drug Administration tory at the Sepulveda VA Hospital where they were tested for morphine, barbiturates, Patients were randomly assigned to levo- amphetamines, and a variety of other sub- alpha-acetylmethadol or one of two dose stances. Whenever a patient concluded levels of methadone. The two methadone treatment, an attempt was made to repeat all groups received active medication daily but evaluations and the staff recorded their the acetylmethadol group received active consensus judgment of outcome in a number of medication on Monday, Wednesday, and Friday different areas. with placebo (dextromethorphan plus quinine) on all other days. Take-home doses (of the RESULTS Tuesday, Thursday, Saturday, Sunday doses only) were permitted at the physicians’ Characteristics of Sample discretion after the twelfth week of treatment. Take-home doses of acetylmethadol were The sample consisted of 430 men whose median not permitted; any take-home dose in this length of addiction to opiates was 7.2 group was placebo. All doses were dispensed years. They were reasonably young (58% were in a masking-diluting liquid such as Tang or below the mean age of 31 years) and reason- grapefruit juice. ably well educated 62% had graduated from high school and 21% had gone on to do some The first dose in all three groups was 30 mg college work. Mast had been married at one which was incremented by 10 mg on each suc- time but 37% were still single. Racially, ceeding Monday until the patient achieved 46% were black, 39% white, and 11% had his target dose of 50 mg of methadone (M-50), Spanish surnames. Other characteristics 100 mg of methadone (M-100), or 80 mg of were consistent with expectation in an acetylmethadol (L-80). All doses were dis- addict group. pensed double-blind with the sequence of dosage increments and placebo doses con- Early Termination trolled by bottle number. Duration of treatment was 40 weeks (280 days). Only 42% of the starting sample completed the full 40 weeks of the study. If all Psychotrophic drug use was permitted only reasons for termination are combined, 69% for occasional nighttime sedation. All use terminated early from the L-80 group (N=142), of supplemental medication during the trial 58% from the M-50 group (N=146), and 48% was recorded. from the M-100 group (N=142). This difference between the L-80 and M-100 groups is Clinical Evaluations statistically significant. Not all of these patients terminated for drug related reasons Patients were evaluated immediately before but since the nondrug related terminators and every four weeks during their tenure in should have been equally distributed among the study. The evaluation included a brief groups except for chance, it has to be con- history, a current status record of their cluded that high-dose methadone maintenance employment activity, legal involvement, (M-100) was superior in retention to the interpersonal relationships and drug use L-80 group. It does not necessarily follow during the preceding four weeks, a supple- that high-dose methadone is the superior mentary medication record of all drugs pre- maintenance drug, however, because there are scribed during the preceding four weeks, and other dimensions of outcome that must be a symptom-sign checklist. The complete considered. physical examination was repeated at the twelfth week and at the end of the study, The average length of stay in the study with abbreviated physical exams at all other before early termination was remarkably four week evaluations. Vital signs (blood similar for the three groups: 82 days for pressure, temperature, pulse) and weight were the two methadone groups and 81 days for recorded on these occasions and fluid samples the L-80 group. Of the 251 early termina- were obtained for laboratory tests. tions, 45% occurred by the end of the seventh week (which marked the end of the In addition, daily entries were required on induction period for the M-100 group). A a treatment record of each patient’s greater number of terminations had occurred

95 in the L-80 group by this time but when the differences between groups for specific groups were adjusted for their total number categories of dropout were: a greater of dropouts, there was no apparent trend for number for side effects in the L-80 group patients to drop earlier from one group than than in the M-50 group, and a greater number another. of "No shows" in the L-80 group than the M-100 group. (Note: In these and all sub- Table 1 presents the number of patients in sequent analyses, p<.05 was accepted as the each group who terminated early for a level of statistical significance.) variety of reasons. The only significant

TABLE 1

Reasons for Early Termination

Reaons M-50 M-100 L-80 Total

Jail 11 5 10 26 Side effects 0 3 8 11 No show for 7 days 4 1 8 13 Moved from area 11 11 12 34 Medication not holding 11 8 16 35 Dose too high 4 10 5 19 Disciplinary discharge 7 3 3 13 Didn't like study 16 11 14 41 Didn't like drug 1 1 2 4 Detoxification 6 8 7 21 Couldn't attend clinic 5 1 3 9 Psychiatric 6 4 5 15 Miscellaneous 2 1 4 7 Excessive drug use (illicit) 1 1 1 3

Total 85 68 98 251

96 Safety as Total Symptomatology were subsequently monitored along with the individual symptom- There were no deaths of study patients, nor signs. were there any serious adverse reactions reported. There were 11 patients terminated As a general statement, reporting of any primarily for side effects. Four L-80 symptom-signs was infrequent and of a low patients terminated because of inability to level of severity when reported. All three ejaculate and another L-80 patient who ter- factor scores and total symptomatology had minated because of swelling of joints listed their highest level in the first week or decreased sexual interest along with heart- two of treatment but rapidly decreased to burn, nodding, and constipation. The other nearly absent levels. There were no differ- L-80 terminators were: a patient who ences between drugs worth noting. Because couldn’t keep medication down (nausea, vomit- of special interest in several specific ing); another who complained of being tired symptom-signs, this analysis was supple- and dizzy with chest and arm pain; and one mented by another approach which used the who experienced jerking of extremities at patient as the unit of analysis and examined bedtime and some nausea. The three high-dose individual symptom-signs (rather than deal- methadone patients were terminated because ing with the mean level of a cluster). For of: a pruritic maculo-papular rash that each symptom-sign separately, a patient was developed on a second day while the patient tallied as "severe" if he had even one such was still on 30 mg; abnormally high liver rating at any time during his tenure in the function tests which were present before study. A patient who was never rated as treatment but showed only minor trends toward "severe" but had at least one rating of stabilization at a lower level; and an "moderate" was tallied in that category and apparent case of hone marrow suppression. if a patient was never rated as "moderate" or "severe" but had at least one rating of The symptom-sign data were collected by a "mild", he was tallied in that category. research assistant, nurse, or primary Patients tallied under "none" were those therapist before the Monday dose every week rated as asymptomatic throughout. In this for the first eight weeks and every four particular approach, the pretreatment rating weeks thereafter. The schedule consisted was ignored completely. To be tallied some- of 30 symptom-signs and an "OTHER" category. where in the table, a patient had to have Specific symptom-signs were not enumerated, at least one rating during treatment; but when their presence was elicited by patients who completed the study could have general questioning, their severity was as many as 16. This approach defines the judged as mild, moderate, or severe. highest rating obtained during treatment per patient as a unit of analysis. Table 2 Initially each symptom-sign was monitored presents these data for all three drug independently as well as in a priori clusters. regimens combined. When sufficient data had accumulated, the schedule was factor analyzed and a three factor solution accepted as the best repre- sentation of the data. The first factor (14 items) is clearly an Underdosing withdrawal factor. It consists of Aching Bones and Joints, Yawning, Runny Nose, Watery Eyes, Muscle Cramps, Goose Bumps, Loss of Appetite, Abdominal Cramps, Nausea and Vomiting, Diarrhea, Insomnia, Excessive Sweating, Irritability, and Anxiety (tension, nervousness). The second factor (five items) is an Overdosing factor which consists of Feeling High, Nodding, Dizziness on Standing, Poor Concentration, and Impotence. The remaining 11 items made up a third factor which was termed Somatic: Heartburn-Gastric Distress, Constipation,Bad Dreams and Nightmares, Drowsiness, Blurring of Vision, Urinary Frequency, Decreased Sexual Interest, Delayed Ejaculation, Numbers of Hands and Feet, Involuntary Jerking Movements of Lower Extrem- ities, and Edema of Extremities. These three factors and their sum which was referred to

97 TABLE 2

Number and Percent of Patients in Terms of Highest Severity Rating Obtained During Treatment

None Mild Moderate Severe N % N % N % N % Aching bones and joints 152 37 130 32 108 27 18 4 Yawning 171 42 152 37 75 18 10 2 Runny nose 136 33 163 40 97 24 12 3 watery eyes 160 39 158 39 79 19 11 3 Musle cramps 212 52 118 29 60 15 17 4 Goose bumps 221 54 106 26 70 17 10 2 Loss of appetite 117 29 156 38 117 29 18 4 Abdominal cramps 181 45 134 33 76 19 17 4 Nausea or vomiting 160 39 141 35 84 21 23 6 Diarrhea 288 71 81 20 37 9 2 0 Insomnia 113 28 139 34 129 32 27 7 Excessive sweating 92 23 111 27 177 44 28 7 Irritability 124 30 144 35 123 30 17 4 Anxiety (tension, nervousness) 91 22 136 33 150 37 31 8 Feeling high 298 74 74 19 25 6 3 1 Nodding 260 65 96 24 38 10 6 2 Dizziness on standing 297 74 75 19 24 6 4 1 Poor concentration 252 63 107 27 31 8 10 2 Impotence 297 74 44 11 44 11 15 4 Heartburn-gastric distress 221 54 123 30 54 13 9 2 Constipation 78 19 129 32 167 41 34 8 Bad dreams or nightmares 205 50 110 27 81 20 12 3 Drowsiness 162 40 156 38 83 20 7 2 Blurring of vision 286 70 84 21 32 8 5 1 Urinary frequency 244 60 101 25 54 13 9 2 Decreased sexual interest 164 40 116 29 97 24 30 7 Delayed ejaculation 185 45 98 24 84 21 40 10 Numbness of hands or feet 231 57 114 28 46 11 16 4 Involuntary jerking movements of lower extremities 180 44 136 33 83 20 8 2 Edema of extremities 335 82 47 12 23 6 2 0 Other 253 62 46 11 81 20 27 7

The data shown in Table 2 were also generated Anxiety for which M-50 significantly exceeded separately by drug regimen and differences L-80 in terms of moderate-severe ratings. between groups evaluated by 2 x 3 chi-square or Fisher’s exact probability test. For these tests, rating was dichotomized as None- Mild and Moderate-Severe. In only three instances was there a significant drug difference: Aching Bones and Joints for which the M-50 group had a significantly higher frequency of moderate-severe ratings than either of the other groups; and

98 Although Delayed Ejaculation (and possibly 24 weeks. Usually this consisted of 60 M-50 other problems in sexual function) seemed to patients, 57 M-100 patients, and 45 L-80 be associated with the L-80 patients in the patients. The 40-week cohort usually con- early termination data, this was not sup- sisted of 39 M-50 patients, 45 M-100 ported by the symptom-sign data where ratings patients and 31 L-80 patients. Although the of moderate and/or severe on Impotence, statistical testing provided a variety of Decreased Sexual Interest, and Delayed Ejacu- information about within-group and between- lation are all more frequent (but not sig- group differences, the primary interest was nificantly so) in the methadone groups. in two tests of between-drug regimen differ- Irritability is another symptom-sign of ence. One of these was essentially in terms special interest because of observations of of the average of all tests periods--the animals on acetylmethadol in the preclinical height of the curve. The other tested the studies. In this study, irritability is variation of means across time between drug represented in higher frequency in the groups (the drug by time interaction). In methadone groups but not significantly so. the analysis of the 25 variables using the 24-week cohort, there was a single signifi- The "Other" category included a wide array cant finding--the interaction of drug and of symptom-signs, many of which seem to be time on weight. In the analysis of the same either trivial or clearly nondrug related, variables using the 40-week cohort, there most of which were reported at a single was a significant interaction for total WBC, rating period only rather than persistently total RBC, hematocrit, hemoglobin, and and some of which were elaborations of one weight. In addition, there was a signifi- or more of the 30 symptom-signs on the cant difference between groups for SGOT when checklist. all values were collapsed across time. The laboratory studies were conducted before In another series of analyses, a cohort of treatment and every four weeks thereafter. 128 patients from three hospitals who had a Hematologic tests consisted of total WBC, complete set of values over a 20-week total RBC, neutrophils, lymphocytes, eosino- period were used to provide similar but phils, monocytes, basophils, hematocrit, and somewhat different information. In these hemoglobin. Blood chemistry was the usual analyses, the pretreatment value was SW-12 panel, specifically calcium, FBS, BUN, included as a covariate and all subsequent uric acid, total protein, albumin, total values were adjusted for initial level. bilirubin, alkaline phosphatase, LDH, and Hospital was included as a factor in the SGOT. (Globulin was calculated as the design which permitted a comparison of difference between total protein and albu- hospitals and the various interactions of min.) Urinalysis included albumin, sugar, hospital with drug and time. Both of these WBC, and RBC. Vital signs recorded at the changes in design were introduced to pro- same intervals included blood pressure, vide greater sensitivity for the analyses pulse and temperature, plus weight. of drug difference, although it was accomplished by reduction in time to 20 weeks, a The hematologic tests, blood chemistries, reduction of sample size and a restriction vital signs and weight provided 25 compari- to the three hospitals that had sufficient sons for each of the 10 test periods (weeks data to be included. In these analyses, the 4, 8, 12, 16, 20, 24, 28, 32, 36, 40)--a only main effects of treatment that reached total of 250 analyses of covariance with significance were on weight and pulse. initial level as the covariate. Only six of There were significant interactions between these were statistically significant. Three drug and time on hematocrit, hemoglobin, and of these occurred on a single variable-- SGOT. weight. The others represented a difference between groups at one period only: WBC at A final attempt to gain precision and week 20, calcium at week 36, and alkaline extract information about any drug group phosphatase at week 16. Sample sizes for changes present in the data consisted of a these tests ranged from slightly over 300 series of multivariate analyses of covari- cases for the pre- to four-week analyses to ance. The following hematologic tests were around 160 cases for the 40th week analyses. analyzed simultaneously: WBC, RBC, neutrophils, lymphocytes, hematocrit, and herno- Two cohorts of patients were established to globin. The pretreatment values on all six look specifically at changes over time variables were used as covariates and the rather than cross-sectionally. The 24-week values at each test point were used as cohort consisted of patients who had a com- dependent variables. Hospital was included plete set of data on a variable at pretreat- as a factor, and in each analysis as many ment and every test period for the first patients and as many hospitals were included

99 as possible. There were no significant The evidence for RBC is not convincing. differences involving treatment group in There appeared to be a predominately linear these analyses. The renal tests (calcium, downward trend particularly in the two metha- BUN, and uric acid) were analyzed in the done groups over the first 20 to 24 weeks but same manner and with the same result. In the trend did not continue and in fact the analysis of liver function tests (total seemed to reverse itself. It may be more bilirubin, alkaline phosphatase, LDH, SGOT accurate to say that there was some initial and an index defined as albumin divided by decline which then leveled off. The only globulin), there was a significant differ- between-groups difference was the drug by ence between groups at the 16th week only. time interaction in the 40-week cohort, and The multivariate test of vital signs and even in this analysis only at week 8 was weight was significant at the 4th week only. there a significant difference between drugs (M-100 highest, L-80 lowest, all means within These different analyses each supply some- normal values). It is difficult to conclude what different information and need to be that there is anything clinically significant further examined and integrated. In the in RBC. The situation is much the same for hematologic tests, there is reason to look hematocrit and hemoglobin. The trend analy- closer at WC, RBC, hematocrit, and hemo- ses suggest an initial decline in all three globin. In the covariance analyses of WC, groups and then a leveling off after about a significant difference between groups was the eighth week. There is no clear and con- obtained at week 20. The adjusted means sistent separation of groups across time. were M-50 7180, M-100 7720, and L-80 8060. Finally, considering also the results of the In addition there were significant differ- multivariate tests that included all of ences in unadjusted post means at week 16 these variables, it seems reasonable to con- and 20. In a total of 30 tests of pre-post clude that the occasional between-groups within-groups change (three drug groups differences that did emerge as statistically times 10 time periods), only the change from significant have no clinical importance. In pre- to week 8 in the L-80 group was signifi- no case were the blood changes sufficient to cant. Furthermore, all means at all test necessitate termination from the study. points were within the normal range (all means varied from 7260 to 8020). In both The evaluation of renal and liver function the 24 and 40-week cohorts, there was sig- tests was similarly reassuring from a clin- nificant within-group variation of means ical point of view. SGOT was noteworthy across time in the L-80 group but this for the fact that the means of all three drug variation represented considerable scatter groups before and throughout treatment were in values from one test period to the next well above the usual normal range (from a low rather than an increasing or decreasing of 56 to 107) and the pretreatment values for trend in WBC. The same scatter was present many individual patients were high enough to but not significantly so in the two metha- be of serious concern in a nonaddict sample. done groups. In the 40-week cohort analysis, The main finding for SGOT is that the L-80 this variation across time was significantly curve is at a somewhat higher level at pre- greater in the L-80 group than in the two treatment and throughout the 40 weeks than methadone groups (significant interaction) the methadone groups. All three groups show and there were significant differences essentially no change across time on SKIT. between drugs at week 16, 20 and 28. The The significant difference between groups at drug by time interaction was not significant week 16 in the multivariate analysis of the in the 24-week cohort. At each of these test liver function tests is paradoxical and not points (week 16, 20, 28) the L-80 mean was likely to be of clinical importance because highest and the M-50 mean was lowest. All there is so little supporting evidence of means were in the normal range. There were differences at other weeks either in the no drug differences in the 20-week cohort univariate or multivariate tests. analysis. In summary, there is a suggestion that something might have been happening The analysis of vital signs and weight had a with WBC in at least some patients during generally low yield, except for weight, the middle weeks but it is difficult to give which is clearlv affected bv all three drug clinical meaning to it because it did not regimens, and particularly acetylmethadol. persist, all means are comfortably in the There is clearly an upward trend in all normal range and a review of individual groups, and somewhat more substantially so in patient's data did not identify anything the L-80 group. There was no morbid obesity remarkable about this part of the treatment reported. period. RBC, hematocrit, and hemoglobin surfaced as possibly significant (in a clinical sense) on the cohort analyses only.

100 Efficacy a simple variable. The amount of drug use is, of course, important but the pattern is This study was not designed to evaluate probably even more so. A patient who com- efficacy in the usual manner, i.e., there is pleted the study with 50% urines positive no placebo or nontreatment group. However, for morphine could have been entirely clean acetylmethadol has previously been shown to in the first or the last 20 weeks. The be pharmacologically effective in suppressing latter seems to be a clearly superior out- the abstinence syndrome and there is abun- came. dant evidence in this study that both drugs will maintain addicted individuals without An index of illicit morphine use has been their having to resort to supplementary derived which takes into account total use (illicit) narcotic use to avoid withdrawal. and pattern of use. With a single exception It seems reasonable to assume efficacy in to be noted later, this index was developed this sense and turn to the question of the completely independent of the study data and relative efficacy of the three drug regimens. was therefore not biased by knowledge of drug group outcomes. This index has some There are a number of variables that indi- arbitrary features end some defects but vidually or collectively could be used to experience with its use has not revealed deal with the issue of relative efficacy. serious distortions. The rules are entirely All of these are imperfect indices. The objective and do not require clinical judg- amount of discomfort indicated on the Under- ment . The entire operation can be performed dosing factor of the Symptom-Sign Record by the computer. provides a measure of efficacy but would need to be evaluated sirmultaneously with illicit Rule 1: A score cannot be derived for a drug use to be unambiguous as an outcome patient who is in the study for less than 50 index. Early termination is obviously days (seven weeks). related to efficacy in some complex manner but is less than ideal as an indicator for Rule 2: Urine tests Positive for morphine some equally obvious reasons. A patient are given a weight of five if they occur in who completes 40 weeks of treatment but the last 8 weeks of a patient’s tenure in the tests positive for morphine at every week study, a weight of four if they occur in the cannot be considered more of a treatment next to last 8 weeks, three if they occur in success than a patient who is clean for 32 the next block of 8 weeks and so on. weeks and then moves to another part of the country Both kinds of patients are repre- Rule 3: A missing urine test result is sented in this study. Conformity to sched- handled in exactly the same manner as a uled clinic visits is equally ambiguous. positive urine except that it is not weighed Some patients who faithfully attend clinic as heavily. A positive urine in the last show a heavy illicit drug use pattern. It 8 weeks would be weighted 5 x 1 = 5; a is not even safe to assune that missed clinic missing value would be weighted 5 x .22 = visits are accompanied by illicit drug use. 1.1. The value .22 is not totally arbitrary Many other outcome variables are clearly but is derived from the data. It represents secondary, i.e., have no direct pharmaco- the percent of all urine samples collected in logical relationship to the drug. Examples the study that tested positive for morphine are employment variables, encounters with the and its use for missing value introduces some law, and interpersonal relationship variables. notion of the probability that a missing It is the hope and the expectation that value would have been positive. patients being adequately maintained will show improvement in these areas and it may Rule 4: All scores derived by the rules be appropriate to use such variables to above are adjusted to a comparable range of evaluate a total program of rehabilitation 0 to 120. Patients who have 40 negative including the whole array of supportive urines would be scored 0; patients with 40 services but it seems unjustified to use positive urines would be scored 120. them as criteria of primary drug effect. They seem, instead, to be contingency Although the index seems to have the desired variables. The use of these variables as characteristic in an abstract sense, the test outcome indicators of maintenance treatment of its value must be in terms of actual data. is contingent upon achievement of the primary Preliminary attempts to establish construct goal which is to decrease illicit drug use. validity have been encouraging. It was predicted that the drug use index would corres- Urine test data is considered to be the key pond to staff judgments of outcome made at to evaluation of the results of this study. the time of termination of a patient’s par- Unfortunately, even illicit drug use is not ticipation in the study. The patients rated

101 as being better or much better had a mean outcome, which was a combined staff judgment urine index of 17.5, the patients rated made shortly after a patient's termination, unchanged had a mean of 38.3, and the taking into account all known information patients who were worse or much worse had a about the patient. This was a five-point man of 39.9. The F was 24.16 (p< 001). A scale: much improved, improved, changed, similar relationship was predicted for worse, and much worse. The M-50 group was percent clinic attendance. Patients who had judged to be significantly less improved than a perfect attendance record had a mean urine either the M-100 group or the L-80 group. index of 17.7, those patients that had a near perfect attendance record (96-99.9%) Preliminary review of secondary (contingent) had an index of 20.5, the patients who outcome variables such as number of arrests, attended 90 to 95.9% of the time had an hours of employment, income, etc. has not index of 33.0 and patients whose attendance yielded evidence of advantage of any one was below 90% had an index of 36.3. The F group over another but a conclusive summary was 7.82 (p< .001). A series of more care- of these variables will have to be deferred fully planned analyses will need to be con- until more definitive analyses have been ducted to further define the index. However, done. Similarly, there are many other using this index to compare the three drug aspects of the data that will have to await regimens gave the following results: 110 subsequent publication. M-50 patients had a urine index of 33.3, 111 M-100 patients had an index of 22.6, and REFERENCES 96 L-80 patients had an index of 20.8. The F was 6.19 (p< .005). The M-50 group is 1. Dole, V.P. et al: Methadone maintenance. significantly higher on the urine index than A report of two years experience. Pre- either M-100 or L-80. sented at Annual Conference of National Research Council Cormittee on Problems Urine test data were analyzed in other ways of Drug Dependence, New York, 1966. as well. For each patient, the number of National Academy of Sciences, urines positive for morphine was divided by Washington, D. C. the number of his specimens tested. This gave a "percent dirty for morphine" score 2. Garbutt, G.D., Goldstein, A.: Blind for that patient which was then used in a comparison of three methadone maintenance comparison of groups. A similar score was dosages in 180 patients. Proceedings calculated for barbiturate positive, amphet- of Fourth National Conference on Methadone amine positive, and "something" positive, Treatment. National Association for the latter being the number of specimens Prevention of Addiction to Narcotics, positive for either morphine, barbiturates, New York, 1972, pp. 411-414. amphetamines, or cocaine (tested randomly) at any one week divided by the total number of specimens for that patient. The results of these analyses showed the L-80 group less likely to use illicit barbiturates than the AUTHORS M-50 group. Affiliation of the authors of this article is Another kind of outcome index is program as follows: From the Veterans Administration conformity, which was defined as each Hospitals, Sepulveda, California (Dr. Ling), patient's number of actual scheduled clinic Brentwoti, California (Dr. Charuvastra) and visits divided by his total number of Perry Point, Maryland (Dr. Klett) and from expected scheduled visits for however long the National Pharmaceutical Council, Inc., he was in the study. The M-50 group had an Washington, D.C. (Dr. Kaim). average of 92% attendance, M-100 95%, and L-80 90%. The difference between M-100 and L-80 on this clinic visit index was significant. However, since the acetylmethadol patients only received active medication on MWF, the analysis was redone comparing the three groups on percent attendance for those days only. L-80 still had a lower average attendance rate than M-50 or M-100 but the difference is not significant. Still another evaluation of relative efficacy was possible using the global rating of

102 SUMMARY OF SAODAP PHASE II COOPERATIVE STUDY OF LAAM VS. METHADONE

Waltor Ling, M.D. C. James Klett, Ph.D. Roderic D. Gillis

The primary purpose of the trial was to pending criminal charges. It was further compare the efficacy and safety of LAAM and specified that any addicted spouce or rela- methadone for treating heroin addicts in a tive in the same household must be under maintenance program. The program was treatment and that there be a reasonable designed to be conducted with uniformity, expectation that the patient would continue supervision and coordination based upon to reside in the vicinity of the clinic and adherence to three common protocols. Data be able to attend for the full duration of were recorded on a uniform set of forms and the trial. Eligible patients who signed an submitted to a central data coordinating informed consent for voluntary participation center for analysis. Safety was evaluated in the study were then given a general by monitoring patients for symptoms, signs physical examination with neurologic and and laboratory evidence of toxicity. psychiatric evaluation and including chest Although the primary endpoint for statistical x-ray, electrocardiogram, urinalysis, and evaluation of efficacy was use of illicit blood studies. Patients began treatment on drugs, changes in social adjustment, arrest the following Monday. rate, employment and retention in treatment were also considered indications of effec- Drug Administration tiveness. Patients were randomly assigned to LAAM or METHOD methadone. Methadone patients were continued on their regular daily dosage of methadone, Patients unless an adjustment was required. Patients assigned to LAAM received a first dose equal Patients were eligible for the study if they to their previous methadone dose. After the were currently in a methadone maintenance initial dose, adjustments could be made but program as defined by the FDA and were males in no case could the dosage exceed 100 mg ages 18 or older. Patients were excluded TIW. Psychotropic drug use was discouraged for incapacitating or life-threatening con- except for occasional sedation. All use of ditions, disease requiring regular repeated supplemental medication during the trial was medication, frankly psychotic states, recorded. epilepsy, current severe alcoholism, and

103 Initially the following three protocols were combined, 61% terminated early from the LAAM used for the study: Protocol 1. Random group (N = 200) and 40% from the methadone assignment to LAAM or methadone. LAAM group group (N = 122). This difference is statis- receives LAAM three times a week at the tically significant. Not all of these clinic. Methadone group receives methadone patients terminated for drug related reasons daily, with take-home privileges as deter- but since the nondrug related terminators mined by the clinic; Protocol 2. Same as should have been equally distributed between Protocol 1, but no take-home privileges groups except for chance, it has to be con- for methadone group; Protocol 3. Random cluded that methadone maintenance was super- assignment to LAAM or methadone. Methadone ior to LAAM in retention, at least under the group receives methadone daily. LAAM group conditions of an open comparison of an receives methadone MTWTH, LAAM on Friday, no approved and an experimental drug. medication Saturday or Sunday. There was also a difference between the Twelve investigators chose Protocol 1, three length of stay in the study before early close Protocol 2, and three chose Protocol 3 termination. The average drop-out in the (one investigator chose both 1 and 3). LAAM group occurred after 72 days, whereas however, changes in clinic policy and the the early terminator in the methadone group resultant small number of subjects in dropped out after 122 days. 43% of the Protocol 2 led to the combined analysis of drop-outs occurred before the ninth week, patients in these protocols. with the LAAM group drop-outs occurring earlier as well as more frequently than metha- Clinical Evaluations done group drop-outs. Evaluation was essentially identical to that Protocol 3. The pattern of drop-out was of the VA cooperative study described in the remarkably similar for Protocol 3, although preceding chapter except that urine testing there was a higher drop-out rate for both was done locally rather than in a central groups. 44% of the total sample conpleted laboratory. the full 40 weeks of the study. 48% (N=34) of the methadone group and 65% (N=42) of the Characteristics of the Sample LAAM group dropped out early. This difference is statistically significant. The (Protocols 1 and 2)--The sample consisted of average drop-out in the LAAM group occurred 636 men, with 308 maintained on methadone after 81 days in the study, whereas the and 328 maintained on LAAM 61% of the sam- average methadone drop-out occurred after ple had been addicted to opiates for more 141 days. than five years. The mean age was 28.8 years 54% of the sample had graduated from high It should be noted that there was a great school and 25% had gone on to college. 61% deal of variation in percentage and timing of the sample were, or had been, married. of drop-outs between clinics, which suggests 55% of the sample was white, 28% black and that factors other than the drugs themselves 15% had Spanish surnames. Almost two-thirds contributed to drop-out rates. of the sample was employed, and 54% worked full-time. 73% had been in some form of Table 1 presents the number of patients in voluntary treatment program previously, but each group who terminated early for a variety only 20% had been in some form of involun- of reasons under Protocols 1 and 2. Table 2 tary drug treatment program. There were no presents the same data for Protocol 3. significant differences between the LAAM and methadone groups. The major differences between groups for reasons for early termination were Medication The sample for Protocol 3 consisted of 136 Not Holding (all three protocols) and Side men, 71 of whom were assigned to methadone Effects, Psychiatric, Medical unrelated, and 65 of whom were assigned to LAAM This irritability, detoxification, and did not sample was somewhat older (mean age 31.3) like drug (protocols 1 and 2). In each than the sample in Protocols 1 and 2, but instance, there were more LAAM drop-outs than the other demographic characteristics were methadone drop-outs. similar. There were no significant differences between the LAAM and methadone groups. SAFETY-TOXICITY Early Termination Protocols 1 and 2 (Protocols 1 and 2)--49% of the starting Laboratory data, vital signs and weight were sample completed the full 40 weeks of the obtained before treatment and every four study. If all reasons for termination are weeks during treatment. At each of ten test 104 TABLE 1

Reasons for Early Termination (Protocols 1 and 2)

Reasons M L T Medication not holding 0 62 62 Jail 28 19 47 Moved from area 21 18 39 Detoxification 29 9 38 Did not like study 15 7 22 Disciplinary discharge 12 5 17 Psychiatric 0 14 14 No show for 14 days 8 4 12 Excessive drug use 4 8 12 0 11 11 Side effects 10 Medical unrelated 1 9 Irritability 0 9 10 0 7 7 Did not like drug 5 Miscellaneous 0 5 Excessive alcohol use 2 3 5 Dose too high 0 4 4 Could not attend clinic 1 3 4 Abnormal laboratory value 1 2 3 Not eligible for inclusion 0 2 2 Death 0 1 1 Total 122 200 322

TABLE 2 Reasons for Early Termination Protocol 3 (Friday only LAAM)

Reasons Meth LAAM Total 20 Medication not holding 0 20 11 5 16 Detoxification 10 Jail 6 4 6 1 7 Moved from area 6 Disciplinary discharge 5 1 4 0 4 No show for 14 days 4 Medical unrelated 1 3 Excessive alcohol use 0 3 3 0 2 2 Did not like drug 1 Did not like study 1 0 0 1 1 Side effects 1 Psychiatric 0 1 Irritability 0 1 1 Total 34 42 76

105 paints differences between the means of the individual patients records did not identify methadone and acetylmethadol groups were patients with dramatic and systematic changes evaluated by analysis of covariance with in these tests but there does seem to be a adjustments for pretreatment value. Out of pattern of small decreases by a fairly large 250 such analyses (25 variables x 10 occa- number of patients. Similar trends were sions) there were 35 significant differences noted in both the methadone and LAAM groups between adjusted means: WBC at week 8; RBC in the VA study. The current speculation at weeks 16, 20 and 24; basophils at week 8 is that the introduction of a new drug and 12; hematocrit at weeks 8, 16, 20, 24, (methadone or LAAM in the VA study or LAAM 28, 36, 40; hemoglobin at weeks 8, 16, 20, but not methadone in the SAODAP study) 36; calcim at week 28; RBS at week 16, uric causes some initial physiologic disturbance acid at week 32; albumin at weeks 4, 32 end which then stabilizes. It may be that there 40; weight at week 4; systolic blood pressure is an association with weight gain i.e., at weeks 8, 12, 16, 24, 28, 32, 36; diastolic fluid retention, or some other simple pressure at weeks 8, 20, 24. and 28. Most explanation. In any case, there is no impressive of those are hematocrit and hemo- corresponding clinical evidence of drug globin and perhaps RBC end basophils. The toxicity and unless additional data (or new blood pressure results are of less interest analyses of existing data) are forthcoming, as far as LAAM is concerned because the these changes do not seem to be at all changes are essentially all due to increased alarming. blood pressure in the methadone group with little or no change in LAAM patients. The SAFETY-TOXICITY other scattered differences between groups (WBC, RBS, uric acid, albmin and weight) are Protocol 3 probably not of much clinical consequence. In Protocol 3, laboratory values were On each of the ten occasions that blood was obtained only at pre, week 12 and week 40. drawn during treatment, the LAAM group Differences between the means of methadone showed a statistically significant reduction and acetylmethadol on these tests at week in hematocrit compared to their baseline 12 were evaluated by analysis of covariance average. These changes were very small. The with adjustments for pretreatment level largest average change was a drop of 1.53. using all patients that had pretreatment None of the tests of pre-post changes in the and 12th week values. Differences at week methadone group were significant but except 40 were evaluated in the same manner. Out for one test (week 40) the post mean was of 40 such analyses (20 lab tests x 2 always lower then the pre mean. These occasions), there were four significant changes were also small. In other words, differences between adjusted means: WBC both groups showed reduction of hematocrit at week 40, Random Blood Sugar at week 12, values during treatment but the changes were Globulin at week 12, SGOT at week 12. a little larger in the LAAM group. With sample sizes of 100-200 in a group for all Vital signs and weight were obtained at pre tests, even very small differences can be and every four weeks thereafter. These five statistically significant. All of the mean variables were analyzed in the same manner values of both groups at all times were at each of 10 occasions yielding 50 more within the normal range. The LAAM group analyses of covariance. Only one of these tended to have somewhat higher values at pre tests of adjusted means was statistically than the methadone group and this could con- significant: weight at week 20. These tribute to the observed difference in variables were also analyzed by trend analy- adjusted means. The changes across time are sis across the 40 weeks as described in the not progressive, i.e., there is no discern- summary of the main study. There were no able trend for continuing decrease in hema- between groups differences in any of these tocrit as treatment progresses. Instead analyses that reached a significant level. there appeared to be an initial drop in the first 4-8 weeks of treatment and a restabili- SYMPTOM-SIGN RECORD zation of average hematocrit at a somewhat lower level then pretreatment. Essentially, Protocols 1 and 2 the same things can be said for the differences in hemoglobin. Symptom-signs were examined individually in a number of ways and in scoring clusters The decrease in average hematocrit (or established by factor analysis. In one hemoglobin) could be caused either by large approach to individual evaluation of symp- drops in a few patients or by smaller drops tom-signs, the highest rating obtained in a larger number of patients. Review of during treatment per patient was used as a unit of analysis as described in the VA 10 6 study. To test differences between drug groups, rating was dichotomized as None-Mild andModerate-Severe. The following symptoms were significantly different between groups.

None Mild Moderate Severe METH LAAM METH LAAM METH LAAM METH LAAM Yawning 181 147 84 110 40 58 3 12 Runny nose 151 126 107 109 47 80 3 12 watery eyes 170 128 95 110 40 77 3 12 Muscle cramps 169 128 91 112 42 75 6 12 Goose bumps 182 150 93 109 29 60 4 8 Abdominal cramps 177 122 80 106 44 80 7 19 Nausea or vomiting 186 127 74 102 43 82 5 16 Insomnia 118 73 69 94 97 119 24 41 Excessive sweating 114 93 85 75 92 126 17 33 Irritability 134 108 92 84 69 105 13 30 Anxiety (tension, nervousness) 118 86 82 87 87 109 21 45 Nodding 262 255 35 47 9 21 2 4 Impotence 255 249 42 52 8 21 3 5 Drowsiness 195 191 79 80 29 45 5 11 Other 203 180 36 40 40 62 29 45

Efficacy experimental drug. Even if the effect of psychological factors is discounted, reten- The Discussion of issues involved in estab- tion rates on LAAM had to be influenced by listing eficacy of LAAM in the VA Coopera- the fact that there was a clinical choice tive Study applies equally well to the possible with LAAM patients--they could stay SAODAP Cooperative Study. There are a number on LAAM or be switched back to methadone-- of criteria of efficacy that can be used but but this choice did not exist for methadone all have certain limitations or defects. patients--their only choice was to drop out of maintenance altogether. Because of these Generalization about efficacy from the VA problems, the SAODAP cooperative study pro- study has to be qualified because of the vides almost no useful information about fixed dose design and the induction schedule efficacy relative to methadone. The excep- which may have been too slow. In theory, tion may be the urine index as defined in the SAODAP study does not suffer from this the VA study. In protocols 1 and 2, 28 meth- particular problem because dosage was flex- adone patients had a urine index of 15.0 ible after the first dose. However, any while 227 LAAM patients had an index of 14.9. suggestion that LAAM is a less effective In protocol 3, 71 methadone patients had a maintenance drug then methadone has to urine index of 19.9 while 65 LAAM patients consider how effectively this option to had an index of 16.2. Thus, in both adjust dose was exercized by the clinicians, instances, LAAM had a slightly better (non- most of whom were initially inexperienced in significant) index of illicit opiate use. the use of LAAM. To the extent that dosage was not individually optimized, LAAM could Another kind of outcome index is program be expected to appear somewhat less effec- conformity, which is defined as each tive than methadone which is not only a patient's number of actual scheduled clinic more familiar drug but was the drug on which visits divided by his total expected sched- all patients were stabilized prior to the uled visits for however long he was in the study. Furthermore, the price paid in the study. In Protocols 1 and 2 the percentage design of this study to provide for flexible of clinic visits were essentially the same dosage was to drop the double-blind control. with averages of 97.75% and 97.71% for the Patients and staff were aware of the treat- methadone and LAAM groups, respectively. In ment assignment and this allowed for the protocol 3, the methadone patients attended full effect of psychological factors asso- 97.24% of their scheduled clinic visits while ciated with treatment with an unfamiliar the LAAM group attended 97.49% of the time.

107 Still another evaluation of relative efficacy scale: much improved, unchanged, worse and was possible using the global rating of out- much worse. In protocols 1 and 2, the mean come, which was a combined staff judgment score for both groups was 2.96. In protocol made shortly after a patient's termination, 3, the mean scores were 3.00 and 2.90 for taking into account all known infomation the methadone and LAAM groups, respectively. about the patient. This was a four point

AUTHORS

Affiliation of the authors of this article is as follows: From the Veterans Administration Hospitals, Sepulveda, California (Dr. Ling), and Perry Point, Maryland (Dr. Klett and Paderic Gillis).

108 PHASE III CLINICAL STUDY OF LEVO-ALPHA-ACETYLMETHADOL

John A. Whysner, M.D., Ph.D.

INTRODUCTION

The purpose of the Phase III trial of levo- The subject population will be approximately alpha-acetylmethadol (LAAM) is to establish 6,000 men and woman over the age of 18 who efficacy of this medication for the main- meet the current criteria for entrance into tenance of persons addicted too opioids. methadone maintenance programs or who are Also during the course of the Phase III currently clients of such proqrarm. The trials additional data relating to the clinical trial will last up to 40 weeks for safety of LAAM will be obtained. It is the each patient. Each clinic will participate intended purpose of the Phase III clinical in one of two studies whichcc are being con- trials to provide sufficient information ducted as part of these Phase III trials. to alllow the FDA to grant a New Drug Applic- In one study all patients will be put on cation for LAAM. LAAM. In a second a random assignment of patients will be made to LAAM or methadone The administrative stucture which has been providing a comparative analysis of efficacy developed for these Phase III clinical trials and safety measures. is intended to provide for a centralized drug supply, data collection, and adminstrative MEASURES OF EFFICACY system with a maximun national clinical participation. Whysner Asscciates is the prime The proof of efficacy for maintenance of per- contractor for NIDA and is responsible for sons addicted to opioids may be defined as the Coordination of the Study which includes the relief of abstinence over a prolonged filing of the IND application, medical sup- period of time when the drug is given on a ervision, review of results, administration regular basis. There are three aspects of of all subcontractors, and development of the abstinence syndrome: drug seeking be- the final NDA application. Subcontractors havior, physiological, and psychological include the Vitarine Company, who will be the changes. A drug such as LAAM must prevent formulator of the liquid concentrate, Friends the development of abstinence inall three Medical Science Research Center, Inc., who areas. Therefore, measures of efficacy must will provide data managemement and analysis be aimed at measuring the signs and symptoms support, and approximately 50 methadone of the develpment of abstinence in these clinics who will perfom the clinical trials three areas. and provide the data for analysis. A Medical Advisory Panel has been established which is The measure of drug seeking behavior can be responsible for approval of the study proto- attempted through history taking, direct col, analysis of any adverse reactions, and measurement of illicit drugs in body fluids, review of the conclusions of the study. or assessment of the consequences of taking 109 illicit drugs. During the past several years dropping out of the study to attempt detoxi- our ability to measure illicit drugs in body ficationn would be viewed as a positive fluids has been developed to the point where result. these methods are both reliable and are a regulaar part of the methadone program rou- SAFETY MEASUREMENTS tine. Therefore, in the Phase III studies this will be the most important measure of Previous Phase II clinical studies have in- drug seeking. Assessment of the use of il- dicated that for a 40 week period LAAM does licit drugs through history taking or an in- not cause any consistent abnormalities in dependent measure of the consequences of the CBS, SMA-12, urine analysis, EKG, or heroin use such as number of arrests, employ- EEG which would be cause for concern. How- ment, etc. is not reliable or easy quan- ever, these Phase II studies have only been titrate. accomplisked on 170 males for 40 weeks. Therefore, it is desirable to test a large Physiological signs of abstinence will be number of males and femailes to determine if measured through the analysis of a synptom- there are any untoward reactions which occur sign checklist. The components of the on a low frequency basis. It is hoped that checklist are well known parts of the phy- the Phase III studies will include approxi- sical abstinence syndrome; for example, mately 2,000 patients om LAAM for 40 weeks. sweating, gooseflesh, and rinorrhea. This should test enough individuals to give an estimate of the incidence of adverse re- For the psychological componence patients may actions to the medication. became anxious, hostile, irritable, require other drugs such as traquilizers, develop Another problem which must be studied during other patterns Of drug abuse such as poly- Phase III is the use of other medication drug abuse, or adjust poorly to the social concurrently with LAAM. It is known that and work environment. Many of these aspects drug interactions may occur which would of psychological abstinence may be difficult either potentiate or preventthe effective to measure; however, measures will be attemp- action of narcotics. me use of both pre- ted. The Profile of Mood States will be scription and illicit drugs may have un- used to measure anxiety, hostility, and toward interactions effects. Although it has irritability. Also questions involving been suspected that certain other drugs my hours of emp1oyment, number of arrests, and interact favorably, not enough patients have a global assessment Of client's progress been studied to gather any quantificable will be made. data. In the Phase III studies the use of all medications will be documenteds and the There are no fixed scales against which ef- possibility of any drug interactions will be ficacy can be measured. It is not known investigated thoroughly. what is an acceptable level of abstinence or what are acceptable drug seeking, phy- OPEN VERSUS BLIND STUDY siolcgical or psychological changes. There- fore, a heavy reliance must be made on com- The use of any maintenance drug for the parative measures with a control group. treatment of heroin addiction has a strong subjective component to its effectiveness The only applicable control group for this for both the patient and the physician. A study would be persons who are currently on double-blind study is designed to eliminate methadone maintenance therapy. Comparisons the impact of these subjective effects om of the efficacy and safety measures will be the outcome of the study. Double-blind made between the methadone and LAAM patients studies have been used in the past to com- in part of the Phase III study. pare the effectiveness of LAAM to methadone and the results of these studies have been Another determinant of an acceptable level described elsewhere. There are several of abstinence would be the willingness of reasons for which the Phase III study has the participant to stay on the drug. If one been designed as an open rather than a can make the assumption that remaining on double-blind study. These are the following: the drug is the equivalent of efficacy, dropout rates are very useful. The reason 1. The primary advantage of using LAAM in- for dropout and a judgment by the clinic of stead of methadone is the need for only wheter such a dropout is drug related will three day a week pickup. If a double- be determined. Only those dropouts which blind study was done a schedule of are drug related such as side effects, feel- either daily pickup or of three day a ings of under medication on weekends,etc. week pickup would be necessary in both will be used as efficacy measures. However, LAAM and methadone groups. This would negate the scheduling effect of LAAM. 110 2. The large number of patients needed for given LAAM througout pregnacy or whether the phase III study and the use of mul- all woman who become pregnant while on LAAM tiple clinic sites makes the logistical should be switched to methadone. The argu- problems associated with such a study ments on both sides of this question are very difficult. valid. The use of LAAM through pregnancy would mean exposing pregnantfemales and neo- 3. A double-blind study may adversely effect nates to a new drug with which the medical the efficacy of either methadone or LAAM community is unfamiliar. However, LAAM may in an unpredictable way. The patient prove to be a drug with fewer problems in population is very anxious concerning the pregnant female and the neonate than does the medication they are receiving and methadone. The long duration of action of about participation in a clinical study. LAAM may make the neonatal withdrawal syn- One of the greatest difficulties en- drome less severe. countered in the PhaseII study was that the efficacy results had a large number CURRENT STATUS OF THE STUDY (MARCH, 1976) of patients who dropped out because of the nature of the study rather than the The current planning for the Phase III study drug of LAAM has been almost completed. The final study design, forms, data management 4. The blind is difficult to keep because system, formulation of the drug, and analy- patients and physicians would be able sis have all been in progress and should be to break the code due to the subjective completed within a couple of months. It is effects of the drug. anticipated that the Phase III study will begin in the Spring of 1976 and that induction of these patients will be completed by USE OF LAAM IN FEMALES the Fall of 1976. An additional 40 week period will be needed for the follow-up of The Phase III study will be the first large- the last patients included in the Study and scale use of this drug in femles. A small time will need to be available for the final group of famales was tested before the FDA data analysis and collection. Therefore, it restrictions on the use of LAAM. During the is anticipated that the Phase III study will course of the Phase II studies there was a be completed late in 1977. Hopefully by study of seventeen females of non-childbear- that time of the other animal and human ing potential. The use of LAAM in females data will be comleted to allow the award of at this stage is essential,otherwise another a NDA for LAAM. Therefore, beginning in large-scale study in females would need to 1978 there may be another maintenance treat- be canstructed. It is currently being de- ment modality available for the treatment cided whether or not some females should be of heroin addiction.

AUTHOR John A. Whysner, M.D., Ph.D. is president of John Whysner Assciates, Inc., 2600 Virginia Avenue, N.W. Suite 209, Washington, D.C. 20037.

111 Dr. Cooper is Special Assistant to the Director of NIDA's Division of Commmunity Assistance (DCA). He has been its liason to the Division of Research during Phase II and III of the LAAM studies. Beyond Phase III DCA will continue to OVersee NIDA-funded LAAM treatment programs. Like methadone, LAAM will be dispensed only through licensed narcotic maintenance programs. Once LAAM's New Drug Applica- tion is approved, responsibility for continous monitoring of treatment programs will pass from NIDA's Division of Research to the Division of Community Assistance.

THE USE OF LAAM IN TREATMENT

James Cooper, M.D.

The purpose of this chapter is to present the client relationship and cast the physician National Institute of Drug Abuse, Division in a primary decision-marking role. The of Community Assistance’s (DCA), perspective medication was considered the primary treat- on the usefulness of LAAM as a maintenance ment and the understanding of its properties drug in the treatment and rehabilitation of and actions was deemed of utmost importance opiate addicts. One of the major responsi- to staff and the client. bilities of the DCA is to administer, monitor, evaluate and establish treatment standards However, it was appreciated from the for all National Institute of Drug Abuse beginning that although methadone corrected funded treatment programs. It will become a biological condition by medically sta- the Division’s responsibility to oversee bilizing the addict, this was only one part those Federal programs which will administer of the treatment. Pharmacological treatment and dispense LAAM once the drug has received was only one factor in a program which a New Drug Application (NDA) and is marketed. should include counseling as well as supportive services such as legal vocational In order to understand our current thinking and educational counseling. These supportive regarding the utility of a maintenance drug services were believed necessary to provide in the treatment of narcotic dependence, it the addict with the skills he may never have is important to review, from a historical developed or had lost during his addiction. perspective, methadone maintenance treatment over the last ten years. Initially, there In the following years there was a rapid was a tendency to view the addict simply as proliferation of methadone maintenance a person afflicted with a metabolic problem clinics, due to the heroin epidemic of the or disease. Methadone was prescribed to late 60's and the success of this prototype treat the symptoms of this chronic metabolic treatment. Unfortunately, the speed of disease. In this model, methadone was proliferation and the great number of addicts analagous to insulin for diabetes and so needing treatment overwhelmed the treatment perceived as a life-saving treatment. In the capacity. The need for supportive services same model, LAAM would be similar to a long- also outstripped available resources, as a acting form of insulin that relieved the result, treatment effectiveness declined. patient of the need for frequent dosing. In the last several years more knowledge has In the early stages of development, the accumulated from treating larger and more methadone clinic emphasized the physician/ diverse populations of addicts. The model

112 has been made more comprehensive with aware- clinic usually will have some clients who ness that individualized treatment is needed are receiving methadone and very low-key which recognizes the unique psychological programming either because the initial characteristics of each addict. Most clini- assessment of the client revealed that they cians have come to view methadone as a sta- could not tolerate intensive psycho-social bilizing treatment tool which can be effec- intervention or because there was no indica- tively used to engage the client in broader tion of need for such service. However, rehabilitation. Once this engagement occurs, many other clients will require varying an individualized evaluation and provision degrees of psycho-social and vocational of appropriate treatment services can pro- intervention based on the client’s past and ceed. Many, now believe that these services current behavioral performance. are the primary rehabilitative tool for most clients. Each program has been encouraged to view each patient as a unique individual with This gradual shift in emphasis was a result his own personal combination of strengths of our better understanding of the diversity and weaknesses which must be continually of the people applying for treatment. The assessed in order to tailor a treatment only common trait shared by all is that they regimen appropriate for each patient. are narcotic users and are dependent upon opiates. Those who make up this population The Federal Funding Criteria for Drug Treat- have different reasons for initiating drug ment Services was developed in part to use, exhibit different patterns of drug use, insure that this individualized approach be relapse for different reasons and have widely incorporated by all Federally-funded pro- differing experiences as a result of their grams. One section of the Federal Funding drug using behavior. The Division’s experi- Criteria requires that an individualized ence has demonstrated that the etiologies of treatment plan be developed for each patient addiction are diverse and complex. While and that periodic evaluation of the plan under-education, unemployment, racial or occur. Such a requirement should provide ethnic discrimination and environmental the staff with an instrument to insure that stress may result in drug-taking behavior (1) each patient’s strengths and weaknesses for some, other psychodynamic factors are assessed, (2) a determination is made including excessive dependency needs, a of the appropriate types of supportive compulsive desire to escape from reality and services needed (if any) and (3) the extent a lack of poor coping mechanisms for stress of counselor involvement necessary to meet play an important role in addiction for the objectives of the treatment plan is others. Further, total abstinence from ascertained. The ongoing individual evalua- drugs may not be a realistic goal for all tive process will provide the staff with a drug abusers. Thus, the objectives of periodic testing and redefining of the treatment have become more complicated and patient’s progress (or lack of progress) achievement of the goals sometimes become and encourage the counselor to search for more elusive. the contributing dynamics of the patient’s success or failure. With the knowledge gained from experience, DCA is currently encouraging all maintenance Although the advent of LAAM may not intro- programs to develop the resource capabilities duce treatment changes, for some patients for treating a diverse population. Such a and programs, LAAM may provide some distinct heterogeneous group requires a number of pharmacologic and therapeutic advantages to distinct treatment, rehabilitative and methadone based on existing clinical studies. resocialization approaches. Pragmatically this entails that a program have the capa- The 1975 White Paper on Drug Abuse produced bilities of providing legal, vocational, edu- by the Domestic Council Drug Abuse Task cational, psychological and medical services Force recommends "switching from methadone either within the program or through referral to LAAM...in treating opiate-dependent per- sources. sons as soon as its safety and efficacy have been determined." This recommendation The diversity in the treatment population is based on the potential benefits to pro- has resulted in wide variation as to the grams and patients of three times a week length of time an individual receives metha- dosage. Some of these benefits are: less done and the intensity of the counseling drug diversion into illicit channels; more intervention. Some patients only want detox- cost-effective treatment; and less inter- ification or short-term maintenance, while ference with patients’ daily work schedules, others may need or request long periods of education and rehabilitation efforts or maintenance and services. The well-run responsible homemaking.

113 Several other potentially advantageous thera- tive euphoria and less dependence on the peutic characteristics of LAAM have been clinic. This novel approach would naturally observed. Among them are that LAAM helps have to be investigated with a limited change the individual’s and clinic’s focus number of individuals to determine its from daily preoccupation with drugs and drug- effectiveness but does provide a potential taking to an emphasis upon human relation- alternative, particularly for those who have ships and development of alternative activ- been unsuccessful in remaining abstinent ities, life style and peer group relation- following a particular maintenance regime. ships. Furthermore, LAAM’s smoother, sustained, drug effect apparently allows some individuals to feel more alert, more emotion- The Division of Commmunity Assistance does ally level, less "high", and less habituated. not currently anticipate that LAAM implemen- It’s longer duration of action may allow tation will lead to dramatic alteration in LAAM to be used for detoxification from the current Federal opiate addiction treat- methadone maintenance or heroin. Clinicians ment policy or philosophy. LAAM appears to have noticed that some patients appear to be be an alternative to, rather than a replace- able to detoxify from LAAM maintenance ment for, methadone. Some individuals do easier than from methadone maintenance. This better on one or the other drug, probably Division will watch the Phase III LAAM due to either pharmacological, psychological Studies closely to determine if these obser- or social factors not yet understood. vations/findings are substantiated in the Furthermore, LAAM is not viewed as a pharma- larger population to be studied in Phase III cologic panacea for all opiate addicts. No large scale clinical trial. known drug, including LAAM, can cure or alleviate psychosocial and economic impover- The availability of two maintenance agents ishment. For some opiate addicts, LAAM, like may provide for increased treatment flexi- methadone, may be the primary treatment. bility. For example, Sequential Treatment For others, temporary pharmacotherapeutic Employing Pharmacologic Support (STEPS) has stabilization will act merely as a tool to been proposed by Dr. Avram Goldstein as an engage the narcotic-dependent individual alternative treatment method. STEPS is into participation in a comprehensive characterized by sequential use of a variety treatment program, concomitantly utilizing of pharmacologic agents each progressively extensive psychological socio-economical and decreasing narcotic induced euphoria and vocational rehabilitation services. And increasing social rehabilitation. The STEP others may require no pharmacological sup- from daily methadone to three times weekly port at all. LAAM provides one more choice LAAM would represent a safe and very stable in tailoring treatment to each individual’s opiate dependence with virtually no subjec- needs.

114 The following article is from a transcript of remarks given by Dr. Avram Goldstein at NIDA, Rockville, Maryland, May 19, 1976.

A CLINICAL EXPERIENCE WITH LAAM

Avram Goldstein, M. D.

I would like to discuss our clinical experi- tricky operation, because when you gave the ence with LAAM. Several years ago we did a insulin, you got too much insulin effect; pilot trial with LAAM in the Santa Clara then it wore off and you had too little County Methadone Program with about 60 insulin effect. The problem was to stablize patients. Some of them were Put directly on- things so that there would be a lasting effect to LAAM, off the street, so we had that of insulin in the patient. Tremendous effort experience; and others crossed over from was directed toward developing a long-acting methadone to LAAM. Now in the last year we insulin which you could give once a day to get have put 165 addicts directly off the street stable coverage. Finally that was achieved. onto LAAM. So that my remarks here are based For almost every drug there is the same prob- on this accumulation of experience. lem of developing stability of action, so that there will not be fluctuation up into the tox- PHARMACOLOGY ic range and then down below the therapeutic range. There is the pharmacology issue. That’s turned out, I think, to be the most inter- Now, let's look at methadone in those terms. esting part of our experience with LAAM. Let Methadone is a tremendous improvement over me start by stating that: I think LAAM is a heroin! which has to be administered four or better drug than methadone, from a pharmaco- five tunes a day, giving continual highs and logical point of view. I think patients know lows. That's why methadone was introduced, of that and understand it too. Let me describe course. Nevertheless, you all know that when what I mean. patients come in, in the morning, for their methadone, many are at the very edge of with- Now, in pharmacology, quite apart from any drawal; they feel "icky" (as they say). You regulatory questions or the issue of diversion, also know that after they take their methadone, in the development of any drug, one of the within the next hour or so, they feel it hit important objectives is to get a lasting them; they feel a sense of warmth that starts stable effect. I need only refresh your mem- in the abdomen and spreads through the body. ory about the history of insulin. As you They're getting partially "loaded" every morn- know the early insulins had to be admininis- ing with methadone, and they’re partially tered several times a day. It was a very 115 "sick" every morning before they get their that ceiling patients can set their own dos- methadone. That's not a comfortable condi- ages. Our rule is that on Friday the patient tion to be in, but they’re a lot better off is allowed to increase, if he wants to, by than they were when they were using heroin. about 30%. Thus, if he is taking 75 he can increase to 100, if he is on 50 he can raise The lasting effect that LAAM produces makes it to 65, and so on. the patients feel better. Every patient I’ve spoken to who has been on both methadone and The question is, with that opportunity, do LAAM remarks on this--how he feels just gen- patients actually do it? Now, obviously, if erally better--more under control, more stable they felt sick on Monday morning, they would less of this up and down. And they don’t feel raise their Friday dose to try to take care sick at the end of the period. of that feeling of being sick. The interesting thing we found is that the great majority Now, if patients have enjoyed the feeling of of patients do not make any increase in their methadone relieving an incipient withdrawal! Friday dose; in other words, they’re voting and if that’s been an important part of their that the LAAM takes care of them over the daily pattern, transferring their getting weekend. About one-third of the patients do high on heroin to getting drug-induced satis- make a Friday increase of varying degree. faction once a day on methadone, then they’re The average increase on Friday is very small, not going to like LAAM; there is no question but some patients do take full advantage of about it. Some patients really want that the opportunity. This result tells us that feeling on methadone, so that in the long run the "weekend problem" is largely a non-problem, we're probably not going to just replace as long as anxiety is minimized. If the staff methadone with LAAM. There are going to be is worried that LAAM is not going to last patients who need that feeling and it may take through the weekend, and conveys their anxie- them a long time before they’re ready to-give ties to the patient, then you get this tre- it up. But there are also a lot of patients mendous psychological effect. who don’t want that. who are really willing to make the transition and give up that sen- sation, and those patients much, much prefer Patient Reaction to LAAM to be on LAAM. If you ask our patients: "How do you like The So-Called "Week-end Problem" LAAM," they vote affirmatively. I have not known an exception to that. Some of the Let me give you an example of a pseudoproblem patients who have experienced methadone in that turned out not to exist with LAAM. In the past prefer LAAM; others have never some places LAAM was introduced as "48-hour experienced methadone and have nothing to methadone". The patients, who are by no means compare it to but they feel that it "holds" stupid, immediately thought, "Well, if it’s them in a stable way. Our experience with a two-day methadone, then how will I get the laboratory data has been the same as in through the weekend? I’ll be sick on Monday the Phase II study. We don't find any signif- morning." And they were sick on Monday morn- icant abnormalities in all of the careful ing ! But LAAM actually has a very long dura- checks that we have been making. Efficacy is tion of action, at least over a three- to four- very good, as measured by suppression of day period. Without going into the compli- heroin use. It's as good or better than cated pharmacokinetics, that means if you get seen in methadone clinics in our area. the dose of LAAM on Monday you’re in a stable state when you come in Wednesday morning. Finally, we have been pleasantly surprised to That Monday dose hasn’t disappeared; it is to find, at least in some patients, that LAAM picked up and carried along by the Wednesday can be discontinued with less discomfort than dose and that is picked up and carried along we were used to with methadone withdrawal. by the Friday dose, and on Monday morning the There is still the problem of anxiety exacer- effect of the Friday dose is still there. In bating withdrawal problems for some patients, other words, you’re getting a stable effect. and there are certainly patients who have the We have some very interesting data on that. usual problems with withdrawal (especially insomnia, as with methadone withdrawal). We To have you understand the data, I will have have observed some patients, however, who to tell you the way we control dosage. Dos- simply stopped taking LAAM at a dosage of 50 age is self-controlled by patients, who follow mg or above, and experienced no withdrawal the same principle we described in that art- symptoms at all. It is possible that the long icle about patient control of methadone dos- duration of action and the long persistence of age (J. Amer. Med. Ass. 234:734, 1975). The the LAAM metabolites in the body produce a absolute ceiling is 75 mg. of LAAM on Monday situation in which the drug detoxifies itself and Wednesday, 100 mg. on Friday. Now up to (so to speak), tapering itself over a long 116 enough time to minimize any acute withdrawal time and energy and argumentation is related distress. This requires more research, how- to that issue of takehome. It corrupts the ever; we are not now claiming that most urine collection system. As long as takehome patients can detoxify more easily from LAAM depends on clean urines, you really cannot than from methadone. trust the urine collection, because it pays to cheat. It doesn't make any difference if it’s called an "observed" urine collection TAKE-HOME POLICY or not. The potential for cheating and cor- ruption is always there. With LAAM, sud- denly, all that disappears. There is a quite The third point is a very significant one. incredible change in the whole attitude of In our clinic we, of course, have no takehome the clinic. There is just no more argumenta- -- ever. Patients understand from the out- tion about things like that. Patients level set that takehome just doesn't arrive; it's with their counselors about their drug use, not in the cards. We never use any methadone and urines can be believed. I think it’s on the premises--exclusively LAAN consumed fair to say that an awful lot of staff time right there. For patients who are to be away and energy is wasted otherwise. This time for a while, we have had no difficulty at all and energy can now be devoted to patient in substituting methadone (e.g., by arrange- welfare and to effective counseling, once ment at a clinic in another city) and then you eliminate the takehome business and resuming LAAM when they return. everything that goes with it. Unfortunately, I don’t know how to measure these effects; There is a remarkable consequence of this they are major effects; everybody on our policy. You may not realize how much of the staff is convinced of that, but I don’t know unpleasantness and hassle in your clinic how to produce objective data to prove it, operation is related to the issue of takehome so I can only report it anecdotally to you. privileges, and how much of the deceit and I think it is one of the major advantages gameplaying, manipulation and wasted staff of LAAM.

AUTHOR Dr. Avram Goldstein is Director of the Addiction Research Foundation, 701 Welsh Road, Palo Alto, California, 94304.

117 LAAM BIBLIOGRAPHY

PRECLINICAL

Adler, F.L. Excerpts from LAAM-relevant re- Addiction Control Commission, Brooklyn, search. 1975. (Unpublished) public New York. Health Research Institute of the City of New York, Inc. ------. Annual report on studies in the monkey (Macacca mulatta) designed to de- Billings, R.E., Booher, R., Smits, S., Poh- termine the value of this animal for ore- land, A., McMahon, R.E. Metabolism of dieting addiction liability to the newer acetylmethadol. A sensitive assay for synthetic analgesics. Committee on Drug noracetylmethadol and the identification Addiction and Narcotics and The Cammittee of a new active metabolite. Journal of on Problems of Drug Dependence, National Medical Chemistry, 16:305-306, 1973. Research Council, Division of Medical Sciences. 15th Meet., App. K, p. 1150, Billings, Q.E., McMahon, R.E. The metabo- 1955. (Unpublished) State of New York lism of acetylmethadol in the rat: a sen- Narcotic Addiction Control Commission, sitive assay for nor-acetylmethadol and Brooklyn, New York. the identification of a new active metabolite. Federation Proceedings, 32:764A ------. Evaluation of morphine-like physical bs, 1973. dependence in the Rhesus monkey (Macacca mulatta). Committee on Drug Addiction Booher, R., Pohland, A. Synthesis of a new and Narcotics and The Committee on Prob- metabolite of acetylmethadol. Journal of lems of Drug Dependence, National Research Medical Chemistry, 18:266-268, 1975. Council, Division of Medical Sciences, 24th Meet., Addendum 2, 1962. (Unpublish- Casy, A.F., Hassan, M.M.A. Configurational ed) State of New York Narcotic Addiction influences in methadol and nonnethadol Control Commission, Brooklyn, New York. analgesics. Journal of Medicinal Chemis- try, 11:3, p. 601-603, 1968. Eddy, N.B., May, E.L., Mosettig, E. Chemis- try and pharmacology of the methadols and Chatterjie, N., Inturrisi, C.E. Synthesis acetylmethadols. Journal of Organic Che- of alpha-1-noracetylmethadol. A facile mistry, 17(2):321-326, 1952. N-demethylation of alpha-1-acetylmethadol. Journal of Medicinal Chemistry, 18(6):630- Eddy, N.B., Touchberry, C.F., Lieberman, J.E., 631, 1975. Khazan, N. Synthetic analgesics; methadone isomers and derivatives. Journal of Chen, K.K. Pharmacology of methadone and Pharmacology and Experimental Therapeutics related compounds. Annals of the New York 98:121-137, 1950. Academy of Sciences, 51:83-97, 1948. Farrand, R.L., McNamara, B.P., Christensen, Deneau, G.A., Seevers, M.H. Annual report M.K. Final report. Toxicological testing on drug evaluation. Committee on Drug of 1-alpha-acetylmethadol. 1974. (Unpub- Addiction and Narcotics and The Committee lished) Prepared at Edgewood Arsenal, A- on Problems of Drug Dependence, National berdeen Prooving Ground, Maryland. Research Council, Division of Medical Sciences. 21st Meet., Addendum 1, 1960. (Unpublished) State of New York Narcotic

118 Henderson, G.L. Third-quarter progress re- New York, March 28, 1976. port. Two-year pharmacokinetic study of LAAM. 1974a. (Unpublished) Prepared Iwang, E.E., Primm, B.J., Bath, P.E. Evi- under Contract HSM 42-73-211 at the Uni- dence for the stimulant and depressant versity of California at Davis. central effects of L-a-acetylmethadol. Experientia, 31:203-205, 1975. Fourth quarter 1974b. Kaufman, J.J., Koski, W.S., Benson, D.W., Fifth quarter 1974c. Semo, N.M. Measurement of the pka's, partition and drug distribution coefi- Sixth quarter 1975a. cients of narcotics and narcotic antagonists, their PH and temperature dependence Seventh quarter 1975b. and their significance in clinical practice . Problems of Drug Dependence, 435- Eighth quarter 1975c. 452, 1975. Ninth and final quarter 1975d. Kepler, J.A., Sparacino, C.M., Wall, M.E. Synthesis of labeled narcotics and nar- Henderson, G.L., Westkaemper, R. Stereotypy cotic antagonists. Quarterly Report No.2, following acute administration of l-alpha- 1974a. (Unpublished) Prepared under acetyl-methadol (LAAM) in the rat. Pro- Contract HSM-42-73-184 (ND) at Research ceedings of the Western Pharmacological Triangle Institute, Research Triangle park, society, 18:204-207, 1975. North Carolina. 3 Henderson, G.L. Biological fate of H-LAAM Synthesis of labeled narcotics and in rat, dog and monkeys. Proceedings of narcotic antagonists. Quarterly Report the National Drug Abuse Conference, New No. 3, 1974b. York, March 28, 1976. Synthesis of labeled narcotics and Industrial Biotest. Report to National In- narcotic antagonists. Annual Report, stitute on Drug Abuse. One-year chronic 1974c. oral toxicity study with LAAM in beagle dogs. 1975. (Unpublished) Prepared Synthesis of labeled narcotic and under Contract HSM-42-73-178 at North- narcotic antagonists. Combined 5th Quar brook, Illinois. terly Report and 6th Quarterly Report, 1975. Industrial Biotest. Report to the National Institute of Mental Health. Perinatal Khazan, N. Progress report. Narcotic anta- and lactation performance study with LAAM gonists methadone and morphine addiction. in albino rats. 1973. (Unpublished) (Unpublished) Prepared under Grant DA Prepared under Contract HSM-42-72-171 at 00461 at New York State Narcotic Addiction Northbrook, Illinois. Control Commission, Brooklyn, New York. Teratogenic study with LAAM in al- Killam, K. Cumulative report. Interaction bino rabbits. 1973. (Unpublished) Pre- studies on narcotics and narcotic anta- pared under Contract HSU-42-72-171 at gonists in animals. 1974. (Unpublished) Northbrook, Illnois. Prepared under Contract HSM-42-73-263 at University of California at Davis. Industrial Biotest. Report to National Institute on Drug Abuse. Acute oral Progress report. Interaction stu- toxicity study with LAAM in albino rats. dies in morphine-dependent monkeys. 1975. 1975. (Unpublished) Prepared under Contract HSM-42-72-171 at Northbrook, Comparison of the effect of 1-alpha- Illinois. acetylmethadol (LAAM) and methadone in macaca mulatta. Proceedings of the West- 42-day pilot study with LAAM in ern Pharmacological Society, 17:519-561, female albino rabbits. 1975. (Unpub- 1974. lished) Prepared under Contract HSM-42- 72-171 at Northbrook, Illinois. Kochhar, M. Isolation and identification of metabolites of alpha-l-acetylmethadol. Inturrisi, C.E., Kaiko, R.F. The role of Summary report. 1975. (Unpublished) active metabolites in the duration of ac- Auburn University, Auburn, Alabama. tion of acetylmethadol in man. Proceed- ings of the Naional Drug Abuse Conference 119 Leimbach, D.G., Eddy, N.B. Synthetic anal- probable active metabolite. Journal of gesics: III. Methadols, isomethadols, Phamracology and Experimental Therapeutics and their acyl derivatives. Journal of 149(3):436-445, 1965. Pharmacology and Ezperimental Therapeu- tics, 110(2):135-147, 1954. Merck Institute. MK-790 preclinical evaluation. 1965. (Unpublished) Merck and Levine, W.G. Letter report on l-alpha-ace- Co., Inc., West Point, Pennsylvania. tylmethadol (LAAM). 1975. (Unpublished) Albert Einstein Medical College, Bronx, Misra, A.L., Bloch, R., Mule, S.J. Estima- New York. tion of (2-3H) l-acetylmethadol in biological materials and its separation Maickel, R. Progress reports for contract from some metabolites and congeners on number PHS HSM 42-73-226. Excerpts about glass fibre sheets. Journal of Chroma- LAAM from: quarterly progress reports tography, 106(1):184-187, 1975. #4, #5 and #6. 1974. (Unpublished) Indiana University, Bloomington, Indiana. Misra, A.L., Vadlamani, N.L., Mula, S.J. Chromatographic Separation of methadone, May, E.L. The methadone story. Aldrichimi- some of its metabolites and congeners. ca Acta, 5:38-40, 1972. Journal of Chromatography, 67(2):379-381, 1972. May, E.L., Eddy, N.B. The isomethadols and their acetyl derivatives. Journal of Misra, A.L., Vardy, J., Block, R. Pharmaco- Organic Chemistry, 17(2):1210-1215, 1952. kinetics, metabolism of (3 H) LAAM in the montez and disposition of (3 H) naltrexone May, E.L., Mosetting, E. Some reactions of in the CNS of the rat. Proceedings of amidone. Journal of Organic Chemistry, the National Drug Abuse Conference, New 13:459-464, 1948. York, March 28, 1976. ------. Some reactions of isoamidone. Jour- Moreton, .J.E., Roehrs, T., and Khazan, N. nal of Organic Chemistry, 13:663-665, Patterns of drug self-administration and 1948. sleep-awake activity during the state of dependence on morphine, methadone and 1- May, E.L., Perrine, T.D. Wagner rearrange- alpha-acetyl-methadol (LAAM) in the rat. ment of a-dl-6-dimethyl-amino-4, 4-di- Proc. Comm. Drug Dependence 36th Meet., phenyl-3-heptanol (a-dl-methadol). Jour- National Academy of Sciences, National nal of Organic Chemistry, l8:1572-1577, Research Council, 1008-1016, (1974). 1953. Sleep-awake activity and self-in- McCarthy, D.A. Preclinical toxicity and jection pattern of rats dependent on mor- pharmacology testing of narcotic anta- phine, methadone, or L-alpha-acetyl-me- gonists. #46, l-d-acetylmethadol: anti- thadol (LAAM). Federation Proceedings, nociceptive studies in rats. 1974a. 33(3):516, 1974. (Unpublished) Prepared under Contract HSM-42-72-167 at Parke, Davis, and Com- Nakamura, J., Henderson, G.L., Winters, W.D. pany, Ann Arbor, Michigan. Behavioral and EEG electroenceohalography effects of 1-alpha-acetylmethadol(LAAM) Preclinical toxicity and pharma- in the rat. Proceedings of the Western cology testing of narcotic antagonists. Pharmacological Society, 17:155-158, 1974. #40: Sixth quarterly report. 1973. Nickander, R., Booher, R., Miles, H. -1- Preclinical toxicity and pharma- acetylmethadol and its N-demethylated me- cology testing of narcotic antagonists. tabolites have potent opoiate action in #47: Seventh quarterly report. 1974a. the guinea pig isolated ileum. Life Sci- ences, 14:2011-2017, 1974. McIntyre, J.A., Armandi, A.E., Risen, L.P., Ling, W., Harberfelde, G.C. This-large Morphine-like agonist effects of chromatography and enzyme inmunassy of a-acetylmethadol, d-methadone and their 1-alpha-acetyl-methadol and methadone metabolites on the-guinea pig isolated metabolites in urine. Clinical Chemistry ileum. Federation Proceedings, 32:764Abs, (Winston-Salem, N.C.) 21(1):109-112, 1975. 1973. McMahon, R.E., Culp, H.W., Marshall, F.J. North-Root, H., Kuttab, S.H., Henderson, G.L. The metabolism of -dl-acetylmethadol in Biological disposition and transformation the rat: the identification of the of 1-a-acetylmethadol in the monkey, dog, 120 and rat. Problems of Drug Dependence, Smits, S.E. The analgesic activity of -l- 645-657, National Research Council, acetylmethadol and two of its metabolites National Academy of Sciences. 37th Annu- in mice. Research Communications in Che- al Scientific Meeting, 1975. mical Pathology and Pharmacology, 8(3): 575-578, 1974. Biliary metabolism and excretion of 3H LAAM in the rat. Problems of Drug Speeter, M.E., Byrd, W.M., Cheney, L.C., Dependence, 1012-1017. 37th Annual Sci- Binkley, S.B. Analgesic carbinols and entific Meeting, 1975. esters related to amidone (methadon). Journal of American Chemistry Society, Perrine, T.D., May, E.L. Synthesis of 6- 71:57-60, 1949. dimethylamino-4, 4-dinhenyl-heptane and other compounds related to methadone. Stickney, J.L. L-alpha-acetylmethadol(LAAM) Journal of Organic Chemistry, 19:773-779, cardiovascular effects. Summary state- 1954. ment, 1974. (Unpublished) Michigan State University, East Lansing, Michigan. Phatak, N.M., David, N.A. Addiction poten- tialities of some methadone analgesics Sullivan, H.Q., Due, S.L., McMahon, R.E. and alpha acetylmethadol as determined Enzymatic reduction. An important path- by their hyperglycemic responses in rab- way in the biotransformation of metha- bits. Current Research in Anesthesia and done in man and rat. Federation Pro- Analgesia, 32:242-249, 1953. ceedings, 32:764Abs, 1973. Metabolism of --l -methadol. N-ace- Pohland, A., Marshall, F.J., Carney, T.P. tylation, a new metabolic oathway. Re- optically active compounds related to search Communications in Chemical Patho- methadon. Journal of the American Chemi- logy and Pharmacology, 6(3):1073-1078, cal Society, 71:460-462, 1949. 1973. Portaghese, P.S., Williams, D.A. Stereo- Sung, C.Y., Way, E.L. The fate of the opti- chemistry of methadol diastereomers. cal isomers of alpha-acetylmethadol. Journal of Phamacological Science, 55: Journal of Pharmacology and Expeperimental 990-991 , 1966. Therapeutics, 110:260-270, 1954. Rosenkranz, R.P., Henderson, G.L. Renal Van Arsdel III, W.C., David, N.A. Modification- toxicity of 1-aloha-acetylmethadol (LAAM) tion of morphine, l-isomethadone, dl-al- in the rat. Proceedings of the Western pha-acetylmethadol, and n-allylnormor- Pharmacological Society, 18:284-287, phine constipation by hydergine. Journal 1975. of the American Pharmaceutical Associa- tion, 45:645-649, 1956. SAODAP. Background information on the use of l-alpha-acetylmethadol (LAAM) and Veatch, R.M., Adler, T.K., Way, E.L. The methadone as maintenance drugs during importance of steric configuration in the rehabilitation of heroin addicts. certain morphine-mimetic actions of syn- (Unpublished) (Office disbanded; duties thetic analgesics. Journal of Pharmaco- assumed by NIDA). logy and Experimental Therapeutics, 145: 11-19, 1964. Seevers, M.H. Summary of data on Wy-401. Committee on Drug Addiction and Narcotics Venkateswaran, N., Cholewa, R. Final report and The Committee on Problems of Drug on research Contract No. HSM 42-72-124. Dependence, National Research Council, 1973. (Unpublished) Regis Chemical Com- Division of Medical Sciences. 13th Meet., pany, Morton Grove, Illinois. App. K, p. 936, 1954. (Unpublished) University of Michigan Medical Center. Way, E.L., Adler, T.K. The biological disposition of morphine and its surrogates. Sherrod, T.R., Kaiser, R., Santos-Martinez, III. Synthetic surrogates of morphine. J., Pfeiffer, C.C. Methadone derivatives Bulletin of the World Health Organization of pharmacological interest. Federation (Geneva), 26(2):261-284, 1962. Proceedings, 7:255, 1948. The biological disposition of mor- Smith, C.C., Lehman, E.G. Effects of anal- phine and its surrogates--2. Bulletin gesic combinations on reaction time in of the World Health Organization, 26:51- rats. Journal of Pharmacology and Expeperi- 66, 1962. mental Therapeutics, 108:336-339, 1953.

121 The pharmacologic implications of the fate of morphine and its surrogates. Pharmacological review, 12:383-446, 1960. Welling, P.G. Pharmacokinetic studies on L-alpha-acetylmethadol (LAAM) in dogs. Protocol for study, 1974. (Unpublished) University of Wisconsin, Madison, Wiscon- sin. Young, G.A., J.E. Moreton, L.T. Meltzer, N. Khazan. Abstinence from Morphine, Methadone, and Z-alpha acetyl methadol (LAAM) in Dependent Rats: EEG and Be- havioral Correlates. Proceedings of the 38th Annual Scientific Meeting of the Committee on Problems of Drug Dependence, Richmond, Va., June 7-9, 1976. National Academy of Sciences, 1976.

12 2 LAAM BIBLIOGRAPHY

CLINICAL

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Summary progress report, 1973. Comparison dl-alpha-acetylmetha- (Unpublished) Prepared under Grant RO1- dol and methadone in the treatment of DA-00084 at University of Oregon Medical narcotics addicts. Pharmacologist, School, Portland, Oregon. 11(2):256, 1969.

124 Jaffe, J.H., Senay, E.C. Methadone and SAODAP cooperative study of levo- l-methadylacetate. Use in management alpha-acetylmethadol vs methadone. Final of narcotics addicts. Journal of the report 1976. (Unpublished). NIDA Grant American Medical Association, 216: 1303- No. DA01383, Friends Medical Science 1305, 1971. Research Center, Baltimore, Maryland. Lehmann, W.X. The use of l-alpha-acetylmethadol (LAAM) as compared to methadone Jaffe, J.H., Senay, E.C., Renault, P.F. A in the maintenance and detoxification of six-month preliminary report of the re- young heroin addicts. 1973. (Unpub- habilitative efficacy of l-methadyl ace- lished) Vitam Center, Norwalk, Connec- tate compared to methadone. Proc. of ticut. Fourth Natioral Conference on Methadone Treatment, San Francisco, Jan. 1972, Pp. Levine, R., Zaks, A. Duration of action 199-201. (cross-tolerance) of levomethadyl. 1972. (Unpublished) New York Medical College, Jaffe, J.H., Senay, E.C., Schuster, C.R., New York, New York. Renault, P.F., Smith, B., DiMenza, S. Methadyl acetate vs methadone. A double- Levine, R., Zaks, A., Fink, M., Freedman, blind study in heroin users. Journal of A.M. Levomethadyl acetate. Prolonged the American Medical Association, 222(4): duration of opioid effects, including 437-442, 1972. cross tolerance to heroin, in man. Jour- nal of the American Medical Association, Kaiko, R.P., Chatterjie, N., Inturrisi, C.E. 226(3):316-318, 1973. Simultaneous determination of acetylmethadol and its active biotransformation Ling, w., Charuvastra, V., Klett, J.C. products in human biofluids. Jounnal of Current status of the evaluation of Chromatography, 109(2):847-858, 1975. LAAM as a maintenance drug for heroin addicts. NIDA Narcotic Antagonist Clini Kaiko, R.F., Inturrisi, C.E. A gas-liquid cal Research Conference, Seattle, Wash- chromatographic method for the quantita- ington, 1974. (Unpublished) VA Hospi- tive determination of acetylmethadol and tal, Sepulveda, California. its metabolites in human urine. Journal of Chromatography, 82(2):315-321, 1973. Ling, W., V.C. Charuvastra, and C.J. Klett: Current Status of the Evaluation of LAAM as Disposition of acetylmethadol in a Maintenance Drug for Heroin Addicts. relation to the pharmacological activity. The Amer. Journal of Drug and Alcohol Clinical Pharmacology and Therapeutics, Abuse, 2:3 and 4 307-319, 1975. 18(1):96-103, 1975. Identification of some biotrans- Ling, W., Charuvastra, V.C., Kaim, S.C., formation products of acetylmethadol in Klett, C.J. Acetylmethadol and metha- human urine. Federation Proceedings, 32: done as maintenance treatments for heroin 764Abs, 1973. addicts. A Veterans Administration Co- operative Study. Archives of General Time course of plasma levels of Psychiatry, 1976. acetvlmethadol and biotransformation products in relation to pharmacological Ling, W., Klett, G.J. Clinical safety and activity in man. Federation Proceedings, efficacy of LAAM - the collective V.A., 33(3):473, 1974. and SAODAP-NIDA experience. Proceedings of the National Drug Abuse Conference, Keats, A.S., Beecher, H.K. Analgesic acti- New York, March 28, 1976. vity and toxic effects of acetylmethadol isomers in man. Journal of Pharmacology Mendelson, J.H., Inturrisi, C.E., Renault, and Experimental Thempeutics, 105:210- P., and Senay, E.C. Effects of acetyl- 215, 1952. methadol on plasma testosterone. Clini- cal Pharmacology and Therapeutics, 19(3) : Klett, C.J. VA-SAODAP cooperative study of 371-374, 1976. l-alpha-acetylmethl vs methadone. Re- Misra, A.L. and S.J. Mule: l-a-Acetylmethadol port.. 1975. (Unpublished) Central (LAAM) Pharmacokinetics and Metabolism: Neuropsvchiatric Research Laboratory. Current status. The Amer. Journal of Drug Veterans Administration Hospital, Perry and Alcohol Abuse, 2:3 and 4 301-306, 1975. Point, Maryland. 125 Newmann, M.C., C.J. Klett, and R. Stillman: vices. Chapter in Fisher, S. and Freed- Implementing a National Study of a New man, A.M., eds. opiate Addiction: Ori- Maintenance Drug. The Amer. Journal of gins and Treatment, V.H. Winston Sons, Drug and Alcohol Abuse. 2:3 and 4 289- 1974. 300. 1975. Senay, E.C., Renault, P.F., diMenza, S., Parwatikar, S., J. Crawford, and C. Unverdi: Collier, W.E., Daniels, S.J., and Dorus, WULM (l -a-Acetylmethadol) Study in St. W. Three times a week LAAM equals seven Louis. The Amer. Journal of Drug and times a week methadone: A preliminary Alcohol Abuse, 2:3 and 4 341-352, 1975. report of a control study. Problems of Drug Dependence, 543-550, 1975. Resnick, R., Orlin, L., Geyer, G., Schuyten, E., Kestenbaum, R., Freedman, A.M. l- Sullivan, H.R., Due, S.L., McMahon, R.E. alpha-acetylmethadol (LAAM): Prognostic Enzymatic reduction. An important path- considerations. Presented at the 128th way in the biotransformation of methadone Annual Meeting of the American Psychia- in man and rat. Federation Proceedings, tric Association, 1975. (Unpublished) 32:764Abs, 1973. New York Medical College Hospital, New York, New York. Metabolism of a-l-methadol. N- acetylation, a new metabolic pathway. SAODAP. Background information on the use Res. Comm. in Chem. Path. and Pharm., of l-alpha-acetylmethadol (LAAM) and 6(3):1073-1078, 1973. methadone as maintenance drugs during the rehabilitation of heroin addicts. Taintor, Z., G. Hough, M. Plumb, B.F. Murphy, (Unpublished) (Office disbanded; duties and C. D'Amanda: l-a-Acetylmethado1 and assumed by NIDA). Methadone in Buffalo: Safety and Efficacy. The Amer. Journal of Drug and Alcohol Abuse, Savage, C., Karp, E., Curran, S. A metha- 2:3 and 4 317-330, 1975. done/l-alpha-acetylmethadol (LAAM) maintenance study. Comprehensive Psychiatry, Whysner, J., Current progress in the plan- 1976. (In press) ning of phase III levo-alpha-acetylmetha. dol studies. Proceedings of the Nation- Schecter, A., Kauders, F. Patient deaths al Drug Abuse Conference, New York, in a narcotic antagonist and long-acting March 28, 1976. methadone program. NIDA Narcotic Anta- gonist Clinical Research Conference, Wilson, B.K. Research report of clinical Seattle, Washington, 1974. (Unpublished) effects of l-alpha-acetylmethadol on Kings County Hospital, Brooklyn, New man observed during pharmacokinetic stu- York. dies. (Unpublished) Yolo County Mental Schecter, A., and F. Kauders: Methadone and Health Service, Broderick, California. l-a-Acetylmethadol in a Treatment Program in Brooklyn. The Amer. Journal of Drug Wilson, T.G.G., Goldstein, A. Fran heroin and Alcohol Abuse, 2:3 and 4 331-340, 1975. addiction to abstinence, by stages, using LAAM and naltrexone. Proceedings of the Schecter, A. Historical perspectives on National Drug Abuse Conference, New York, the use of LAAM in rehabilitating opiate March 28 1976. dependent persons. Proceedings of the National Drug Abuse Conference, New Zaks, A., Derman, R. Comparison of main- York, March 28, 1976. tenance with high- and low-dose l-alpha- acetylmethadol. 1972. (Unpublished) Senay, E.C. and diMenza, S. Methadyl ace- New York Medical College, New York, New tate in the treatment of heroin addic- York. tion: A review, 34th Annual Scientific Meeting of the Committee on Problems Zaks, A., Fink, M., Freedman, A.M. 1-alpha- of Drug Dependence, 1972, Ann Arbor, acetylmethadol in maintenance treatment Michigan. of opiate dependence. proc. of Fourth Senay, E.C. A 48-week study of methadone, National Conference on Methadone Treat- methadyl acetate, and minimal services. ment, San Francisco, Jan. 1972, pp. 207- Psychopharmacology Bulletin, 9(4) :37, 210. 1973. Levomethadol in maintenance treat- Senay, E.C., Jaffe, J.H., diMenza, S., and ment of opiate dependence. Journal of Renault, P.F. A 48-week study of metha- the American Medical Association, 220(6): done, methadyl acetate, and minimal ser- 811-813, 1972.

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