monograph series

8R :3x/WEEK LAAMX

ALTERNATIVETO METHADONE

U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE • PUBLIC HEALTH SERVlCE • ALCOHOL, DRUG ABUSE, AND MENTAL HEALTH ADMINISTRATION

PX : 3 X /WEEK LAAMALTERNATIVE 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 theDivision of Research of the National Institute on Drug Abuse. Itsprimary objective is to provide critical reviews of research problemareas and techniques, the content of state-of-the-art conferences,integrative research reviews and significant original research. Itsdual publication emphasis is rapid and targeted dissemination to thescientific and professional community.

EDITORIAL ADVISORY BOARD

Avram Goldstein, M.D.

Jerome Jaffe, M.D.

Reese T. Jones, M.D.

William McGlothlin, Ph.D.

Jack Mendelson, M.D. Alchohol and Drug abuse Research CenterHavard Medical SchoolMcLean HospitalBelmont, Massachusettts

Helen Nowlis, Ph.D.

Lee Robins, Ph.D.

Addiction Research FoundationPalo Alto, California

College of Physicians and SurgeonsColumbia University. New York

Langly Porter Neuropsychiatric InstituteUnversity of CaliforniaSan Francisco, California

Department of Psychology, UCLALos Angeles, California

Office of Drug Education, DHEWWashington, D.C.

Walhington University School, of MedicineSt. 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 LAAMALTERNATIVE TO METHADONE

EDITORS

JACK D. BLAINE, M.D.

PIERRE F. RENAULT, M.D.Division of ResearchNational Institute on Drug Abuse

July 1976

NIDA Reseach Monograph 8THE NATlONAL INSTlTUTE ON DRUG ABUSE5600 Fishers LaneRockville. Maryland 20857

U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFAREPublic Health Service

DHEW Publication No. (ADM)78-347Formerly DHEW Publication No. (ADM)76-347Printed 1976 Reprinted 1977

Library of Congress catalog number 76-20257

For sale by the National Technical Information ServiceSpringfield, Va. 22161

Stock order #PB 253 763; Papercopy: $7.25; Microfiche: $3.00

iv

FOREWORD

This monograph is a biomedical review and assessmentof LAAM (Levo-alpha acetylmethadol), a new treatmentdrug for heroin addiction now undergoing large scaleclinical trials, following several years' intensiveresearch and development under the auspices of theNational Institute on Drug Abuse (NIDA) and its pre-decessor, the Special Action Office for Drug AbusePrevention (SAODAP).

LAAM was developed as an alternative to methadone.Over 800 methadone-related deaths per year are beingreported 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 (from1,440 in 1973 to over 2,000 in 1975) reported byDAWN also involve methadone.

Many of these deaths are directly attributable toillicit methadone diversion from drug treatment pro-grams to street sale. Because methadone patientsmust take their dose daily while simultaneously try-ing to stabilize their work, school, training, familyand personal lives, they have been allowed take-homedoses to reduce the number of clinic visits they mustmake. But this practice has made methadone widelyavailable, accounting for much illicit diversion andsubsequent painful record of methadone overdose deaths.In contrast, LAAM dosage is three times a week, itdoes not yield a quick high and appears to provide alevel, sustained effect. Animal toxicity studiesand clinical research experience indicate that LAAMis a safe and effective opiate maintenance drug,under appropriate medical supervision.

A wide spectrum of treatments is needed for variousdegrees of addiction and kinds of dependent persons.But LAAM seems promising for patients who may needopiate stabilization to ease the difficult switchfrom a drug-hustling street life to a less self-destructive one. LAAM provides one more choice intailoring treatment to each individual's needs.

Robert L. DuPont, M.D.DirectorNational Institute on Drug Abuse

v

CONTENTS

ForewordRobert L. DuPont, M.D.

v

IntroductionJack Blaine, M.D. and Pierre Renault, M.D.

1

The Chemistry of LAAMSydney Archer, Ph.D.

10

PRECLINICAL STUDIES

Pharmacology of LAAMSydney Archer, Ph.D.

15

Toxicology of LAAM 29Ms. Ann Wolven and Sydney Archer, Ph.D.

CLINICAL STUDIES

Phase I 39Ralph M. Sollod, M.S., and Marcia G. Goldstein, M.A.

Selected Clinical Studies Synopses

Sumnary of Veterans Administration Phase II Cooperative Study for LAAM and MethadoneWalter 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. MethadoneWalter Ling, M.D.C. James Klett, Ph.D.Roderic D. Gillis

Phase III Clinical Study of Levo-Alpha-AcetylmethadolJohn A. Whysener, M.D., Ph.D.

The Use of LAAM in TreatmentJames Cooper, M.D.

A Clinical Experience with LAAMAvram Goldstein, M.D.

A LAAM BibliographyPreclinicalClinical

52

94

103

109

112

115

118123

v i i

INTRODUCTION

Jack Blaine, M.D. and Pierre Renault, MD.

MEDICAL DETOXIFICATION

For many years heroin addicted individualswere "treated" by abrupt or gradual discon-tinuation of heroin, leading to abstinence.Resulting withdrawal symptoms were eitheruntreated or treated palliatively with non-opiate medications including sleeping pills,tranquilizers, analgesics, antidiarrheals,and/or antispasmodics. The failure of heroinwithdrawal alone as a treatment with the goalof long-term continued abstinence has beenvoluminously documented.

At best, medically controlled detoxificationhas only inmediate and temporary value as afirst step in a comprehensive rehabilitationprogram. Thus, regulated detoxificationreduces human suffering and frees the indi-vidual from his compulsive search for and useof the drug, permitting a shift in attentionto other more constructive pursuits. Longperiods of confinement in a hospital, thera-peutic commmity, or prison, even with tradi-tional psychotherapeutic intervention have notsignificantly altered subsequent relapse toheroin abuse for the vast majority of addicts.

Further, efforts at treatment by large scalemaintenance of heroin addicts on legallydispensed heroin appears to be an inadequatetreatment approach due to the practical

problems arising from the need to administerthe drug intravenously several times daily.

METHADONE DETOXIFICATION

During World War II, German chemists at theI.G. Farbenindustrie developed a syntheticnarcotic analgesic, 6-dimethylamino-4-4-diphen-y1-3-heptanone (methadone, dolorphine) as a sub-stitute for morphine. After the war, Americaninvestigators (Isbell et al. 1948) found thatmethadone’s pharmacological pmfile wassimilar to that of morphine and demonstratedthat methadone could substitute for morphinein morphine-dependent subjects to relieve theabstinence symptoms after discontinuation ofmorphine. Furthermore, methadone could pre-vent the appearance of withdrawal signs andsymptoms when substituted for morphine inequipotent doses. So methadone seemed alikely candidate to substitute for heroin whendetoxifying heroin addicts.

Methadone has several advantages over morphinefor detoxification of heroin dependent persons.Methadone is almost as effective orally asparenterally, thus avoiding problems of intra-venous dosage. Also, methadone is metabolizedto inactive substances more slowly thanmorphine. These two factors extend the dura-tion of action of methadone to 24 hours whichpermits once-a-day &sage and smooths thetime-effect curve. Thus, an oral daily dose of

1

methadone can be substituted for severaltimes daily intravenous doses of morphine orheroin. The dose of methadone can then belowered gradually until it is completelywithdrawn, producing only a mild abstinencesyndrome.

METHADONE MAINTENANCE

In 1965, Dole and Nyswander (1965) extendedthe clinical use of methadone to a medicalmaintenance or stablization treatment, usedwith a comprehensive program of rehabilitation.In a clinical research setting, they demon-strated that heroin addicts could be"stabilized" for many months on a single dailyoral dose of methadone (50-150 mg) achievedby gradually increasing the dose over aperiod of four weeks as tolerance developedto the dose which relieved the abstinencesyndrome. At the stabilization-maintenancedose, the medication appears to relievenarcotic “hunger” or craving, inducesufficient tolerance to prevent an abstinencesyndrome and block the euphoric effect ofintravenous heroin. The maintenance dose isnot intoxicating itself. Thus methadonestabilization produces a normal steady func-tional state rather than the wave-like fluctu-ating feeling states of euphoric intoxication("high"), normality ("straight"), andabstinence ("sick") commonly experienced inthe street heroin addict life style. Thisstabilization on methadone appears to freethe patient from heroin-oriented hustling,allowing participation in the treatment andrehabilitation program and development ofless destructive interests and activities.

In the ensuing several years, many otherclinical researchers, some with support fromthe Division of Narcotic Addiction and DrugAbuse, National Institute for Mental Health(DNADA, NIMH) NIDA’s precursor, intensivelyevaluated the use of methadone as a maintenancedrug for the treatment and rehabilitation ofheroin addicts. (Jaffe 1972; Goldstein 1971,1972; Blachly 1972; Zaks and Feldman 1972).By 1970 a rapid proliferation of methadonemaintenance programs had occurred across thecountry, and almost 9,000 heroin addicts werein treatment (Dole, 3rd Methadone MaintenanceConference, November 1970). Data from thesepatients indicated safety and efficacy of thisform of treatment under good medical super-vision.

The concept of methadone maintenance, withseveral variations from the original prototypeof Dole and Nyswander, achieved widespreadacceptance. Programs and number of patientsin treatment continued to expand. On December15, 1972 the Food and Drug Administration,after an extensive review of the methadone

treatment experience, approved the New DrugApplication for methadone maintenance treat-ment of heroin or morphine-like drug dependentpersons and published rules and regulationsin the Federal Register controlling its use.

METHADONE DISADVANTAGE

While methadone maintenance had been shownrepeatedly to be the most effective treatmentof opiate addiction available, severalinvestigators realized in the late sixties(Jaffe et al. 1970; Blachly 1971) thatsignificant problems related to the pharma-cology of methadone existed. Methadone didnot suppress the narcotic craving for a full24 hours in many addicts. Very large doses ofmethadone were necessary to provide sustainedrelief of abstinence of symptoms for 24 hoursfor these patients. These doses often producedunwanted sedation causing the patient to "nod"for the first several hours after consumption.

Furthermore, the patient was required toattend a methadone dispensing clinic daily toconsume his medication under staff supervision.This inconvenient and burdensome time andtravel demand was often draining physicallyand emotionally. When the patient was assumingresponsibility and trying to engage in work,rehabilitation or education programs, orresponsible homemaking, this requirement wasconsidered by some to be antitherapeutic. Acompromise solution was reached.

After demonstrating satisfactory adher-ence to the program regulations for atleast 3 months, and showing substantialprogress in rehabilitation by partici-pating actively in the programs’activities and/or participating ineducational, vocational and homemakingactivities, those patients whoseemployment, education, or homemakingresponsibilities would be hindered bydaily attendance may be permitted toreduce to three times weekly the timeswhen they must ingest the drug underobservation.

(Federal Register, Vol. 37,No. 242 page 26790, Dec. 15,1972).

Take-home doses were dispensed for theother four days.

Unfortunately, the practice of permittingtake home supplies of methadone for unsuper-vised self-administration away from the cliniccontributed to new problems (Jaffe et al.1970; Fink 1973). Accidental ingestion ofmethadone by non-tolerant persons, especiallychildren, led to an alarming increase inmethadone toxic reactions and overdose

2

fatalities. Also, a market developed forillicit sale and redistribution of methadoneto heroin addict peers suffering from with-drawal or to non-addict drug users seeking anew euphorient. More recently, the phenomenonof primary methadone abuse without priorheroin addiction surfaced. That is the treat-ment agent was becoming a new source ofaddiction. Finally, the patient might skipor delay a dose of methadone in order to"shoot up" with heroin after the blockade hasdiminished. Thus, the take-home privilegesinadvertently negated much of the usefulnessof random urine monitoring for illicit heroinuse. Furthermore, an adversary system orgame was created in which the patient mightattempt to deceive the staff in order to gainor retain take-home privileges (Goldsteinand Judson 1974).

Thus, a longer lasting medication would havemany practical therapeutic advantages overmethadone and partially resolve some of theseproblems encountered in clinical treatmentprograms. Fortunately, chemical and pharma-cological data were already available onoptical and structural isomers of methadoneas well as several derivatives (Pohland etal. 1949; Chen 1948; Eddy et al. 1950,1952;Speeter et al. 1949; Sung and Way 1954).This data suggested potential clinical useful-ness for L-alpha-acetyl-methadol (LAAM, l-methadyl-acetate) because of its high oraleffectiveness, long duration of action, andlow toxicity.

NEW DRUG DEVELOPMENT

The development of a new drug product is along and complex process. The 1962 KefauverHarris Amendments to the Federal Food, Drug,and Comestic Act established investigativeprocedures to supply substantial scientificevidence that a drug is safe and effective.Before a new drug can be marketed to thegeneral public, thorough testing must occurboth in animals and humans under carefullycontrolled circumstances.

Before a new drug may be tested clinically onhumans, the sponsor, usually a pharmaceuticalcompany, must provide FDA with information asspecified as a “Notice of Claimed Investi-gational Exemption for a New Drug" known as anIND. Among the requirements are:

(1) Complete composition of the drug, itssource and manufacturing data.

( 2 ) Results of all preclinical investigationsdemonstrating that there will not beunreasonable hazard in initiating studiesin humans. The minimmum data required arethe pharmacological profile, acute toxi-city and short term (two weeks to three

months) toxicity studies in several animalspecies.

(3) A detailed protocol of the plannedinvestigation.

Following preclinical animal studies indicatingthe drugs presumptive safety for humans, theclinical investigation, consisting of threephases, accumulates substantial scientificevidence of safety and effectiveness in man.This is needed to approve or disapprove thedrug for marketing. The Phase I clinicalinvestigation involves a small number of healthypatients to establish baseline data. Pharma-cological studies are used to determine drugaction, toxicity, metabolism, absorption,elimination, preferred route of administrationand safe dosage range. Phase II clinical trialsare conducted on a limited number of diseasedpatients to determine safety and effectivenessof the drug. If Phase II studies indicate thatthe drug may be useful and safe in treatinga disease and the long-term animal testingperformed concomitantly indicates no unwarrantedtoxicity, Phase III studies may commence. ThePhase III investigation involves extensive,careful controlled and monitored clinicaltrials assessing the drug’s safety, effective-ness and most desirable dosage in treating aspecific disease in a large number of patients.Phase III study approximates general clinicaluse.

Once Phase III is completed and claims ofsafety and effectiveness of the drug arcsupported, a New Drug Application (NDA) issubmitted to FDA requesting approval to marketthe drug. The NDA contains all the informationavailable about the drug which has accumulatedfrom studies in animals and several hundredto several thousands patients. The FDA reviewsthe NDA to determine whether the benefits ofthe drug when used properly outweigh the risks.Once an NDA is approved, the drug can bemarketed to the general public. However, themanufacturer is still required to reportregularly to FDA on any adverse reactions ortoxicity which occurs. At any stage in thisentire process the FDA may prohibit furthertesting or marketing based on unacceptabletoxicity or ineffectiveness.

LEVO-ALPHA ACETYL METHADOL (LAAM)

The early clinical work on LAAM focused onmorphine-like analgesic properties (Keats andBeecher 1952; David et al. 1956; David andSemler 1952). However, at the AddictionResearch Center, NIDA, Fraser, Isbell andcoworkers (1952, 1954) demonstrated LAAM’sability to relieve and prevent opiate with-drawal symptoms in addicts for long periods oftime, up to 72 hours. They also noted thatabrupt withdrawal from LAAM resulted in a mildbut prolonged abstinence syndrome.

3

Merck Company in the early and mid-sixtiesinvestigated LAAM’s usefulness as an analgesic.However, the delayed onset of action and pro-longed time course limited its clinical useful-ness for analgesia. Thus, Merck did not pro-ceed with LAAM beyond the early InvestigationalNew Drug stage.

Jaffe and co-workers first utilized alpha-acetyl-methadol in a clinical narcotic treat-ment program (Jaffe et al. 1969, 1970). Theysubstituted D, L-alpha-acetylmethadl (DLAAM)three times weekly for methadone daily ina small group of methadone maintenancepatients in 1968. TIhe results of that initialpilot study corroborated the findings of Fraserand Isbell that D-LAAM could suppress opiatewithdrawal symptoms for up to 72 hours andmight be a useful agent for the treatment ofheroin addicts.

Eased on the positive results of this pilotstudy, Dr. Sidney Cohen, Director, Divisionof Narcotic Addiction and Drug Abuse, NIMH,contracted with Merck Company for productionof four kilograms of LAAM in 1969. DNADAencouraged further clinical investigation byDNADA funded clinical research centers in theearly seventies. Research by this group sub-stantiated the comparable usefulness andsafety of LAAM as a maintenance treatment ofheroin addiction (Jaffe et al. 1971, 1972;Blachly et al. 1972; Zaks et al. 1972; Senayet al. 1974).

LAAM ADVANTAGES

These researchers found that LAAM offers thepatient, clinician and treatment programseveral advantages over methadone. Due toLAAM’s long duration of action, the frequencyof visits to clinic can be reduced from dailyto three times weekly even for patients justentering treatment (Levine et al. 1973).Addicts find participation in treatment moreacceptable and return more regularly,especially those trying to engage in work,education or rehabilitation activities outsideof the clinic, because travel time and effortis greatly reduced.

Some investigators found that LAAM offers thepatient a smoother, sustained drug effect. Thepatients appeared more alert and more emotion-ally level. Oral consumption even during theperiod of escalating doses did not produceexcessive sedation or subjective euphoria, i.e.the patients do not report being "loaded" or"nodding" (Blachly 1971). This effect isconsistent with phanmacokinetic data on LAAMand its active metabolites (Goldstein 1975;Billings et al. 1974; Henderson 1974, 1975)

Jaffe et al. (1970), Goldstein and Judson(1974). and Senay and diMenza (1972) emphasized

that LAAM is less likely to be a reinforcerof daily drug taking behavior than methadone.The three times weekly dosage schedule freesthe patient from the daily necessity ofengaging in drug seeking and drug takingbehavior. This represents an important thera-peutic step forward because the destructive,habitual pattern of behavior associated withthe heroin addict daily life style is broken.The individual feels less psychologically andphysically dependent when not involved withdaily drug taking. This strengthens theaddict’s identification with the drug freepopulation and breaks association with thedrug taking culture.

These factors are consistent with the treat-ment program goal of de-emphasizing of themystique of drugs and drug taking while emphasizing human relationship and alternatepursuits as sources of gratification. In thecontext of treatment, LAAM allows a reductionof emphasis on chemicals, since the life styleno longer pivots around the consumingpreoccupations associated with taking drugsseveral times a day or even once a day at thetreatment clinic. So there can be less talk-ing, seeking, taking and relating aroundchemicals. More energy is available forachievement of psychological, social, educa-tional and vocational goals rather than biolog-ical stabilization (Senay and diMenza 1972;Jaffe et al. 1970).

Also, LAAM offers a practical answer to theproblems related to take-home methadone.Illicit redistribution can be lessened becausethree times weekly LAAM reduces the amount oftake-home medication a clinic must providepatients for out of clinic administration. Ifnecessary, a no-take-home policy can be estab-lished by a clinic or program where redistri-bution and accidental overdose is especiallyprevalent (Jaffe et al. 1970; Fink 1973).

Further, several pharmacological propertiesmake LAAM less prone than methadone to abuse.LAAM itself is one-tenth as active as itsmetabolites (Smits 1974; Nickander et al. 1974).Because metabolism requires time, severalhours pass between taking LAAM and the onsetof psychoactivity (Billings et al. 1974).Therefore, LAAM is less likely to be a rein-forcer of drug taking because substances witha rapid, immediate onset of euphoric effectsare much more desired by drug users. LAAM hasanother unique characteristic which makes itless desired. Unlike other narcotics? LAAMis more rapidly effective orally than intra-venously, the preferred route of heroin addicts(Blachly 1971; Fraser 1952).

LAAM may offer treatment programs advantagesover methadone by improving the logistics of

4

drug distribution. Three times weekly dosageallows for more controlled drug delivery toincreasingly large numbers of patients. Byreducing the required number of clinic visits,efficiency of treatment may be increased dueto savings of staff dispensing and pharmacyservices (Senay et al. 1972; Blachly 1971).Thus, conversion from methadone to LAAM canpotentially either reduce the cost of treat-ment or increase the number of availabletreatment slots.

SAODAP UNDERTAKES COORDINATION OF LAAMDEVELOPMENT

In June 1971, the Special Action Office forDrug Abuse Prevention (SAODAP) was establishedby Executive Order "to focus the comprehensiveresources of the Federal Government.... andto develop a comprehensive, coordinated, long-term federal strategy to combat drug abuse."The Drug Abuse Office and Treatment Act of1972 (Public Law 92-255, Sec. 224, 86 stat.72, March 21, 1972) mandated the expansion ofresearch on "long-lasting, non-addictive,blocking and antagonist drugs or other pharma-cological substances for the treatment ofheroin addiciton." Based on the potentialadvantages of LAAM over methadone, Dr. JeromeJaffe, SAODAP's first director, initiated inthe summer of 1971 a comprehensive review ofthe status of LAAM and other long-lastingblocking drugs utilizing experts from thevarious government agencies and the privatesector.

The conclusion of the review was that LAAM wasthe most promising compound available at thetime, but that the pharmacological developmentof LAAM was not proceeding rapidly enough.Several problems were found to be delayingLAAM development. There was little generalinterest in or knowledge about LAAM in thetreatment, research or pharmaceutical fields.No one in Federal Agencies or industry waspromoting the drug. LAAM investigation waslimited to a few research centers. Largequantities of LAAM necessary for use in treat-ment were not available from any source, andonly a few kilograms remained from the LAAMproduced for DNADA several years previously.

Furthermore, unlike methadone, which wasmarketed as an analgesic prior to its use innarcotic addiction treatment, LAAM was notpatented or marketed for any indication. LAAMwas not patentable because it had been in thepublic domain for many years. Thus, thepharmaceutical companies were not interestedin spending research and development funds fora drug without exclusivity and with a limitedmarket. Also, the pharmaceutical industrydrew attention to the special precautions andregulatory controls pertaining to developmentof controlled, Schedule I, narcotic substances.

Facilities were not available in the industryfor preclinical narcotic testing nor was therean existing structure to perform the carefullymonitored clinical studies required.

Thus, SAODAP recognized that LAAM was notproceeding because the pharmaceutical industrydid not want to develop and promote it.Therefore SAODAP set a high priority on creat-ing and coordinating a governmental mechanismfor developing this type of drug using LAAMas the prototype. Therapeutic drug developmenthad previously been the function of thepharmaceutical industry and not a practic ofgovernment. In fact, the recognized functionof the Federal Government was to regulate thepharmaceutical industry. This led to theinteresting and potentially anomolous situationof the government attempting to develop andalso regulate the same compound, the formerat SAODAP and DNADA and the latter at FDA.

Although LAAM was to be developed as rapidlyas possible, it was imperative to avoid themany problems encountered by methadone dueto inadequate and incomplete study. FederalAgencies had the assigned responsiblity tobe certain that LAAM was a safe and effectivedrug before marketing. Therefore, SAODAPorganized and promoted interagency cooperationin LAAM development, with DNADA and FDAplaying the leading roles. SAODAP effectivelyutilized the expertise in academic andphamaceutical communities for advice andmonitoring the process. A LAAM MedicalAdvisory Panel served this latter purpose.

The amount of LAAM available severely limitedthe progress of both animal and clinicalinvestigation. A larger supply of LAAM wasobtained through the cooperation of thePenick Pharmaceutical Company in 1972 andarrangements were made for an additionalsupply when needed. The recognition thatfurther animal studies were needed to establishintermediate and long-term nontoxicity ofLAAM prompted an agreement between DNADA andDepartment of Army’s research facilities atEdgewcod Arsenal to perform the necessarystudies in December 1971. In the Spring of1972 an interagency Pharmacology Task Forcewas formed of representatives from SAODAP,the Veterans Administration, Department of theArmy, Food and Drug Administration, FM,National Academy of Sciences. and the Divisionof Narcotic Addiction and Drug Abuse, NationalInstitute of Mental Health DNADA,(NIMH). Thisgroup reviewed previous and ongoing work onLAAM and planned and coordinated the subse-quent development toward the New Drug Appli-cation stage.

Through this coordinated effort, the necessaryanimal toxicological and teratological studiescould be phased with the subsequent clinical

5

studies of humans. The animal toxicologystudies done previously by Merck and Companywere utilized for the clinical Phase IInvestigational New Drug studies begun inJune 1972 by DNADA. DNADA initiated extensivechronic animal studies including a one yearstudy in dogs and rats to provide requiredtoxicological data to support safe, prolongedadministration in man.

The existence of these animal and earlyclinical studies stimulated clinical interestin LAAM. Planning began early in 1972 forlarger scale cooperative clinical studies totest LAAM safety and efficacy which couldfollow by 6 to 8 months the chronic animalstudies required to support long term admini-stration to humans. Dr. Samuel Kaim, Directorof the Alcohol and Drug Dependence Service ofthe Veterans Administration expressed V.A.‘sinterest to SAODAP. The VA had vast experiencewith large scale clinical cooperative studiesof other psychotropic drugs. The administra-tive mechanism including the data gatheringand analysis section and pharmacy was alreadyfunctional at V.A. Hospital, Perry Point,Maryland, under the direction of James Klett,Ph.D. Also, the VA had recently establisheda network of Drug Dependence Treatment Centersfor returning addicted soldiers.

The planning and initiation of further clinicalstudies proceeded cautiously. To protect thewell-being of potential subjects, the AdvisoryCommittee and Pharmacology Task Force wantedsome data from the long-term animal studiesavailable before long-term clinical studieswere initiated. By the Spring of 1973sufficient animal toxicity data was availablefrom the Edgewood Arsenal study to support thecautious initiation of Phase II clinicalstudies. These studies were to proceed insuccessive stages contingent upon continuedevidence of lack of toxicity in animalsindicating probable safety in man.

In April 1973, pilot studies were initiated inthree VA Hospitals to evaluate the safety andefficacy of LAAM maintenance (80 mg three timesweekly) compared to high (100 mg daily) andlow (50 mg daily) dose methadone maintenance.The study was conducted double-blind andutilized a common protocol for random selectionof subjects, induction of street heroin addictsonto the study drugs, maintenance dosage, andfor evaluating safety and efficacy. In thesummer of 1973 based on the up&ted animaldata, the existing data from the pilot studiesand other available clinical data, the decisionwas made to continue tentatively the study fora total of 40 weeks and to proceed with theaddition of nine more Veterans AdministrationHospitals in the Cooperative Study. Theclinical study was carried out over a 2 year

period, terminating in the Spring of 1975.Four hundred thirty (430) male heroin addictswere studied. Of these, 142 received LAAM andthe remainder were equally divided betweenhigh and low dose methadone.

Because of technical inadequacies in the Edge-wood Arsenal Study, DNADA initiated additionalacute and chronic rat and dog studies of LAAMin 1973. At approximately this time, SAODAPbegan planning and organizing another largercooperative clinical study of LAAM to providemore patient data. The study was designedto complement the VA study.

Interested patients were selected from thosealready in methadone maintenance programs.In the major part of the new clinical study,patients were randomly assigned to the LAAMstudy group or the methadone control group.The study was open rather than double-blind.Take-home methadone was permitted accordingto clinic policy, while all LAAM patientsattended the clinic three times a week. Cross-over dose from methadone to LAAM was fixed,but subsequent dose levels were flexible at thediscretion of the clinic physician. In addi-tion, sub-study was performed to examinefurther the use of LAAM on Friday only inplace of weekend methadone.

The SAODAP cooperative study was initiatedin February 1974 when the safety data fromthe second animal toxicity study and theclinical data from the VA Cooperative Studywas adequate to support an additional 40 weekhuman safety and efficacy study. Sixteen (16)outpatient drug treatment clinics throughoutthe country were chosen for participation inorder to provide widespread experience withLAAM in local treatment programs in acontrolled, carefully monitored and coordinatedmanner. Seven hundred sixty seven (767) malepatients, of whom 383 received LAAM, partici-pated in this study. Of these, 136 patients,of whom 65 received LAAM, participated in theLAAM Friday only substudy.

COORDINATION OF LAAM DEVELOPMENT TRANSFERREDTO NIDA

When SAODAP began to phase out in the Fallof 1974, the coordination and direction ofthe LAAM project, including the PharmacologyTask Force and Cooperative Studies wereofficially transferred to the recentlyestablished Division of Research, NationalInstitute on Drug Abuse, (NIDA), successorto DNADA,(NIMH). Shortly thereafter, based onthe available results of the animal andclinical studies, the Food and Drug Adminis-tration permitted the use of LAAM for up to80 weeks to provide longer comparative toxi-city data. Also, the inclusion of women withno child-bearing potential was permitted.Accordingly, NIDA extended the SAODAP clinical

6

studies until the Spring of 1976 to performadditional studies of LAAM.

Thus, by the Fall of 1974 all of the basicwork necessary to initiate Phase III largescale clinical study of LAAM had been completedor was in the process of completion. LAAMappeared to be a safe and efficacious drugfor use in the treatment and rehabilitation ofchronic opioid dependent persons. The staffsof the Clinical-Behavorial Branch, Division ofResearch, NIDA and the Drug Abuse Section,Division of Neuroharmacology, FDA, began toplan the Phase III clinical study of LAAMthrough the Pharmacology Task Force. A PhaseIII clinical study is a full scale clinicaltrial of the drug under the conditions of theuse in the general population. Thus, thosegroups of heroin addicts excluded from parti-cipation in a Phase II study can be includedin Phase III. These Phase III studies caninclude subjects with medical and/orpsychiatric illnesses, subjects concurrentlytaking other medication and women of child-bearing potential.

In the Spring of 1975, NIDA advertised a RFPto perform the Phase III study under a costsharing contract. In return for the cost-sharing NIDA provides patent-like protectionfor the contractor to protect his investmentin LAAM and to assure the marketing of thedrurg in the public’s interest. NIDA agreedto give the contractor the right to exclusivepossession and use of all data generated inthe performance of this contract which wouldbe necessary to prepare and file a New DrugApplication on LAAM for eight years pendingsatisfactory performance of the contract.

Despite the investment and commitment alreadymade by Federal Agencies the pharmaceuticalindustry did not respond. However, othercompetitive bids were received. In July 1975,a medical consulting firm, Whysner Associates,was contracted by NIDA to conduct Phase IIIClinical Evaluation of LAAM for the treatmentof chronic opioid dependence and to makeappropriate arrangements for the eventualfiling of the New Drug Application andmarketing of LAAM.

The contract is currently ongoing and arrange-ments are made to formulate and distributeLAAM The Phase III Investigational New DrugApplication has been submitted and clinics arebeing enlisted to carry out the clinical study.An estimated 6000 patients, including thosealready maintained on methadone and heroinaddicts entering treatment, will be asked toparticipate in a 40 week study of safety andefficacy of LAAM. The open study will beperformed in approximately 50 cooperatingmethadone maintenance programs nationwide. A

common protocol for medical monitoring andevaluation of clinical efficacy will be utilizedto produce uniform data. The study willrequire approxmiately two years to completeafter which the New Drug Application for LAAMcan be submitted to FDA to permit its marketingto interested chronic opioid dependence treat-ment programs.

Pending successful completion of this Phase IIIlarge scale clinical trial, the project hasaccomplished the formidable task of developingat an accelerated pace a drug which offersconsiderable potential benefit to heroin addictsand treatment programs. The task of developinga drug the private sector was unwilling orunable to undertake has been carried out, andin accordance with stringently applied FederalRegulations designed both to ensure the kindof scientific baseline data establishingLAAM safety and efficacy and to provide amechanism that can be a model for future drugdevelopment in the narcotic dependence treatmentfield. Conjointly the task has entailed creat-ing the means for cooperation between the manyagencies and individuals involved in a far-flungand large scale project. This also, is alegacy for future drug development.

REFERENCES

Billings, R. E., McMhahon, R. E., Blake, D.A.1-acetylmethadol (LAM) treatment of opiatedependence: plasma and urine levels of twopharmacologically active metabolites. LifeSciences 14:1437-1446, 1974a.

Blachly, Paul., Recent developments in theTherapy of Addictions. Current PsychiatricTherapies 12:98-103, 1972.

Billings, R. E., McMahon, R. E., Blake, D.A.1-acetylmethadol treatment of opiate dependence:the crucial role of active metabolites.Federation Proceedings 33(3):473, 1974b.

Blachly, P. H. L-alpha acetylmethadol in thetreatment of opiate addiction: Progress Report,1971. Methadone, 1971 Workshop Proceedings,P. H. Blachly, ed., ACEB Books, Corvallis,Oregon, 1971. p. 23-25.

Blachly, P. H., David, N. A., Irwin, S. Alpha-acetylmethadol (LAM) : comparison of laboratoryfindings, electmencephalograms, and CornellMedical Index of patients stabilized on LAMwith those on methadone. Proc. of Fourth Natl.Conf. on Methadone Treatment, San Francisco,Jan. 1972, pp. 203-205.

Chen, K. K. Pharmacology of methadone andrelated compounds. Annals of the New YorkAcademy of Sciences 51:83-97, 1948.

7

David, N. A., Semler, H. J., Clinical trial ofalpha acetylmethadol (dl-6-dimethylamino-4,4-diphenyl-3-acetoxy-heptane) as an analgesic.Journal of Phamcology and ExperimentalTherapeutics 106:380, 1952.

David, N. A., Semler, H. J., Burgner, P. R.Control of chronic pain by dl-alpha-acetyl-methadol. Journal of the American MedicalAssociation 161(7):599-603, 1956.

Dole, U. P., Nyswander, M. A. A medical treat-ment for diacetylmorphine (heroin) addiction.Journal of the American Association 193:646-650, 1965.

Eddy, N. B., May, E. L., Mosettig, E. Chemistryand pharmacology of the methadols and acetyl-methadols. Journal of Organic Chemistry 17(2):321-326, 1952.

Eddy, N. B., Touchberry, C. F., Lieberman,J. E., Khazan, N. Synthetic analgesics; metha-done isomers and derivatives. Journal ofPharmacology and Experimental Therapeutics98:121-137, 1950.

Fraser, H. F., Isbell, H. Actions and addic-tion liabilities of alpha-acetylmethadols inman. Journal of Pharmacology and ExperimentalTherapeutics 105(4):458-465, 1952.

Fraser, H. F., Nash, T. L., Vanhorn, G. D., andIsbell, H. Use of miotic effect in evaluatinganagesic drugs in man. Archives Internationalesde Phamacodynamie et de therapie 98:443-451,1954.

Goldstein, A. Blind controlled dosage compari-sons in Two hundred patients. Proceedings ofthe Third National Conference on MethadoneTreatment. p. 31. Washington, D.C.: U.S.Government Printing Office 1971.

Goldstein, A. Heroin Addiction and the roleof methadone in its treatment. Archives ofGeneral Psychiatry 26:291-297, 1972.

Goldstein, A. LAAM and LAAM metabolites: plasmalevels in patients.1975 (Unpublished)

Summary progress report.

Goldstein, A., and Judson, B. Three criticalissues in the management of methadone programs:Critical Issue 3: Can the community be pro-tected against the hazards of take-home metha-done. Addiction. Peter G. Bourne, ed.Academic Press, New York, p. 140-148, 1974.

Henderson, G. L., A two-year pharmacokineticstudy of LAAM. Fourth quarter progress report.1974. (Unpublished)

Henderson, G. L., Two-year pharmacokineticstudy of LAAM. Sixth quarter progress report.

8

1975. (Unpublished)

Henderson, G. L. Two-year pharmacokineticstudy of LAAM.. Seventh quarter progressreport. 1975b. (Unpublished)

Isbell, H., Wickler, A., Eisenman, A. J.,Daingerfield, M., Frank, E. Liability ofaddiction to 6-dimethlamino-4-4-diphenyl-3-hepatone in man. Archives of Internal Medicine82:362-392, 1948.

Jaffe, J. H. The maintenance approach to themanagement of opiod dependence. In: Zarafo-netis, Chris J. D., ed. Drug Abuse: Proceed-ings of the International Conference. Phila-delphia: Lea and Febiger, 1972, pp.161-170.

Jaffe, J. H., Schuster, C. R., Smith, B. B.,Blachly, P. H. Comparison of acetylmethadoland methadone in the treatment of long-termheroin users: A pilot study. Journal of theAmerican Medical Association 211:1834-1836,1970.

Jaffe, J. H., Schuster, C. R., Smith, B. B.,Blachly, P. Comparison of dl alpha-acetylmethadol and methadone in the treatment ofnarcotics addicts.1969.

Phamacologist 11(2):256,

Jaffe, J. H., Senay, E. C. Methadone and1-methadyl acetate. Use in managment ofnarcotics addicts. Journal of the AmericanMedical Association 216:1303-1305, 1971.

Jaffe, J. H., Senay, E. C., Rehault, P. F.A six-month preliminary report of the rehabil-itative efficacy of 1-methadyl acetate comparedto methadone. Proc. of Fourth National Confer-ence on Methadone Treatment, San Francisco,Jan. 1972, pp. 199-201.

Jaffe, J. H., Senay, E. C., Schuster, C. R.,Renault, P. F., Smith B., diMenza, S. Methadylacetate vs methadone. A double-blind study inheroin users. Journal of the American MedicalAssociation 222(4):437-442, 1972.

Levine, R., Zaks, A., Fink, M., Freedman, A. M.Levomethadyl acetate. Prolonged duration ofopiod effects, including cross tolerance toheroin, in man. Journal of the AmericanMedical Association 226(3):316-318, 1973.

Moreton, J. E., Roehrs, T., Khazan, N. Sleep-awake activity and self-injection pattern ofrats dependent on morphine, methadone, orL-alpha-acetyl-methadol (LAAM). FederationProceedings 33(3):516, 1974.

Nickander, R., Booher, R., Miles, H. a-l-ace-tylmethadol and its N-demethylated metaboliteshave potent opiate action in the guinea pig

isolated ileum. Life Sciences 14:2011-2017,

Pohland, A., Marshall, F. J., Carney, T. P.Optically active compounds related to methadonJournal of the American Chemical Society 71:460-462, 1949.

Senay, E. C. and diMenza, S. Methadyl acetatein the treatment of heroin addiction: A review,34th Annual Scientific Meeting of the Committeeon Problems of Drug Dependence, 1972, AnnArbor, Michigan.

Senay, E. C., Jaffe, J. H., diMenza, S., andRenault, P. F. A 48-week study of methadone,methadyl acetate, and minimal services. Chapterin Fisher, S. and Freedman, A. M., eds., OpiateAddiction: Origins and Treatment, V. H. Winston

Sons, 1974.

Senay, E. C., Renault, P. F., diMenza, S.,Collier! W. E., Daniels, S. J., and Dorus, W.Three times a week LAAM equals seven times aweek methadone: A preliminary report of acontrol study. Proceedings of the FirstNational Drug Abuse Conference, 1974. (In Press)

Smits, S. E. The analgesic activity of a-l-acetylmethadol and two of its metabolites inmice. Research Communications in ChemicalPathology and Pharmacology 8(3): 575-578, 1974.

Speeter, M. E., Byrd, W. M., Cheney, L. C.,Binkley, S. B. Analgesic carbinols and estersrelated to amidone (methadon). Journal ofAmerican Chemistry Society 71:57-60, 1949.

Sung, C. Y., Way, E. L. The fate of theoptical isomers of alpha-acetyl-methadol.Journal of Pharmacology and Experimental Thera-peutics 110:260-270, 1954.

Zaks, A., Feldman, Martin. Private methadonemaintenance: analysis of a program after oneyear. Journal of the American Medical Associa-tion 222(10):1279-1280, 1972.

Zaks, A., Fink, M., Freedman, A. M. 1-alpha-acetylmethadol in maintenance treatment ofopiate dependence. Proc. of Fourth NationalConference on Methadone Treatment, SanFrancisco, Jan. 1972, pp. 207-210.

Zaks, A., Fink, M., Freedman, A. M. Levo-methadyl in maintenance treatment of opiatedependence. Journal of the American MedicalAssociation 220(6):811-813, 1972.

9

THE CHEMISTRY OF LAAM

Sydney Archer, Ph. D.

CHEMICAL S’TRUCTURAL. FORMULA AND DESCRIPTION

Levo-alpha-acetylmethadol (LAAM) is levo-alpha-6-dimethylamino-4, 4-diphenyl-3-heptylacetate and is used as its hydrochloride salt.The chemical structure of LAAM is as follows:

It is a white crystalline compound with amelting point of 215-218°C. It is levorotary

and has a specific rotation of -59.0 to-61.3°. 25 D (c=1 in water). Infraredabsorption conforms to structure in CHCl3solution and KBr Pellet.

RELATIONSHIP TO OTHER RELATED DRUGS

The compound was first reported by Pohland,Marshall and Carney (1949)l as a water-solublesubstance with a melting point of 201-202°Cand 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-sion of the monograph in the LAAM PreclinicalBibliography.

10

Pohland, Marshall and Carney (1949) also per-formed the same sequence of reactions on 1-methadone. This yielded d-alpha-acetylmethadolwhose hydrochloride was also water-soluble andmelted at 200-303°C. The optical rotation was

25 D = +57° (c=0.2 in water).

It will be noted that the dextrorotary form ofmethadone gave levorotatory acetylmethadol,whereas the analgetically more active l-meth-adone gave the dextrorotatory isomer.

It will also be noted that whereas methadone(II) has only one chiral center (starred car-bon) the acetylmethadols have two chiral cen-ters (starred carbons). Two diastereomeric

pairs of isomers are possible. However, cata-lytic hydrogenation gave only the alpha-seriesas reported by Pohland et al. May and Mosettig(1948) showed that catalytic hydrogenation ofdl-methadone furnished the alpha-series exclu-sively and Speeter, Byrd, Cheney and Binkley(1949) found that lithium aluminun hydridereduction of dl-methadone furnished dl-methadol exclusively also.

On the other hand Eddy, May, Mosettig (1952)found that sodium propanol reduction of eitherracemic or optically active methadone gave thebeta-methadols, as the major but not exclusiveproducts. These results are summarized inChart I.

11

These authors converted the isomers to thecorresponding acetates. Thus, all four poss-ible isometric acetates were synthesized.

In the course of studying the metabolism ofLAAM, two new matabolites were discovered.These are 1-alpha-6-methylamino-4, 4-diphenyl-3-heptyl acetate (V), (Nor-LAAM), and 1-alpha-6-amino-4, 4-diphenyl-3-heptyl acetate (VII),(DiNor-LAAM). Their synthesis was reportedby Booher and Pohland (1975) and is outlinedin Chart II.

LAAM (I) was treated with trichlororthylchloroformate to give the amide (IV), whichwas reduced with zinc in formic acid to giveNor-LAAM (V) in 44 percent overall yield fromI. Oxidation with potassium permanganate gavethe nitro ester VI in 24 percent yield. Re-duction using Raney nickel gave DiNor-LAAM(VII) in 72 percent yield.

Chatterjie and Inturissi (1975) were able toprepare Nor-LAAM from LAAM in one step usinga mercuric acetate demethylation procedure.The yield was 50 percent and is shorter thanthe method of Booher and Pohland (1975).

DESCRIPTION OF DOSAGE FORM ANDQUANTITATIVE COMPOSITION

The dosage form of 1-alpha-acetylmethadol isa colorless, clear liquid with the odor ofparabens. One ml of concentrate contains:

1-alpha-acetylmethadol 10 mgmethyl paraben 0-18 percentpropyl paraben 0.02 percent

in distilled water.

ASSAY OF LAAM FOR STABILITY

The following procedures were developed bythe United States Public Health Service HSHMASupply Service Center, Perry Point, Maryland(January, 1974), for the assay of samples ofLAAM packaged in 16-ounce amber, polyethylenebottles and stored at 25°C and 45°C. Thetitrimetric procedure which follows is amodification of the USP XVIII procedure forMethadone Hydrochloride Injection:

12

Transfer a volume of concentrate equivalent to about 50 mg. of LAAM to a separatory funnel and washwith 25 Ml. of either. Transfer the aqueous layer quantitatively to the Watkins Continuous ExtractionApparatus 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 evaporatethe 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 wasdeveloped 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 of10.0 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 volumewith water, and mix. Inject 1 microliter of each solution into the apparatus. Run at least 3 injectionsof each standard and the sample. From the chromatograms obtained calculate the ratio of the peak areaof LAAM-CHCl to the peak area of Diphenhydramine HCl. Plot the peak area ratios of the two standardsolutions 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:

13

PRECLINICAL STUDIES

PHARMACOLOGY OF LAAMSydney Archer, Ph.D.

The synthesis of levo-alpha-acetylmethadol(LAAM) and early preclinical investigationsinto toxic and analgesic properties werecarried out in 1948. The delayed onset andlong duration of action of this compound wassuggestive of the activity of metabolites,and further studies showed that two metabo-lites, noracetylmethadol (N-LAAM) anddinoracetylmethadol (DN-LAAM), were responsi-ble for the unique time-response character-istics of 1-alpha-acetylmethadol. Currently,research is being carried out into thepharmacokinetics of 1-alpha-acetylmethadol,as well as long-term toxicity studies andstudies of the effects of the drugs uponreproduction.

This chapter is devoted to an account ofLAAM preclinical animal studies and providesa summary of all pharmacological studies ofLAAM. The following chapter offers anaccount of the preclinical toxicology ofLAAM.

PHARMACOLOGICAL SUMMARY OF FINDINGS

The following summary of LAAM preclinicalstudies presents a comprehensive overview ofthe pharmacological research which had beenconducted with LAAM in animals, throughsummer of 1975.

Five areas of LAAM animal pharmacologyresearch findings are discussed below:

Analgesic Activity of LAAMand Related compounds

K. K. Chen (1948)1 first reported on theanalgesic activity of 1-alpha-acetylmethadol(LAAM) and d-alpha-acetylmethadol (DAAM)LAAM was prepared from d-methadone which isless active as an analgesic than l-methadone.The latter is the precursor of DAAM. Chenfound that in rats l-methadone is seven timesas potent as d-methadone but in higher ani-mals the difference in potency is evengreater. The l-isomer is 25 times as activein dogs and 50 times as active in man. Thus,it may be expected that the analgesic activ-ity of DAAM will be greater than LAAM. Thisproved to be the case. It was found that inrats using the Haffner technique for deter-mining analgesic activity (F. Haffner,Deutsch, Med. Wochenschrift 55: 731, 1929)DAAM was 5.4 times as active as LAAM by thesubcutaneous (s. c.) route of injection and

References cited my be found at the con-clusion of the Monograph in the LAAM Pre-clinical Biography.

15

twice as active as dl-methadone. It wasnoted that LAAM had a delayed onset but along duration of activity as compared withthe d-isomer.

Smith and Lehman (1953) found that theanalgesic effects of methadone and LAAM inrats were additive when both were injectedsubcutaneously using the D'Armour-Smith test.

Using the pinch test with rats, McCarthy(1974) found that at 30 minutes after sub-cutaneous administration, LAAM was about

0.67 (0.53-0.86) times as potent as morphinesulfate but at peak activity, which occurredthree and one-half hours after drug admin-istration, it was six times as potent asmorphine. The onset of analgesic action wasconsiderably later than that of morphine ormethadone.

Leimbach and Eddy (1954) determined theanalgesic activity in mice (s.c.) of allfour of the stereoisomers as well as theLD50 values. Their analgesic results aresummarized in Table I and Table II.

In agreement with K. K. Chen, these authorsfound that d-a-acetylmethadol (DAAM) isabout six times as active as an analgesicthan 1-a-acetylmethadol (LAAM). They alsonoted a delay in onset and a longer durationfor LAAM as compared with DAAM. However,these differences tended to disappear whenthe durgs were administered orally (TableII). When the oral route was used, the ED50

doses, the onset, and duration were almostidentical. When compared with dl-methadone,LAAM was more active orally (ED50 =1.1 vs9.2) and had a greater duration of action.

The LD50 data for these compounds issummarized in Table III.

16

LAAM turned out to be the least toxicstereoisomer whether given orally or sub-cutaneously and was less toxic than dl-methadone also. It must be emphasized thatthese acute toxicities were determined innondependent mice and caution must beobserved in extrapolation of these results.

Veatch, Alder, and Way (1964) studied thenalorphine reversibility of the analgesic

effects of DAAM and LAAM as compared withl-methadone and d-methadone. The ED valueswere obtained by intraventricular injection.Because of the long duration of action ofLAAM and the relative short duration ofaction of nalorphine, the latter (50/mg/kg)was administered 40 minutes after the doseof LAAM and doses of the antagonist weregiven every hour thereafter for a total ofsix hours. The results are summarized inTable IV.

It is surprising that no nalorphinereversibility was noted after administrationof LAAM or d-methadone. The results areself-consistent in the sense that d-methadoneis the precursor of LAAM and l-methadone isthe precursor of DAAM.

Nevertheless, it would be expected thatnalorphine would reverse these morphine-likeeffects of all the compounds. In contrast,Killam (1974) found that in monkeys therespiratory depressant effects of LAAM werenalorphine and naloxone reversible.

Analgesic Activity of LAAM Metabolites

When it became known that LAAM was metabol-ically converted to 1-alpha-noracetylmethadol(N-LAAM) and 1-alpha-dinoracetylmethadol(DN-LAAM), Nickander, Booher, and Miles(1973) compared the analgesic activity ofthese three compounds on the guinea pig ileumpreparation. The results are summarized inTable V.

17

Smits (1974 studied these drugs for analge-sic activity in the acetic acid-inducedwrithing test in mice. The results are sum-marized in Table VI.

It was noted that LAAM had a slower onset ofaction than its metabolites.

1-alpha-noracetylmethadol (N-LAAM) is moreactive than LAAM. The slow onset of thelatter coupled with the high activity of themetabolite, N-LAAM, is highly suggestive thatLAAM is metabolically transformed to anactive drug which is probably N-LAAM. Thestudies of Way using SKF-525A stronglysupport this proposition.

Billings, Booher, Smits, Pohland, andMcMahon (1973) found that ED50 of l-alpha-dinoracetylmethadol (DN-LAAM) in the aceticacid-induced mouse writhing test for analge-sia was 1.5 mg/kg S.C. and 5.6 mg/kg peroral(p.o.)

Addiction Potential of LAAM and Its Cogeners

Deneau and Seevers (1960, 1955) determinedthe physical dependence capacity (PDC) ofsome compounds related to LAAM although LAAMitself was not run. The usual single dosesuppression technique, using morphine-depend-

It is clear that in both the in vitro and ent monkeys was employed. The results arein 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-self, the racemic mixture of its primary me-tabolite (dl-alpha-noracetylmethadol) was runas was the d-isomer of alpha-noracetylmetha-dol. The former had an equivalent dose of0.75 mg/kg and the latter required a dose of3.5 mg/kg to suppress signs of morphine ab-stinence. Thus, it may be concluded that thel-isomer is more active than the d-isomer insuppressing abstinence in morphine-dependentmonkeys. Since the 1-isomer is a metaboliteof LAAM it may be concluded that LAAM willhave a high PDC.

During the development of tolerance tomorphine in rabbits, the hyperglycemia pro-duced by regularly spaced injections of thedrug gradually diminished and even turned toa hypoglycemia as tolerance developed.Phatak and David (1953) noted that LAAMproduced a hyperglycemia on initial injec-tion in rabbits which gradually diminishedas tolerance developed. Abrupt withdrawalof the drug produced a hypoglycemic effect.

Moreton, Roehrs, and Khazan (1974) studiedthe pattern of self-administration of mor-phine, methadone, and LAAM in rats. Adultfemale albino rats weighing 250-300 g weremade physically dependent on morphine andintravenous (i.v.) cannulated to permitself-administration of morphine (10 mg/kg/injection). EEG and EMG activity wasrecorded continuously.

Morphine was available 24 hours per day.Methadone (2 mg/kg/injection) was substi-tuted for morphine and LAAM (1 mg/kg/injec-tion) was then substituted for methadone.

In the naive rat, administration of morphineat 10 mg/kg intraperitoneal (i.p.) wasfollowed by a biphasic pattern of behavioralstupor and subsequent stimulation. Thedepressed phase lasted 60-90 minutes and theEEG tracings showed the occurrence of high-voltage slow bursts. During the phase ofstimulation, lasting 60-90 minutes, the EEGrevealed desynchronized awake tracings.Only a few short episodes of behavioralstupor with EEG slow bursts intervened inthis period. This phase was characterizedby increased locomotor activity, stereotypedbehavior, and episodes of startle reactions.

In the dependent rat, the duration of thebiphasic response after self-injection ofmorphine was reduced by about 50 percent.The behavioral stuporous phase, concomitantwith EEG slow bursts, appeared within a fewminutes and lasted for only 15 to 30 minutes.The behavioral stimulation and EEG activationlasted for only 30-60 minutes. Sleep andREM sleep predominated before the next

injection. Upon methadone substitution,the sleep-awake distribution within theinterinjection intervals was qualitativelysimilar. In the case of LAAM self-admini-stration, EEG slow bursts usually occurredseveral minutes after injection and werefollowed by brief episodes of sleep and REMsleep. These few sleep and REM sleep epi-sodes were terminated by the appearance ofwakefulness with EEG slow bursts and thenbehavioral arousal which lasted for two tothree hours. The arousal state, as in thecase of morphine and methadone, was followedby alternating episodes of sleep, REM sleep,and wakefulness prior to the next injection.

Under these experimental conditions of freeaccess to the drug, morphine (10 mg/kg/injection) was self-administered as a singleor multiple injection at intervals of2.5±0.1 hours. When methadone (2 mg/kg/injection) was substituted for the morphine,the injection intervals were 1.4±0.1 hours.With LAAM, the interinjection interval was8.8±0.8 hours.

LAAM possessed a relatively slow onset andlong duration of action in dependent ratshaving free access to the drug. When lowdoses of naloxone were administered intra-venously, there was an immediate precipita-tion of abstinence signs.

Killam (1974) studied the effects of LAAM onthe morphine uptake of morphine-dependentmonkeys. At 2.0 mg/kg intramuscular (i.m.)three morphine-dependent monkeys exhibiteda slight decrease (2-16 percent) in morphineuptake, but a fourth showed a significantincrease (40-50 percent). The next day allmonkeys showed a significant increase whichdropped on the second day and returned tobaseline on the third day. At 4.0 mg/kgthere was a 30.6 percent decrease in morphineuptake followed by an increase of 50-87 per-cent on the second day. On the third day,the intake returned to baseline values. At6.0 mg/kg, both monkeys were depressed andataxic. This lasted for 8-16 hours duringwhich time there was no uptake of morphine.There was a rebound effect on the secondday and morphine uptake varied for thefollowing three days.

Other Pharmacological Effects

Henderson (1974a) found that a dose-dependentacute necrosis of the kidney of rats occurredfollowing administration of LAAM (2 mg/kg(0 percent), 5 mg/kg (65 percent), 10 mg/kg(73 percent)). This effect was also notedafter administration of 50 mg/kg of morphinesulfate (83 percent). Complete reversal

19

occurred after 32 hours. The fact that nal-oxone prevented this phenomenon indicatedthat it was the result of the pharmacologicalaction of the analgesics rather than anintrinsic effect of LAAM.Maickel (1974) found that at 0-10 minutespostadministration, LAAM caused a decreasein spontaneous activity of mice. At dosesof 50 to 100 mg/kg s.c., the activity of themice was about 50 percent of that of thecontrol group and at 200 mg/kg the spontan-enous activity decreased to only 60 percentof control. In comparison, methadone at15 mg/kg S.C. increased spontaneous activityto about 200 percent of control. There wasa marked decrease (<50 percent of control)at 45 mg/kg s.c.

Killam (1974) studied the effects of LAAMin the monkey. Using doses of 1 to 8 mg/kgi.m. and 2-6 mg/kg p.o., it was noted thatthe drug produced an initial decrease inhostility and increase in salivation follow-ed by a markedly depressed state with lowmuscle tone. Respiratory arrest occurredwhich was reversible by nalorphine or nalox-one. The EEG changes paralleled the behav-ioral changes. There was a delayed onsetof action which occurred about 10-12 hoursafter oral administration and lasted 38hours. Drug effects were noticed 40-50minutes after intramuscular injection andlasted about 24 hours.

The interaction of LAAM with other drugs wasalso examined in the monkey (Killam, 1974).These were secobarbital, diazepam, ethanol,amphetamine, and diphenylhydantoin. Theeffects of amphetamine and secobarbital wereslightly enhanced; those of ethanol anddiazepam were slightly obtunded, and therewere no effects on diphenylhydantoin.

Inwang et al., (1975) showed that LAAM wasqualitatively similar but differed quanti-tatively from methadone in its effect onthe rabbit cortex. New Zealand rabbitswhich had chronically implanted electrodes inthe optic and posterior sensory motor cortexwere treated by intracortical administrationwith 0.5 mg/kg and 1.25 mg/kg of LAAM. Atthe lower dose, an initial, facilitatoryeffect occurred four minutes postinjectionand lasted 52 minutes. The onset of peakamplitude of the slow negative wave (SNW)was delayed, followed by a depression of theamplitude of the SNW with no recovery indelay of the SNW. At the higher dose, com-plete abolition of the SNW occurred withoutrecovery.

Mice were electroshocked with 140 mV of D.C.by contacting their eyes with electricalterminals 10 or 20 minutes after intraperi-

toneal (i.p.) administration of LAAM(0.1-2.0 mg/kg); they had prolonged post-ictal recovery. At 0.21-0.5 mg/kg, theprolongation was followed by a decrease inpost-ictal recovery.

Gary Henderson has studied the behavioraleffects of LAAM in beagle dogs. One mg/kgdose was administered intravenously and twomg/kg doses were administered both intra-venously and orally.

One Mg/Kg Intravenously--Immediately afterdosing, dogs started to pant, becomequiet, and lay down. By 30 minutes, threeof four dogs defecated. The females werecoordinated but moved slowly. The maleswere slightly ataxic. By one to one andone-half hours after drug administration,all dogs were quiet and unwilling to move.One male had vomited. At two to two andone-half hours postinjection, all dogswere laterally recumbent but alert. Atthe fourth hours, they were alert andfairly well-coordinated. At the eighthhours, they had recovered.

The body temperature fell from 98 degreesF to 94 degrees F, leveling at two hoursand returning to normal after six hours.Heart rates decreased from about 65 to55 and started to return to normal aftersix hours. Respiration rose initiallydue to panting, but became normal aftertwo hours. The males seemed to be moreaffected with respect to changes in tem-perature, respiration and heart rate,whereas the females showed greater degreesof ataxia, vocalization, and shivering.Owing to the small number of animalsinvolved, no firm conclusions about sexdifferences can be drawn.

Two Mg/Kg Intravenously--Stimulation orexcitement appeared immediately after drugadministration. There was salivation,increased motor activity (circling), uri-nation, and defecation. Respirationincreased but temperature and pulsedecreased. This was followed by prolongedhind limb ataxia, decreased motoractivity, and a sleep-like state. Respi-ration was only mildly depressed but bodytemperature dropped from 101.5 degrees Fto 95 degrees F and returned to normal in24 hours. The pulse was low and irregularduring the first 24 hours.

Two Mg/Kg Orally--The beagles whichreceived 2 mg/kg i.v. also received2 mg/kg perorally (p.o.) after a suitablerecovery period. After 30-45 minutes, thedogs licked their lips, panted, and sali-vated. One male vomited. The males were

20

depressed and were in a state of lateralrecumbency, eyes partly closed and pupilsconstricted. At one to one and one-halfhours, one female was also depressed.One male could only be aroused by shakingand did not respond to audio or visualstimuli. At two hours, the other femalewas depressed and showed hindquarterweakness. By the third to fourth hours,the males dragged their hindquarters andwere ataxic. The ataxia in the maleslasted for two hours and about four hoursin the female.

In both the i.v. and p.o. studies, themales seemed to be more affected than thefemales. The only major differencebetween the two routes of administrationis that, as expected, the onset of actionby i.v. injection was more rapid.

Behavioral effects of LAAM in monkeys werealso studied by Henderson (1975). Fournaive and one morephine-depent monkeyreceived 2 mg/kg (i.v.) H3 -LAAM. Drugeffects were noted within five minutes post-injection and lasted about one hour. Eye-lids drooped or closed completely, pupilswere dilated, and the frequency of eyeblinking was decreased. Some catalepsy,muscle twitching, and shivering wereobserved.

There were little change in respiratory rate.The heart rate decreased slightly in thefirst three hours. The body temperaturefell from 100 degrees F to 96 degrees F.The pupils and body temperature returned tonormal within four hours.

In one morphine-dependent monkey, 2 mg/kgi.v. of LAAM had little effect. Papillarysize did not change but there was a slightdecrease in heart rate from 150 b.p.m. to120 b.p.m. Heart rate was normal in two andone-half hours.

One naive male monkey was given 5 mg/kg p.o.of H3 -LAAM. After three and one-half hourshe was sedated and cataleptic. After sixhours there was marked sedation, shallowbreathing, and a rapid heart rate. Heexpired one hour after drug administration.The levels of radioactivity were high in thelung and liver but very high in the bilewhich indicated that biliary excretion wasthe major pathway of disposal of the drug.

H3 -LAAN (2 mg/kg p.o.) was given to fournaive monkeys and one morphine-dependentmonkey. In the naive monkey, there was adecrease in heart rate and a slight decreasein respiratory rate beginning about one hourafter drug ingestion which lasted about fourhours. The pupils began to dilate in 30

minutes, reached a maximum in one hour, andlasted about 12 hours. By the end of thefirst hour, the animals were sedated andshowed signs of muscle twitching and shiver-ing. They were alert to external stimuli.Rectal temperature fell from 100 degrees Fto 96 degrees F and stayed below normal foreight hours. Two monkeys were anorexic.

Absorption, Distribution, Excretion,and Metabolism

The first metabolic study on LAAM was carriedout by Sung and Way in 1954. The compoundwas determined in tissues by a modificationof Brodie's methyl orange technique. Thesensitivity of this procedure is very poorwhen compared to modern methods.

After subcutaneous injection in rats, about70 percent of the dose (20 mg/kg) wasabsorbed from the injection site after onehour. About 7 percent was recoverable after13 hours. The rate of disappearance wasmuch slower after oral administration; about80 percent of the dose was recovered from thestomach after one hour and 50 percent of thedose was recovered after 24 hours. There wassome experimental evidence adduced to sug-gest that the drug was being secreted intothe stomach, because appreciable amounts ofLAAM were found in the stomach after intra-venous and subcutaneous administration.

The tissue levels of LAAM in Long-Evans ratswere compared after administration of 20mg/kg of the drug. Except for the gastro-intestinal tract, levels in all other organswere higher after subcutaneous than oraladministration. The highest concentrationswere found in the lung. The kidney, spleen,liver, and fat contained appreciable levels,whereas very low levels were present in theheart, blood, and brain. As noted above,high concentrations were found in the stomachafter oral and even subcutaneous and intra-venous administration. A large proportionof the drug was accounted for in the carcass(chiefly muscle and bone). Tissue levels ofthe drug persisted for at least 24 hours.

Despite the rapid uptake and high tissuelevels noticed after parenteral administra-tion, the morphine-like effects did notbecome manifest until four-six hours afterthe injection. The effects lasted as longas 24 hours. Following oral administration,the tissue levels were lower, but the onsetof action occurred about one hour later. Inview of these results, the authors concludedthat LAAM was being converted to an active

21

metabolite, a process which occurs morerapidly after oral than parenteraladministration.

Very little (less than 3 percent) of theoriginal dose was found in the feces andurine of rats after subcutaneous administra-tion. Bile taken continuously from cannu-lated bile ducts yielded very small amountsof LAAM. The low recovery of LAAM supportedthe view that the drug was being metabolized.

Sung and Way found that in mice 40-50 per-cent of the drug was still present after12 hours. Appreciable amounts were detectedafter 24 hours, but by 48-72 hours, LAAM wasbarely detectable. In rats, the decline intissue levels was more rapid, but thepharmacological effects were more sustained.

Veatch, Adler, and Way (1964) studied theeffect of prior administration of the meta-bolic inhibitor SKF-525A. If microsomalbiotransformation is converting LAAM to anactive metabolite, then SKF-525A ought tointerfere with the analgesic effectivenessof the drug. In preliminary experiments,they determined that in the Eddy-Leimbach

hot-plate test for analgesia, the ED50 ofLAAM is 3.25 mg/kg with an onset of 135minutes, a peak effect at 210 minutes, anda duration of greater than six hours. TheED90 dose was 21 mg/kg. At this dose theonset time was reduced to 15 minutes andthe peak was 110 minutes, after injectionof the drug into the right thigh. 50 mg/kgof SKF-525A was given 20 minutes before theED90 dose of LAAM and the mean analgesicresponse was recorded as the percentage ofthe control dose. After the first hour, theSKF-525A treated animals responded at 92 per-cent of the controls, after two hours at72 percent, after three hours at 67 percent,after four hours at 59 percent, and afterthe fifth and sixth hours at about 28 percentof controls. Thus, it was clear that SKF-525A did decrease the analgesic response ofLAAM.

McMahon, Culp, and Marshall (1965) succeededin identifying the major metabolites ofdl-alpha-acetylmethadol "sing radio-labeleddrug. They labeled the N-methyl group andthe O-acetyl group, using the syntheticmethods 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 preparedaccording to equation (3) and (4).

For in vivo studies, 150 g male albino rats(Harlan Industries) were used. Since thisstrain was sensitive to the drug, the doseof dl-alpha-acetylmethadol used was 2.5 mg/kg. The identity of the metabolites wassecured by the isotope dilution technique.When C14 -labeled N-methyl was used, therate and extent of expired C14O2 wasmeasured. Urine samples were assayeddirectly in a scintillation counter and feceswere treated by the Schoniger method beforeassay.

The in vitro metabolism of dl-alpha-acetyl-methadol studied using rat liver homoge-nates. It was found that the drug was deme-thylated by microsomal N-demethylase to givedl-alpha-noracetylmethadol. The latter wasalso a substrate for this enzyme and fur-nished dl-alpha-dinoracetylmethadol but ata considerably slower rate.

The N-demethylation was studied in vivo byusing N-C14CH3 dl-alpha-acetylmethadol andfollowing the respiration of C14O2. Onintravenous injection, C14O2 formed rapidly.In five hours, 50 percent of the dose corre-sponding to complete removal of one N-methylgroup was recovered in the respired air. Ex-cretion continued until nearly 80 percent ofthe administered dose was recovered as C14O2

showing that a second N-methyl group wascoming off. The half-life for the removal ofone N-methyl group was about two hours.

Orally, the initial rate of N-demethylationwas slower, but after 16 hours, it wasalmost as great as that following intravenousinjection.

C14 -acetyl labeled dl-alpha-acetylmethadolwas administered to rats. By following lossof the acetyl label (due to ester hydrolysis)it was found that this occurred to the ex-tent of 30 percent following intravenous(i.v.) injection. About 15 percent ofdl-alpha-noracetylmethadol hydrolyzed in thefirst 18 hours.

The tissue levels of radioactivity weremeasured following administration of N-methylC14 -labeled dl-alpha-acetylmethadol anddl-alpha-noracetylmethadol. Following intra-venous injection, peak levels of radioactiv-ity were found in lung, muscle, and brainone to five minutes after injection. Peaklevels in the liver and kidney occurredlater. Plasma levels were low, tended todrop, and then reached a new maximum atabout eight hours. Orally, much lower tissuelevels were found except for the liver. Peaklevels were observed to occur 0.5 to 1.0hours postadministration of the drug.

23

At 0.5 hour postinjection, dl-alpha-acetyl-methadol predominates over the nor-analog bya ratio of 2:1 in lung and liver and 6:1 inthe brain. After two hours, the ratiosdecreased and at four hours, dl-alpha-nor-acetylmethadol predominated in the liver andthe radio was about 1:1 in the lung. In thebrain, the isomer ratio shifted from 6:1 to2:1 in this period of time. No quantitativestudies were carried out because of the lowlevel radioactivity.

With NC14 methyl dl-alpha-noracetylmethadol,unmetabolized drug was found in the lung,

liver, and brain at eight hours followingintravenous injection. The drug persistedin the lung and liver for 24 hours. Radio-activity was detected for 14 days afteradministration, but this long-lasting effectcould be due to the fact that some of theC14O2 from the N-C14 methyl. group was beingincorporated into the body pool.

The radioactivity in the urine and fecesfoIlowing administration of C14 labeleddl-alpha-noracetylmethadol is shown inTable VIII.

The metabolites from the N-methyl labeleddrug can be either unchanged dl-alpha-nor-acetylmethadol or dl-alpha-normethadol. Themetabolites from the acetyl-labeled drug canbe unchanged drug, dl-alpha-denoracetyl-methadol or a derivative of the latter.Inspection of the column on urinary excre-tion shows that the percentages for N-methyland adetyl-labeled drug are almost the same.Thus, unchanged drug is the primary excre-tion product accompanied by some bisnor-acetylmethadol. However, the differencesin the fecal excretion patterns are verylarge. The major product in the feces isdl-alpha-dinoracetylmethadol or some conju-gate thereof.

Biliary excretion studies show that themajor metabolic pathway involves retentionof the C14 -acetyl group and loss of theC14 -N-methyl group. About 60 percent ofthe administered drug is excreted via thebile in 24 hours.

Thus, the conclusion of Sung and Way thatbiliary excretion is a minor pathway for thedisposition of LAAM requires modification.

It will be recalled that these authorslooked for unchanged LAAM whereas thematerial secreted in the bile are metabolitesof the drug.

Billings, Booher, Smits, Pohland, andMcMahon (1973) developed a gas-chromato-graphic method for the determination ofalpha-noracetylmethadol and alpha-dinor-acetylmethadol. They formed the trichlor-acetyl derivatives of these metabolites.These were separated on a two-foot silicon-ized glass colunm containing 3 percent OV 1on 100-200 mesh Gas Chrom Q at 205 degrees.A 63 Ni Ec-detector was used. Under theseconditions, alpha-noracetylmethadol had aretention time of 3.4 minutes and alpha-dinoracetylmethadol had a retention time of2.4 minutes. The identity of the metaboliteswas confirmed by mass spectrographic analy-sis.

These authors determined the tissue levelsof dl-alpha-noracetylmethadol after i.p.administration. The results are summarizedin Table IX.

24

From these data, it is clear that the tissuebuild-up of dl-alpha-noracetylmethadol is arelatively slow process and confirms thesuspicions voiced by Sung and Way (1954)about twenty years earlier.

Gary Henderson (1975b) is studying themetabolism and pharmacokinetics of LAAM inrats, dogs, and monkeys. These studies arenot yet complete. The current Status ofthis work is reviewed below.

Rats (Excretion Patterns)--Four maleSprague-Dawley rats weighing between 204and 273 g were given 2 mg/kg of H3 -LAAMorally. The rats were constipated forabout 12 hours. About 8 percent of theradioactivity was recovered from theurine in 96 hours and about 85 percent wasfound in the feces. Most of the urinaryradioactivity was excreted in the first48 hours and little (about 16 percent)

was excreted in free form. The metabo-lites were separated on thin-layer chroma-tography (TLC) and quantitated. Asummary of the findings is given inTable X.

Preliminary experiments showed that therecovery of l-alpha-acetylmethadol (LAAMwas 91 percent, l-alpha-noracetylmethadol(N-LAAM) was 91 percent, alpha-methadol(MOL) was about 88 percent, nor-alpha-methadol (N-MOL) was 90 percent, andl-alpha-dinoracetylmethadol (DN-LAAM) was96 percent. The pH had to be kept at 9.5because at pH 13 acetyl migrationoccurred rapidly.

It is clear that N-LAAM and DN-LAAM werethe major metabolites excreted inunbound form and that most of the urinarymetabolites were excreted as conjugates.

25

Higher doses of LAAM were also studied.Two male and four female Sprague-Dawleyrats weighting between 212 and 371 g weregiven 5 mg/kg of H3 -LAAM by gavage.Food was supplied ad lib and urine andfeces were collected every 24 hours upthrough 96 hours. At this dose, themales exhibited hematuria. At the end of96 hours, the males had excreted 6.66percent of the administered radioactivityin the urine and 87.32 percent in the

feces. The females excreted 13.55 per-cent in the urine and 59.86 percent inthe feces.

Rats (Tissue Distribution)--Four of themale rats which received 2 mg/kc H3 -LAAMp.o. were sacrificed after 96 hours andselected tissues were assayed for radio-activity. No attempt was made to iden-tify the compounds in the tissues. Theresults are summerized in Table XI.

In contrast to Sung and Way’s results(1954), very little material was found inthe stomach. This discrepancy can beexplained by the difference in timeinterval between the initial medicationand the subsequent sacrificing. InHenderson’s case, the sacrificing tookplace much later than the originaldosing. Despite the fact that tissueswere examined 96 hours post-dosing, it isinteresting to note that the only organwhich contained more than trace amountsof LAAM and/or its metabolites was theliver.

Kinetics of H3 -LAAM Elimination In RatBile--In the initial experiments, theinterval between cannulation and dosingwas so long that several rats were toosick to be used. The remaining animalswere used to determine the nature of thebiliary excretion patterns. Free meta-bolites were determined and then theremaining bile was treated with -gluc-uronidase (Sigma) to deconjugate thewater-soluble fraction. Hydrolysis wasincomplete even after 36 hours incubationat pH 5.0 at 37 degrees. Thirty percentof the radioactivity was excreted in thebile as unbound drug and metabolites. Ofthe remaining 70 percent, about 81 per-cent underwent deconjugation. Aftersix hours the bile contained detectablelevels of free LAAM, N-LAAM, DN-LAAM,MOL, and N-acetyl-N-Mol. The major

26

metabolites were DN-LAAM and N-acetyl-N-MOL. Following enzymic hydrolysis,N-acetyl-N-MOL and DN-LAAM proved to bethe major metabolites. In addition,LAAM, N-LAAM, MOL, and N-MOL were detect-ed. It is difficult to see what sort ofconjugate LAAM itself can form.

The experiment was repeated with a modi-fication which consisted of medicationinmediately after the animals recoveredfrom the surgery. The rats were given 5mg/kg of H3 -LAAM p.o. Bile was col-lected every 30-60 minutes up to 96 hours.This experiment is incomplete; however,initial results have been reported andare summarized below.

Biliary excretion appears to follow zero-order kinetics until 72-96 hours when itthen apparently follows first-orderkinetics. In two male rats, 80-85 per-cent of the administered radioactivitywas recovered from the bile after 96hours. The radioactivity appears in thebile five minutes after dosing and lessthan 10 percent of the dose appears inthe feces of bile-cannulated rats. Thus,greater than 90 percent of LAAM isabsorbed by the oral route. After 96hours, about 96 percent of the adminis-tered radioactivity is eliminated in themale rats and about 74 percent in thefemales. The nature and abundance ofLAAM and its metabolites was the same as

in the previous experiment. In rat urineDN-LAAM was the major metabolite followedby N-LAAM, LAAM, and MOL.

Dogs (Blood Levels)--Blood levels peakedin 30 seconds following a dose of 2 mg/kgi.v. and about the same time after 1mg/kg i.v. The levels drowned in 15minutes and were negligible after 96hours. After 2 mg/kg p.o., blood levelspeaked one hour postadministration.

Dogs (Excretion)--In dogs given 1 mg/kgi.v., 79 percent of the radioactivity was

accounted for in the urine and feces after96 hours. After 2 mg/kg i.v., 89 percentwas accounted for in this time period.Urinary excretion peaked in the first 24hours, whereas in the feces, peak excre-tion occurred at 24-48 hours. After 2mg/kg p.o., 81 percent of the dose wasexcreted in 96 hours by the males andsomewhat less by the females.

The urinary recovery of LAAM and itsmetabolites after 2 mg/kg p.o. is shownin Table XII.

Monkeys (Blood Levels)--After some pre-liminary dosing, four naive and one mor-phine-dependent monkey were given 2 mg/kg(i.v.) of H3 -LAAM. These same animalswere used for the oral studies. Thehighest level of radioactivity was notedone minute after injection. This cor-responded to a blood level of LAAM equalto 0.47 ug/ml. There was a rapiddecrease in 15 minutes followed by a newpeak one hour after injection which cor-responded to a drug blood level of 0.35ug/ml. This was followed by a steadydecline in radioactivity which was neg-ligible after 72 hours.

H3 -LAAM (2 mg/kg p.o.) was given to fournaive monkeys and one morphine-dependentmonkey.

The blood levels of radioactivity appear-ed in 30 minutes, peaked four to eighthours after drug administration, and werestill detectable after 96 hours.

of threeMonkeys (Excretion)--The urinesfemale monkeys which were given 2 mg/kgof H3 -LAAM i.v. were examined. A totalof 21.55 percent of the radioactivitvwas excreted over a 96-hour period. O fthis, 19.11 percent was in the conjugatedform, and 2.44 percent was free. Thedistribution of the radioactivity issummarized in Table XIII. The morphine-dependent monkeys excreted 13.7 percentof the radioactivity in 96 hours.

27

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

As usual, the amount of free LAAM and itsmetabolites in the urine was very low.The bulk of the metabolites were excretedas conjugates.

Sullivan, Due, and McMahon (1973) reportedsome preliminary results on the metabolismof a l-alpha-methadol. They used the 2-C14

labeled derivative having a specific activityof 14.1 µCi/mg. Bile-cannulated Wistar ratswere given 40 mg/kg s.c. and the urine andbile were collected for 24 hours. Unconju-gated drug and metabolites were extractedwith butyl chloride at pH 9.5. The pH ofthe body fluids was adjusted to 3.5 and thematerials were incubated with gluselase todeconjugate metabolites and these were thentaken up in butyl chloride.

After 24 hours, 10 percent of the adminis-tered radioactivity was found in the urineand 36 percent was found in the bile. Thefollowing were identified in the urine:

Unaltered 1-alpha-methadol1-alpha-nonethadol (N-MOL)1-alpha-bisnormethadol (DN-MOL)l-alpha-6-acetamido-4, 4-diphenyl-3-heptanol

The bile had only one major component whichappeared to be a conjugate of 1-alpha-6-acet-amido-4, 4-diphenyl-3-heptanol. Theseresults suggest that the major biliary excre-tion product of LAAM itself may be a conju-gate of 1-alpha-6-acetamido-4, 4-diphenyl-3-heptyl acetate. However, Henderson (1975b)found that DN-LAAM readily undergoes OtNacetyl migration so that the actual metabo-lite my be DN-LAAM rather than the N-acetylderivative.

Kochhar (1975) isolated and identifiedmetabolites of LAAM after incubation of thedrug with a microsomal supernatant fractionobtained from liver homogenates of Sprague-Dawley rats and also from the urine of ratswhich were given the drug intraperitoneally.He identified methadol (MOL), nonnethadol(N-MOL) 2-ethyl, 1, 5-dimethyl-3, 3-diphe-nylpyrroline, noracetylmethadol (N-LAAM), anddinoracetylmethadol (DN-LAAM). The pyrrolinemay be an artifact derived from DN-LAAM.

AUTHOR

Sydney Archer, Ph.D., is Research Professorof 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,pre-clinical toxicity studies must be carriedout to demonstrate that there will not be anunreasonable hazard to subjects to whom thedrug will be administered. Acute and chronictoxicity studies can also demonstrate whetherthe observed toxic effects are such as topreclude administration of the drug to manand also to alert the clinician to thoseeffects which would require particular atten-tion. For these reasons the doses which areused in toxicity studies are selected so thatsome toxic effects will be produced.

Toxicity studies are so designed that informa-tion will be obtained about the relationshipof toxic to effective doses. It must be keptin mind that such studies are not directlytranslatable to presumed effects in humans.The doses used in animals are much higher thanthe expected clinical dose. The life spans ofman and the test animals are not comparable sothat an 18 month chronic study in rats meansthat the drug is administered for at leasthalf the life span of that species. There isusually a rapid increase in rodent mortalityafter 12 months so that deaths that occur inthe second year of medication may be due to

aging, the effects of the drug, or both.

The Food and Drug Administration (FDA) guide-lines suggest that at least one rodent andone non-rodent species undergo toxicity tests.In this case, rats and beagle dogs were util-ized. Fats are often used in toxicity stud-ies for their test convenience and in additionbecause of their metabolic closeness to humans.Rabbits and rats are used in reproductionstudies because of their reproductive capacityand because of their sensitivity to terato-genic agents.

For these chronic toxicity studies, animalsof a given species were divided into fourgroups: a control group, and low, medium andhigh dosage groups. Hematological and clini-cal chemistry evaluations on the four groupswere done periodically: e.g.,13 weeks, 26 weeks,52 weeks, 79 weeks. At the end of eachperiod, some portion of each group was sacri-ficed for gross and microscopic pathologicexamination to determine possible effects ofthe drug. Postmortem examinations were alsoperformed on animals which died during theexperiment.

29

An additional complication occurs when thetest drug is one in which drug tolerance oc-curs. In such a case tolerance is induced inthe medium and high dosage groups by graduallyincreasing the dosage to the predeterminedmedim and high dosage level, in order to reachtruly toxic levels while avoiding lethal depres-sant reactions that would occur if such doseswere given to naive animals.

The initial chronic toxicity study on LAAM wascarried out for one year in rats and dogs atEdgewood Arsenal. Because LAAM was adminis-tered for 5 days per week, further studieswere carried out by Industrial Biotest whereinthe drug was given daily to the test animalsfor a longer period of time.

ACUTE ORAL TOXICITY OF LAAMIN RATS (Industrial Biotest)

The acute oral toxicity of LAAM was determinedin naive albino Charles River male and femalerats. The LD50 of LAAM in the males was 28.6mg/kg and in the females it was 35.0 mg/kg.The acute toxicity was determined in tolerantrats also. Rats were made tolerant by start-ing with a 2.0 mg/kg dose which was increasedat two-week intervals until they were receiv-ing 12.0 mg/kg/day. This dose level was main-tained for a 13 week period of medication andthen the LD50 values were determined. TheLD50 in males was 93.0 mg/kg and in femalesit was 220.0 mg/kg. Thus prior exposure tothe drug had a considerable effect on theacute toxicity of LAAM.

CHRONIC TOXICITY STUDIES

One Year Chronic Oral Toxicityin Rats (Edgewood Arsenal)

In this study Sprague-Dawley albino rats wereused. The drug was administered by gavage atdose levels of 5.0, 10.0 and 15.0 mg/kg fivedays a week for 52 weeks. No induction sched-ule was employed. After the first 10 weeksall the rats that died during that time periodwere replaced by fresh rats in order to havea sufficient number of animals for terminalsacrifice and pathological examination. Themortality data is summarized in Table 1.Several rats that died after the first dose ofLAAM were found to have intracellular calci-fication in the heart, liver and kidney. Thisphenomenon was not observed in any of theanimals which died later or in any of the ratsin the replacement groups. This effect wasnot observed in a later Industrial Biotest study.A special study was carried out in an addi-tional group of rats to assess the signifi-cance of the intracellular calcification ofthe heart, liver and kidney observed in therats dying after the first dose of LAAM in theoriginal study. To this end 75 rats weregiven 15.0 mg/kg of the drug for 5 days and atthe end of that time were sacrificed and exam-ined. None of the animals in this groupshowed signs of calcification in the previous-ly affected organs. As a result it was con-cluded that this phenomenon which was notedonce was not drug related.

TABLE 1

Mortality of Rats Medicated With LAAM 5 days/week

Original Group

# deaths/treatedWeek of last death

Dose LevelsControl 5.0 mg/kg 10.0 mg/kg 15.0 mg/kg

4/80 3/40 17/40 52/8036 4 39 47

Replacement Group

# deaths at 2 days/treated# deaths at 38 weeks/treated

TOTAL

0/12 0/240/3 4/120/12 4/24

30

14/746/33

21/74

All of the test animals on the chronic tox-icity study were observed for behavioral re-actions and general physical appearance aftereach daily dosing and prior to the next dos-ing. Body weights, food and water consump-tian and several clinical parameters, includ-ing hematology and blood chemistry weremeasured at specific intervals. A specialstudy was carried out to determine the effectof hepatic N-demethylase on LAAM in vitro.In the latter study it was noted that likemeperidine and 1,1-dimethylhydrazine, the twopositive controls used in the experiment,hepatic microsomes did demethylate LAAM asevidenced by the production of formaldehydein the incubation media.

Food and water consumption in all three groupson LAAM was decreased when compared to thecontrol rats but only the decreased food con-sumption was felt to be dose related. Bloodyeyes, and analgesia, as evidenced by adecreased response to pinching of the tail,were observed during the first two weeks ofdosing. After that time sensitivity to tailpinching appeared to increase. Piloerection,exophthalmos and the Straub tail phenomenonwere present during the entire period of medi-cation. Hematological and blood chemistryvalues were all within normal limits for boththe test and control groups, with the excep-tion of plasma lactic dehydrogenase (LDH)which was higher in the 10.0 mg/kg and 15.0mg/kg groups than in the controls at both the6 month period of sacrifice and at the end ofthe year. After 12 months the LDH valueswere: 1072 (controls), 1688 (10.0 mg/kg) and1833 (15.0 mg/kg).

Gross examination of tissues at necropsy andorgan weights showed that with one exceptionthere were no significant differences betweenthe treated and control groups. Only theliver/body weight ratios in the female ratsat all doses were higher than the controlsafter completion of medication. Histopatha-logical examination of the tissues failed toreveal any incidence of dose related lesions.The most frequent finding was inflammation orcongestion of the respiratory tract.

During the first two weeks of exposure toLAAM there was little if any gain in weightby the medicated rats. During the course ofthe study the rate of gain in weight in thetreated groups was greatly retarded and ap-peared to be dose related. After the firsttwo weeks the dosed rats began to show aweekly cyclic patter” of a large increase inbody weight on the first two or three days ofthe week followed by a loss in weight duringthe remainder of the week. It is believedthat this pattern was related to the fact thatafter the first weeks of medication the rats

became tolerant to and dependent on the drug,because when medication was omitted over theweekend the animals showed withdrawal signs.The most prominent such sign in dependentrats upon abrupt withdrawal of an opiate-likedrug is a rapid loss in body weight. Usuallythis body weight loss can be reversed byrenewed administration of the drug.

One Year Chronic Oral Toxicity-in Dogs (Edgewood Arsenal)

Beagle dogs were medicated by capsule 5 daysa week for 52 weeks at dose levels of 2.0,6.0 and 11.0 mg/kg. Dosing was started at2.0 mg/kg in all test groups and was thengradually raised in the medium and high levelgroups until by the end of the sixth week thedesired dose levels were achieved. Fourteendogs served as controls. There were 12 dogsat the low and medium levels and 14 at thehigh dose.

All of the test animals were examined dailyfor clinical signs of systemic toxicity. Bodyweights, food consumption and clinical para-meters including hematology and blood chemistrywere measured at specific intervals during thecourse of the medication. Complete physicalexaminations were performed monthly includingelectrocardiograms and ophthalmologic exams.

Body weight, food and water consumption decrea-sed for all three test groups. Behavioral re-actions were observed at all dose levels andconsisted of depression, hind limb weakness,emesis, salivation and prostration. The fre-quency and intensity of some of these signs de-creased as the study progressed. Three dogsdied at the high dose level, none at lower levels.Hematology and blood chemistry values in thetest groups were comparable to those of thecontrols. Physical examination revealed thepresence of tachycardia, slower reflexes anddecreased respiration rates but these didnot appear to be dose related. The medicateddogs had rough coats, appeared to be thin andpresented a generally unkempt appearance asif they did not do any grooming. Electro-cardiogram (EKG) recordings taken immediatelyafter dosing showed an increase in durationof the S-T segment usually accompanied bybradycardia. Seventy-two hours after dosingthe EKG tracings were normal. Reversibilitycan be determined since the dogs were notmedicated on the weekend. Other than a largeabsolute liver weight in the high dose dogswhen compared to controls, no other signifi-cant differences in organ weights were appar-ant. Histopathological examination of tissuesdisclosed no drug related abnormalities. Thiswas true also for the three dogs which diedspontaneously during the course of the medi-cations.

31

79-Week Chronic Oral Toxicityin Rats (Industrial Biotest)

Charles River albino rats were used in thisstudy. The final doses used were 2.0, 6.0and 12.0 mg/kg administered daily by gavagethroughtout the 79 week period of medication.The dose schedule is shown in Table 2.

The middle group (T-11) did not reach the 6.0mg/kg daily dose until the 9th week and thehigh dose (12.0 mg/kg) was not reached untilthe 21st week.

All of the test animals were examined dailyfor behavioral reactions and general physicalappearance including tumor palpation. Bodyweights, food consumption and clinical param-aters were determined at specific intervals.

Group

ControlT-IT-II

T-III

tion period all values were in the normalrange. Blood chemistry values were essen-tially normal for the test animals exceptfor some scattered slightly elevated serumalkaline phosphatase (SAP) readings in medi-cated males. The females were comparable tountreated controls. The serum glutamic-pyruvic transaminase (SGPT) values were essen-tially normal but the serum glutamic-oxalo-acetic transaminase (SCOT) values were slightlyelevated in the high dose male and female rats.The albmin/globulin ratios of both male andfemale animals in the 6.0 and 12.0 mg/kggroups showed a moderate decrease at 52 and78 weeks. All test females showed a moderatedecrease at 52 and 78 weeks. All test femalesshowed a moderate increase in total protein atweek 52 but this parameter normalized by the78th week. The remaining blood chemistrystudies were normal.

TABLE 2Schedule for Administration of LAAM

No. of Animals Dose Levelmg/kg/day

Male Female Week:

1-4 5-8 9-12 13-16 17-20 21-79110 110 0 0 0 0 0 0110 110 2 2 2 2 2 2110 110 2 4 6 6 6 6

110 110 2 4 6 8 10 12

The Body weight gain of all test animals wasreduced significantly with the males showinga greater initial reduction, but at the endof the 79th week body weight gain depressionsfor both sexes were about the same. During theperiod of recovery the surviving animals atthe 6.0 and 12.0 mg/kg dose levels exhibitedbody weight gains comparable to the controls.The test females consumed less food duringthe first 27 weeks of the medication periodbut thereafter their food consumption was thesame as the controls.

Observations for phammcological and behavior-al reactions during the 79-week treatmentperiod showed that the rats displayed hyper-irritability and hyperactivity graduallyshifting to hypoactivity. The males in alltest groups showed greater hyperirritabilitythan the females. Alopecia and excretion ofloosely formed stools were noted in the medi-cated groups. Hematological parameters forthe test and control animals were comparable

The rat mortalities which occurred in thisstudy are shown in Table 3 Also includedare the animals which were deliberately sacri-ficed at 13, 26 and 52 weeks. There was anexcessive mortality rate in the control ani-mals between weeks 23 and 26. Mortality inall test groups at the end of week 52 wasmoderate, but increased markedly from week52 to week 79. Mortality was high in thecontrol group throughout the test period. Inboth control and treated groups mortality washigher in the male rats. The vast majority(if not all) of the deaths was attributed tonaturally occurring disease characterized bybronchoneumonia associated with metastaticinfections and polyserositis. None of thedeaths was attributed to the medication butmortality did appear to be related to thelength of exposure to LAAM.

There was a significant reduction of absoluteexcept for slight varlatlons in total leuko- organ weights of the livers of the 6.0 mg/kgcyte and erythrocyte counts in all groups male rats and of the kidneys of the 6.0 mg/kg

of test animals. At the end of the medica- and 12.0 mg/kg tiles but the organ to body32

Dose Levelmg/kg

Control

2.0

6.0

12.0

TABLE 3

Rat Mortality in the 79-Week StudySex Treatment Time Period (wks)

Accumulated Deaths RecoveryTotal MortalityNumber Tested

0-52 53-79

M 37 54F 18 34

M 24 69F 10 31

M 16 73F 14 35

M 35 78F 27 54

and organ to brain weight ratios were normaland in most instances comparable to the con-trols. Histopathological changes in thetissue, except for the liver, were judged tobe caused by spontaneous disease and were notunusual for the strain and age of the rats.

Treatment related changes were observed inthe livers of most of the test animals at alldose levels of LAAM. These changes were char-acterized by hypertrophy of hepatocytes dueprimarily to an increase in cytoplasmic mass.The relative extent of the changes could becorrelated with the dose of the drug and dur-ation of treatment. These changes were con-sidered to be an adaptive response of thehepatocytes to the metabolism of LAAM. Aseparate study demonstrated that there was anincrease of microsomal enzyme activity inrats receiving LAAM. (A similar observationwas made in the Edgewood Arsenal study).During the recovery period surviving ratswere sacrificed the first and second monthsafter cessation of medication. Marked but notcomplete regression of the hepatocyte hyper-trophy was noted.

The remaining organ changes observed at eachsacrifice interval were judged to be relatedto naturally occurring diseases or associatedwith the age of the animals at autopsy. Thesechanges were present in the control as wellas medicated groups, The types of tumorspresent in all groups were not unusualfor a random population of the strainof rats used and there were no significantdifferences in numbers between test and con-trol groups.

80-87

4 58/1105 39/110

2 71/1103 34/110

3 76/1100 35/110

0 78/1102 56/110

52-Week Chronic Oral Toxicityin Dogs (Industrial Biotest)

LAAM was administered orally, via gelatincapsule at final dose levels of 2.0, 4.0 and8.0 mg/kg seven days a week for one yearA fourth group served as controls. The medi-cation schedule is shown in Table 4.

An initial dose of 4.0 mg/kg produced severereactions, particularly sedation. Graduallyincreasing the dose from 0.5 mg/kg to 4.0ng/kg over a twelve week period resulted inthe production of only slight reactions tothe drug, i.e. tolerance developed. Increasedtolerance to the drug developed at all doselevels. Only one high (8.0 mg/kg) and onelow (2.0 mg/kg) dose level male died at 26and 49 weeks respectively. Neither death wasconsidered to be drug related.

All of the test animals were examined dailyfor clinical signs of systemic toxicity, par-ticularly after dosing. Body weight, foodconsuption and clinical parameters weremeasured at specific intervals during the med-ication period. Opthalmological examinationsand EKG recordings were made.

Food consumption during the first six monthswas similar for both treated and controlgroups. In the latter half of the study therewas a noticeable increase in food intake inthe treated groups which was not reflected ina corresponding increase in body weight. Whenthe dogs became tolerant to LAAM their weightswere comparable to that of the controls.

33

TABLE 4

Medication Schedule For LAAM in Dogs

Group Dose(mg/kg/day)

Weeksat dose level

T-I

T-II

0.51.02.0

0.51.02.04.0

1-45-20

21-52

1-45-89-1213-52

T-III 0.5 l-41.0 5-82.0 9-12

4.0 13-16

6.0 17-208.0 21-52

Behavioral reactions were observed in the ani-mals at the 4.0 and 8.0 mg/kg doses. Theseconsisted of salivation, hyperactivity, vomit-ing and sedation. Increased tolerance to thedrug occurred at all dose levels. The hemat-ological parameters remained normal throughoutthe study. The only change in blood chemistrywas a slight elevation of the serum alkalinephosphatase (SAP) levels at the 4.0 mg/kg and8.0 mg/kg dose levels. These returned tonormal during the 4 week recovery period.

Electrocardiogram tracings during the earlystages of the study showed some T-wave and S-Tchanges, some tachycardia at the 4.0 mg/kgdose level. At 8.0 mg/kg QRS complex irregu-larities were observed and significant S-Tand T wave changes as well as significant rateand rhythm disturbances were noted. Thesechanges were present on later tracings but nofurther deterioration occurred. The tracingsmade during the 4-week recovery period wereconsidered to be within normal limits. Histo-pathological examination of cardiac tissue atnecropsy showed no significant abnormalities.Gross and histopathological examination ofother organs and organ weights disclosed nosignificant differences between treated andcontrol groups.

REPRODUCTIVE STUDIES WITH LAAM(Industrial Biotest)

Teratogenic Studies

1. Non-tolerant Rabbits

LAAM was administered orally via gelatin cap-sules to non-tolerant, pregnant, New Zealandrabbits at doses of 0.2, 0.6 and 2.0 mg/kgfrom day 6 through day 18 of gestation. Aslight weight loss occurred during the treat-ment period but it was comparable to the un-treated and thalidomide-treated control groups.No deaths or unusual reactions occurred. Alldams were sacrificed on day 29 of the gesta-tion period. Fetal examination revealed noexternal, internal or skeletal teratogenicabnormalities among the fetuses of the LAAM-treated rabbits and untreated controls. Thethalidomide controls yielded the expected anom-alies. The numbers of resorption sites and liveyoung per 100 implantation sites was similarfor LAAM and unmedicated controls. Body weightsof fetuses from treated and untreated damswere comparable also.

2. Tolerant RabbitsRabbits were made tolerant to LAAM by adminis-tering the drug over a twelve week period

34

starting with 2.0 mg/kg/day and incrementallyincreasing the dose until the desired levelswere reached. Then doses of 6.0, 8.0 and10.0 mg/kg/day of LAAM were given to threegroups of tolerant animals from day 6 to day18 of gestation. A decrease in body weightwas noted at the two higher dose levels andsome non-dose related deaths occurred. Itis concluded that pre-natal exposure to LAAMdid not alter fetal skeletal development ascompared to unmedicated controls. The numberof implantation sites, resorption sites andlive young were not adversely affected byLAAM.

3. Tolerant Rats

Rats were made tolerant to LAAM by graduallyescalating the doses from 2 mg/kg/day to 12.0mg/kg/day over a period of 90 days. The doselevels of LAAM were 2.0, 6.0 and 12.0 mg/kg/day administered to day 20 of gestation. Thedrug had no effect on the numbers of corporalutea, implantation sites, resorption sitesand viable fetuses. There was no effect onexternal and internal development but therewas an increased incidence of angulated ribsamong fetuses obtained from dams exposed to6.0 and 12.0 mg/kg/day. No other skeletalabnormalities were found.

Perinatal and Lactation Performancein Albino Rats

0.06, 0.20 and 0.60 mp/kg to non-tolerantpregnant rats from day 15 of gestationthroughout the period of lactation. A totalof 28 or 29 doses were used. All dams wereallowed to deliver their litters and carrythem through weaning. In the cross-over por-tion of the study litters from the 0.6 mg/kg/day test group were exchanged with a controlgroup with both dams carrying their littersthrough weaning.

In the first phase of this study no deathsoccurred and no unusual behavior was observed.Only the dams at the 0.60 mg/kd/day dose show-ed a reduction in body weight from day 15 ofgestation through day 4 of lactation. Thisdose group retained fewer pups than the con-trols but the difference did not appear to bestatistically significant. The high dosegroup did show a statistically significantreduction in survival of the pups and re-duction in body weight as lactation progressed.During the cross-over study both groups ofdams exhibited a reduction in the number ofpups surviving to weaning. The groups of pupsexposed to LAAM in utero and reared by controldams revealed slightly meduced body weightsthrough day 21. Pups untreated in utero butreared by treated dams also showed slightlyreduced body weights.

Reproduction and Progeny Cross-over Studiesin Tolerant Rats

Using the same dosing schedule described inSection A-3 above it was noted that bodyweight reductions and hyperirritability occurred in a dose related manner in both sexes.Mating experiments showed that there was nodifference in reproductive performance amongtreated animals as compared to controls.

Female rats exposed to LAAM showed an increas-ed number of stillbirths. Following deliverylitters from drug treated rats were exchangedfor litters from control rats and the progenyremained with the foster mothers tnrougnoutthe lactation period. Concurrent groups ofprogeny delivered by treated and control ratswere retained by their natural mothers. Sur-vival of each group of progeny exposed toLAAM was reduced during lactation. Progenyfostered by LAAN-treated rats did not exhibitas great a reduction in survival as thosepups; exposed to the drug in utero and thenfostered by non-treated rats or those deliv-ered and retained by LAAM-treated mothers.

The body weights of progeny exposed to LAAMin utero and then fostered by unmedicatedmothers were similar to drug-free controls.Those not exposed in utero but fostered bytreated mothers showed reductions in bodyweight. Progeny delivered and retained bydrug-treated rats showed body weight reduc-tions only on day 1 and 4 of lactation. Byday 12 of lactation only 1 litter was viableand at weaning these 4 pups displayed weightsequal to that of the untreated controls.

DISCUSSION:

Methadone and LAAM were developed in the1940’s as analgesics. Although acute toxico-logical studies had been performed, relativelylittle animal toxicological data is availableon subacute or chronic toxicity in the toler-ant animal. Therefore, these current studieswere performed because the drugs are now be-ing utilized or proposed for long term, highdose maintenance in man. Because LAAM isbeing developed as an alternative to metha-done, it is appropriate to compare the toxic-ological effects of both drugs in the samespecies.

al data for LAAM. (A.S. Keats andOnly one previous study reported toxicologic-

N.K. Beacher,Analgesic activity-and toxic effects of acetyl-methadol isomers in man, Journal of Pharma-cology and Experimental Therapeutics, 105:210-215. 1952). The authors report that Merck andCompany studies found that racemic-levo- anddextro-forms of acetylmethadol have a subcu-taneous LD50 in mice of about 40 mg/kg. Thelevo- form exhibited delayed onset of toxicity.

35

In comparison, the subcutaneous LD50 of race-mic methadone (the form used clinically) inmice is 33-48 mg/kg. (National ResearchCouncil Handbook of Toxicology, 1956, pp.186-187). Although previous data is not avail-able for LAAM in other animals or by otherroutes of administration, several studies havebeen performed for methadone. In the mouse,the following LD50’s have been noted: oral93.8 mg/kg, i.v., 17.3-9 mg/kg. In the rat,the following LD50’s are reported: oral90-95 mg/kg, subcutaneous, 45-48 mg/kg, andintravenous 9.2-14.6 mg /kg In the monkeysubcutaneous LD50 of 10-20 mg/kg was reportedNo studies previously reported evaluated theLD50 or chronic toxicity for methadone or LAAMin animals dosed chronically. In the studiessupported by NIDA, Industrial Biotest carriedout similar studies using similar protocolsin the same laboratory simultaneously withmethadone and LAAM. These studies utilizedthe oral route of administration which is usedclinically in man.

The LD50 of methadone in non-tolerant malerats was 94.0 mg/kg and 102-0 mg/kg in females.The corresponding values for LAAM were 28.6mg/kg for males and 35.0 mg/kg for females. Intolerant male rats the methadone LD50 was 102mg/kg in males and 114 mg/kg for females. TheLAAM values in tolerant rats were 93.0 mg/kgfor males and 220.0 mg/kg for females.

In the case of methadone there was no sexdifference in toxicity in either naive or tol-erant rats nor were there significant differ-ences between naive and tolerant rats. In thecase of LAAM there was a slight difference be-tween sexes in the non-tolerant animals but amuch larger difference in the tolerant ones.Of even greater interest is the fact that tol-erant animals of both sexes were less sensi-tive to the acute toxic effects of LAAM givenorally than naive rats, whereas no such dif-ference occurred with methadone. An explana-tion for this finding requires further study.

Although LAAM and methadone are structurallysimilar there are major differences in theirmetabolism and pharmacokinetic behavior. Themajor metabolites of LAAM are two N-demethyl-ated derivatives, nor-LAAM and bisnor-LAAMwhich persist in the animal for long periodsof time and are almost certainly responsiblefor the long duration of the pharmacologicaleffects of LAAM. In contrast the metabolicproducts of methadone do not persist and prob-ably contribute little to its pharmacologicalaction.

In the Edgewood Arsenal rat and dog chronictoxicity studies, the animals were medicatedfor five rather than seven days a week and theduration of each study was 52 weeks. Because

the dosage regimen may have influenced thetoxicity findings, and in view of the non-reproducible organ calcifications which appear-ed after the initial dosing in rats, it wasconsidered advisable to perform other chronictoxicity studies, using a seven day dosageregimen.

A Toxicity panel consisting of outside con-sultants was constituted to act as advisors toNIDA, review data and generally oversee theprogress of the new chronic toxicity studiesof LAAM and methadone, run simultaneously inthe same laboratory (Industrial Bio-Test).

An 80-week chronic toxicity study in rats wascarried out using gradually increasing dosesof methadone to reach the final doses of 5,10 and 15 mg/kg/day of methadone, 7 days aweek. The protocol and design of the studyresembled the LAAM experiment. The mortalityata for methadone is summarized in Table 5.

The above mortality also includes animalswhich were deliberately sacrificed and thusis comparable with Table 3. The dosages inboth protocols are approximately the same,there was a greater mortality in males in bothstudies and a great number of animals diedafter the first year of treatment. In bothstudies a large number of animals died and thecause of death for LAAM, methadone and controlanimals was attributed to naturally occurringrespiratory infections and are not drugrelated.

On the basis of mortality figures alone, intolerant rats LAAM does not appear to be moretoxic than methadone. In both studies thedrugs were administered daily whereas it isanticipated that in man LAAM will be giventhree times a week with an average weekly in-take of 180 to 240 mg. The average weeklyintake of methadone is about 350 mg.

Hepatic changes were noted in both the LAAMand methadone studies. Separate experimentsshowed that administration of either druginduced an increase in N-demethylase activity.Such a phenomenon is commonly encountered onchronic administration of many drugs such asphenobarbital and diazepam which are subjectto hepatic metabolism. In the case of metha-done hepatic changes reverted to normal with-in one month of cessation of treatment.Recovery was not complete two months afterLAAM treatment was stopped, but definitesigns of normalization were apparent. Thedifference in metabolic behavior of the twodrugs may account for this difference.

36

TABLE 5

Frequency and Distribution of Deaths in Rats Treated With

Methadone

Groupand Dose Level

Control

5 mg/kg/day

10 mg/kg/day

15 mg/kg/day

Sex

MF

MF

MF

MF

Accumulated Deathsin Treatment Period52 weeks 80 weeks

3312

3915

3715

5848

Changes in the electrocardiogrm tracings ofdogs on the middle and high dose levels ofLAAM were noted in the Edgewood Arsenal andIndustrial Bio-Test Studies. Owing to themedication schedule in the former study thereversibility of these changes could be ob-served. This could not be seen in the latterstudy, but four weeks after medication theEKG tracings in the Industrial Bio-Testexperiment were essentially normal. Histo-pathological examination of cardiac tissuerevealed no drug related abnormalities. How-ever. in view of these findings careful atten-tion was paid to the possibility of cardio-toxic effects of LAAM in the Phase I andPhase II clinical trials. No evidence ofcardiotoxicity in man has been found to date.

Teratogenic studies were carried out innaive and tolerant rabbits and in tolerantrats. The highest dose used in naive rabbitswas 2.0 mg/kg/day but it was possible to goto 10 mg/kg/day in tolerant rabbits. In bothexperiments no embryotoxic or teratogenic eff-fects were observed. In tolerant rats theonly abnormality noted was an increased inci-dence of angulated ribs at the middle andhigh dose levels.

Reproduction, perinatal and lactation perform-ance studies with progeny cross-over werecarried out in LAAM nontolerant and tolerantrats. The effects seen in the nontolerantanimals were similar to but of lesser magni-tude than those observed in the tolerantrats.

6229

6537

6830

77JO

Recovery

65

41

25

10

Total MortalityTotal Treated

68/11034/110

69/11038/110

70/11035/110

78/11070/110

In the studies with tolerant rats the drugtreated group evidenced an increased numberof stillbirths, a decrease in progeny duringlactation, and lower body weight of the pro-geny, although the weights were within thenormal range. The cross-over studies indi-cated that in utero exposure to LAAM was themain cause for the decreased progeny survival.These findings would appear to be consistent

with the effects of large, repeated doses ofa narcotic drug, resulting in fetal LAAM ex-posure and neonatal dependence via placentaltranser. The decrease in progeny survivalcould be related to narcotic withdrawal dur-ing the neonatal period. The increase innumber of stillbirths was also found in sin-ilar studies with methadone. The decreasein progeny survival and lowered birth weightis consistent with clinical observationsfor infants born to heroin and methadonedependent women.

On the basis of the toxicological studiescarried out thus far it can be concluded thatwhen the human dose regimens are taken intoaccount the toxicity of LAAM and methadoneare comparable in tolerant animals. Thehepatic changes that were found are in allprobability an adaptive response of the hep-atocytes to the metabolism of both drugs.

The major difference between the two drugs isthe greater sensitivity of non-tolerant ani-mals to the toxicological and pharmacologicaleffects of LAAM by the oral route. The dif-ference should be kept in mind when LAAM isto be administered to humans.

37

REFERENCES AUTHORS

Farrand, R. L., McNamara, B.P., Christensen,M.K., Toxicological Testing of l-Alpha-Acetylmethodol, 1974. (Unpublished).Prepared at Edgewood Arsenal, AberdeenProving Grounds, Maryland.

Industrial Bio-Test Laboratories, Inc.One Year Chronic Feeding Study with LAAMin Beagle Dogs, 1975. (Unpublished).Prepared under Contract HSM-42-73-178at Northbrook, Illinois.

Ms. Ann Wolven is associated with the ShellChemical Company, 2401 Crow Canyon Road,San Ramon, Calif., 94022.

Sydney Archer, Ph.D. is Research Professorof Medicinal Chemistry, Chemistry Department.Rensselaer Polytechnic Institute, Troy, N.Y.,12181.

Industrial Bio-Test laboratories, Inc.Chronic Oral Toxicity Study with LAAMin Albino Rats for 79 Weeks, 1975.(Unpublished). Prepared under ContractHSM-42-73-178 at Northbrook, Illinois.

Industrial Bio-Test Laboratories, Inc.Teratogenic Study with LAAM in AlbinoRats, 1973. (Unpublished). Preparedunder Contract HSM-42-72-171 at North-brook, Illinois.

Industrial Bio-Test Laboratories, Inc.Perinatal and Lactation PerformanceStudy with LAAM in Albino Rats, 1973.(Unpublished). Prepared under ContractHSM-42-72-171 at Northbrook, Illinois.

38

PHASE I

Ralph M. Sollod, M.S.

Marcia G. Goldstein, M.A.

Clinical studies on LAAM were conducted asearly as 1952. Most investigations with thedrug in the 1950’s tested the use of LAAMas an analgesic. However, in the late 1960'sand early 1970's, an interest developed inthis drug as an alternative to methadone inthe treatment of heroin addiction. Thesestudies preceded the Phase II clinical trialson LAAM initiated by SAODAP in 1973. Herethey are grouped as Phase I studies. TableXVII, provides a list of LAAM Preclinical,Phase I, and Phase II clinical investigators.

PHASE I S’IUDIES--CROSS S’IUDY SUMMARY OFFINDINGS

This section provides a comprehensive sum-mary of clinical studies on LAAM exclusiveof the current VA/SAODAP Phase II clinicaltrials. The summary has been organized intothe following sections:

PharmacokineticsClinical PharmacologyControlled Clinical StudiesOther Clinical StudiesSummary of Toxicity-Safety Findings

and Observations

The sumnary of toxicity-safety findings andobservations covers all clinical studiesprior to Phase II (1952-1974).

Pharmcokinetics

The delayed onset and long duration of ac-tion of 1-alpha-acetylmethadol has been at-tributed to its biotransformation to twoactive metabolites, noracetylmethadol (N-LAAM) and dinoracetylmethadol (DN-LAAM) (Bil-lings et al. 1974a). Other products of me-

CLINICAL STUDIES

tabolism are methadol (MOL) and normethadol(NMOL) which are the result of deacetylation.

LAAM has two methyl groups attached to nitro-gen, These are N-demethylated byN-demethylating enzymes in vivo to 1-alpha-noracetylmethadol by the removal of one me-thyl group and its replacement by hydrogen.This, in turn, may be converted to a di-norform by the enzymatic removal of the secondmethyl group and its replacement by hydrogen(Billings 1974a). The demethylating enzymesare located in the liver and, hence, accountfor the more rapid onset of action of LAAMwhen orally administered , and also explainthe delayed onset of effect when LAAM isadministered intravenously, intramuscular-ly, and subcutaneously (Fraser 1952).

Techniques for identifying and quantitatingplasma and urine levels of acetylmethadoland its metabolites in human biofluids havebeen developed by Kaiko and Inturrisi (1973).Plasma and urine samples were obtained frompatients receiving maintenance dose of LAAM(level unspecified) for treatment of heroinaddiction. Peak plasma levels of acetylme-thadol were found to occur at four hourspostadministration and had nearly disappear-ed at 24 hours. N-LAAM plasma levels peakedin four-eight hours and declined slowly overthe next 40 hours. DN-LAAM levels remainedconstant during the dosing interval. Thetime cource of pupillary effect was foundto be related to the plasma levels of theactive metabolites. (Kaiko and Inturrisi1975, in press). Henderson (1974, 1975) hasfound the time course of peak plasma levelsof LAAM and its metabolites (N-LAAM and DN-LAAM) following acute administration of 60mg LAAM to be similar to those for racemic

39

acetylmethadol: LAAM, 6 hours; N-LAAM, 2-6hours; DN-LAAM 2-48 hours. After 90 days, adose level of 85 mg of LAAM three timesweekly was attained. LAAM plasma levelswere only slightly higher than initiallywhile N-LAAM and DN-LAAM levels were 5-10times higher. Billings et al. (1974) foundthat DN-LAAM levels were substantially high-er after repeated doses of LAAM, while LAAMand N-LAAM levels tended to remain the same.

Goldstein (1975 unpublished) found thatplasma levels of LAAM were very low at 72hours postadministration in patients main-tained on LAAM; the plasma levels of N-LAAMand DN-LAAM, on the other hand, increasedfrom 24 to 48 hours and were almost as highat 72 hours as at 48 hours. This is con-sistent with the proposition that it is theactive metabolites which are responsiblefor the long duration of action of LAAM: thedosage was "holding" at 72 hours when LAAMplasma levels were practically nonexistentand N-LAAM and DN-LAAM plasma levels werestill high.

The active metabolites of LAAM play a cen-tral role in the profile of action of thiscompound. An appreciation of their role ishelpful in understanding the slow onset,long duration of action, and cumulativeeffects which have been observed.

In addition, individual variations in therates of formation and elimination of thesecompounds have been noted (Billings et al.1974 a; Kaiko and Inturrisi 1975, in press).Goldstein (1975 unpublished) has also founda great deal of variation among individualsin LAAM plasma levels (from 15 to 170 ng/mlat 24 hours postadministration). DN-LAAMlevels also varied considerably among pa-tients from undetectable (<30 ng/ml) to 278ng/ml at 72 hours postadministration.

These individual variations with respect tothe metabolism of LAAM may help to explainthe differences in response which have beenobserved among LAAM patients in therapy.The extent of individual variability in themetabolism of this compound appears to bean important factor which should be takeninto consideration in the formulation ofdosage levels and intervals. Several phar-macokinetic studies are currently investi-gating these clinical issues.

Clinical Pharmacology

LAAM investigational studies on clinicalpharmacology have been summarized below un-der four areas: (1) analgesic activity, (2)relief of abstinence syndrome (withdrawal),(3) opiate effects, and (4) cross tolerance.

(1) Analgesic Activity--Early interest inthe acetylmethadols centered around theirappropriateness for use as analgesics. Cli-nical trials were undertaken to evaluate thepotential of these compounds as substitutesfor morphine.

David et al. (1952) found that 20-30 mg ofracemic alpha-acetylmethadol, administeredorally and subcutaneously, relieved chronicpain for four to five hours and bad a cumu-lative effectiveness which enabled patientsto skip doses in some instances.

Keats and Beecher (1952) in clinical trialswith the levo isomer (LAAM) administeredsubcutaneously found it to be less effectiveas an analgesic than morphine. LAAM admini-stered subcutaneously in a dose of 20 mg/70kg produced analgesia within 90 minutes, butthe analgesia was less than that producedby 10 mg of morphine. By extrapolation theyestimated that 50 mg of LAAM would be neededto equal 10 mg of morphine in efffectiveness.They did not find the duration of action ofLAAM to be longer than that of morphine.Cumulative toxic effects were noted afteradministration of LAAM, and coma occurredin four patients at dose levels below theestimated equivalent effective dose. Theyconcluded that the margin of safety of thisdrug was too small to encourage its use asan analgesic.

There were subsequent interest in the anal-gesic potential of noracetylmethadol. Gru-ber and Baptisti (1962) found that oraldoses of noracymethadol were three and one-fourth times as potent as morphine and alsohad fewer undesirable side effects.

Houde et al. (1962) found that noracetylme-thadol subcutaneously administered was equi-valent to morphine in 8 and 16 mg doses andhad a similar duration of action.

The analgesic potential of the acetylmetha-dols has not been of interest currently andthe results of the early studies, while ofhistorical interest do not have particularrelevance to the consideration of LAAM as asubstitute for methadone in the treatmentof heroin addiction. Adverse experiencesand side effects noted in the course of theseclinical investigations will be of interestin a consideration of the evidence pertinentto the safety of the drug to follow laterin this summary.

(2) Relief Of Abstinence Syndrome (With-drawal)--The early clinical investigationsof Fraser and Isbell (1952) with alpha-ace-tylmethadol included the racemic form of thecompound, as well as both optical isomers.

42

While only dl- and 1-alpha-acetylmethadolhave been of clinical interest as substitutesfor methadone in the treatment of heroin ad-diction, some findings on the dextro isomerare discussed herein to provide a perspec-tive of the background of the developmentof interest in LAAM.

Fraser and Isbell (1952) investigated thepotential of dl-, l-, and d-acetylmethadolto relieve withdrawal symptoms after absti-nence from morphine. They found that 15-50 mg doses of dl-acetylmethadol adminis-tered subcutaneously between the 28th and34th hours of abstinence from morphinebrought relief from the abstinence syndromewithin two hours and that relief of symptomswas complete after a second dose. d-acetyl-methadol, on the other hand, was less effec-tive than methadone in relieving abstinencesyndrome. Fifteen-twenty mg doses of d-ace-tylmethadol administered subcutaneouslyat the 28th and 32nd hours of abstinencebrought little relief; with 30-40 mg doses,relief was marked. Oral administration ofthe d-isomer resulted in a less rapid onsetof action and less pronounced effects. Do-ses of d-alpha-acetylmethadol sufficientsuppress all signs of abstinence resulted

to

in the development of toxic symptoms.

1-alpha-acetylmetbadol, on the other hand,was more effective than the parent compound,d-methadone, in relieving abstinence. Onemg of LAAM was equivalent to 6-8 mg of meth-adone. Thirty mg of LAAM administered sub-cutaneously bad inconsistent results withrespect to relief of abstinence; however,30-60 mg administered orally completelyabolished all signs of abstinence.

Fraser and Isbell (1952) also found thatwithdrawal from LAAM resulted in a mild butdefinite abstinence syndrome, similar incourse and intensity to that following with-drawal from methadone. There appeared tobe no significant difference in abstinencesyndrome following either abrupt or gradualwithdrawal from LAAM.

Suppression of abstinence syndrome with LAAMwas of long duration. Sixty mg of LAAM ad-ministered orally was shown to be sufficientto prevent abstinence syndrome for 72 hours.Mild but definite abstinence symptoms didnot appear until 84 hours postadministration.Significant withdrawal symptomes were notmanifested until the interval was extendedto 96 hours.

Levine et al. (1973) found that 20-50 mg do-ses of LAAM resulted in discomfort 48-72hours posttreatment, 70 mg doses producedmild abstinence syndrome 60-72 hours post-treatment. and 80 mg doses prevented absti-

nence syndrome completely for 72 hours.

Subsequent clinical research has confirmedthe ability of LAAM to prevent the develop-ment of withdrawal syndrome for long periods.

(3) Opiate Effects--Several investigatorshave established data on the onset, peak,and duration of opiate effects following ad-ministration of the acetylmethadols.

Fraser and Isbell (1952) used subjects whowere formerly addicted to morphine and with-drawn ("post-addicts") to evaluate the ef-fects of single doses of racemic acetylmeth-ado1 and both isomers.

dl-alpha-acetylmethadadol produced morphine-like effects which included increased psy-chomotor activity, somnolence, garrulous-ness, pupillay constriction, itching,scratching, nausea, and insomnia. Fifteen-forty mg of dl-acetylmethadol administeredsubcutaneously produced morphine-like effectsin 30 minutes which persisted for 24 hours.

The d-isomer produced morphine-like effectswhich were subjectively pleasing to the pa-tients in 15 minutes following subcutaneousadministration of single 5-20 mg doses. Theduration of action was 24 hours. Twenty mgdoses of d-alpha-acetylmethadol administeredorally bad no effects on any patients tested.

Single ten-thirty mg subcutaneous doses of1-alpha-acetylmetbadol bad a delay in onsetof action of four-six hours. Effects wereslow to appear (14 hours in some cases) andwere always evident at 24 hours, usuallyevident at 48 hours, and occasionally evidentat 72 hours postadministration. Thirty mgof 1-alpha-acetylmethl administered intra-venously bad effects which were the same asthose following subcutaneous administration.Thirty-forty mg of 1-alpha-acetylmethadoladministered orally had a more rapid onsetof action than that following subcutaneousor intravenous administration, effects beingevident in one and one-half hours and per-sisting in all cases for 24 hours and insome cases for 72 hours.

The time course of miotic effects (decreasein pupillary diameter) was shown to parallelthat of other drug effects. Following oraladministration of the levo isomer, pupillarymiosis began in 2 hours and was maximal in4 hours with a return to baseline measuresat 24 hours. Following subcutaneous and in-travenous administration of the levo isomer,pupillary constriction appeared more slowly,was more intense, and lasted longer (48 hours),

Fraser et al. (1954) confined earlier find-

43

ings of more rapid onset of action followingoral rather than subcutaneous administrationof LAAM. Miotic effects were observed tolast 72 hours and the time course of theseeffects were related to patient subjectivereports of "euphoria." Oral administrationof LAAM produced an earlier, more intenseeuphoria which diminished more rapidly thanthat following subcutaneous administration.Miosis correlated with the delay of absti-nence until three days postadministration,but did not correlate well with analgesicactions of the drug.

In an unpublished study using nonaddictedsubjects, Irwin, Blachly, Marks and Carteradministered .2 mg/kg of LAAM and methadoneorally and observed that the profile ofaction following acute administration wasthe same for both drugs. Peak effects, mea-sured by the Irwin Comprehensive Humans As-sessment Procedures, occurred in four hoursand the duration of action of LAAM was notsignificantly longer than that of methadone.The period of observation was 10 hours. Theonly significant difference in effects werereductions in wakefulness and attentivenessfollowing administration of LAAM.

In another unpublished study, Irwin, Kinohi,Cooler and Bottomly (1973) administered .8mg/kg and .16 mg/kg oral doses of LAAM and.1 mg/kg and .2 mg/kg oral doses of metha-done to nonaddicted subjects. Peak effectsoccurred three hours posttreatment with bothdrugs. The duration of action of LAAM wasover 24 hours; that of methadone was 12hours. The higher dose of LAAM producedeffects similar to but less intense thanthose produced by the lower dose of metha-done. LAAM and methadone produced bi-phasiceffects which were: early activation, ele-vation of mood, and liking for the drug fol-lowed by later depressant effect and dis-like of the drug. The effects of LAAM wereprimarily activating while those of metha-done were generally depressant.

Levine et al. (1973) administered 100 mgdoses of LAAM to heroin-addicted subjectsand evaluated the effects on pupillarydiameter. Twenty mg of LAAM produced maxi-mum miosis in 24 hours. Greater doses ofLAAM produced no further constriction; 30-50 mg doses sustained maximum constrictionfor 48 hours, and 80-90 mg doses sustainedmaximun constriction for 72 hours.

(4) Cross Tolerance--The ability of LAAMto provide blockade to the effects of heroinand the dose levels necessary for completeblockade have been studied by several inves-tigators. Irwin, Blachly, Marks, and Carter(unpublished) studied the development of

cross tolerance to 30 mg morphine sulfatein LAAM-maintenance subjects. It was foundthat most subjects experienced a slight rushafter administration of morphine and coulddistinguish morphine from placebo. Res-ponses were unrelated to levels of LAAM doses.One subject receiving 20 mg of LAAM showeda marked response to morphine injections,while subjects receiving 30, 85, and 140 mgdoses all showed slight euphoric responses.Occasionally, a slight "high" was reported,usually either during the earlier (3-8 hours)or later (52-54 hours) intervals postadmin-istration. LAAM was usually, but not always,effective in suppressing the effects of mor-phine.

Levine et al. (1973) undertook a study todetermine the dosage of LAAM which is re-quired to provide blockade to 25 mg heroinusing heroin-addicted subjects who weredetoxified and drug free at least seven daysbefore the experiment. Patients were start-ed on 10 mg of LAAM three times a week anddosages were increased by 10 mg per week upto 100 mg. Heroin challenges were performedat 72 hours after administration of varyingdoses of LAAM. At dose levels of 30 mg LAAM,four of six subjects reported some effectsof heroin and two felt none. At dose levelsof 50 mg, no effect of heroin was perceivedand at dose levels of 70 and 100 mg LAAMblockade was complete.

Zaks et al. (1972) found that three of foursubjects receiving 30-40 mg doses of LAAMresponded to challenge with 50 mg heroin 24hours after administration of LAAM withmile, transient euphoria, while blockade wascomplete in the fourth subject. All subjectsreceiving 80 mg of LAAM demonstrated completeblockade to 50 mg of heroin at 24 hours: onesubject was challenged at 48 hours postad-ministration and demonstrated completeblockade to heroin.

Controlled Clinical Studies

Clinical trials prior to Phase I have pro-vided some evidence as to the safety andeffectiveness of LAAM as a substitute formethadone in the treatment of heroin addic-tion. A review of the studies undertakenand their results pertinent to the effective-ness of LAAM as a substitute for methadonewill be presented here. Discussion of datafrom these studies pertinent to the safetyof LAAM will be presented in the sectiontitled Summary of Toxicity-Safety Findingsand Observations. A summary of all control-led clinical studies prior to Phase II ispresented in table XVIII, which follows thispage

44

The term "controlled clinical studies" asused here refers to all studies in which acontrol group, i.e., a group of patientswho are taking methadone, is used to providea basis for comparison of outcomes with theLAAM-treated group. The study design maybe open, where the patients are aware ofthe medication they are receiving; blind,where the patients are unaware of the medi-cation they are receiving and are givenplacebo in place of active medication onnondrug days; or double-blind, where theidentity of the medications which patientsreceive is not known to patients or thestaff who administer the medication and ev-aluate the results.

The following section will discuss other cli-nical studies which likewise may be open orblind, but in which no control group is used.

The first clinical trial (Jaffe et al. 1970)was a double blind study of the effective-ness of dl-alpha-acetylmethadadol as a sub-stitute for methadone in the treatment of21 patients. Doses were administered inthe ratio of 1.2 mg of dl-alpha-acetyl-methadol to 1 mg of methadone. At 24 and48 hours postadministration, there was nochange from baseline measures on the Addic-tion Research Center Inventory (ARCI) anda withdrawal symptom checklist. At 72 hours,there was a slight rise in the opiate with-drawal subscale of the ARCI; however, therewere no complaints on the checklist or ininterviews with experimenters. Ninety-sixhours postadministration there was a sharprise in withdrawal symptoms and complaints.No differences were found between groupswith respect to relief of withdrawal symp-toms, illicit drug use or other indicatorsof social adjustment. One-third of theLAAM patients and 11 Percent of methadonepatients dropped out of the study.

In a subsequent double-blind experimentcomparing dl-alpha-acetylmethadol and metha-done, 34 patients were studied for 15 weeks(Jaffe et al. 1972). The withdrawal symp-toms of patients taking a mean dose of 36-80 mg of dl-alpha-acetylmethadol/activedose three times weekly did not differ fromthose of patients taking a mean of 30-90 mgof methadone daily. There were no signifi-cant differences between the two groups forthe following outcome measures: dropoutrate, employment, arrests, percentage ofurines negative for illicit drugs, clinicattendance and requests for dose levelchanges. Twenty-six percent of the dl-alpha-acetylmethadol patients and 13 percent ofmethadone patients dropped out. The dif-ference was not significant.

A double-blind, controlled study was carriedout with 10 patients to determine if LAAMcould be effectively substituted for metha-done on weekends (Jaffe and Senay 1971).The duration of the study was three weekendsand no differences were found between theexperimental and control groups with respectto morphine-positive urines, clinic atten-dance, interviewer observations, self-reportsof symptoms, or requests for change in medi-cation. It was found that LAAM in dosesequivalent to the patient’s usual dose ofmethadone were sufficient to prevent absti-nence symptoms for 48 hours. Abstinencesyndrome was prevented for 72 hours by dosesof a mean of 1.3 mg of LAAM for every 1 mgof daily methadone. Mean dose levels were60 mg of LAAM and 68 mg of methadone. LAAMwas found to be similar in potency to theracemic compound, not higher as anticipated.

Senay, Jaffe, diMenza and Renault (1974) ina 48-week, double-blind study started 157patients on mean doses of 57.8 mg of LAAMthree times weekly, with placebo on alter-nate days, 40.6 mg of methadone daily (FullService Group), or 41.3 mg of methadone daily(Dispensary Group). Few significant differ-ences were found between the LAAM Full Ser-vice group, the Methadone Full Service group,and a third treatment group (Dispensary) re-ceiving methadone only and no counseling orother services. There were no significantdifferences in total number of weeks accumu-lated by patients in their original treatmentgroups. At the end of 48 weeks, 49 percentof the Dispensary group, 50 percent of theLAAM Full Service group, and 29 percent ofthe Methadone Full Service group had droppedout. There were no significant differencesbetween treatment groups with respect to useof illicit drugs and employment and arrestrates. Requests for dose-level changes weresignificantly less in the Dispensary group.

Zaks, Fink and Freedman (1972) compared 40LAAM (30-80mg/three times a week) and metha-done (100 mg/day) patients in an open studyof six months duration and found the groupsto be equivalent with respect to patientacceptance, withdrawal symptoms, responseto heroin challenges, and number of positiveurines tested for morphine. Patients taking40-50 mg doses of LAAM evidenced withdrawalsymptoms 40-48 hours posttreatment and 80mg of LAAM completely prevented abstinencesyndrome for 72 hours. Twenty percent ofmethadone patients and 11 percent of LAAMpatients dropped out.

In a controlled study with both double-blindand open comparisons, Lehmann (unpublished)studied 42 16-21 year olds on LAAM every 72hours. Some camplaints of mild discomfort

45

after 60 hours were made by patients in theopen group (who knew they were taking LAAM);however, complaints were not severe enoughto warrant change in dosages or inter-emo-tional reactions, performance in jobs,school, athletics, and therapy. Withdrawalwas accomplished from both drugs at the endof 16 weeks with equal ease.

Savage, Karp and Curran (unpublished) car-ried out a six-month double-blind crossovercomparison between 99 patients on LAAM (1.3times their usual methadone dose) and metha-done. Treatment groups did not differ infrequency of positive urines, clinic atten-dance, and social and emotional adjustment.Those patients who were induced on LAAM ini-tially dropped out at a significantly high-er rate than those who started on methadoneand transferred to LAAM (x2 5.49, p=0.2).The dropout rate was also higher for LAAMpatients in the second half of the study,after the crossover, but the difference wasnot significant. Fifty-three percent of allpatients taking LAAM dropped out and 35 per-cent of all patients taking methadone drop-ped out.

Irwin, Blachly, Marks, Carlson, Loewen andReade (1973) in an eight-month open studyof 109 LAAM patients (mean dose 55 mg/day,group one; mean dose 57 mg/day, group two),methadone patients (mean dose 50 mg/day),and nonaddict controls found that dropoutsfrom the study were disproportionately malesand tended to occur in the first two monthsof the study. There was a higher percentageof dropouts in the LAAM group (42 percent)than in the methadone group (23 percent) oramong the nonaddict controls (20 percent).There were no differences between treatmentgroups in social adjustment indicators.

In an open study comparing 65 patients onLAAM and methadone, Senay, Renault, diMenza,Collier, Daniels and Dorus (1974, unpub-lished) found that patients can be main-tained on a mean dosage of 44.4 mg of LAAMthree times weekly in comparison with pa-tients maintained on 36.5 mg of methadonedaily. Mean initial dose levels were 44.7mg of LAAM and 33.5 mg of methadone. Nosignificant differences in illicit drug useand employment and arrest records were no-ted at 14 weeks. LAAM patients tended todrop out earlier than methadone patients.The difference was significant at five weeksbut was no longer significant by 14 weeks.The dropout rate was 32 percent for LAAMpatients and 22 percent for methadone pa-tients.

Goldstein and Judson (1974) compared 44 pa-tients receiving 50 mg of methadone daily

to 14 patients receiving 75 mg of LAAM threetimes weekly on a double-blind basis and 16patients taking 75 mg of LAAM three timesweekly on an open basis. No significantdifferences were noted in dropout rates, at-tendance records, and jailings. Urine testsfor opiate use indicated the LAAM groupswere superior to the methadone group in hav-ing less illicit use of narcotics. Metha-done group members were superior in reduc-tion of amphetamine and barbiturate use.Goldstein also investigated the question ofwhether complaints of medication not holdingover the weekend were psychological or phar-macological in nature. He increased theFriday dose of LAAM from 75 mg to 100 mg onthree successive weekends on a limited ba-sis with the expectation that complaintswould decrease if their origin was pharmaco-logical rather than psychological. The ef-fects of this dosage increase were inconsis-tent, indicating that complaints of withdraw-al may well arise out of patients' concernthat their medication will not hold than,rather than being pharmacological in origin.

The overall results of all controlled clini-cal studies prior to Phase II reveal fewdifferences between LAAM and methadone pa-tients on outcome measures such as use ofillicit drugs, illegal activity and arrests,employment, clinic attendance and dose-levelchanges. A large number of studies haveconfirmed the initial findings of Fraserand Isbell that LAAM is capable of suppres-sing the development of abstinence syndromefor 72 hours. The dose levels necessary toachieve this have been shown to vary great-ly, and the patient’s attitudes and concernsabout the ability of the medication to holdhim for this period of time are important.The main differences between treatment groupsappear to be in the percentage of patientswho drop out of the studies. With one ex-ception (Zaks et al. 1972), all studies re-ported a greater percentage of LAAM patientsdropping out than methadone patients, al-though the differences between groups wereoften not significant.

Dropouts among LAAM patients tended to occurearly in the studies. Goldstein and Judson(1974) noted a greater number of dropoutsamong LAAM patients than among methadonepatients during the stabilization phase.Savage et al. (unpublished) noted a signifi-cantly greater number of dropouts among LAAMpatients in the first half of their cross-over study. Dropouts were also greater amongLAAM patients after medications were switched,but not significantly so.

Senay et al. (1974 unpublished) noted thatthe significant difference in percentage of

46

dropouts among LAAM and methadone patientsat the 5th week of their study had disap-peared by the end of the 14th week when therate of dropouts for methadone patients in-creased to a level similar to that of LAAMpatients.

Jaffe et al. (1970) noted that the four pa-tients taking dl-alpha-acetylmethadol whodropped out of his study did so on the firstday. Jaffe et al. (1972) found that theaverage stay of patients on dl-alpha-acetyl-methadol was 5.8 weeks compared to 10 weeksfor methadone patients.

In summary, investigators have found thaton most outcome measures, LAAM compares fa-vorably with methadone as a substitute drugin the treatment of heroin addiction. Thedropout rate among LAAM patients has beenshown to be generally higher than that formethadone patients, although differencesare often not significant. Dropouts amongLAAM patients often occur during the early,stabilization phase and may be related tophysiological problems in inducing patientsonto a new drug or to psychological concernsabout the taking of an "experimental" drug.If, as is suspected, the metabolite N-LAAMis the active agent, there is a lag inbuildup of pharmacologically active bloodlevels. During the period when patientsare off methadone and just starting on LAAM,the blood levels of the desired agent maybe too low and initial discomfort may occur.

Other Clinical Studies

Other clinical investigations have beencarried out with LAAM where a methadone orother control group was not employed andhave produced findings pertinent to the ef-fectiveness of LAAM in the treatment ofheroin addiction.

Blachly (1971) reported starting 74 patientson LAAM in an open study. The initial con-version factor of one-sixth the patient’susual dose of methadone proved to be inade-quate, and all patients suffered withdrawa1.Twenty-two out of twenty-three patientsstarted at those dose levels returned tomethadone within a week. Twenty-four of51 other patients continued on dose levelsequal to their methadone dose. Doses ofLAAM equivalent to the patient’s usual metha-done dose were sufficient to prevent absti-nence in 18 patients for 48 hours and in6 for 24 hours.

Wilson, in an unpublished open study, ob-served three treatment groups for 85 days:

Five patients transferred to 60-65 mg

of LAAM on Monday and Wednesday and 80-85 mg of LAAM on Friday after havingbeen maintained on methadone for threemonths

Five patients induced directly on LAAM(60-65 mg Monday and Wednesday and 80-85 mg on Friday) who had never takenmethadone

Six patients who received methadoneMonday through Thursday, and 80-85 mgof LAAM on Friday

The dropout rate was identical in both groupstaking only LAMM (40 percent). The groupwho had never taken methadone stabilized onLAAM with less distress and fewer complaintsthan the group who had been transferred frommethadone maintenance. The group of patientstaking methadone during the week and LAAMon the weekends all experienced withdrawalon the third day after the Friday dose. Two-thirds of them dropped out of the study afterfive weekend doses; this part of the studywas discontinued after two months.

Summary Of Toxicity-Safety Findings And Ob-servations

When all the research which has been donewith LAAM prior to Phase II is taken intoconsideration, it appears that there havebeen few unusual reports of toxicity; suchadverse experiences as did occur resembledthose of methadone, and particularly occurredafter excessive dosage. The cumulative na-ture of the drug effects and the variabilityamong individuals in the rate at which LAAMis metabolized necessitate close attentionto dosage levels and intervals. Followingis a summary of clinical experience whichhas accumulated as a result of investigationsprior to Phase II and which has relevanceto the safety of the drug. This summary isorganized in the following categories: re-sults of laboratory tests, adverse expe-riences, and side effects

Results Of Laboratory Tests

Laboratory tests have revealed few diffe-rences between LAAM and methadone patientsand most results have been within normal li-mits, or unchanged from pretreatment valueswhere pretreatment values were not normal.Following is a description of those resultswhich are unusual in any respect.

Blachly et al. (1972) canpared 21 LAAM Pa-tients to a matched sample of 19 methadonepatients on laboratory findings (results ofSMA 12 and SMA 6 screen and automated reagintests) and electroencephalograms. The only

48

statistically significant finding (p.025)for LAAM patients was hyperglycemia (meanblood glucose 117 percent for LAAM patients103 percent for methadone patients where110 is defined as the upper limit of normal).Sixty-three percent of the methadone pa-tients and 38.5 percent of the LAAM patientshad EEG abnormalities but the difference wasnot significant (p 0.1-0.2, chi square=2.44).

Irwin, Blachly, Marks and Carter (unpublish-ed) in another discussion of the same studyalso noted a higher incidence of abnor-malities in SGOT, albumin, and alkalinephosphatese determinations in both the LAAMand the methadone groups, suggesting aslight impairment in liver function. ‘Ihir-ty-five and 29 percent of methadone and LAAMsubjects, respectively, also had abnormallyhigh white blood counts. LAAM subjects’performance on cognitive tasks involvingmemory, learning, speed, and accuracy wassignificantly better than was methadonesubject’s performance.

Jaffe, Senay, Schuster, Renault, Smith anddiMenza (1972) in a study of dl-alpha-acetyl-methadol noted that only 7 of 66 patientsbad normal results on liver-function testsupon entry and that profiles remained un-changed at the end of the study. With re-spect to hematology, most subjects were nor-mal initially and at the end of the study.In one subject, the hematocrit dropped from48 percent to 39 percent but hemoglobinlevel, RBC, and WBC remained normal. Whiteblood cell counts decreased in two patientsand increased in one; no symptoms were as-sociated with any of these changes. Thir-teen subjects had positive results for VDRLand PTA tests initially, which were unchangedat the end of the study, except for one sub-ject whose values reverted to negative.

Wilson (unpublished) noted elevated SGOTdeterminations and slightly decreased hemo-globin, hematocrit, and white blood countin five of six LAAM patients.

Zaks et al. (1972) reported elevated trans-aminase levels which were sporadic and notdose-related for both the LAAM and the metha-done groups. Results of all other labora-tory tests (fasting, blood glucose, bloodurea nitrogen, uric acid, blood cell count,and urinalysis) were normal.

Irwin, Blachly, Marks, Carlson, Leowen andReade (1973) found the incidence of EBG ab-normalities among methadone patients was 43percent upon entry into the study and hadincreased to 53 percent at eight months.Incidence of EEG abnormalities increasedless markedly for 48-hour LAAM patients

(31 percent upon entry to 40 percent ateight months). There was a statisticallysignificant increase in incidence of EEGabnormalities for 24-hour LAAM patients (34percent upon entry to 100 percent at eightmonths) . There was no significant altera-tion of cognitive performance for LAAM ormethadone patients and EEG abnormalitiesdid not seem to be reflected in performanceon cognitive tests.

Blood chemistry analysis revealed that bothLAAM and methadone produced elevations inSGOT determinations and that methadone pro-duced a greater incidence of lowered abnor-mal T-3 value. Incidence of abnormalitieswas sustained for methadone patients anddecreased for LAAM patients over the eight-month study period. Urine analysis revealedno abnormalities.

Savage et al. (1974, unpublished) found nodifferences in LAAM patients pre- and post-treatment in EEG, blood chemistry analysis,or hematology. Methadone patients evidencedsignificant changes on three of seven hema-tology measures; the mean values of neutro-philes decreased and the mean values oflymphocytes and basophiles increased. Allvalues were still within normal range, how-ever.

Adverse Experiences

There have been several reports of adverseexperiences in the course of investigationswith LAAM prior to Phase II.

Keats and Beecher (1950) noted four inci-dents of coma among 81 patients receivingsubcutaneous doses of LAAM for relief ofchronic pain. The patients bad received 1640 mg LAAM twice in 24-34 hours with one tothree 6-10 mg doses of morphine in the sameinterval. Coma occurred 12-24 hours afterthe last dose of LAAM and lasted an averageof 20 hours.

Blachly (1971) noted four cases of toxicityto LAAM at dose levels above 100 mg among74 patients taking LAAM. Two patients hadseizures while on 180 mg and 120 mg LAAMevery 24 hours. A female patient on 110 mgLAAM every 24 hours lost consciosness, suf-fered cardiac arrest, and showed EEG ab-normalities, and a patient on 220 mg LAAMper day complained of feeling as though hewere going to have a fit and was returnedto methadone. A fifth patient bad a manicattack when his dosage was reduced to 35 mg/48 hours from 55 mg/48 hours during voluntarywithdrawal. He was returned to methadone(55 mg/day), treated with lithium and thora-zine, and subsequently completed withdrawal

49

while on LAAM.

Side Effects

The response of patients on LAAM has beenshown to vary considerably among individuals.Some patients evidence no side effects orcomplaints, while others experience distressfrom either withdrawal or side effects.

Billings et al. (1974) observed differentresponses in three LAAM subjects studied.The subject with the highest plasma levelsNAM and NNAM reported only mild sweatingand constipation. The two other subjects,whose plasma levels of the metabolites weresimilar to each other, reported more severeside effects. One reported anxiety, sweat-ing, and gooseflesh in the early weeks ofthe study which disappeared later; the otherreported considerable dysphoria, irritabi-lity, muscle weakness, tremors, and paranoia.

Zaks et al. (1972) received no complaintsof side effects from methadone patients ex-cept constipation (4 out of 10 patients).Of the nine LAAM patients, three complainedof irritability, one of anxiety, and twoof involuntary, jerky movements of theextremities before falling asleep.

Jaffe, Senay, Schuster, Renault, Smith anddiMenza (1972) noted few complaints of sideeffects in the 66 subjects in their study,and no toxic reactions. Two patients com-plained of impotence and two complained ofjerking and twitching of arms and legs whenat rest.

Withdrawal, irritability, restlessness, gas-trointestinal upset, and anxiety were com-plained of by methadone patients who weretaking LAAM on weekends (Wilson, unpub-lished). All five patients in the treatmentgroups who were transferred to LAAM frommethadone all complained of amphetamine-like effects, irritability, anorexia, con-stipation, and diminished libido in theearly weeks of the study. Other complaintswere appetite and weight loss. The fivepatients in the treatment group who wereinduced directly on to LAAM stabilized withfewer side effects than the group which wastransferred from methadone.

David and Semler (1956) found that sideeffects were minimal among patients receiv-ing small doses of LAAN orally and subcut-aneously for relief of chronic pain. Twen-ty-five of seventy-six patients were nau-seated or vomited at some time while receiv-ing LAAM. Ten of thirty-one patients treat-ed for longer than 31 days complained ofmoderately severe constipation. Six patients

in the total sample complained of dizziness,thirteen reported feeling lethargic, and twoexperienced severe depression attributableto intolerance to LAAM.

Fraser and Isbell (1952) found that repeateddoses of dl-alpha-acetylmethadol and LAAMresulted in cumulative toxic effects infour patients: depression, approaching coma,nausea, respiratory depression, and mentalconfusion.

Reports of loss of sexual desire, constipa-tion, drowsiness, and loss of energy werereceived from patients in both LAAM and meth-adone groups. The mean number of complaintswas the same for each group, 2.6 (Irwin,Blachly, Marks, Carlson, Loewen and Reade,1973).

Gruber and Baptisti (1962) found that nausea,dizziness, and drowsiness increased in pro-portion to the dose level of nor-acetylmetha-dol; constipation, headache, nervousness,and abdominal discomfort were reported asside effects but were not dose-related.Itching was volunteered as a complaint oftenenough to be added to the list.

Houde et al. (1962) observed that nauseaand drowsiness occurred in some patients athigher doses of noracetylmethadol (8 and16 mg) administered subcutaneously, and burn-ing at the site of injection occurred after25 percent of the 16 mg doses.

Jaffe et al. (1970) reported that four oftwelve patients taking dl-alpha-acetylmetha-dol dropped out on the first day becauseof complaints of anxiety and nervousness.The d-isomer has been suspected of producinganxiety and nervousness (Fraser and Isbell1952) and may be responsible for the sideeffects noted in this instance.

In an open study with LAAM, Levine (1973)noted that three of seven patients reportedloss of appetite and abdominal discomfortat doses greater than 50 mg; all patientsreported constipation.

Senay et al. (1974) found no instances ofconfusion, psychotic symptoms, or unpleasantsubjective states among 157 patients studied.Anxiety was observed in all treatment groups.There were two deaths during the course ofthe study: a methadone patient committedsuicide and a LAAM patient died of lung can-cer .

Senay et al. (1974, in press) reported that5 of 34 patients taking LAAM experiencedside effects; four suffered from anxiety andnightmares early in treatment and one patient

5 0

exhibited bizarre behavior of which he hadno recollection. One LAAM patient died asa result of heroin overdose 48 hours afterhis second dose of LAAM.

* * * * * * * *

This chapter has summerized the clinical tri-als 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 areassociated with Macro Systems, Inc., 1110Fidler Lane, Silver Spring, Md., 20910.

51

The following synopses were prepared to astandard format by Macro System, Inc., froma review of LA A M research, published and un-published, up to July, 1975.

SELECTED CLINICAL STUDIES SYNOPSES

INDEX

1 Billings, R. E., McMahon, R. E., Blake, D. A.1-Acetylmethadol (LAM) Treatment Of OpiateDependence: Plasma And Urine Levels Of TwoPhamacologically Active Metabolites. 1974

2 Blachly, P. H.1-Alpha-Acetylmethadol In The Treatment OfOpiate Addiction: Progress Report, 1971

3 Blachly, P. H., David, N. A., Irwin, S.1-Alpha-Acetylmethadol (LAM): ComparisonOf Laboratory Findings, Electmencephalo-grams, And Cornell Medical Index Of PatientsStabilized On LAM With Those On Methadone.1972

4 Fraser, H. F., Isbell, H.Actions And Addiction Liabilities Of Alpha-Acetylmethadols In Man. 1952

5 Fraser, H. F., Nash, T. L., Vanhorn, G. D.,Isbell, H.Use Of Miotic Effect In Evaluating AnalgesicDrugs In Man. 1954

6 Goldstein, A.LAAM And LAAM Metabolites: Plasma Levels InPatients. Summary Progress Report. 1975(Unpublished)

7 Goldstein, A., Judson, B. A.Can The Community Be Protected Against TheHazards Of Take-Home Methadone? 1974

8 Henderson, G. L.Pharmacodynamics Of LAAM In Man: PlasmaLevels Of LAAM And Its Metabolites FollowingAcute And Chronic Administration In Man(Fourth And Sixth Quarter Progress Reports).1974-75

9 Irwin. S., Blachly, P. H., Marks, J.,Carlson, E., Loewen, J., Reade, N.The Behavioral, Cognitive, And PhysiologicEffects Of Long-Term Methadone And MethadylTreatment. 1973

10 Irwin, S., Blachly, P., Marks, J.,Carter, C. C.Preliminary Observations With Acute AndChronic Methadone And I-Alpha-AcetylmethadolAdministration In Humans. Unpublished

11 Irwin, S., Kinohi, R. G., Cooler, P. M.,Bottomly, D. R.Acute Time-Dose-Response Effects Of Cyclaz-ocine, Methadone, And Methadyl In Man.April, 1973 (Unpublished Report)

12 Jaffe, J. H., Schuster, C. R., Smith, B. B.,Blachly, P. H.Comparison Of Acetylmethadol And MethadoneIn The Treatment Of Long-Term Heroin Users:A Pilot Study. 1970

13 Jaffe, J. H., Senay, E. C.Methadone And 1-Methadyl Acetate: Use InManagement Of Narcotic Addicts. 1971

52

14 Jaffe, J. H., Senay, E. C., Schuster, C. R.,Renault, P. F., Smith, B., diMenza, S.Methadyl Acetate vs Methadone: A Double-Blind Study In Heroin Users. 1972

15 Kaiko. R. F., Chatterjie, N.,Inturrisi, C. E.Simultaneous Determination Of AcetylmethadolAnd Its Active Biotransformation ProductsIn Human Biofluids. 1975 (In Press)

16 Kaiko, R. F., Inturrisi, C. E.Disposition Of Acetylmethadol In RelationTo Pharmacological Activity. 1975 (In Press)

17 Lehmann, W. X.The Use Of 1-Alpha-Acetyl-Methadol (LAAM)As Compared To Methadone In The MaintenanceAnd Detoxification Of Young Heroin Addicts.1973

18 Levine. R.. Zaks. A.. Fink. M.,

19 Savage, C., Karp, E., Curran, S.A Methadone/l-Alpha-Acetylmethadol (LAAM)Maintenance Study. Unpublished

20 Senay, E. C., Jaffe, J. H., diMenza, S.,Renault, P. F.A 48-Week Study Of Methadone, MethadylAcetate, And Minimal Services. 1974 (InPress)

21 Senay, E. C., Renault, P. F., diMenza, S.,Collier, W. E., Daniels, S. J., Dorus, W.Three Times A Week LAAM Equals Seven TimesA Week Methadone: A Preliminary Report OfA Control Study. 1974 (In Press)

22 Zaks, A., Fink, M., Freedman, A. M.Levomethadyl In Maintenance Treatment OfOpiate Dependence. 1972

Freedman, A. M.Levomethadyl Acetate: Prolonged durationOf Opioid Effects, Including Cross ToleranceTo Heroin, In Man. 1973

53

Methodology

One hundred mg of LAAM was taken orally onMondays, Wednesdays, and Fridays. Bloodsamples (5-10 ml.) were taken at intervalsin the succeeding 48 hours; total urinevoided was collected for two days. Electroncapture gas chromatography was used todetermine the content of NAM and NNAM.

11-ACETYLMETHADOL (LAM) TREATMENT OF

OPIATE DEPENDENCE: PLASMA AND URINE

LEVELS OF TWO PHARMACOLOGICALLY

ACTIVE METABOLITES. 1974

RUTH E. BILLINGS, ROBERT E. MCMAHON,

DAVID A. BLAKE

INTRODUCTION

Two active metabolites of LAAM, 1-noracetyl-methadol (NAM) and 1-denoracetylmethadol(NNAM) have been identified and are thoughtto explain the characteristic pharmacologicaleffects of LAAM. (Sung and Way, 1954;Billings et al., 1973). The determination ofNAMl and NNAM levels in blood and urine ofpatients receiving LAAM for treatment ofopiate addiction was undertaken in order tosupport the proposition that the activity ofLAAM is due to its conversion to NAM andNNAM.

EXPERIMENTAL DESIGN

Subjects

Three white male ex-heroin addicts, ages 25,28, and 37, previously stabilized on 80 mg/day methadone for two to six years, weretaking 100 mg LAAM three times a week asvolunteers in an experiment comparing LAAMto methadone and were asked to provide sam-ples of blood and urine.

RESULTS

Plasma Levels

Plasma levels of both metabolites wereestablished soon after dosing. During thefirst day, the levels of NAM were higherthan those of NNAM. As time went on, NAMlevels declined steadily while NNAM levelsremained at peak levels (50-75 ng/ml) up tothe time of the second dose. NHAM levelswere higher after a repeat dose of LAAM thanafter the initial dose (100-300 ng/ml). NAMlevels varied in all three subjects.

Urine Levels

Less unmetabolized LAM was excreted than NAMor NNAM. Excretion levels of all three weremuch greater (six to eight times greater)after repeat dose than after the initialdose. This is felt to be due to LAAM, NAM,and NNAM becoming tissue bound easily andnot being excreted until subsequent doseshave saturated the abilitv of the tissuesto bind amines, at which point the rate ofexcretion will increase.

Adverse Reactions

The three subjects varied in the side effectsthey experienced.

One subject reported only mild excessivesweating and constipation during the firstweek. He had higher plasma and urinelevels of NAM and NNAM than the other twosubjects.

The second subject had difficulty withamphetamine-like stimulation, anxiety,sweating, and goose flesh for six weeks.

The third subject evidenced dysphoria,irritability, muscle weakness, tremors,and paranoia which decreased during thefirst four weeks. He asked to be switch-ed back to methadone at the seventh weekbecause of discomfort. Significantplasma levels of NAM and NHAM were stillpresent seven days after his last doseof LAM.

54

21-ALPHA-ACETYLMETHADOL IN THE TREATMENT EXPERIMENTAL DESIGN

OF OPIATE ADDICTION: PROGRESS REPORT, Subjects

1971 Seventy-four patients were started on LAAM.They were told it was an experimental drug,that they might return to methadone if theywished, and there would be a transitionalperiod during which dosages would beadjusted.

P.H. BLACHLY

INTRODUCTION

Jaffe et al. (1970), demonstrated that dlalpha-acetylmethadol could be substitutedfor methadone and that it suppressed absti-nence symptoms for 72-96 hours confirmingthe earlier findings of Fraser and Isbell(1952). In an unreported pilot study bythis investigator using higher doses (mean106 mg), dl-alpha-acetylmethadol producedoversedation and gradually increasing tox-icity. Further studies have been limitedto the levo isomer which has two featuresof interest:

It is more effective orally thanparentera11y.

It is not psychologically addictive.

Methodology

Induction--Conversion from methadone wasinitially one-sixth the usual dose ofmethadone but was revised to doses ofLAAM equal to the regular methadone dose.

Dose Levels--The mean dose was 89.1 mg(range 25-140 mg).

Frequency Of Administration--Six patientsreceived their dose of LAAM every 24hours; 18 received theirs every 48 hours.

RESULTS

Dropout Rate

Of the 23 patients started on doses of LAAMequal to one-sixth their methadone dose,all but one returned to methadone within aweek because of withdrawal symptoms.

Of the 51 patients induced on LAAM in doselevels equal to their methadone dose, 24continued on LAAM.

The mean number of days on LAAM of those whoprefer it is 132 (range 18-300).

Reasons For Preference Of LAAM

The following reasons were given for pre-ferring LAAM by the number of personsindicated:

55

Methadone did not hold them (19)LAAM is cheaper (4)They nodded too much on methadone (3)LAAM is more convenient (2)They are more emotionally level (3)Sex life is improved (1)

Reasons For Discontinuing LAAM

The following reasons were given for return-ing to methadone by the number of personsindicated:

Somnolence and agitation (2)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 reasonsfor wanting to return to methadone

Toxicity

There were four cases of toxicity to LAAM,all occurring in patients for whom high dosemethadone would not prevent abstinencecraving for a full 24 hours; all were re-ceiving daily doses of LAAM in excess of100 mg. In all cases toxicity developedbetween the 8th and 14th day.

Female patient switched to 180 mg LAAM dailydeveloped panic and “seizures” on the 14thday which disappeared when dose was loweredto 110 mg every 48 hours; she also was aRitalin addict. EEG was normal.

Female patient switched to 110 mg of LAAMevery 24 hours experienced episodes of de-personalization and loss of contact withenvironment on the 9th day. She lost con-sciousness, suffered cardiac arrest, andshowed EEG abnormalities; she had been aDoriden abuser with withdrawal seizures inthe past.

Male patient started on 200 mg LAAM every24 hours from 235 mg methadone. Dose was notholding him and was raised to 220 mg. Onthe 8th day he complained of feeling asthough he were going to have a fit and wasreturned to methadone.

Male patient increased from 85 to 120 mgLAAM had an undocumented "seizure" but didnot lose consciousness. Symptoms disappear-ed when dose was lowered below 100 mg.

A fifth patient had a manic attack duringwithdrawal from LAAM (at 35 mg from pre-vious stabilization dose of 55 mg). Hewas placed on regular dose of methadone,treated with lithium and thorazine. In afew days when the manic attack disappearedhe returned to LAAM, and accomplishedwithdrawal without further difficulty whileon lithium.

56

31-ALPHA-ACETYLMETHADOL (LAM):

COMPARISON OF LABORATORY FINDINGS,

ELECTROENCEPHALOGRAMS, AND CORNELL

MEDICAL INDEX OF PATIENTS STABILIZED

ON LAM WITH THOSE ON METHADONE. 1972

P.H. BLACHLY, N.A. DAVID, SAMUEL IRWIN

INTRODUCTION

LAAM, an effective alternative to methadone(Jaffe et al., 1970; Jaffe and Senay, 1971),has several advantages over methadone:

Suppression of abstinence syndrome twotimes longer than methadone (Fraser andIsbell, 1952)

"Smoother" action

Less “nodding”

Oral effectiveness

Less subjective euphoria

Several disadvantages are:

Amphetamine-like effect and dysphoria insome patients

Occasional complaints of feeling less"mellow"

Occasional complaints of abdominal cramps

This paper reports on clinical laboratorystudies in patients maintained on LAAM com-pared to those on methadone.

EXPERIMENTAL DESIGN

Subjects

Twenty--one patients were matched to 19methadone patients on age, sex, race andyears of opiate use.

Methadone--Mean age 31.4, seven females,two blacks, mean 10 years opiate use, mean17 months on methadone program, mea” dose95 mg (range 35-190 mg)

LAAM--Mean age 32.2, seven females, oneblack, one oriental, mean 10 years opiateuse, mean 15 months in methadone program,mean 7 months on LAAM, mean dose 75 mg(range 60-100)

Methodology

LAAM dosages were adjusted to patient's pre-ference.

Seven patients consumed their doses at24-hour intervals because it would not"hold" them 48 hours.

Fourteen consumed theirs at 48-hourintervals.

Blood and urine samples were collected inthe fasting state and before administrationof regular dose of LAAM and methadone. Bloodanalysis was by SMA 12 and SMA 6 screen andautomated reagin tests.

Eight channel EEG's were obtained at one orsix hours after drug administration by a"blind" experimenter.

RESULTS

The results are as follows:

Urine And Blood Values

The only statistically significant finding(p <.025) for LAAM patients is hyperglycemia.Mean blood glucose was 117 percent for LAAMpatients, 103 percent for methadone patientswhere 110 percent is given as the upper limitof normal.

EEG

Fifty-three percent of all patients had EEGabnormalities: 63 percent of those onmethadone and 38.5 percent of those on LAAM.The difference was not statistically sig-nificant.

Cornell Medical Index

Those patients with normal EEG's differedsignificantly (p <.001) from those withabnormal EEG's on their total CornellMedical Index score. The mean score forthose with normal EEG's was 35.0, forabnormal EEG's, 69.3.

57

4ACTIONS AND ADDICTION LIABILITIES OF

ALPHA-ACETYLMETHADOLS IN MAN 1952

Subjects in the single-dose studies were"post-addicts," previously addicted tomorphine but withdrawn and no longertolerant.

H.F. FRASER AND HARRIS ISBELL

INTRODUCTION

The pharmacology and analgesic effects of theacetylmethadols have been studied in animals(Chen, 1948; Specter, Byrd, Cheney andBinkley, 1949; Eddy, Touchberry andLieberman, 1950; Eddy, May and Mosettig,1952); this paper reports on some of theactions and addiction liabilities of dl-, d-,and 1-alpha-acetylmethadol in man. Thefindings with respect to l-alpha-acetylmeth-adol will be of primary interest in thissummary.

EXPERIMENTAL DESIGN

Subjects

Subjects were adult white male volunteers.

Subjects in the abstinence-alleviationstudies were addicted to morphine at thetime of the study.

Methodology

Single-Dose Studies (Post-Addict)--l-alpha-acetylmethadol was administered:

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 beforeand at intervals after oral, subcutaneous,and intravenous administration of 30 mgm1-alpha-acetylmethadol.

Subcutaneous (15 mgm) doses were admin-istered twice daily for several days tosix patients.

Relief Of Abstinence From Morphine--1-alpha-acetylmethadol was administered tocurrently addicted subjects:

Subcutaneously (30 mgm) at the 28th and36th hour of abstinence to two subjects

Orally (30-60 mgm) at the 28th hour ofabstinence to three subjects

Substitution Of 1-Alpha-Acetylmethadol ForMorphine--Seventeen addicts received oralor subcutaneous doses of l-alpha-acetyl-methadol; the administration of morphine

58

was then discontinued. Ten subjects whoreceived the drug orally remained on itfor fourteen days; the five who receivedit subcutaneously and two who receivedit orally returned to morphine after twodays on the drug.

The 10 orally dosed subjects were with-drawn abruptly from the drug. Fouradditional subjects were withdrawn grad-ually over five to seven days.

Prolonged Suppression Of Abstinence By1-Alpha-Acetylmethadol--Five addictedsubjects received 40 mgm orally on adaily basis for 10 days after which thedosage was increased to 60 mgm and theinterval was lengthened to 48 hours fora week, 72 hours-for two weeks, and 96hours for two weeks.

RESULTS

Single Dose Studies

Single doses of 1-alpha-acetylmethadol pro-duced the following results:

Symptoms of euphoria did not developuntil 4-6 hours after subcutaneousadministration and persisted 48 andsometimes 72 hours.

Intravenous administration of the drugproduced results similar to subcutaneousadministration.

Following oral administration, morphine-like effects were observed within oneand one-half hours and persisted 24 andsometimes 72 hours.

Pupillary constriction following oral admin-istration was observed in two hours, peakedin four hours, and disappeared in 24 hours.The onset of pupillary constriction wasslower and less intense following subcutane-ous or intravenous administration but per-sisted for 48 hours.

Repeated doses of 1-alpha-acetylmethadolresulted in the development of cumulativetoxic effects which were depression,approaching coma; respiratory depression;severe nausea and vomiting; mental confusion.

Relief Of Abstinence From Morphine

Subcutaneous administration 1-alpha-acetyl-methadol had inconsistent effects withrespect to abstinence relief.

Oral administration of the drug abolishedall signs of abstinence.

Substitution Of 1-Alpha-Acetylmethadol ForMorphine

1-alpha-acetylmethadol was substituted formorphine effectively at a ratio of 1 mgm toeach 6-8 mgm of the subject’s usual dose ofmorphine.

Abrupt withdrawal from 1-alpha-acetylmetha-do1 produced an abstinence syndrome whichwas mild and similar to that from methadone.Gradual withdrawal from the drug produce anabstinence syndrome that did not differ incourse and intensity from that observed afterabrupt withdrawal.

Prolonged Suppression Of Abstinence By1-Alpha-Acetylmethadol

Sixty mgm oral doses of 1-alpha-acetylmetha-do1 successfully prevented development ofsignificant withdrawal symptoms for 72 hoursin subjects stabilized on 240 mgm morphinedaily.

59

5USE OF MIOTIC EFFECT IN EVALUATING

ANALGESIC DRUGS IN MAN 1954

Methodology

Predrug measures and observations providedbaseline data; each individual served as hisown control. An individual was studied onplacebo and four to ten analgesics (one perweek) and observed at intervals up to 72hours.

The following observations were made:

Pulse and respiratory ratesBlood pressuresTemperaturePupillary sizeRespiratory minute volumeBehavioral changes ("euphoria")Adverse side reactions

RESULTS

Route Of Administration

1-alpha-acetylmethadol induced effects morerapidly 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-acetylmethadollasted as long as 72 hours.

INTRODUCTION

The purpose of this report is to show theextent to which miotic effects of opiate-like drugs correlate with analgesic effects,side effects, and addiction liability as anaid to clinical evaluation of these drugs.Only the results with respect to l-alpha-acetylmethadol will be summarized here.

EXPERIMENTAL DESIGN

Subjects

Former opiate addicts were used as subjects;they were hospitalized and observed under“basal” conditions. Eight to ten men wereused in each experiment.

Correlation Of Miosis With Fuphoria

The time-course of morphine-like "euphoria"relates to miotic measurements. l-alpha-acetylmethadol administered orally producedan earlier and more intense euphoria whichdiminished more rapidly than that producedby subcutaneous administration.

Correlation Of Miosis With Relief OfAbstinence Syndrome

1-alpha-acetylmethadol produced a long-lasting papillary constriction whichcorrelates with the delay of abstinencesymptoms until three days after withdrawal.

Correlation Of Miosis With Toxic Effects

The curves of miotic effect indicate thattoxic effects would persist for long periodsand too short an interval between doseswould result in cumulative toxicity.

Correlation Of Miosis With Relief From Pain

Pupillay miosis does not correlate wellwith analgesic properties. 1-alpha-acetylmethadol is a potent pupillary con-strictor hut a poor analgesic.

60

6

LAAM AND LAAM METABOLITES: PLASMA

LEVELS IN PATIENTS.

SUMMARY PROGRESS REPORT. 1975

AVRAM GOLDSTEIN

EXPERIMENTAL DESIGN

Plasma levels were determined on 14 patientsbeing maintained on LAAM. In a few of thesepatients, it was possible to obtain blood at24, 48, and 72 hours after a LAAM dose. Inmost patients, a blood sample could only beobtained at one or two occasions.

Determinations were carried out by GLC, usinga modification of the customary method fordetermining methadone levels in plasma. TheLAAM and its two N-demethylated metabolites--norxetylmethadol (NAM) and dinoracetylmetha-do1 (NNAM)--were identified by retention timeon the column, as verified by standardsobtained from Eli Lilly Co. Quantitation ismost accurate for LAAM, less so for NAM andNNAM, because of their broader peak shapes.Peak areas rather than heights were used forthis reason.

RESULTS

Plasma Levels

As with methadone plasma levels, the LAAMplasma levels at any given LAAM dosage areextremely variable from patient to patient;at 24 hours, for example, the levels rangedfrom 15 to 170 ng/ml. The same is true ofthe metabolites, which are considered to bethe active compounds pharmacologically. At72 hours, NNAM levels varied from undetect-able (<30 ng/ml) to 278 ng/ml).

Time Course Of Plasma Levels And Drug Effects

LAAM itself was virtually absent from plasma72 hours after a dose, but the dose seemedto "hold" quite well over that period. Thisis consistent with the view that the metabo-lites are primarily responsible for the LAAMeffect, and also with the plasma levels ofthe metabolites, which were approximately ashigh as 72 hours as at 48 hours, and higherthan at 24 hours.

63

7CAN THE COMMUNITY BE PROTECTED AGAINST EXPERIMENTAL DESIGN

THE HAZARDS OF TAKE-HOME METHADONE? Subjects

1974 Patients were randomly assigned to one offive groups of 20 patients each. Femaleswere subsequently excluded, hence, groupshad fewer than 20 patients.

Methodology

AVRAM GOLDSTEIN AND BARBARA JUDSON

INTRODUCTION

It is desirable to have methadone patientsconsume all medication under observationto eliminate:

Accidental poisonings

Diversion of methadone as a drug of abuse

Adversary nature of routine urine checks

However, seven day a week clinic attendanceis a demand which may interfere with employ-ment . LAAM is a long-acting substitute formethadone which has shown clinical promise(Jaffe et al., 1972; Zaks et al., 1972;Senay et al., 1973). This report covers thefirst three months of a clinical trial ofLAAM.

Control Groups--Three groups (M-l, M-2,M-3) were stabilized on 50 mg of methadonedaily and maintained at that level.

Experimental Groups--LAAM subjects werestarted on 30 mg LAAM and increased by10 mg increments to 75 mg LAAM three timesa week.

One group (L) was "open" and had knowl-edge that they were on LAAM; they cameto clinic only Mondays, Wednesdays, andFridays.

The other group (L-P) was "blind", cameto clinic six days a week but receivedquinine placebo on Tuesdays, Thursdays,Saturdays, and Sundays. Take-homeprivileges were given on Sundays andother placebo days. (Comments bypatients about taste differences haveraised doubts in the minds of theinvestigator about the validity of the“blind” nature of the experiment.)

An additional experiment was carried outto determine whether Monday morningsickness was psychological or phannaco-logical. The Friday LAAM dose wasincreased from 75 mg to 100 mg on threealternate Fridays for both LAAM groupson a "blind" basis.

62

Criteria For Effectiveness--The groupswere compared on the following criteriaof effectiveness:

Weekly urinalysis for opiates, bar-biturates and amphetamines

Dropout rates (after a two-weekstabilization phase)

Attendance records

Suspensions for absences

Jailing

Monday morning questionnaire concerningwithdrawal symptoms (“feeling sick”)experienced on Sunday morning, Sundayevening, and Monday morning

RESULTS

The results for all five groups at threemonths are reproduced in the followingtable.

Dropout Rates

During the stabilization phase, dropoutswere as follows:

M-1, (0)M-2, (0)M-3, (2)L , (3)L-P, (1)

Survivorship was slightly lower in the LAAMgroups but not significantly so.

Attendance Records, Suspensions, AndJailings

Differences among groups in these dimensionswere variable with neither LAAN nor metha-done groups favored.

Urine Testing

Three-quarters of all patients discontinuedheroin use by week 13, and at week 13, noconsistent difference is evident betweenLAAM and methadone groups (see table, pre-ceding this page). A running average ofincidence of clean urines for opiates forthe entire quarter was computed whichshowed both LAAM groups to be superior tothe methadone groups.

"Feeling Sick"

Methadone groups had large differencesinitially in percentage of patients withcomplaints; the differences tended to de-crease toward the end of the quarter.

The "open" LAAM group (L) showed an increasein percentage of patients with complaintsfrom Sunday morning through Sunday eveningto Monday morning. The "blind" LAAM group(L-P), however, did not show an increasein percent feeling sick between Sundaymorning and Monday morning.

Increasing the Friday dose has inconsistenteffects in reducing the percent of complaintsin the LAAM groups. Complaints may be morepsychological than pharmacological in origin.

Adverse Experiences

During induction to LAAM when tolerance wasnot established, delayed sedative actions ofLAAM were noted (four to six hours). Aproblem of additive toxicity could developif a patient were to take another drug inthis interval on the assumption that the LAAMdose was not effective.

63

8PHARMACODYNAMICS OF LAAM IN MAN: PLASMA

LEVELS OF LAAM AND ITS METABOLITES

FOLLOWING ACUTE AND CHRONIC ADMINISTRA-

TION IN MAN

(FOURTH AND SIXTH QUARTER PROGRESS

REPORTS). 1974-75

GARY L. HENDERSON

Day 3

INTRODUCTION

The purpose of this study was to investigatethe pharmacokinetics of LAAM in man.

EXPERIMENTAL DESIGN

Subjects

Five male patients maintained on methadonefor at least 90 days comprised Group 1.Addicts with no previous experience withmethadone comprised Group 2.

Methodology

Day 1, Group 1

Patients were hospitalized. A symptomchecklist was completed, blood and urinewere collected, and temperature, pulse,

respiration, blood pressure, and pupil sizewere recorded prior to administration ofdaily dose of methadone. Group 2 patientswere started directly on 20 mg LAAM. Bloodand urine were collected at six intervalsafter administration of methadone or LAAM.The following laboratory tests were done:CBC, urinalysis, SGOT, alkaline phosphatase,bilirubin, BUN, blood sugar, LDH, HAA, VDRL,and chest X-ray.

Day 2

A blood sample was taken 24 hours afterhospitalization just prior to administrationof 60 mg LAAM (1.2 times the usual methadonedose). Urine and blood were collected andthe symptom checklist completed at six inter-vals on Day 2 and every 12 hours afterwarduntil discharge from the hospital.

Patients were discharged after final bloodand urine sampling and the second dose ofLAAM Weekly blood and urine samples werecollected on an outpatient basis. Groups1 and 2 received LAAM every three days for90 days at which point they were rehospital-ized, and laboratory and physical examina-tions were repeated.

Urinalysis

Urine was analyzed for pH, protein, glucose,ketones, bilirubin, and blood. Drug con-centrations were calculated, and recoverystudies for drug and metabolites were con-ducted at the beginning and end of theexperiment.

Plasma

Plasma was analyzed by standard GLC proce-dures

64

RESULTS

Urine (Group 1)

Urine excretion patterns for LAAM and N-LAAM(noracetylmethadol) did not vary much amongpatients. Less than 2 percent of the drugdose was excreted as LAAM and N-LAAM at theend of the 72 hours.

Plasma

Group 1--Peak plasma levels of LAAM andits metabolites following acute admin-istration were:

LAAM, 135 ng/ml at 6 hours

N-LAAM, 50 ng/ml at 2-6 hours

DN-LAAM (dinoracetylmethadol), 20 ng/mlat 2-48 or more hours

Plasma levels of LAAM decreased rapidlyafter 12 hours; N-LAAM and DN-LAAMlevels remained fairly constant overa 48-hour period.

Plasma kinetics of methadone appeared tobe altered by subsequent administrationof LAAM; a slight increase in methadoneplasma levels occurred 4-12 hours afterLAAM administration.

Three patients completed 90 days on LAAM.After 90 days on LAAM, the LAAM plasmalevels were only slightly higher thanafter the acute dose, but N-LAAM andDN-LAAM levels were 5-10 times higherthan after the acute dose. The levelsof DN-LAAM were highest followed byN-LAAM and LAAM. LAAM and N-LAAM de-creased with time, while DN-LAAM levelsremained at a constant high level for72 hours.

N-MOL (normethadol) could not be detectedin plasma after the first or the last doseof LAAM.

Group-2--After the initial dose of 20 mgLAAM, plasma levels of the drug were toolow to quantitate. After 90 days (dose,85 mg), the peak LAAM plasma levels werereached two and four hours after the lastdose of LAAM, but the concentration wasthe same as that of Group 1.

65

9THE BEHAVIORAL, COGNITIVE, AND

PHYSIOLOGIC EFFECTS OF LONG-TERM

METHADONE AND METHADYL TREATMENT

1973

SAMUEL IRWIN, PAUL H. BLACHLY, JOHN MARKS,

ELAINE CARLSON, JAMES LOEWEN, NANCY READE

INTRODUCTION

1-alpha-acetylmethadol (LAAM) has beenshown to be an effective, longer-actingsubstitute for methadone in maintenancetherapy (Chen, 1948; Fraser and Isbell, 1952;Jaffe et al., 1970; Jaffe and Senay, 1971).The purpose of this study was to establishthe basic data on the pharmacology, potentialtoxicity, and comparative safety of methadoneand LAAM. The study will last 16 months;this report is based on 8 months’ data.

EXPERIMENTAL DESIGN

Subjects

Subjects were 54 male and 31 female heroinaddicts and 15 male and 9 female nonaddictedcontrols of similar socioeconomic status.

Methodology

Dosages--Three treatment groups wereestablished.

Daily methadone (mean stabilizationdose, 50 mg; range 25-115 mg)

Daily LAAM (mean stabilization dose55 mg; range 30-90 mg)

Forty-eight hour LAAM (mean stabiliza-tion dose 57 mg; range 20-80 mg)

Assessments--Subjects were assessed justprior to receiving medication and atfour hours afterward (time of peak drugaction) 11-14 days after entry with theprogram (0 time) and at l-, 2-, 4-, 8-,and 16-month intervals by EEG, blood andurine analysis, Irwin Comprehensive HumanAssessment Procedure, Subjective StateQuestionnaire, Adverse Symptom Checklist,Special Performance tests, social adjust-ment questionnaire, and oral interview.Urine was monitored weekly for thepresence of illicit drugs.

RESULTS

Dropouts

Dropouts occurred most in the first twomonths of treatment and were disproportion-ately males, fairly equally divided betweenthe races and much higher with LAAM (42 per-cent) than methadone (23 percent) or controls29 percent).

The 16 LAAM patients who dropped out weredistributed as follows:

Non-LAAM related hospitalization, (3)Imprisonment, (4)Switch to methadone, (6)Withdrawal by request, (1)Disappeared from study, (2)

66

The 11 methadone patients who dropped outwere distributed as follows:

Nonmethadone related hospitalization, (1)Imprisonment, (2)Withddrawal by request, (2)Suicide, (1)Disappeared from study, (2)

The dropout rate was higher among thosereceiving 24-hour LAAM than among thosereceiving 48-hour LAAM.

Dose Level Changes

Mean daily methadone doses were 50 mg(range 25-115 mg) after stabilization andhad increased to 90 mg (range 50-170 mg) ateight months.

Mean daily LAAM doses were 55 mg (range 30-90 mg) after stabilization and increased to63 mg (range 35-90) at eight months.

Mean 48-hour LAAM doses were 57 mg (range20-80 mg) after stabilization and decreasedto 56 mg (10-100 mg) at eight months.

Blood Chemistry Abnormalities

Subjects had a high incidence of abnormal-ities consisting of lowered T-3 and elevatedSGOT determinations upon entry into thestudy. The incidence of abnomality wassustained over time for methadone patientsbut decreased to almost normal values forLAAM patients by the eighth month.

EEG Abnormalities

There was an increased incidence of EEGabnormalities over time for all treatmentgroups, characterized primarily by diffuseor focal slowing.

The incidence of abnormalities for 48-hourLAAM patients was not statistically signif-icant and changed from 31 percent at 0 timeto 29 percent at four months to 40 percentat eight months.

The increase in abnormalities for methadonepatients was significant (p<0.01) and changedfrom 43 percent at 0 time to 41 percent atfour months to 53 percent at eight months.

The incidence of EEG abnormalities for 24-hour LAAM patients was statistically signif-icant (p<0.01) and illustrated the cumulativeeffects of chronic administration. The in-cidence of abnormalities was 34 percent at0 time, 75 percent at four months, and 100percent at eight months.

Cognitive Performance Testing

Data analysis thus far has revealed little orno depressant effects or neurologic impair-ment. There was slightly less overallimpairment of cognitive performance andfunctioning with LAAM than with methadone.Overall data, however, show very littlealteration of cognitive performance witheither drug and levels of cognitive per-formance do not seem to be affected by theincreased incidence of EEG abnormalities.

Subjective State

LAAM patients indicated they felt a slightlygreater intensity of drug effects than didmethadone patients, and tolerance to drugeffects did not develop during the study.Both drug treatment groups demonstratedimproved affect relative to controls; theChange was greater for methadone than forLAAM patients hut not significantly so.

Social Adjustment

No major changes were seen in areas of socialadjustment and only minor differences wereevident between the two groups.

Conformity to law and work adjustment wereincreased for both treatment groups; andsexual performance, and illegal activitiesand earnings diminished. A slight but sig-nificant decrease in marihuana use wasreported by LAAM patients.

Illicit Drug Use

There were no significant differences in theincidence of use of illicit narcotic andnon-narcotic drugs between treatment groups.

Side Effects

Most frequent complaints for both drugswere loss of sexual desire, constipation,drowsiness, loss of energy, headache, in-creased or decreased appetite, and nausea.There were no significant differencesbetweem treatment groups in either the natureof complaints or mean number of complaints.

67

10

PRELIMINARY OBSERVATIONS WITH ACUTE EXPERIMENTAL DESIGN

AND CHRONIC METHADONE AND 1-ALPHA- Time-Course Of Action

ACETYLMETHADOL ADMINISTRATION Five nonaddicted male subjects received .2mg/kg oral doses of LAAM and methadone in across-over study with one week between tests.The Irwin Comprehensive Human Assessmentprocedure was used to quantify the time-course of action and effects of the drugs

IN HUMANS

SAMUEL IRWIN, PAUL BLACHLY, JOHN MARKS

C.CONRAD CARTER

INTRODUCTION

This paper reports the results of studies todetermine:

Peak time effects for LAAM and methadoneover 10 hours

Development of cross-tolerance to mor-phine in LAAM-treated subjects

Possible adverse effects of LAAM andmethadone on:

EEGBlood chemistryHematologyThyroid functionUrinary functionCognitive performance

on the psychosocial, physiologic, and cog-nitive state of the subjects.

Cross-Tolerance Of LAAM-Treated Subjects ToIntravenous Morphine

Nine subjects maintained on LAAM were testedfor cross-tolerance to 30 mg morphine sul-fate, administered intravenously 3-54 hoursafter their LAAM dose. They were assessedfor cross-tolerance with the procedure ofDole et al. (1966).

Clinical Laboratory Studies

Twenty methadone maintenance subjects (meandose 93.5 mg, range 35-190 mg) were matchedby age, sex, race, and years of opiate usewith 21 LAAM maintenance subjects (mean dose79.6 mg, range 12-140 mg). LAAM subjectswere on methadone therapy an average of 13.9months followed by an average of 8 months onLAAM. Methadone subjects were on methadonean average of 17.9 months.

They were assessed for electroencephalo-graphic findings, blood chemistry, thyroidand urinary function, and cognitive perform-ance.

RESULTS

Time Course Of Action

Peak effects with LAAM and methadone occurredfour hours post-treatment and durations ofaction were similar with subjects reporting

68

an earlier peak and greater intensity andduration of effects with LAAM than withmethadone. The only significant differenceswere greater reduction of wakefulness andattentiveness, and a higher incidence ofnausea and vomiting with LAAM than withmethadone.

The duration of action of LAAM was not sig-nificantly longer for LAAM than methadone.

Cross-Tolerance Of LAAM-Treated Subjects ToIntravenous Morphine

Subjects experienced a slight rush and coulddistinguish morphine from placebo. Aslight "high" was reported, usually soon(3-8 hours) or long (52-54 hours) aftertreatment with LAAM. Responses were notcompletely dose related and LAAM was notinvariably effective in suppressing theeffects of morphine.

Clinical Laboratory Studies

Electroencephalograph Findings--Sixty-five percent of methadone and 33 percentof LAAM subjects had abnormal EEGfindings (p < .10, two-tailed test), con-sisting of diffuse slowing (usually intemporal and occipital regions), lowlevel of paroxysmal activity and bursts.

All methadone subjects with high CornellMedical Index scores on admission hadsignificant EEG abnormalities (8/8);none of the LAAM subjects with highC.M. I. scores did (0/5).

The increase in slow wave activity whichusually follows hyperventilation wassuppressed in both groups with only 19-29percent showing the expected response.

The "driving" of the EEG which generallyoccurs with photic stimulation was like-wise suppressed in LAAM and methadonesubjects occurring in only 35 percentand 5 percent.

Hyperglycemic Response--Both drugs pro-duced a significant hyperglycemicresponse; the difference between meanblood glucose levels for methadone (103mg percent) and LAAM (117 mg percent) wassignificant (p.<0.05). There was also asignificant difference (p.<0.05) betweenthe number of subjects with abnormallyhigh blood glucose levels with LAAM (14)and with methadone (5).

Liver Function Abnormalities--The SGOT,albumin, and alkaline phosphatase deter-minations in both groups showed a higherincidence of abnormalities, suggestingslight impairment in liver function.

Hematology--Abnormally high white bloodcounts occurred in 35 percent of metha-done and 29 percent of LAAM subjects.

Thyroid Function And Urine Analysis--Nosignificant abnormalities were found inthese areas.

Effects On Cognitive Performance

LAAM maintenance subjects' performance oncognitive tasks was significantly betterthan methadone maintenance subjects’ ontests involving memory, learning, speed, andaccuracy, and did not differ significantlyfrom the past performance of a control groupof college students.

69

11ACUTE TIME-DOSE-RESPONSE EFFECTS OF

CYCLAZOCINE, METHADONE, AND METHADYL

IN MAN. 1973

SAMUEL IRWIN, ROBERTA G. KINOHI,

PAUL M. COOLER, DOUGLAS R. BOTTOMLY

INTRODUCTION

This study proposed to investigate the acutetime-dose-response effects of cyclazocine,methadone, and 1-alpha-acetylmethadol withrespect to psychosocial, cognitive, andphysiologic functions. The profiles anddurations of action were of particular inter-est, as were the nature of the differencesbetween the three drugs. The investigationsand findings with respect to cyclazocinewill not he reported in this summary.

EXPERIMENTAL DESIGN

Subjects

Twenty-eight male, nonaddicted volunteers21-35 years of age were paid to participatein the experiment and were screened formental and physical health.

Methodology

Subjects received two doses of drug orallyat least one week apart on a randomized,coded, double-blind basis. Fourteen sub-jects received placebo. Seven subjects wereused per dose level of drug. Dosages were.l and .2 mg/kg methadone hydrochloride and0.8 and .16 mg/kg l-alpha-acetylmethadol.

Trained observers assessed the subjects on ascale of 0.8 at -60, 20, 80, 160, 220, and280 minutes before and after treatment usingthe Irwin Comprehensive human AssessmentProcedures. A subjective state question-naire (SSQ) and adverse symptom checklist(ASC) were completed by the subject at 12and 24 hours posttreatment. A variety ofspecial performance tests were also used.Placebo effects were subtracted from thescores in reporting data.

RESULTS

Peak, Duration, And Intensity

Peak time effects for all drugs testedoccurred about three hours posttreatment.

The duration of effects with the high doseof 1-alpha-acetylmethadol was over 24 hours;for methadone it was 12 hours or less.

With respect to the intensity of drugeffects, the higher dose of 1-alpha-acetyl-methadol produces effects similar to hutsomewhat less in intensity than the lowerdose of methadone.

The two modes of assessment, observer ratingand subject's self-reporting, correlatehighly with each other.

70

Profiles Of Action

All drugs produced biphasic effects, mostoften an early activation, elevation ofmood, and liking for the drug followed by alater depressant effect and dislike for thedrug.

The effects of 1-alpha-acetylmethadol wereprimarily activating and included:

Slightly increased capacity for func-tioning

Increased arousal, drives, energy, speedand durations of movement and expressive-ness

Slightly improved mood and emotions

Methadone, on the other hand was generallydepressant and its effects were:

Impairing arousal, focusing, and psycho-mator activity

Distorted perceptions

Worsened moods and emotions

On several measures, however, 1-alpha-acetyl-methadol produced effects similar to theeffects of methadone in reducing:

Impulse controlMemoryRespiratory ratePupil sizeFacial skin color

and in promoting:

AtaxiaUnusual body sensationsDistorted sensesLight headachesItching

As these effects are characteristic of theeffects of narcotics in general, it wouldseem that methadone and 1-alpha-acetylmetha-dol are similar in potency but differ intheir qualitative effects.

71

12COMPARISON OF ACETYLMETHADOL AND

METHADONE IN THE TREATMENT OF LONG-

Methodology

Study design

TERM HEROIN USERS: A PILOT STUDY. 1970 The study was a double-blind, controlledstudy lasting seven weeks.

JEROME H. JAFFE, CHARLES R. SCHUSTER,

BETH B. SMITH, PAUL H. BUCHLY

Dosages--control groupsINTRODUCTION

dl-alpha-acetylmethadol has been shown toprevent withdrawal symptoms for more than72 hours (Fraser and Isbell, 1952). Itseffectiveness as a substitute for methadonein maintenance treatment of narcotic addictswas the subject of this study.

The control group received their usualdaily dose of methadone hydrochloride.

The average dose was 37 mg/day (range20-55 mg).

Criteria for effectiveness

EXPERIMENTAL DESIGN

Subjects

Urines were checked for illicit opiateuse at each clinic visit (three times/week).

Twentyy-one participants in a methadone The opiate withdrawal subscale of themaintenance clinic stabilized on 20-90 mg Addiction Research Center Inventory (ARCI)of methadone per day served as subjects. and a symptom checklist measuringTwelve were randomly assigned to the experi- intensity of withdrawal were filled outmental group and nine to the control group. three times weekly.

Patients reported to the clinic threedays per week.

Dosages--experimental group

Dosages were computed initially at 1.2times the usual methadone dose andincreased slightly in two cases.

Subjects received dl-alpha-acetylmetha-dol on Mondays, Wednesdays, and Fridays,and placebo (dextromethorphan hydro-bromide added to the usual vehicle) onalternate days.

The average dose of dl-alpha-acetyl-methadol was 50 mg three times weekly(range 24-66 mg).

72

Open-ended interviews were held with thestaff three times weekly.

Baseline measures were obtained for twoweeks before the new drug was introduced.

Intensity of withdrawal from methadoneand dl-alpha-acetylmethadol was studiedby administering placebo in place ofactive medication in six control and sixexperimental patients. This was done onMonday of the seventh week, 48 hoursafter the last dose of methadone, and96 hours after the last dose of dl-alpha-acetylmethadol. All patients were pro-vided with a dose of methadone to takein case of emergency.

RESULTS

Dropout Rate

Four patients in the experimental groupdropped out on the first day complaining ofabdominal pain.

There were eight patients in each group atthe end of the study.

Withdrawal Symptom Reports

There were no significant differencesbetween the experimental and control groupson the opiate withdrawal subscale of theARCI and the withdrawal symptoms checklistduring the two week baseline period.

Control group

No change was evidenced from baselinewith a 24-hour interval between doses.

of the six patients who experienced a48-hour interval with placebo, two tooktheir emergency doses of methadone at36 hours and the remaining fourexperienced intense withdrawal distressat 48 hours.

Experimental group

No change was evidenced from baselineat 24- and 48-hour intervals betweendoses.

At 72 hours there was a slight rise inthe opiate withdrawal subscale of theARCI, but no change in the symptomchecklist or during the interview.

At 96 hours there was a marked rise inintensity of withdrawal Symptoms asmeasured by the test and interviews.

Measures Of General Functioning

Urine analysis showed no difference betweenthe two groups in illicit drug use.

The two groups also did not differ withrespect to numbers employed, arrest rate, oradmissions of illegal activity.

Adverse Experiences

Side effects of anxiety and nervousness wereperceived as sufficiently troublesome to 4out of 12 subjects in the experimental groupto cause them to drop out of the study.

73

13

METHADONE AND 1-METHADYL ACETATE: USE EXPERIMENTAL DESIGN

IN MANAGEMENT OF NARCOTIC ADDICTS, 1971 A controlled clinical study was carried outto determine if 1-alpha-acetylmethadol couldbe effectively substituted for methadone onweekends.

JEROME H. JAFFE AND EDWARD C. SENAY

INTRODUCTION

Racemic methadyl acetate (dl-alpha-acetyl-nethadol) has been shown to be effective insuppressing narcotic withdrawal syndromefor periods up to three days (Jaffe, 1970).There are substantial differences betweenthe d- and l-isomers in effectiveness insuppressing the withdrawal syndrome (Fraserand Isbell, 1952). In view of the limitedclinical experience with either isomer, thepurposes of this study were:

To gain further clinical experience with1-alpha-acetylmethadol

To determine if 1-alpha-acetylmethadolcould be used interchangeably withmethadone

Subjects

The subjects were volunteers participatingin a methadone maintenance program, stabil-ized on a 30-100 mg. dose of methadone perday for three weeks prior to the experiment.

Experimental Group--The experimentalgroup consisted of five male patientstaking a mean daily dose of 50 mg. (range,40-60 mg/day) of methadone.

Control Group--The control group con-sisted of five male patients taking amean daily dose of 68 mg (range, 30-100mg/day) of methadone.

Methodology

Study Desire

The groups were studied for threeweekends.

Patients were randomly assigned to drugor control groups; clinical observerswere blind to who was in which group.

The experimental group received 1.2 mgof 1-alpha-acetylmethadol for every 1 mgof methadone in his daily dose (a three-day dose); they were given two 30 mgdoses of dextromethorphan hydrobromideto take home as placebos.

The control group received their usualdose of methadone at the clinic and twodoses of methadone to take at home.

74

Criteria For Effectiveness

Urine was collected and tested for thepresence of narcotics.

Clinical interviews were held onFridays and Mondays.

Symptom checklists were filled out bythe subjects on Fridays and Mondaysprior to receiving their medication.

Clinic attendance was noted.

Requests for increase in medication wasnoted.

RESULTS

The frequency of urine specimens positivefor morphine was the same in both groups(one in each group).

"Blind" experimenters found nothing in thebehavior or reports of subjects to indicatewhich medication they had received.

Patients in both groups complained ofsweating; all had reported problems withsweating prior to the study.

No side effects were reported by eithergroup.

The rates of clinic attendance did notdiffer.

Subjects in both groups complained of theirmedication not holding; the conversionfactor was increased in the experimentalgroup to 1.2 - 1.5 mg (mean 1.3 mg) 1-alpha.acetylmethadol to 1 mg methadone hydrochlo-ride.

75

14

METHADYL ACETATE VS METHADONE: A

DOUBLE-BLIND STUDY IN HEROIN USERS.1972

JEROME H. JAFFE, EDWARD C. SENAY,

CHARLES R. SCHUSTER, PIERRE F. RENAULT,

BETH SMITH, SALVATORE DIMENZA

INTRODUCTION

A pilot study using dl-alpha-acetylmethadol(DLAAM) interchangeably with methadone in amaintenance program (Jaffe et al., 1970),confirmed earlier findings of the abilityof this drug to prevent development of ab-stinence syndrome for 72 hours (Fraser andIsbell, 1952). The purpose of this studywas to gain further experience with the drugin more extensive trials.

EXPERIMENTAL DESIGN

Subjects

Subjects were 66 male heroin addicts, age 20through 50, screened by physical and labora-tory examination.

Methodology

The study was carried out under double-blind conditions and lasted 15 weeks.

Subjects were randomly assigned to one offour groups in the study design.

Experimental group receiving DLAAM threetimes a week and dextromethorphan placeboon alternate days (19 subjects)

Control group receiving methadone daily(15 subjects)

Waiting list detoxified with methadonereceiving no further medication (16subjects)

Treatment group of the patient’s choiceexclusive of the experimental and controlgroups in the study (16 subjects)

Adjustments were made in dosage of medicationby patients' requests to the weekly visitingphysician. The program physician was blindto medications and levels.

All medication was initially taken at theclinic under observation; take-home doses ofmethadone and placebo were later allowed.

Criteria For Effectiveness

The following measures were used to determinethe relative effectiveness of the drugs:

Frequency of illicit drug use as deter-mined by urinalysis

Twice weekly completion of the morphineand opiate withdrawal subscales of theAddition Research Center Inventory (ARCI)and a withdrawal symptom checklist

76

Weekly self-report of illicit drug use,criminal activity, and legitimate employment

Clinic participation defined as keepingclinic appointments and group therapy; adropout was defined as a person who didnot attend for two consecutive weeks andwas discontinued in the study

Adverse Experiences Looked For

The following tests were taken initially andat the end of the study as indicators of thesafety of the drug:

CBCUrinalysisLiver-function testsBUNSerrum uric acid determinations

RESULTS

Data for those subjects in the group assignedto clinics of their choice will not bereported; 12 of 16 of these patients did notreport to clinics assigned to them.

Statistical analysis of data was based uponpatients who completed at least eight weeksof treatment: 15 subjects in the experi-mental and 15 in the control group.

Dropout Rate

Five (26.3 percent) subjects left the DLAAMgroup; two (13.3 percent) left the methadonecontrol group. This difference was notstatistically significant.

The average length of stay for the dropoutswas 5.8 weeks in the experimental group and10 weeks in the control group.

Employment

Both groups evidenced increases in employ-ment. The experimental group had 12 (80percent) employed at the end of the studyand 4 (26.7 percent) employed at the beginning; 10 (66.7 percent) of the methadonecontrol group were employed at the end, 4(26.7 percent) at the beginning. Thesechanges were statistically significant.

Arrests

Decreases were observed in arrest rates forboth groups compared to arrest rates in thetwo years prior, however, the sample sizewas too small for a determination of statis-tical significance either between groups oras a result of treatment.

Illicit Drug Use

Seventy-one and one-tenth percent of thetreatment weeks were characterized by"clean" urines for the control group and 49percent for the experimental group. Thedifference was not statistically significant.

Clinic And Group Therapy Attendance

Clinic attendance was high for both groupsand quite similar (93.3 percent, experi-mental; 91.8 percent, control). Grouptherapy attendance was lower for both groups(60.5 percent, experimental; 61 percent,control) and the difference between them wasnot significant.

Clinical Observations

There were no differences in the subjectivereports of patients; the "blind" physiciancould not distinguish between DLAAM andmethadone groups.

Dose Level Changes

Dosages were 30-80 mg methadone hydrochlo-ride/day and 36-80 mg DLAAM/active dose.All patients requested increases in theinitial two weeks; an equal number fromeach group requested increases thereafter.Most patients required a higher dose ofDLAAM for the 72-hour (Friday to Monday)interval than the 48-hour intervals.

Withdrawal Scales

There was no significant difference betweenthe two groups on any withdrawal scale.

Medical Data And Adverse Experiences

Liver Function--Only seven of the 66patients had normal results on liver-function tests upon initial examination;profiles remained unchanged at the endof the study

Hematology--Most subjects were normalinitially and at the end of the study.

Four reverted to normaltie remained the sameTwo did not return for reevaluation

In one subject, the hematocrit droppedfrom 48 percent to 39 percent but hemo-globin level, RBC, and WBC remainednormal.

White Blood Cell Counts--All were stableexcept in three subjects.

77

In one subject, the initial count was12,800/cu mm and the count at reevalua-tion was 3,400/cu mm; he had beentreated with trifluoperazine hydrochlo-ride prior to reevaluation.

Changes from 8,500 to 4,000/cu mm and7,100 to 41,000 cu mm were observed intwo other patients. No symptoms wereassociated with any of these changes.

VDRL And Fluorescent Treponemal AntibodyTests (FTA)--Thirteen subjects had posi-

tive results for VDRL and FTA testsinitially; these values were unchanged atreevaluation except in one subject whoseresults reverted to negative.

Side Effects--There were few complaintsof side effects and no toxic reactions.Complaints of decreased libido came outin conversations; two patients com-plained of impotence. Jerking andtwitching of arms and legs when at restwas complained of by two subjects.

78

15SIMULTANEOUS DETERMINATION OF ACETYL- quantitation procedures are beyond the

scope of this summary; results will beMETHADOL AND ITS ACTIVE BIOTRANSFORMA- reported.

ROBERT F. KAIKI, NITHIANANDA CHATTERJIE,

CHARLES E. INTURRISI

Summary

The long duration of acetylmethadol (AM)suggests the biotransformation of AM toactive metabolites.

INTRODUCTION

TION PRODUCTS IN HUMAN BIOFLUIDS. 1975 RESULTS

Plasma

Most plasma samples contained AM, NAM, andNNAM in concentrations above 0.020 ug/ml.Concentrations of MOL and NMOL above thiswere not observed in any samples obtained.

Urine

A mean of 20 percent of the administereddose was recovered as AM and biotransfomrma-tion products in total urine collected 48hours after dosing; approximately 2 percentwas recovered as AM, 8 percent as NAM, 5percent as MOL, and 13 percent as NNAM. Thepattern of excretion is the same regardlessof dosage.

Other routes of elimination (the gastroin-testinal tract) and other biotransformationproducts are likely. Biotransformation isa prerequisite for the elimination of AMand N-demethylation is quantitatively moreimportant than deacetylation in the human.

AM, noracetylmethadol (NAM), methadol (MOL)normethadol (NMOL) have been identified inthe urine of AM maintenance subjects (Kaikoand Inturrisi, 1973). Dinoracetylmethadol(NNAM) was identified by Billings (1973) inthe biofluids of rats given AM and has beenfound in plasma and urine of AM maintenancesubjects (Kaiko and Inturrisi, Fed. Proc.,1974).

This report describes a specific and sensi-tive method for quantifying AM, NAM, andNNAM in human plasma and urine. The detailsof the extraction, identification, and

79

16

ROBERT F. KAIKI AND CHARLES INTURRISI

DISPOSITION OF ACETYLMETHADOL IN EXPERIMENTAL DESIGN

RELATION TO PHARMACOLOGICAL ACTIVITY. Subjects

1975 Subjects were 12 adult males; eight weremaintained on a mean dose of 50 mg (range40-60) acetylmethadol three times weeklyfor 4-25 weeks. Four others were inpatients,dosages and history not stated.

Methodology

Plasma--Venous blood samples werecollected just prior to dosing (i.e., 72hours after last dose) and at 4, 8, 24and 48 hours from all patients.

Urine--The eight maintenance subjectsprovided urine specimens at 0, 24 and48 hours after administration of acetyl-methadol; urine was collected at 0, 4,8, 24 and 48 hours from the hospitalizedpatients.

INTRODUCTION

Acetylmethadol has been shown to have a72-hour duration of action (Fraser andIsbell, 1952) which has been attributed tothe biotransformation of acetylmethadol toactive metabolites (McMahon et al., 1965;Sung and Way, 1954; Veatch et al., 1964).Acetylmethadol, noractylmethadol and dinor-acetylmethadol have been identified in humanPlasma (Kaiko et al., in press; Kaiko andInturrisi, 1973; Billings and McMahon, 1974).

Extraction And Estimation--A multistepsolvent extraction procedure (Kaiko et al,in press) was employed; noractylmethadoland dinoracetylmethadol were converted tocorresponding amides and measured asequivalents. Qantitation was achievedby the addition of an internal standard,SKF 525-A, prior to extraction.

Measurement Of Pupil Size--Miotic effectwas calculated by subtracting the sizeof the pupil (determined photograph-ically) at each blood sampling time fromthe baseline (0-hour) size.

This report describes the disposition ofacetylmethadol in maintenance subjects withparticular emphasis on the relationshipbetween the time course of acetylmethadoland its biotransformation products in plasmaand the timeaction of pupillary miosis.

Apparent Half-Life, Renal Clearance AndUrinary pH--Regression analysis programwas used to calculate the apparent half-life for elimination of the compoundsfrom plasma. Renal clearance values were

80

calculated using the average rate ofurinary excretion of each compound forthe four to eight hour collection periodand the corresponding plasma concentra-tion at the midpoint of the collectionperiod (6 hours). Urinary ph was mea-sured with a Metrohm E-512 pH meter.

RESULTS

Time Course, Mean Plasma Levels and MeanPupillary Constriction in the Eight Main-tenance Subjects

Acetylmethadol

None present at 0 hourPeak level 0.060 µg/ml at 4 hoursRapid decline to 0.013 µg/ml at 24 hoursUndetectable at 48 hours

Noracetylmethadol

0.042 ug/ml at 0 hourPeak level 0.114 µg/ml at 4 and 8 hoursSlow decline to 0.068 µg/ml at 48 hours

Dinoracetylmethadol

0.052 µg/ml at 0 hourPeak levels ranged from 0.057-0.123µg/ml at 4 hoursLevels did not decline during sampling

Pupillary Constriction

Pupillary constriction was greatest at8 hours, 1.8 mm.

Return to predose value was slower thanrate of disappearance of acetylmethadolbut faster than rate of disappearanceof noracetylmethadol.

Time-action of miotic effect corres-ponds most closely with noracetylmetha-dol in plasma.

The effect of dinoracetylmethadol couldnot be ascertained since plasma levelsdid not decline.

Apparent Half-Life for elimination ofcompounds from Plasma

Acetylmethadol had an apparent half-life of 7 hours (range 2-12 hours).

Noracetylmethadol had an apparent half-life of 48 hours (range 13-78 hours).

Dinoracetylmethadol levels did notdecline, therefore, no calculation ofhalf-life value was possible.

Renal Clearance and Urinary pH--The sub-ject with the lowest urinary pH exhibitedthe highest renal clearance of all threecompounds; the subject with the highesturinary pH exhibited the lowest renalclearance values.

Correlation Between Plasma Levels andDrug Effect--Miotic effect is moreclosely associated with noracetylmetha-dol plasma levels (p <0.10) than withthe acetylmethadol dose (p <0.10).Spearman's correlation coefficient wasused to determine the relationshipbetween noracetylmethadol plasma levelsand parameters which might influenceits magnitude. High plasma levels ofany one of the compounds tend to beassociated with high levels of theothers.

Noracetylmethadol plasma level is amore reliable correlate of the effectof acetylmethadol than is the acetyl-methadol dose.

Noracetylmethadol plasma level is morea function of other factors relatingto its disposition than the acetyl-methadol dose.

81

17

THE USE OF 1-ALPHA-ACETYL-METHADOL the heroin detoxification program at VitamCenter, Norwalk, Connecticut, served as

(LAAM) AS COMPARED TO METHADONE IN THE subjects.

MAINTENANCE AND DETOXIFICATION OF Methodology

YOUNG HEROIN ADDICTS, 1973 Study Design--The study had two forms:

A double-blind comparison of LAAM andmethadone

WALTER X. LEHMANN

INTRODUCTION

The purposes of the study were to:

Compare LAAM with methadone for effective-ness in a short-term, low-dose mainten-ance program

Determine whether LAAM has potential as amedication of choice for heroin addicts

Compare LAAM with methadone with respectto ease of withdrawal and note any clin-ical problems which might arise

EXPERIMENTAL DESIGN

Subjects

Forty-two male and female heroin addictsbetween the ages of 16 and 21, enrolled in

Fourteen patients received 10 mg dosesof LAAM every 72 hours and placebo onintervening days

Twenty-one patients received methadonedaily in doses sufficient to maintaina comfortable state

An open study in which the drug anddosage were know to the patients

Seven patients received LAAM everythird day

No placebo was given on interveningdays

The duration of the study was 16 weeks afterwhich patients were detoxified; they werefollowed up as long as they remained in theprogram. Withdrawal was accomplished on aninpatient basis by lengthening the intervalbetween doses for a week then stopping thedrug completely.

Criteria For Effectiveness--Patients wereobserved daily with respect to thefollowing:

Physical and emotional reactionPerformance of job functions in thecenterPerformance in group and individualtherapyAtheletic involvement

82

High school and special educationinvolvementCommunity and home involvementToxic reaction

Urines were collected and analyzed threetimes a week during the first two weeks;they were collected three times a week butonly analyzed weekly thereafter.

RESULTS

Physical And Emotional Reactions

There were no differences in the physicalcondition of the three groups. No sideeffects such as nausea, vomiting, constipa-tion, weakness, or fatigue were reported.

Half the patients in the open study com-plained of mild discomfort 60 hours aftermedication which disappeared during thethird week.

Emotional reactions were similar for allpatients with some tension, depression, andhostility noted initially which dissipatedby the third week.

Performance Of Job Functions

There was no difference between groups; per-formance improved in all groups during thethird week.

Performance In Groups And Individual Therapy

There was no difference between grows ineither type of therapy; performance &provedduring the fourth week.

Athletic Involvement

Athletic involvement was the same for allpatients; there was no interference withcoordination or ability to perform.

High School And Special Education Involvement

These activities did not start until the8th and 12th weeks, respectively; thereappeared to be no differences in perform-ance.

Community And Home Improvement

This applied only to those living in; nodifferences were noted between groups andthere was improvement after the fourth week.

Toxic Reactions

No toxic reactions were noted; it was notnecessary to terminate treatment in any cases

Urinalysis

There were no urines positive for nonpre-scribed drugs in either group.

Withdrawal

Withdrawal from LAAM and methadone wasaccomplished with equal ease; no clinicalproblems were manifested during withdrawal

83

18LEVOMETHADYL ACETATE: PROLONGED

DURATION OF OPIOID EFFECTS, INCLUDING

EXPERIMENTAL DESIGN

Subjects

CROSS TOLERANCE TO HEROIN, IN MAN.

1973

Seven male volunteers ranging in age from21-50 years with at least two years ofnarcotic abuse and two previous treatmentfailures were used as subjects. They weredetoxified and drug free at least sevendays before the experiment.

Methodology

ROBERT LEVINE, ARTHUR ZAKS, MAX FINK,

ALFRED M. FREEDMAN

INTRODUCTION

Levomethadyl acetate (LAAM)has been deter-mined to have an onset of action which isdelayed by four to six hours post-adminis-tration and has been demonstrated to havethe ability to prevent the development ofabstinence syndrome in methadone tolerantpatients for 72 hours (Jaffe and Senay, 1971;Zaks et al., 1972), the purpose of this studywas to determine the dosage of LAAM which isrequired to provide blockade to 25 mg ofheroin, to prevent opiate withdrawal symp-toms, and to provide maximal opiate effectfor a minimum of 72 hours.

Oral doses of LAAM were administered threetimes a week beginning with 10 mg andincreasing 10 mg/week until doses of 100 mgwere reached.

Pupillary diameter was measured prior tothe experiment and at 24, 48, and 72 hoursafter the third dose each week. The meanpredrug diameter was 6.7 nun. A symptomchecklist was completed at these timesalso.

Heroin challenge of 25 mg was performed at72 hours following various doses of LAAM.

RESULTS

Adverse Experiences

Three of the seven patients withdrew afterfive weeks. Dose levels of 50 mg had beenobtained by that time.

All patients reported constipation through-out their participation in the study.

Three of the seven patients reported loss ofappetite and abdominal discomforts whichlater disappeared at dose levels greaterthan 40 mg.

84

Abstinence Syndrome

At doses of 20-50 mg, six Out of sevenpatients reported discomfort, yawning, lac-rimation, and uneasiness, occurring 48-72hours post-treatment.

At doses under 70 mg, three out of fourremaining patients reported yawning anduneasiness 60-72 hours post-treatment.Symptoms were milder and of shorter durationthan at lower doses.

At doses greater than 80 mg, there were noreports of discomfort.

Heroin Challenges

One patient refused to receive heroin. Atdose levels of 30 mg LAAM, four patientsreported feeling some effects of heroin, twofelt none. The mean change in pupillarydiameter was 0.8 mm.

At dose levels of 50 mg LAAM, no effect ofheroin was perceived. The mean pupillarydiameter was 0.1 mm greater following theheroin challenges.

At dose levels of 70 and 100 mg LAAM, block-ade was complete.

Sustained Opiate Effects

Twentymg of LAAM produced maximum miosisfor 24 hours.

Doses greater than 20 mg produced no furtherdecrease in pupillary diameter; maximum con-striction was sustained for 48 hours at doselevels of 30-50 mg LAAM and 80-90 mg LAAMsustained a pupillary diameter of 5.0-5.2 mmfor 72 hours.

85

19A METHADONE/1-ALPHA-ACETYLMETHADOL

(LAAM) MAINTENANCE STUDY.

CHARLES SAVAGE, ELAINE KARP, STEPHEN CURRABN

INTRODUCTION

LAAM has had clinical success as a substitutefor methadone (Levine et al., 1973; Jaffe andSenay, 1971; Jaffe et al., 1972). The pur-pose of this study was to validate past clin-ical research, to determine the relativesafety and effectiveness of LAAM and metha-done, and to identify factors associated withtreatment success and failure.

EXPERIMENTAL DESIGN

Subjects

Subjects were 99 male heroin addicts; theywere, on the average, 28 years old with 11thgrade education! seven years narcotic addic-tion, four to five arrests, and two treat-ment failures. Half were employed when theyentered the study.

Prior to treatment the following data werecollected:

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 phos-phatase, and SGOT), hematology (whiteblood 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), WechslerAdult Intelligence Scale (WAIS)

Methodology

Treatment Groups--Assignment to treatmentgroups was random and there were no sig-nificant differences between groups inbackground characteristics, EEG results,blood chemistry and hematology measures,and personality measures. Patients andstaff were blind to the medications.

Group 1, 52 patients, received methadonedaily for three months and then wereswitched to LAAM three times a weekwith dextromethorphan placebo on otherdays.

Group 2, 47 patients started on LAAMand were switched to methadone at threemonths.

Dosages--All Medication was mixed withTang and dextromethorphan. Dosage was

86

flexible. LAAM patients received dosesequal to 1.3 times their usual dose ofmethadone

Assessments--At the end of three and sixmonths, the EEG, physical examination,blood chemistry and hematology tests,and MMPI were repeated.

Urine was checked one to three times aweek for quinine, morphine, amphetamines,and barbiturates.

Clinic attendance and changes in social andoccupational status were monitored through-out the study.

RESULTS

Dropout Rates

Sixty percent of the methadone group(Group 1) completed three months; 31 percentof the LAAM group (Group 2) completed. Thisdifference was significant (X2 5.49, p=0.2).

In the crossover phase of the study, 66 per-cent of the LAAM patients (Group 1) com-pleted the three subsequent months onmethadone; 81 percent of the methadonepatients (Group 2) completed the three sub-sequent months on LAAM. This difference wasnot statistically significant.

With both phases combined, 65 percent of thepatients completed treatment with methadoneand 47 percent with LAAM.

Analysis Of Reasons For termination

Side effects were given as the most frequentreason for withdrawal regardless of whichdrug the patients were on by 31 percent ofLAAN patients and 23 percent of methadonepatients. The difference was not signifi-cant.

The specific symptoms reported were the samefor both medications: experiencing with-drawal or feeling over medicated.

Urinalysis

The mean percentages of urines positive forillicit drugs were 5 and 8 percent for themethadone and LAAM groups, respectively.The difference was not significant.

Clinic Attendance

The mean absentee rates were 2 percent and4 percent for the methadone and LAAM groups,respectively. The difference was not sig-nificant.

Dose levels

There was no difference in the dose levelsof those who completed LAAM treatment andthose who dropped out.

Lower dosage methadone patients dropped outmore frequently than higher dosage patients.

Physiological Assessments

There were no differences between dropoutsand completers in EEG, hematology and bloodchemistry results except for bilirubinwhich was, nonetheless, within normal limitsfor both groups.

Personality

Dropouts differed from completers in severalpersonality characteristics being:

More suspicious and distrustful (MMPI,Pa Scale)

More impulsive (POI Spontaneity Scale)

Less self-accepting (POI, Self-AcceptanceScale)

More grandiose (PEP, Great Cause Scale)

More easily fatigued, more frequentlyfeeling ill, and more incapacitated dueto illness (Cornell Fatigue and Frequencyof Illness Scale)

Safety

No deaths or serious illness occurred inpatients on either drug.

Methadone patients

EEG measures did not differ pre- andpost-treatment

Three hematology measures showed sig-nificant changes, however, all werewithin normal range

Mean value of neutrophiles decreased

Mean values of lumphocytes andbasophiles increased

LAAM patients--there were no differencesin EEG, blood chemistry or hematologymeasures pre- and post-treatment.

87

20A 48-WEEK STUDY OF METHADONE, METHADYLACETATE, AND MINIMAL SERVICES. 1974

EDWARD C. SENAY, JEROME H. JAFFE,

SALVATORE DIMENZA, PIERRE F. RENAULT

INTRODUCTION

dl- and 1-alpha-acetylmethadol have beenshown to be capable of suppressing narcoticwithdrawal symptoms for long periods of time(Fraser and Isbell, 1952). These findingshave been confirmed in pilot comparisons withmethadone (Jaffe et al., 1970; Jaffe andSenay, 1971; Jaffe et al., 1972). This studyreports investigations into the clinicalacceptability and safety of the levo isomer,1-alpha-acetylmethadol, (LAAM), and anevaluation of the role of auxiliary servicesin the treatment of heroin addiction.

EXPERIMENTAL DESIGN

Subjects

The subjects were male narcotic addictsbetween the ages of 20 and 50, randomlyassigned to one of three groups:

Thirty to methadone with full servicesThirty-one to LAAN with full servicesNinety-six to methadone with no otherservices

There were no significant differences in thebackground characteristics of the groupswith respect to race, education, employment,arrests, family stability, and drug useinfluences. The Dispensary group was sig-nificantly younger than the Methadone FullService group but not the LAAM group; theMethadone Full Service group had used heroinlonger than the LAAM group or the Dispensarygroup. The correlation of age with years ofheroin addiction was .81; the difference inage is thought to account for the differencein mean number years of addiction.

Methodology

Study Design--The study was a double-blind, controlled study. The LAAM groupreceived active medication three times aweek and a 30 mg dextromethorphan placeboon alternate days; attendance at grouptherapy sessions was requested weekly, andother counseling, vocational, legal andrecreational services were provided. TheMethadone Full Service group receivedmethadone daily and services as above.The Dispensary group received methadonedaily for four weeks and then three times

88

weekly with take home doses on alternatedays. No counseling or services wereoffered. Dosage modifications were madeduring the study. The mean initial admin-istered doses were 57.8 for the LAAMgroup, 40.6 mg methadone for the MethadoneFull Service group, and 41.3 mg for theDispensary group.

Criteria For Effectiveness--The groupswere compared with respect to the follow-ing variables:

Dropout rateChanges in medication dosagesUse of illicit drugs (as evidenced inbiweekly urine checks)

Employment rateSelf-reports of illegal activity andarrests

RESULTS

Failure Of Research Design With Respect ToDispensary

Inpractice, counseling services, and supportcould not be withheld from the Dispensarypatients by the clinic staff, so the com-parison made by the study was between fulland minimal services rather than between fulland no services as intended.

Methadone with full services appeared to besuperior to LAAM with full services and tomethadone with minimal services.

Dropout Rate

Forty-nine percent of the Dispensary group,50 percent of the LAAM group, and 29 percentof the Methadone Full Service group haddropped out by week 48. There were no sig-nificant differences among treatment groupsin total number of weeks of participation inoriginally assigned group (Dispensary, 30.5weeks; LAAM, 29.7 weeks; Methadone FullService, 35.3 weeks). Methadone with orwithout services had more holding power thanLAAM.

Illicit Drug Use

There was an increase in numbers of urinesnegative for morphine in the Dispensary,and Methadone Full Service groups whether

LAAM,

based on percentages of remaining sample(72.7 percent, 90.9 percent, and 60.0 percent,respectively), or percentages of the totalsample (33.3 percent, 33.3 percent, and 38.7percent, respectively). Differences betweenthe groups were not significant.

Dosage Changes

Dispensary patients requested significantlyfewer changes (p<0.01) than did patients inthe full services groups (Dispensary: 3changes/100 ma” weeks of treatment; LAAM: 7changes/100 man weeks of treatment, Metha-done Full Service: 8 changes/100 weeks oftreatment). The mean LAAM dose at 48 weeks(93.9 mg) was significantly higher than themean dose of the Dispensary group (p<0.01;51.7 mg), or the Methadone Full Servicegroup (p<0.05; 70.9 mg), but total weeklydosage was less than that of patients onmethadone.

Employment Rates

There were no differences in employmentrates among the three treatment groups.

Arrests And Illegal Activity

Self-reported illegal activity decreased inproportion to length of time in treatmentfor all groups. There was no significantdifference among groups in self-reports ofarrests (Dispensary: 2.1 arrests/100 manweeks in treatment; LAAM, 2.3 arrests/100man weeks; Methadone Full Service, 3.0arrests/100 man weeks.

Clinical Observations

There were no observations of confusion,psychotic symptoms, or unpleasant subjectivestates in any subjects. Anxiety was ob-served but was not associated with anytreatment group in particular. Two deathsoccurred, one from suicide and one from lungcancer.

89

21THREE TIMES A WEEK LAAM EQUALS SEVEN

TIMES A WEEK METHADONE: A PRELIMINARY

REPORT OF A CONTROL STUDY. 1974

EXPERIMENTAL DESIGN

Subjects

Subjects were randomly assigned to one oftwo groups.

EDWARD C. SENAY, PIERRE F. RENAULT,

SALVATORE DIMENZA, WESLEY E. COLLIER,

STEPHEN J. DANIELS, WALTER DORUS

INTRODUCTION

LAAM has been shown to be an effective sub-stitute for methadone in the treatment ofheroin addiction (Jaffe and Senay, 1971;Jaffe et al., 1970, 1972; Senay et al., 1973).Medication is only one part of therapy, how-ever; and the decreased frequency with whichLAAM patients need to visit the clinic mayweaken the influence of the rest of the pro-gram, i.e., therapy, vocational rehabilita-tion, and legal services. This paper reportsan extension of previous studies to determinewhether new LAAM patients attend clinic lessfrequently than new methadone patients andif treatment outcome is influenced byattendance.

90

Experimental (LAAM) Group--Thirty-fourmale patients were included in thisgroup with the following characteristics:

Average age, 31.1 years

Average education, 11.2 years

Average years narcotic use, 11.7

32.3 percent married

20.6 percent employed

73.3 percent arrested at least once intwo years prior to entrance in study

100 percent black

At least 14 weeks in treatment

Control (Methadone) Group--Thirty-onemale patients were included in thisgroup with the following characteristics:

Average age, 29.0 years

Average education, 11.5 years

Average years narcotic use, 9.7

30 percent married

25.8 percent employed70 percent arrested at least once intwo years prior to entrance in study

90 percent black, 6.4 percent white,3.2 percent Spanish origin

At least 14 weeks in treatment

Methodology

Two clinics were established; one dispenseLAAM and offered group therapy and individualcounseling three times weekly, remaining openwith support staff and recreational facili-ties Monday through Friday. The other dis-pensed methadone and was open six days aweek with Sunday medication taken home.

The two groups were compared on the followingcriteria:

Dropout rate.Clinic attendanceUrine negative for illegal drugsDosage changesEmploymentArrestSide effects

Dose levels were 10 mg higher on Friday forLAAM patients and dosage in both groups couldbe adjusted weekly. No other medicationswere prescribed.

RESULTS

Retention Rate And Clinic Attendance

LAAM patients dropped out earlier in treat-ment; the difference was significant at fiveweeks. By the end of the fourteenth week,‘however, there was no significant differencebetween the two groups. The LAAM clinicretained 23 of 34 subjects. The methadoneclinic retained 23 of 31 subjects.

LAAM patients attended the clinic on 57.6percent of the days it was open and 94.2percent of the days on which medication wasdispensed.

Methadone patients attended the clinic on90.3 percent of the days it was open, medica-tion being dispensed every day.

Urine Negative For Morphine

The two groups were similar in extent of useof unauthorized drugs. LAAM patients hadurines negative for morphine a” average of10 out of 14 weeks; methadone patients, 9.8out of 14 weeks. The early tendency for themethadone group to have more urines negativefor morphine was reversed after the eighthweek when the LAAM group began to use drugsless.

Dosage Changes

The initial average LAAM dose was 44.7 mg;doses were 10 mg higher on Fridays than onMondays and Wednesdays. At 14 weeks, theaverage LAAM dose was 44.4 mg.

The average initial daily methadone dose was33.5 mg and was 36.5 mg at 14 weeks.

Dose levels were very stable throughout theduration of the study.

Employment And Arrests

Employment and arrest measures were identi-cal in both groups:

Two subjects in each group were arrested.

Five of the six patients who had jobsinitially still had them at 14 weeks.

One of the 17 unemployed in each groupfound a job.

Side Effects

No side effects attributable to methadonewere reported.

No medical complications developed in eithergroup.

One LAAM patient died due to heroin overdose48 hours after his second dose of LAAM.

Five patients experienced side effects inthe LAAM group.

Four patients had anxiety and nightmares,three in the first month of treatment andthe fourth in the second month.

Dose levels were 30 mg (2) and 50 mg(2).

Dose levels were lowered 10 mg in twosubjects, one on 30 mg and one on 50 mg.Symptoms did not persist nor did theyreturn when dose levels were increasedagain.

Dose levels were maintained for theother two patients and symptoms did notpersist more than one week.

One patient on 50 mg LAAM exhibitedbizarre behavior of which he had norecollection. Medication was reduced to40 mg and symptoms persisted. He wastransferred to a methadone clinic. Hesubsequently reported having been hos-pitalized in a mental institution sevenyears before the study.

91

22LEVOMETHADYL IN MAINTENANCE TREATMENT

OF OPIATE DEPENDENCE, 1972

group and ten to the control (methadone)group. The two groups did not differ fromeach other in age, years of drug abuse, orsocial class. They were detoxified and drugfree at least one week before the study.

Methodology

ARTHUR ZAKS, MAX. FINK, ALFRED M. FREEDMAN

The duration of the study was six months.Subjects in the experimental group receivedmedication on Mondays, Wednesdays, andFridays. Dose levels were built up as in-patients; the subjects were discharged whendose levels were attained. Two dose levelsof LAAM were established:

Four patients at low dose, 30-40 mg twiceweekly and 50 mg on Fridays

Five patients at high dose, 80 mg threetimes a week

One subject was discontinued because ofof a prior seizure disorder

INTRODUCTION

The 72-hour duration of action of methadylacetate has been established in single doseand controlled clinical studies (Fraser andIsbell, 1952; Jaffe et al., 1970 and 1971).The purpose of this study was to investigatethe potential of levomethadyl acetate (LAAM)in a maintenance program for narcotic addictsand to define dose levels. duration ofaction, secondary effects; and degree ofblockade to heroin.

EXPERIMENTAL DESIGN

Subjects

Subjects were 20 male narcotic addicts age21 or over with at least a two-year addictionhistory and one treatment failure. Ten wererandomly assigned to the experimental (LAAM)

Subjects in the control group were built upto 100 mg methadone hydrochloride daily inthe hospital and discharged. After the firstmonth, they attended the clinic twice weeklyand received take-home medication.

Criteria For Effectiveness

Subjects were evaluated for changes in voca-tional and social rehabilitation on a scalefrom 0 (no change) to 2 (marked improvement).

Substance abuse was monitored by twice weeklyurine testing for the presence of morphine,heroin, barbiturates, and amphetamines.

Cross-tolerance to 25 mg heroin was estab-lished while drug free and to 25 and 50 mgheroin after induction at 24 hours aftertreatment for all subjects and 48 hours afterfor one high-dose LAAM subject. The quality

92

of the euphoria, voice change, and pupillaryconstriction were observed; subjects wereinterviewed and completed an AddictionResearch Center Inventory (ARCI) question-naire.

Adverse Experiences Look For

Laboratory studies of liver function, fastingblood glucose, blood urea nitrogen, uricacid, blood cell caunt, and urinalysis weremade prior to and weekly during the study.

RESULTS

Dropouts

One of the nine LAAM subjects dropped out atthree months; two of the ten methadonepatients dropped out, one at two months andone at four months. Eight LAMM and eightmethadone patients remained in the study atsix months.

Behavioral Change Ratings

Ratings of change in vocational and socialfunctioning were similar in the two groups;1.4 for the LAAM group and 1.2 for the metha-done group.

Dose Levels

Withdrawal symptoms were experienced bythree of the four low-dose LAAM group, 40-48hours following their last dose.

At the 80 mg LAAM dose level, no withdrawalsymptoms or craving for heroin were reported.

Cross-Tolerance To Heroin

Three low-dose LAAM subjects responded tochallenge with 50 mg heroin with mild, trans-ient euphoria; blockade was complete in thefourth subject.

All five high-dose LAAM subjects demonstratedcomplete blockade to 50 mg heroin.

The high-dose subject challenged at 48 hoursdemonstrated complete blockade to heroin.

All 10 100 mg methadone subjects demonstratedcomplete blockade to 50 mg heroin.

Urine Tests

The LAAM group had 8.9 percent positive testsfor morphine compared to 2.0 percent for themethadone group. High- and low-dose LAAMsubjects had 2.8 percent and 18.9 percent,respectively.

The LAAM group had 2.0 percent positivetests for barbiturates and amphetamines com-pared to 7.9 percent for the methadonegroup.

Adverse Experiences And Side Effects

The methadone group did not complain of sideeffects; constipation at the beginning oftreatment was acknowledged by four subjectswhen asked.

Three of nine LAAM subjects complained ofirritability; one of these also complainedof anxiety. Tranquilizers were prescribedto two patients.

Two of the LAAM subjects complained of in-voluntary, jerky movements of the extremi-ties preceding sleep, persisting inter-mittently throughout the study.

Results of all laboratory tests were normalfor both groups except liver function tests.All subjects manifested intermittent ele-vated transaminase levels which weresporadic and not dose related.

93

This chapter and the following present summaries of the Phase IIclinical studies of LAAM. A8 discussed in the introductory chapter, bothof these studies were initiated by SAODAP to detenmine safety and effec-tiveness of LAAM. The clinical trials in each of the Phase II studieswere carried out simultaneously in multiple participating clinics utiliz-ing a common protocol. This procedure ensured attainment of adequatesample sizes within a reasonable time and of a more geographicallyrepresentative sample of addicts than possible in a single clinic. Also,this procedure permits analysie of variation in outcome between differentclinics. Organization, execution, monitoring of both studies and datacompilation, analysis, interpretation and reporting were performed byC. James Klett, Chief VA Central Neuropsychiatric Research Laboratoryand Cooperative Studies Program Support Center. The following summariesof the VA and SAODAP Cooperative Studies of LAAM and Methadone were pre-pared from progress reports submitted by Dr. Klett to FDA as sponsor ofthe Phase II IWD.

SUMMARY OF VETERANS ADMINISTRATION PHASE IICOOPERATIVE STUDY FOR LAAM AND METHADONEWaltor Ling , M.D.V. Charles Charuvartra, M. D.Samuel C. Kaim, M.D.C. James Klett, Ph.D.

Although early studies tend to substantiatethe observation of the clinical usefulness ofacetylmethadol, the number of patientsstudied was quite small. The present studyattempted to maximize subject availability bymeans of multihospital participation in acommon double blind protocol. The goals ofthe study were to evaluate the safety andtoxicity of a fixed dose of acetylmethadol(80 mg TIW) and to compare its relative effi-cacy with two doses of methadone, a high(100 mg) and a low (50 mg) daily dose.Safety and toxicity were evaluated by a multi-layer clinical and laboratory monitoringsystem. Relative efficacy was measured interms of a number of outcome variables,including positive urines, clinic attendance,employment, and social rehabilitation. Asecondary goal of the study was to comparethe two methadone doses with regard tothese same outcome variables, since thedesirability of high dose versus low dosemethadone maintenance remains an issue ofcontroversy. Originally, Dole and Nyswander(1) had advocated a rather high methadonedose. It was felt that this would produce aphysiological "blockade" against the effectof heroin and would thus discourage furtherexperimentation with illicit drugs. Othershave questioned the need for this high

(80-120 mg) dosage. Garbutt and Goldstein(2), for instance, have found an average of50 mg to be just as effective as 100 mgwith respect to survivorship in the programand cessation of heroin use.

METHOD

Patients

Patients were eligible for the study if theymet all of the criteria for admission tomethadone maintenance programs as defined bythe FDA and were males between the ages of18 and 60. Patients were excluded forincapacitating or life-threatening condi-tions, disease requiring regular repeatedmedication, frankly psychotic states,epilepsy, current severe alcoholism, andpending criminal charges. It was furtherspecified that any addicted spouse or rela-tive in the same household must be undertreatment and that there be a reasonableexpectation that the patient would continueto reside in the vicinity of the clinic andbe able to attend for the full duration ofthe trial. Eligible patients who signed aninformed consent for voluntary participationin the study were then given a general physi-cal examination with neurologic and

94

psychiatric evaluation and including chestx-ray, electrocardiogram, urinalysis, andblood studies. Patients began treatment onthe following Monday.

Drug Administration

Patients were randomly assigned to levo-alpha-acetylmethadol or one of two doselevels of methadone. The two methadonegroups received active medication daily butthe acetylmethadol group received activemedication on Monday, Wednesday, and Fridaywith placebo (dextromethorphan plus quinine)on all other days. Take-home doses (of theTuesday, Thursday, Saturday, Sunday dosesonly) were permitted at the physicians’discretion after the twelfth week of treat-ment. Take-home doses of acetylmethadol werenot permitted; any take-home dose in thisgroup was placebo. All doses were dispensedin a masking-diluting liquid such as Tang orgrapefruit juice.

The first dose in all three groups was 30 mgwhich was incremented by 10 mg on each suc-ceeding Monday until the patient achievedhis target dose of 50 mg of methadone (M-50),100 mg of methadone (M-100), or 80 mg ofacetylmethadol (L-80). All doses were dis-pensed double-blind with the sequence ofdosage increments and placebo doses con-trolled by bottle number. Duration oftreatment was 40 weeks (280 days).

Psychotrophic drug use was permitted onlyfor occasional nighttime sedation. All useof supplemental medication during the trialwas recorded.

Clinical Evaluations

Patients were evaluated immediately beforeand every four weeks during their tenure inthe study. The evaluation included a briefhistory, a current status record of theiremployment activity, legal involvement,interpersonal relationships and drug useduring the preceding four weeks, a supple-mentary medication record of all drugs pre-scribed during the preceding four weeks, anda symptom-sign checklist. The completephysical examination was repeated at thetwelfth week and at the end of the study,with abbreviated physical exams at all otherfour week evaluations. Vital signs (bloodpressure, temperature, pulse) and weight wererecorded on these occasions and fluid sampleswere obtained for laboratory tests.

In addition, daily entries were required ona treatment record of each patient’s

adherence to the clinic schedule of visitsand details of medication dispensed. Urinesamples were collected weekly following arandom testing sequence supplied centrally.Specimens were sent to the clinical labora-tory at the Sepulveda VA Hospital where theywere tested for morphine, barbiturates,amphetamines, and a variety of other sub-stances. Whenever a patient concludedtreatment, an attempt was made to repeat allevaluations and the staff recorded theirconsensus judgment of outcome in a number ofdifferent areas.

RESULTS

Characteristics of Sample

The sample consisted of 430 men whose medianlength of addiction to opiates was 7.2years. They were reasonably young (58% werebelow the mean age of 31 years) and reason-ably well educated 62% had graduated fromhigh school and 21% had gone on to do somecollege work. Mast had been married at onetime but 37% were still single. Racially,46% were black, 39% white, and 11% hadSpanish surnames. Other characteristicswere consistent with expectation in anaddict group.

Early Termination

Only 42% of the starting sample completedthe full 40 weeks of the study. If allreasons for termination are combined, 69%terminated early from the L-80 group (N=142),58% from the M-50 group (N=146), and 48%from the M-100 group (N=142). This differ-ence between the L-80 and M-100 groups isstatistically significant. Not all of thesepatients terminated for drug related reasonsbut since the nondrug related terminatorsshould have been equally distributed amonggroups except for chance, it has to be con-cluded that high-dose methadone maintenance(M-100) was superior in retention to theL-80 group. It does not necessarily followthat high-dose methadone is the superiormaintenance drug, however, because there areother dimensions of outcome that must beconsidered.

The average length of stay in the studybefore early termination was remarkablysimilar for the three groups: 82 days forthe two methadone groups and 81 days forthe L-80 group. Of the 251 early termina-tions, 45% occurred by the end of theseventh week (which marked the end of theinduction period for the M-100 group). Agreater number of terminations had occurred

95

in the L-80 group by this time but when thegroups were adjusted for their total numberof dropouts, there was no apparent trend forpatients to drop earlier from one group thananother.

Table 1 presents the number of patients ineach group who terminated early for avariety of reasons. The only significant

differences between groups for specificcategories of dropout were: a greaternumber for side effects in the L-80 groupthan in the M-50 group, and a greater numberof "No shows" in the L-80 group than theM-100 group. (Note: In these and all sub-sequent analyses, p<.05 was accepted as thelevel of statistical significance.)

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

There were no deaths of study patients, norwere there any serious adverse reactionsreported. There were 11 patients terminatedprimarily for side effects. Four L-80patients terminated because of inability toejaculate and another L-80 patient who ter-minated because of swelling of joints listeddecreased sexual interest along with heart-burn, nodding, and constipation. The otherL-80 terminators were: a patient whocouldn’t keep medication down (nausea, vomit-ing); another who complained of being tiredand dizzy with chest and arm pain; and onewho experienced jerking of extremities atbedtime and some nausea. The three high-dosemethadone patients were terminated becauseof: a pruritic maculo-papular rash thatdeveloped on a second day while the patientwas still on 30 mg; abnormally high liverfunction tests which were present beforetreatment but showed only minor trends towardstabilization at a lower level; and anapparent case of hone marrow suppression.

The symptom-sign data were collected by aresearch assistant, nurse, or primarytherapist before the Monday dose every weekfor the first eight weeks and every fourweeks thereafter. The schedule consistedof 30 symptom-signs and an "OTHER" category.Specific symptom-signs were not enumerated,but when their presence was elicited bygeneral questioning, their severity wasjudged as mild, moderate, or severe.

Initially each symptom-sign was monitoredindependently as well as in a priori clusters.When sufficient data had accumulated, theschedule was factor analyzed and a threefactor solution accepted as the best repre-sentation of the data. The first factor (14items) is clearly an Underdosing with-drawal factor. It consists of Aching Bonesand 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, nervous-ness). The second factor (five items) is anOverdosing factor which consists of FeelingHigh, Nodding, Dizziness on Standing, PoorConcentration, and Impotence. The remaining11 items made up a third factor which wastermed Somatic: Heartburn-Gastric Distress,Constipation,Bad Dreams and Nightmares,Drowsiness, Blurring of Vision, UrinaryFrequency, Decreased Sexual Interest, DelayedEjaculation, Numbers of Hands and Feet,Involuntary Jerking Movements of Lower Extrem-ities, and Edema of Extremities. These threefactors and their sum which was referred to

as Total Symptomatology were subsequentlymonitored along with the individual symptom-signs.

As a general statement, reporting of anysymptom-signs was infrequent and of a lowlevel of severity when reported. All threefactor scores and total symptomatology hadtheir highest level in the first week ortwo of treatment but rapidly decreased tonearly absent levels. There were no differ-ences between drugs worth noting. Becauseof special interest in several specificsymptom-signs, this analysis was supple-mented by another approach which used thepatient as the unit of analysis and examinedindividual symptom-signs (rather than deal-ing with the mean level of a cluster). Foreach symptom-sign separately, a patient wastallied as "severe" if he had even one suchrating at any time during his tenure in thestudy. A patient who was never rated as"severe" but had at least one rating of"moderate" was tallied in that category andif a patient was never rated as "moderate"or "severe" but had at least one rating of"mild", he was tallied in that category.Patients tallied under "none" were thoserated as asymptomatic throughout. In thisparticular approach, the pretreatment ratingwas ignored completely. To be tallied some-where in the table, a patient had to haveat least one rating during treatment;patients who completed the study could haveas many as 16. This approach defines thehighest rating obtained during treatment perpatient as a unit of analysis. Table 2presents these data for all three drugregimens combined.

97

TABLE 2

Number and Percent of Patients in Terms of HighestSeverity Rating Obtained During Treatment

N %

Aching bones and jointsYawningRunny nosewatery eyesMusle crampsGoose bumpsLoss of appetiteAbdominal crampsNausea or vomitingDiarrheaInsomniaExcessive sweatingIrritabilityAnxiety (tension, nervousness)Feeling highNoddingDizziness on standingPoor concentrationImpotenceHeartburn-gastric distressConstipationBad dreams or nightmaresDrowsinessBlurring of visionUrinary frequencyDecreased sexual interestDelayed ejaculationNumbness of hands or feetInvoluntary jerking movements

of lower extremitiesEdema of extremitiesOther

None Mild Moderate

N %

152 37171 42136 33160 39212 52221 54117 29181 45160 39288 71113 2892 23

124 3091 22

298 74260 65297 74252 63297 74221 5478 19

205 50162 40286 70244 60164 40185 45231 57

130 32152 37163 40158 39118 29106 26156 38134 33141 3581 20

139 34111 27144 35136 3374 1996 2475 19

107 2744 11

123 30129 32110 27156 3884 21

101 25116 2998 24

114 28

N %

108 2775 1897 2479 1960 1570 17

117 2976 1984 2137 9

129 32177 44123 30150 3725 638 1024 631 844 1154 13

167 4181 2083 2032 854 1397 2484 2146 11

180 44 136 33 83 20335 82 47 12 23 6253 62 46 11 81 20

The data shown in Table 2 were also generatedseparately by drug regimen and differencesbetween groups evaluated by 2 x 3 chi-squareor Fisher’s exact probability test. Forthese tests, rating was dichotomized as None-Mild and Moderate-Severe. In only threeinstances was there a significant drugdifference: Aching Bones and Joints forwhich the M-50 group had a significantlyhigher frequency of moderate-severe ratingsthan either of the other groups; and

Severe

N %

181012111710181723

227281731

364

10159

3412

759

304016

82

27

42334244607748121242832127

104

207

Anxiety for which M-50 significantly exceededL-80 in terms of moderate-severe ratings.

98

Although Delayed Ejaculation (and possiblyother problems in sexual function) seemed tobe associated with the L-80 patients in theearly termination data, this was not sup-ported by the symptom-sign data where ratingsof moderate and/or severe on Impotence,Decreased Sexual Interest, and Delayed Ejacu-lation are all more frequent (but not sig-nificantly so) in the methadone groups.Irritability is another symptom-sign ofspecial interest because of observations ofanimals on acetylmethadol in the preclinicalstudies. In this study, irritability isrepresented in higher frequency in themethadone groups but not significantly so.

The "Other" category included a wide arrayof symptom-signs, many of which seem to beeither trivial or clearly nondrug related,most of which were reported at a singlerating period only rather than persistentlyand some of which were elaborations of oneor more of the 30 symptom-signs on thechecklist.

The laboratory studies were conducted beforetreatment and every four weeks thereafter.Hematologic tests consisted of total WBC,total RBC, neutrophils, lymphocytes, eosino-phils, monocytes, basophils, hematocrit, andhemoglobin. Blood chemistry was the usualSW-12 panel, specifically calcium, FBS, BUN,uric acid, total protein, albumin, totalbilirubin, alkaline phosphatase, LDH, andSGOT. (Globulin was calculated as thedifference between total protein and albu-min.) Urinalysis included albumin, sugar,WBC, and RBC. Vital signs recorded at thesame intervals included blood pressure,pulse and temperature, plus weight.

The hematologic tests, blood chemistries,vital signs and weight provided 25 compari-sons for each of the 10 test periods (weeks4, 8, 12, 16, 20, 24, 28, 32, 36, 40)--atotal of 250 analyses of covariance withinitial level as the covariate. Only six ofthese were statistically significant. Threeof these occurred on a single variable--weight. The others represented a differencebetween groups at one period only: WBC atweek 20, calcium at week 36, and alkalinephosphatase at week 16. Sample sizes forthese tests ranged from slightly over 300cases for the pre- to four-week analyses toaround 160 cases for the 40th week analyses.

Two cohorts of patients were established tolook specifically at changes over timerather than cross-sectionally. The 24-weekcohort consisted of patients who had a com-plete set of data on a variable at pretreat-ment and every test period for the first

24 weeks. Usually this consisted of 60 M-50patients, 57 M-100 patients, and 45 L-80patients. The 40-week cohort usually con-sisted of 39 M-50 patients, 45 M-100patients and 31 L-80 patients. Although thestatistical testing provided a variety ofinformation about within-group and between-group differences, the primary interest wasin two tests of between-drug regimen differ-ence. One of these was essentially in termsof the average of all tests periods--theheight of the curve. The other tested thevariation of means across time between druggroups (the drug by time interaction). Inthe analysis of the 25 variables using the24-week cohort, there was a single signifi-cant finding--the interaction of drug andtime on weight. In the analysis of the samevariables using the 40-week cohort, therewas a significant interaction for total WBC,total RBC, hematocrit, hemoglobin, andweight. In addition, there was a signifi-cant difference between groups for SGOT whenall values were collapsed across time.

In another series of analyses, a cohort of128 patients from three hospitals who had acomplete set of values over a 20-weekperiod were used to provide similar butsomewhat different information. In theseanalyses, the pretreatment value wasincluded as a covariate and all subsequentvalues were adjusted for initial level.Hospital was included as a factor in thedesign which permitted a comparison ofhospitals and the various interactions ofhospital with drug and time. Both of thesechanges in design were introduced to pro-vide greater sensitivity for the analysesof drug difference, although it was accom-plished by reduction in time to 20 weeks, areduction of sample size and a restrictionto the three hospitals that had sufficientdata to be included. In these analyses, theonly main effects of treatment that reachedsignificance were on weight and pulse.There were significant interactions betweendrug and time on hematocrit, hemoglobin, andSGOT.

A final attempt to gain precision andextract information about any drug groupchanges present in the data consisted of aseries of multivariate analyses of covari-ance. The following hematologic tests wereanalyzed simultaneously: WBC, RBC, neutro-phils, lymphocytes, hematocrit, and herno-globin. The pretreatment values on all sixvariables were used as covariates and thevalues at each test point were used asdependent variables. Hospital was includedas a factor, and in each analysis as manypatients and as many hospitals were included

99

as possible. There were no significantdifferences involving treatment group inthese analyses. The renal tests (calcium,BUN, and uric acid) were analyzed in thesame manner and with the same result. Inthe analysis of liver function tests (totalbilirubin, alkaline phosphatase, LDH, SGOTand an index defined as albumin divided byglobulin), there was a significant differ-ence between groups at the 16th week only.The multivariate test of vital signs andweight was significant at the 4th week only.

These different analyses each supply some-what different information and need to befurther examined and integrated. In thehematologic tests, there is reason to lookcloser at WC, RBC, hematocrit, and hemo-globin. In the covariance analyses of WC,a significant difference between groups wasobtained at week 20. The adjusted meanswere M-50 7180, M-100 7720, and L-80 8060.In addition there were significant differ-ences in unadjusted post means at week 16and 20. In a total of 30 tests of pre-postwithin-groups change (three drug groupstimes 10 time periods), only the change frompre- to week 8 in the L-80 group was signifi-cant. Furthermore, all means at all testpoints were within the normal range (allmeans varied from 7260 to 8020). In boththe 24 and 40-week cohorts, there was sig-nificant within-group variation of meansacross time in the L-80 group but thisvariation represented considerable scatterin values from one test period to the nextrather than an increasing or decreasingtrend in WBC. The same scatter was presentbut not significantly so in the two metha-done groups. In the 40-week cohort analysis,this variation across time was significantlygreater in the L-80 group than in the twomethadone groups (significant interaction)and there were significant differencesbetween drugs at week 16, 20 and 28. Thedrug by time interaction was not significantin the 24-week cohort. At each of these testpoints (week 16, 20, 28) the L-80 mean washighest and the M-50 mean was lowest. Allmeans were in the normal range. There wereno drug differences in the 20-week cohortanalysis. In summary, there is a suggestionthat something might have been happeningwith WBC in at least some patients duringthe middle weeks but it is difficult to giveclinical meaning to it because it did notpersist, all means are comfortably in thenormal range and a review of individualpatient's data did not identify anythingremarkable about this part of the treatmentperiod. RBC, hematocrit, and hemoglobinsurfaced as possibly significant (in aclinical sense) on the cohort analyses only.

The evidence for RBC is not convincing.There appeared to be a predominately lineardownward trend particularly in the two metha-done groups over the first 20 to 24 weeks butthe trend did not continue and in factseemed to reverse itself. It may be moreaccurate to say that there was some initialdecline which then leveled off. The onlybetween-groups difference was the drug bytime interaction in the 40-week cohort, andeven in this analysis only at week 8 wasthere a significant difference between drugs(M-100 highest, L-80 lowest, all means withinnormal values). It is difficult to concludethat there is anything clinically significantin RBC. The situation is much the same forhematocrit and hemoglobin. The trend analy-ses suggest an initial decline in all threegroups and then a leveling off after aboutthe eighth week. There is no clear and con-sistent separation of groups across time.Finally, considering also the results of themultivariate tests that included all ofthese variables, it seems reasonable to con-clude that the occasional between-groupsdifferences that did emerge as statisticallysignificant have no clinical importance. Inno case were the blood changes sufficient tonecessitate termination from the study.

The evaluation of renal and liver functiontests was similarly reassuring from a clin-ical point of view. SGOT was noteworthyfor the fact that the means of all three druggroups before and throughout treatment werewell above the usual normal range (from a lowof 56 to 107) and the pretreatment values formany individual patients were high enough tobe of serious concern in a nonaddict sample.The main finding for SGOT is that the L-80curve is at a somewhat higher level at pre-treatment and throughout the 40 weeks thanthe methadone groups. All three groups showessentially no change across time on SKIT.The significant difference between groups atweek 16 in the multivariate analysis of theliver function tests is paradoxical and notlikely to be of clinical importance becausethere is so little supporting evidence ofdifferences at other weeks either in theunivariate or multivariate tests.

The analysis of vital signs and weight had agenerally low yield, except for weight,which is clearlv affected bv all three drugregimens, and particularly acetylmethadol.There is clearly an upward trend in allgroups, and somewhat more substantially so inthe L-80 group. There was no morbid obesityreported.

100

Efficacy

This study was not designed to evaluateefficacy in the usual manner, i.e., there isno placebo or nontreatment group. However,acetylmethadol has previously been shown tobe pharmacologically effective in suppressingthe abstinence syndrome and there is abun-dant evidence in this study that both drugswill maintain addicted individuals withouttheir having to resort to supplementary(illicit) narcotic use to avoid withdrawal.It seems reasonable to assume efficacy inthis sense and turn to the question of therelative efficacy of the three drug regimens.

There are a number of variables that indi-vidually or collectively could be used todeal with the issue of relative efficacy.All of these are imperfect indices. Theamount of discomfort indicated on the Under-dosing factor of the Symptom-Sign Recordprovides a measure of efficacy but would needto be evaluated sirmultaneously with illicitdrug use to be unambiguous as an outcomeindex. Early termination is obviouslyrelated to efficacy in some complex mannerbut is less than ideal as an indicator forsome equally obvious reasons. A patientwho completes 40 weeks of treatment buttests positive for morphine at every weekcannot be considered more of a treatmentsuccess than a patient who is clean for 32weeks and then moves to another part of thecountry Both kinds of patients are repre-sented in this study. Conformity to sched-uled clinic visits is equally ambiguous.Some patients who faithfully attend clinicshow a heavy illicit drug use pattern. Itis not even safe to assune that missed clinicvisits are accompanied by illicit drug use.Many other outcome variables are clearlysecondary, i.e., have no direct pharmaco-logical relationship to the drug. Examplesare employment variables, encounters with thelaw, and interpersonal relationship variables.It is the hope and the expectation thatpatients being adequately maintained willshow improvement in these areas and it maybe appropriate to use such variables toevaluate a total program of rehabilitationincluding the whole array of supportiveservices but it seems unjustified to usethem as criteria of primary drug effect.They seem, instead, to be contingencyvariables. The use of these variables asoutcome indicators of maintenance treatmentis contingent upon achievement of the primarygoal which is to decrease illicit drug use.

Urine test data is considered to be the keyto evaluation of the results of this study.Unfortunately, even illicit drug use is not

a simple variable. The amount of drug useis, of course, important but the pattern isprobably even more so. A patient who com-pleted the study with 50% urines positivefor morphine could have been entirely cleanin the first or the last 20 weeks. Thelatter seems to be a clearly superior out-came.

An index of illicit morphine use has beenderived which takes into account total useand pattern of use. With a single exceptionto be noted later, this index was developedcompletely independent of the study data andwas therefore not biased by knowledge ofdrug group outcomes. This index has somearbitrary features end some defects butexperience with its use has not revealedserious distortions. The rules are entirelyobjective and do not require clinical judg-ment . The entire operation can be performedby the computer.

Rule 1: A score cannot be derived for apatient who is in the study for less than 50days (seven weeks).

Rule 2: Urine tests Positive for morphineare given a weight of five if they occur inthe last 8 weeks of a patient’s tenure in thestudy, a weight of four if they occur in thenext to last 8 weeks, three if they occur inthe next block of 8 weeks and so on.

Rule 3: A missing urine test result ishandled in exactly the same manner as apositive urine except that it is not weighedas heavily. A positive urine in the last8 weeks would be weighted 5 x 1 = 5; amissing value would be weighted 5 x .22 =1.1. The value .22 is not totally arbitrarybut is derived from the data. It representsthe percent of all urine samples collected inthe study that tested positive for morphineand its use for missing value introduces somenotion of the probability that a missingvalue would have been positive.

Rule 4: All scores derived by the rulesabove are adjusted to a comparable range of0 to 120. Patients who have 40 negativeurines would be scored 0; patients with 40positive urines would be scored 120.

Although the index seems to have the desiredcharacteristic in an abstract sense, the testof its value must be in terms of actual data.Preliminary attempts to establish constructvalidity have been encouraging. It was pre-dicted that the drug use index would corres-pond to staff judgments of outcome made atthe time of termination of a patient’s par-ticipation in the study. The patients rated

101

as being better or much better had a meanurine index of 17.5, the patients ratedunchanged had a mean of 38.3, and thepatients who were worse or much worse had aman of 39.9. The F was 24.16 (p< 001). Asimilar relationship was predicted forpercent clinic attendance. Patients who hada perfect attendance record had a mean urineindex of 17.7, those patients that had anear perfect attendance record (96-99.9%)had an index of 20.5, the patients whoattended 90 to 95.9% of the time had anindex of 33.0 and patients whose attendancewas below 90% had an index of 36.3. The Fwas 7.82 (p< .001). A series of more care-fully planned analyses will need to be con-ducted to further define the index. However,using this index to compare the three drugregimens gave the following results: 110M-50 patients had a urine index of 33.3,111 M-100 patients had an index of 22.6, and96 L-80 patients had an index of 20.8. TheF was 6.19 (p< .005). The M-50 group issignificantly higher on the urine index thaneither M-100 or L-80.

Urine test data were analyzed in other waysas well. For each patient, the number ofurines positive for morphine was divided bythe number of his specimens tested. Thisgave a "percent dirty for morphine" scorefor that patient which was then used in acomparison of groups. A similar score wascalculated for barbiturate positive, amphet-amine positive, and "something" positive,the latter being the number of specimenspositive for either morphine, barbiturates,amphetamines, or cocaine (tested randomly) atany one week divided by the total number ofspecimens for that patient. The results ofthese analyses showed the L-80 group lesslikely to use illicit barbiturates than theM-50 group.

Another kind of outcome index is programconformity, which was defined as eachpatient's number of actual scheduled clinicvisits divided by his total number ofexpected scheduled visits for however longhe was in the study. The M-50 group had anaverage of 92% attendance, M-100 95%, andL-80 90%. The difference between M-100 andL-80 on this clinic visit index was sig-nificant. However, since the acetylmethadolpatients only received active medication onMWF, the analysis was redone comparing thethree groups on percent attendance for thosedays only. L-80 still had a lower averageattendance rate than M-50 or M-100 but thedifference is not significant.

Still another evaluation of relative efficacywas possible using the global rating of

outcome, which was a combined staff judgmentmade shortly after a patient's termination,taking into account all known informationabout the patient. This was a five-pointscale: much improved, improved, changed,worse, and much worse. The M-50 group wasjudged to be significantly less improved thaneither the M-100 group or the L-80 group.

Preliminary review of secondary (contingent)outcome variables such as number of arrests,hours of employment, income, etc. has notyielded evidence of advantage of any onegroup over another but a conclusive summaryof these variables will have to be deferreduntil more definitive analyses have beendone. Similarly, there are many otheraspects of the data that will have to awaitsubsequent publication.

REFERENCES

1.

2.

Dole, V.P. et al: Methadone maintenance.A report of two years experience. Pre-sented at Annual Conference of NationalResearch Council Cormittee on Problemsof Drug Dependence, New York, 1966.National Academy of Sciences,Washington, D. C.

Garbutt, G.D., Goldstein, A.: Blindcomparison of three methadone maintenancedosages in 180 patients. Proceedingsof Fourth National Conference on MethadoneTreatment. National Association forPrevention of Addiction to Narcotics,New York, 1972, pp. 411-414.

AUTHORS

Affiliation of the authors of this article isas follows: From the Veterans AdministrationHospitals, Sepulveda, California (Dr. Ling),Brentwoti, California (Dr. Charuvastra) andPerry Point, Maryland (Dr. Klett) and fromthe National Pharmaceutical Council, Inc.,Washington, D.C. (Dr. Kaim).

102

SUMMARY OF SAODAP PHASE II COOPERATIVE STUDYOF LAAM VS. METHADONE

Waltor Ling, M.D.

C. James Klett, Ph.D.

Roderic D. Gillis

The primary purpose of the trial was tocompare the efficacy and safety of LAAM andmethadone for treating heroin addicts in amaintenance program. The program wasdesigned to be conducted with uniformity,supervision and coordination based uponadherence to three common protocols. Datawere recorded on a uniform set of forms andsubmitted to a central data coordinatingcenter for analysis. Safety was evaluatedby monitoring patients for symptoms, signsand laboratory evidence of toxicity.Although the primary endpoint for statisticalevaluation of efficacy was use of illicitdrugs, changes in social adjustment, arrestrate, employment and retention in treatmentwere also considered indications of effec-tiveness.

METHOD

Patients

Patients were eligible for the study if theywere currently in a methadone maintenanceprogram as defined by the FDA and were malesages 18 or older. Patients were excludedfor incapacitating or life-threatening con-ditions, disease requiring regular repeatedmedication, frankly psychotic states,epilepsy, current severe alcoholism, and

pending criminal charges. It was furtherspecified that any addicted spouce or rela-tive in the same household must be undertreatment and that there be a reasonableexpectation that the patient would continueto reside in the vicinity of the clinic andbe able to attend for the full duration ofthe trial. Eligible patients who signed aninformed consent for voluntary participationin the study were then given a generalphysical examination with neurologic andpsychiatric evaluation and including chestx-ray, electrocardiogram, urinalysis, andblood studies. Patients began treatment onthe following Monday.

Drug Administration

Patients were randomly assigned to LAAM ormethadone. Methadone patients were continuedon their regular daily dosage of methadone,unless an adjustment was required. Patientsassigned to LAAM received a first dose equalto their previous methadone dose. After theinitial dose, adjustments could be made butin no case could the dosage exceed 100 mgTIW. Psychotropic drug use was discouragedexcept for occasional sedation. All use ofsupplemental medication during the trial wasrecorded.

103

Initially the following three protocols wereused for the study: Protocol 1. Randomassignment to LAAM or methadone. LAAM groupreceives LAAM three times a week at theclinic. Methadone group receives methadonedaily, with take-home privileges as deter-mined by the clinic; Protocol 2. Same asProtocol 1, but no take-home privilegesfor methadone group; Protocol 3. Randomassignment to LAAM or methadone. Methadonegroup receives methadone daily. LAAM groupreceives methadone MTWTH, LAAM on Friday, nomedication Saturday or Sunday.

Twelve investigators chose Protocol 1, threeclose Protocol 2, and three chose Protocol 3(one investigator chose both 1 and 3).however, changes in clinic policy and theresultant small number of subjects inProtocol 2 led to the combined analysis ofpatients in these protocols.

Clinical Evaluations

Evaluation was essentially identical to thatof the VA cooperative study described in thepreceding chapter except that urine testingwas done locally rather than in a centrallaboratory.

Characteristics of the Sample

(Protocols 1 and 2)--The sample consisted of636 men, with 308 maintained on methadoneand 328 maintained on LAAM 61% of the sam-ple had been addicted to opiates for morethan five years. The mean age was 28.8 years54% of the sample had graduated from highschool and 25% had gone on to college. 61%of the sample were, or had been, married.55% of the sample was white, 28% black and15% had Spanish surnames. Almost two-thirdsof the sample was employed, and 54% workedfull-time. 73% had been in some form ofvoluntary treatment program previously, butonly 20% had been in some form of involun-tary drug treatment program. There were nosignificant differences between the LAAM andmethadone groups.

The sample for Protocol 3 consisted of 136men, 71 of whom were assigned to methadoneand 65 of whom were assigned to LAAM Thissample was somewhat older (mean age 31.3)than the sample in Protocols 1 and 2, butthe other demographic characteristics weresimilar. There were no significant differ-ences between the LAAM and methadone groups.

Early Termination

(Protocols 1 and 2)--49% of the startingsample completed the full 40 weeks of thestudy. If all reasons for termination are

combined, 61% terminated early from the LAAMgroup (N = 200) and 40% from the methadonegroup (N = 122). This difference is statis-tically significant. Not all of thesepatients terminated for drug related reasonsbut since the nondrug related terminatorsshould have been equally distributed betweengroups except for chance, it has to be con-cluded that methadone maintenance was super-ior to LAAM in retention, at least under theconditions of an open comparison of anapproved and an experimental drug.

There was also a difference between thelength of stay in the study before earlytermination. The average drop-out in theLAAM group occurred after 72 days, whereasthe early terminator in the methadone groupdropped out after 122 days. 43% of thedrop-outs occurred before the ninth week,with the LAAM group drop-outs occurringearlier as well as more frequently than metha-done group drop-outs.

Protocol 3. The pattern of drop-out wasremarkably similar for Protocol 3, althoughthere was a higher drop-out rate for bothgroups. 44% of the total sample conpletedthe full 40 weeks of the study. 48% (N=34)of the methadone group and 65% (N=42) of theLAAM group dropped out early. This differ-ence is statistically significant. Theaverage drop-out in the LAAM group occurredafter 81 days in the study, whereas theaverage methadone drop-out occurred after141 days.

It should be noted that there was a greatdeal of variation in percentage and timingof drop-outs between clinics, which suggeststhat factors other than the drugs themselvescontributed to drop-out rates.

Table 1 presents the number of patients ineach group who terminated early for a varietyof reasons under Protocols 1 and 2. Table 2presents the same data for Protocol 3.

The major differences between groups forreasons for early termination were MedicationNot Holding (all three protocols) and SideEffects, Psychiatric, Medical unrelated,irritability, detoxification, and did notlike drug (protocols 1 and 2). In eachinstance, there were more LAAM drop-outs thanmethadone drop-outs.

SAFETY-TOXICITY

Protocols 1 and 2

Laboratory data, vital signs and weight wereobtained before treatment and every fourweeks during treatment. At each of ten test

104

TABLE 1

Reasons for Early Termination(Protocols 1 and 2)

Reasons M L T

Medication not holdingJailMoved from areaDetoxificationDid not like studyDisciplinary dischargePsychiatricNo show for 14 daysExcessive drug useSide effectsMedical unrelatedIrritabilityDid not like drugMiscellaneousExcessive alcohol useDose too highCould not attend clinicAbnormal laboratory valueNot eligible for inclusionDeath

Total

0 62 6228 19 4721 18 3929 9 3815 7 2212 5 17

0 14 148 4 124 8 120 11 111 9 100 9 100 7 70 5 52 3 50 4 41 3 41 2 30 2 20 1 1

122 200 322

TABLE 2

Reasons for Early TerminationProtocol 3 (Friday only LAAM)

Reasons

Medication not holdingDetoxificationJailMoved from areaDisciplinary dischargeNo show for 14 daysMedical unrelatedExcessive alcohol useDid not like drugDid not like studySide effectsPsychiatricIrritability

011665410010

20541103320111

201610

7644321111

Total

Meth LAAM

00

Total

34 42 76

105

paints differences between the means of themethadone and acetylmethadol groups wereevaluated by analysis of covariance withadjustments for pretreatment value. Out of250 such analyses (25 variables x 10 occa-sions) there were 35 significant differencesbetween adjusted means: WBC at week 8; RBCat weeks 16, 20 and 24; basophils at week 8and 12; hematocrit at weeks 8, 16, 20, 24,28, 36, 40; hemoglobin at weeks 8, 16, 20,36; calcim at week 28; RBS at week 16, uricacid at week 32; albumin at weeks 4, 32 end40; weight at week 4; systolic blood pressureat weeks 8, 12, 16, 24, 28, 32, 36; diastolicpressure at weeks 8, 20, 24. and 28. Mostimpressive of those are hematocrit and hemo-globin and perhaps RBC end basophils. Theblood pressure results are of less interestas far as LAAM is concerned because thechanges are essentially all due to increasedblood pressure in the methadone group withlittle or no change in LAAM patients. Theother scattered differences between groups(WBC, RBS, uric acid, albmin and weight) areprobably not of much clinical consequence.

On each of the ten occasions that blood wasdrawn during treatment, the LAAM groupshowed a statistically significant reductionin hematocrit compared to their baselineaverage. These changes were very small. Thelargest average change was a drop of 1.53.None of the tests of pre-post changes in themethadone group were significant but exceptfor one test (week 40) the post mean wasalways lower then the pre mean. Thesechanges were also small. In other words,both groups showed reduction of hematocritvalues during treatment but the changes werea little larger in the LAAM group. Withsample sizes of 100-200 in a group for alltests, even very small differences can bestatistically significant. All of the meanvalues of both groups at all times werewithin the normal range. The LAAM grouptended to have somewhat higher values at prethan the methadone group and this could con-tribute to the observed difference inadjusted means. The changes across time arenot progressive, i.e., there is no discern-able trend for continuing decrease in hema-tocrit as treatment progresses. Insteadthere appeared to be an initial drop in thefirst 4-8 weeks of treatment and a restabili-zation of average hematocrit at a somewhatlower level then pretreatment. Essentially,the same things can be said for the differ-ences in hemoglobin.

The decrease in average hematocrit (orhemoglobin) could be caused either by largedrops in a few patients or by smaller dropsin a larger number of patients. Review of

individual patients records did not identifypatients with dramatic and systematic changesin these tests but there does seem to be apattern of small decreases by a fairly largenumber of patients. Similar trends werenoted in both the methadone and LAAM groupsin the VA study. The current speculationis that the introduction of a new drug(methadone or LAAM in the VA study or LAAMbut not methadone in the SAODAP study)causes some initial physiologic disturbancewhich then stabilizes. It may be that thereis an association with weight gain i.e.,fluid retention, or some other simpleexplanation. In any case, there is nocorresponding clinical evidence of drugtoxicity and unless additional data (or newanalyses of existing data) are forthcoming,these changes do not seem to be at allalarming.

SAFETY-TOXICITY

Protocol 3

In Protocol 3, laboratory values wereobtained only at pre, week 12 and week 40.Differences between the means of methadoneand acetylmethadol on these tests at week12 were evaluated by analysis of covariancewith adjustments for pretreatment levelusing all patients that had pretreatmentand 12th week values. Differences at week40 were evaluated in the same manner. Outof 40 such analyses (20 lab tests x 2occasions), there were four significantdifferences between adjusted means: WBCat week 40, Random Blood Sugar at week 12,Globulin at week 12, SGOT at week 12.

Vital signs and weight were obtained at preand every four weeks thereafter. These fivevariables were analyzed in the same mannerat each of 10 occasions yielding 50 moreanalyses of covariance. Only one of thesetests of adjusted means was statisticallysignificant: weight at week 20. Thesevariables were also analyzed by trend analy-sis across the 40 weeks as described in thesummary of the main study. There were nobetween groups differences in any of theseanalyses that reached a significant level.

SYMPTOM-SIGN RECORD

Protocols 1 and 2

Symptom-signs were examined individually ina number of ways and in scoring clustersestablished by factor analysis. In oneapproach to individual evaluation of symp-tom-signs, the highest rating obtainedduring treatment per patient was used as aunit of analysis as described in the VA

10 6

study. To test differences between druggroups, rating was dichotomized as None-MildandModerate-Severe. The following symptomswere significantly different between groups.

YawningRunny nosewatery eyesMuscle crampsGoose bumpsAbdominal crampsNausea or vomitingInsomniaExcessive sweatingIrritabilityAnxiety (tension,

nervousness)NoddingImpotenceDrowsiness

NoneMETH LAAM

181 147151 126170 128169 128182 150177 122186 127118 73114 93134 108

118 86262 255255 249195 191

MildMETH LAAM

84 110107 109

95 11091 11293 10980 10674 10269 9485 7592 84

82 8735 4742 5279 80

Other 203 180 36 40 40 62 29 45

Efficacy

The Discussion of issues involved in estab-listing eficacy of LAAM in the VA Coopera-tive Study applies equally well to theSAODAP Cooperative Study. There are a numberof criteria of efficacy that can be used butall have certain limitations or defects.

Generalization about efficacy from the VAstudy has to be qualified because of thefixed dose design and the induction schedulewhich may have been too slow. In theory,the SAODAP study does not suffer from thisparticular problem because dosage was flex-ible after the first dose. However, anysuggestion that LAAM is a less effectivemaintenance drug then methadone has toconsider how effectively this option toadjust dose was exercized by the clinicians,most of whom were initially inexperienced inthe use of LAAM. To the extent that dosagewas not individually optimized, LAAM couldbe expected to appear somewhat less effec-tive than methadone which is not only amore familiar drug but was the drug on whichall patients were stabilized prior to thestudy. Furthermore, the price paid in thedesign of this study to provide for flexibledosage was to drop the double-blind control.Patients and staff were aware of the treat-ment assignment and this allowed for thefull effect of psychological factors asso-ciated with treatment with an unfamiliar

Moderate SevereMETH LAAM METH LAAM

40 5847 8040 7742 7529 6044 8043 8297 1199269

126105

3 123 1236

1212

4 87 195 16

24 4117 3313 30

87 109 21 459 21 2 48 21 3 5

29 45 5 11

experimental drug. Even if the effect ofpsychological factors is discounted, reten-tion rates on LAAM had to be influenced bythe fact that there was a clinical choicepossible with LAAM patients--they could stayon LAAM or be switched back to methadone--but this choice did not exist for methadonepatients--their only choice was to drop outof maintenance altogether. Because of theseproblems, the SAODAP cooperative study pro-vides almost no useful information aboutefficacy relative to methadone. The excep-tion may be the urine index as defined inthe VA study. In protocols 1 and 2, 28 meth-adone patients had a urine index of 15.0while 227 LAAM patients had an index of 14.9.In protocol 3, 71 methadone patients had aurine index of 19.9 while 65 LAAM patientshad an index of 16.2. Thus, in bothinstances, LAAM had a slightly better (non-significant) index of illicit opiate use.

Another kind of outcome index is programconformity, which is defined as eachpatient's number of actual scheduled clinicvisits divided by his total expected sched-uled visits for however long he was in thestudy. In Protocols 1 and 2 the percentageof clinic visits were essentially the samewith averages of 97.75% and 97.71% for themethadone and LAAM groups, respectively. Inprotocol 3, the methadone patients attended97.24% of their scheduled clinic visits whilethe LAAM group attended 97.49% of the time.

107

Still another evaluation of relative efficacy scale: much improved, unchanged, worse andwas possible using the global rating of out- much worse. In protocols 1 and 2, the meancome, which was a combined staff judgment score for both groups was 2.96. In protocolmade shortly after a patient's termination, 3, the mean scores were 3.00 and 2.90 fortaking 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 isas follows: From the Veterans AdministrationHospitals, Sepulveda, California (Dr. Ling),and Perry Point, Maryland (Dr. Klett andPaderic Gillis).

108

PHASE III CLINICAL STUDY OFLEVO-ALPHA-ACETYLMETHADOL

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

INTRODUCTION

The purpose of the Phase III trial of levo-alpha-acetylmethadol (LAAM) is to establishefficacy of this medication for the main-tenance of persons addicted too opioids.Also during the course of the Phase IIItrials additional data relating to thesafety of LAAM will be obtained. It is theintended purpose of the Phase III clinicaltrials to provide sufficient informationto alllow the FDA to grant a New Drug Applic-cation for LAAM.

The administrative stucture which has beendeveloped for these Phase III clinical trialsis intended to provide for a centralized drugsupply, data collection, and adminstrativesystem with a maximun national clinical par-ticipation. Whysner Asscciates is the primecontractor for NIDA and is responsible forthe Coordination of the Study which includesfiling of the IND application, medical sup-ervision, review of results, administrationof all subcontractors, and development ofthe final NDA application. Subcontractorsinclude the Vitarine Company, who will be theformulator of the liquid concentrate, FriendsMedical Science Research Center, Inc., whowill provide data managemement and analysissupport, and approximately 50 methadoneclinics who will perfom the clinical trialsand provide the data for analysis. A MedicalAdvisory Panel has been established which isresponsible for approval of the study proto-col, analysis of any adverse reactions, andreview of the conclusions of the study.

The subject population will be approximately6,000 men and woman over the age of 18 whomeet the current criteria for entrance intomethadone maintenance programs or who arecurrently clients of such proqrarm. Theclinical trial will last up to 40 weeks foreach patient. Each clinic will participatein one of two studies whichcc are being con-ducted as part of these Phase III trials.In one study all patients will be put onLAAM. In a second a random assignmentof patients will be made to LAAM or methadoneproviding a comparative analysis of efficacyand safety measures.

MEASURES OF EFFICACY

The proof of efficacy for maintenance of per-sons addicted to opioids may be defined asthe relief of abstinence over a prolongedperiod of time when the drug is given on aregular basis. There are three aspects ofthe abstinence syndrome: drug seeking be-havior, physiological, and psychologicalchanges. A drug such as LAAM must preventthe development of abstinence inall threeareas. Therefore, measures of efficacy mustbe aimed at measuring the signs and symptomsof the develpment of abstinence in thesethree areas.

The measure of drug seeking behavior can beattempted through history taking, directmeasurement of illicit drugs in body fluids,or assessment of the consequences of taking

109

illicit drugs. During the past several yearsour ability to measure illicit drugs in bodyfluids has been developed to the point wherethese methods are both reliable and are aregulaar part of the methadone program rou-tine. Therefore, in the Phase III studiesthis will be the most important measure ofdrug seeking. Assessment of the use of il-licit drugs through history taking or an in-dependent measure of the consequences ofheroin use such as number of arrests, employ-ment, etc. is not reliable or easy quan-titrate.

SAFETY MEASUREMENTS

Physiological signs of abstinence will bemeasured through the analysis of a synptom-sign checklist. The components of thechecklist are well known parts of the phy-sical abstinence syndrome; for example,sweating, gooseflesh, and rinorrhea.

For the psychological componence patients maybecame anxious, hostile, irritable, requireother drugs such as traquilizers, developother patterns Of drug abuse such as poly-drug abuse, or adjust poorly to the socialand work environment. Many of these aspectsof psychological abstinence may be difficultto measure; however, measures will be attemp-ted. The Profile of Mood States will beused to measure anxiety, hostility, andirritability. Also questions involvinghours of emp1oyment, number of arrests, anda global assessment Of client's progresswill be made.

There are no fixed scales against which ef-ficacy can be measured. It is not knownwhat is an acceptable level of abstinenceor what are acceptable drug seeking, phy-siolcgical or psychological changes. There-fore, a heavy reliance must be made on com-parative measures with a control group.

The only applicable control group for thisstudy would be persons who are currently onmethadone maintenance therapy. Comparisonsof the efficacy and safety measures will bemade between the methadone and LAAM patientsin part of the Phase III study.

Another determinant of an acceptable levelof abstinence would be the willingness ofthe participant to stay on the drug. If onecan make the assumption that remaining onthe drug is the equivalent of efficacy,dropout rates are very useful. The reasonfor dropout and a judgment by the clinic ofwheter such a dropout is drug related willbe determined. Only those dropouts whichare drug related such as side effects, feel-ings of under medication on weekends,etc.will be used as efficacy measures. However,

dropping out of the study to attempt detoxi-ficationn would be viewed as a positiveresult.

Previous Phase II clinical studies have in-dicated that for a 40 week period LAAM doesnot cause any consistent abnormalities inthe CBS, SMA-12, urine analysis, EKG, orEEG which would be cause for concern. How-ever, these Phase II studies have only beenaccomplisked on 170 males for 40 weeks.Therefore, it is desirable to test a largenumber of males and femailes to determine ifthere are any untoward reactions which occuron a low frequency basis. It is hoped thatthe Phase III studies will include approxi-mately 2,000 patients om LAAM for 40 weeks.This should test enough individuals to givean estimate of the incidence of adverse re-actions to the medication.

Another problem which must be studied duringPhase III is the use of other medicationconcurrently with LAAM. It is known thatdrug interactions may occur which wouldeither potentiate or preventthe effectiveaction of narcotics. me use of both pre-scription and illicit drugs may have un-toward interactions effects. Although it hasbeen suspected that certain other drugs myinteract favorably, not enough patients havebeen studied to gather any quantificabledata. In the Phase III studies the use ofall medications will be documenteds and thepossibility of any drug interactions will beinvestigated thoroughly.

OPEN VERSUS BLIND STUDY

The use of any maintenance drug for thetreatment of heroin addiction has a strongsubjective component to its effectivenessfor both the patient and the physician. Adouble-blind study is designed to eliminatethe impact of these subjective effects omthe outcome of the study. Double-blindstudies have been used in the past to com-pare the effectiveness of LAAM to methadoneand the results of these studies have beendescribed elsewhere. There are severalreasons for which the Phase III study hasbeen designed as an open rather than adouble-blind study. These are the following:

1. The primary advantage of using LAAM in-stead of methadone is the need for onlythree day a week pickup. If a double-blind study was done a schedule ofeither daily pickup or of three day aweek pickup would be necessary in bothLAAM and methadone groups. This wouldnegate the scheduling effect of LAAM.

110

2 . The large number of patients needed forthe phase III study and the use of mul-tiple clinic sites makes the logisticalproblems associated with such a studyvery difficult.

3 . A double-blind study may adversely effectthe efficacy of either methadone or LAAMin an unpredictable way. The patientpopulation is very anxious concerningthe medication they are receiving andabout participation in a clinical study.One of the greatest difficulties en-countered in the PhaseII study was thatthe efficacy results had a large numberof patients who dropped out because ofthe nature of the study rather than thedrug

4. The blind is difficult to keep becausepatients and physicians would be ableto break the code due to the subjectiveeffects of the drug.

USE OF LAAM IN FEMALES

The Phase III study will be the first large-scale use of this drug in femles. A smallgroup of famales was tested before the FDArestrictions on the use of LAAM. During thecourse of the Phase II studies there was astudy of seventeen females of non-childbear-ing potential. The use of LAAM in femalesat this stage is essential,otherwise anotherlarge-scale study in females would need tobe canstructed. It is currently being de-cided whether or not some females should be

AUTHOR

John A. Whysner, M.D., Ph.D. is president ofJohn Whysner Assciates, Inc., 2600 VirginiaAvenue, N.W. Suite 209, Washington, D.C.20037.

given LAAM througout pregnacy or whetherall woman who become pregnant while on LAAMshould be switched to methadone. The argu-ments on both sides of this question arevalid. The use of LAAM through pregnancywould mean exposing pregnantfemales and neo-nates to a new drug with which the medicalcommunity is unfamiliar. However, LAAM mayprove to be a drug with fewer problems inthe pregnant female and the neonate than doesmethadone. The long duration of action ofLAAM may make the neonatal withdrawal syn-drome less severe.

CURRENT STATUS OF THE STUDY (MARCH, 1976)

The current planning for the Phase III studyof LAAM has been almost completed. Thefinal study design, forms, data managementsystem, formulation of the drug, and analy-sis have all been in progress and should becompleted within a couple of months. It isanticipated that the Phase III study willbegin in the Spring of 1976 and that induc-tion of these patients will be completed bythe Fall of 1976. An additional 40 weekperiod will be needed for the follow-up ofthe last patients included in the Study andtime will need to be available for the finaldata analysis and collection. Therefore, itis anticipated that the Phase III study willbe completed late in 1977. Hopefully bythat time of the other animal and humandata will be comleted to allow the award ofa NDA for LAAM. Therefore, beginning in1978 there may be another maintenance treat-ment modality available for the treatmentof heroin addiction.

111

Dr. Cooper is Special Assistant to the Director ofNIDA's Division of Commmunity Assistance (DCA). Hehas been its liason to the Division of Researchduring Phase II and III of the LAAM studies. BeyondPhase III DCA will continue to OVersee NIDA-fundedLAAM treatment programs. Like methadone, LAAMwill be dispensed only through licensed narcoticmaintenance programs. Once LAAM's New Drug Applica-tion is approved, responsibility for continousmonitoring of treatment programs will pass fromNIDA's Division of Research to the Division ofCommunity Assistance.

THE USE OF LAAM IN TREATMENT

James Cooper, M.D.

The purpose of this chapter is to present theNational Institute of Drug Abuse, Divisionof Community Assistance’s (DCA), perspectiveon the usefulness of LAAM as a maintenancedrug in the treatment and rehabilitation ofopiate addicts. One of the major responsi-bilities of the DCA is to administer, monitor,evaluate and establish treatment standardsfor all National Institute of Drug Abusefunded treatment programs. It will becomethe Division’s responsibility to overseethose Federal programs which will administerand dispense LAAM once the drug has receiveda New Drug Application (NDA) and is marketed.

In order to understand our current thinkingregarding the utility of a maintenance drugin the treatment of narcotic dependence, itis important to review, from a historicalperspective, methadone maintenance treatmentover the last ten years. Initially, therewas a tendency to view the addict simply asa person afflicted with a metabolic problemor disease. Methadone was prescribed totreat the symptoms of this chronic metabolicdisease. In this model, methadone wasanalagous to insulin for diabetes and soperceived as a life-saving treatment. In thesame model, LAAM would be similar to a long-acting form of insulin that relieved thepatient of the need for frequent dosing.

In the early stages of development, themethadone clinic emphasized the physician/

client relationship and cast the physicianin a primary decision-marking role. Themedication was considered the primary treat-ment and the understanding of its propertiesand actions was deemed of utmost importanceto staff and the client.

However, it was appreciated from thebeginning that although methadone correcteda biological condition by medically sta-bilizing the addict, this was only one partof the treatment. Pharmacological treatmentwas only one factor in a program whichshould include counseling as well as sup-portive services such as legal vocationaland educational counseling. These supportiveservices were believed necessary to providethe addict with the skills he may never havedeveloped or had lost during his addiction.

In the following years there was a rapidproliferation of methadone maintenanceclinics, due to the heroin epidemic of thelate 60's and the success of this prototypetreatment. Unfortunately, the speed ofproliferation and the great number of addictsneeding treatment overwhelmed the treatmentcapacity. The need for supportive servicesalso outstripped available resources, as aresult, treatment effectiveness declined.

In the last several years more knowledge hasaccumulated from treating larger and morediverse populations of addicts. The model

112

has been made more comprehensive with aware-ness that individualized treatment is neededwhich recognizes the unique psychologicalcharacteristics of each addict. Most clini-cians have come to view methadone as a sta-bilizing treatment tool which can be effec-tively used to engage the client in broaderrehabilitation. Once this engagement occurs,an individualized evaluation and provisionof appropriate treatment services can pro-ceed. Many, now believe that these servicesare the primary rehabilitative tool formost clients.

This gradual shift in emphasis was a resultof our better understanding of the diversityof the people applying for treatment. Theonly common trait shared by all is that theyare narcotic users and are dependent uponopiates. Those who make up this populationhave different reasons for initiating druguse, exhibit different patterns of drug use,relapse for different reasons and have widelydiffering experiences as a result of theirdrug using behavior. The Division’s experi-ence has demonstrated that the etiologies ofaddiction are diverse and complex. Whileunder-education, unemployment, racial orethnic discrimination and environmentalstress may result in drug-taking behaviorfor some, other psychodynamic factorsincluding excessive dependency needs, acompulsive desire to escape from reality anda lack of poor coping mechanisms for stressplay an important role in addiction forothers. Further, total abstinence fromdrugs may not be a realistic goal for alldrug abusers. Thus, the objectives oftreatment have become more complicated andachievement of the goals sometimes becomemore elusive.

With the knowledge gained from experience,DCA is currently encouraging all maintenanceprograms to develop the resource capabilitiesfor treating a diverse population. Such aheterogeneous group requires a number ofdistinct treatment, rehabilitative andresocialization approaches. Pragmaticallythis entails that a program have the capa-bilities of providing legal, vocational, edu-cational, psychological and medical serviceseither within the program or through referralsources.

The diversity in the treatment populationhas resulted in wide variation as to thelength of time an individual receives metha-done and the intensity of the counselingintervention. Some patients only want detox-ification or short-term maintenance, whileothers may need or request long periods ofmaintenance and services. The well-run

clinic usually will have some clients whoare receiving methadone and very low-keyprogramming either because the initialassessment of the client revealed that theycould not tolerate intensive psycho-socialintervention or because there was no indica-tion of need for such service. However,many other clients will require varyingdegrees of psycho-social and vocationalintervention based on the client’s past andcurrent behavioral performance.

Each program has been encouraged to vieweach patient as a unique individual withhis own personal combination of strengthsand weaknesses which must be continuallyassessed in order to tailor a treatmentregimen appropriate for each patient.

The Federal Funding Criteria for Drug Treat-ment Services was developed in part toinsure that this individualized approach beincorporated by all Federally-funded pro-grams. One section of the Federal FundingCriteria requires that an individualizedtreatment plan be developed for each patientand that periodic evaluation of the planoccur. Such a requirement should providethe staff with an instrument to insure that(1) each patient’s strengths and weaknessesare assessed, (2) a determination is madeof the appropriate types of supportiveservices needed (if any) and (3) the extentof counselor involvement necessary to meetthe objectives of the treatment plan isascertained. The ongoing individual evalua-tive process will provide the staff with aperiodic testing and redefining of thepatient’s progress (or lack of progress)and encourage the counselor to search forthe contributing dynamics of the patient’ssuccess or failure.

Although the advent of LAAM may not intro-duce treatment changes, for some patientsand programs, LAAM may provide some distinctpharmacologic and therapeutic advantages tomethadone based on existing clinical studies.

The 1975 White Paper on Drug Abuse producedby the Domestic Council Drug Abuse TaskForce recommends "switching from methadoneto LAAM...in treating opiate-dependent per-sons as soon as its safety and efficacyhave been determined." This recommendationis based on the potential benefits to pro-grams and patients of three times a weekdosage. Some of these benefits are: lessdrug diversion into illicit channels; morecost-effective treatment; and less inter-ference with patients’ daily work schedules,education and rehabilitation efforts orresponsible homemaking.

113

Several other potentially advantageous thera-peutic characteristics of LAAM have beenobserved. Among them are that LAAM helpschange the individual’s and clinic’s focusfrom daily preoccupation with drugs and drug-taking to an emphasis upon human relation-ships and development of alternative activ-ities, life style and peer group relation-ships. Furthermore, LAAM’s smoother,sustained, drug effect apparently allows someindividuals to feel more alert, more emotion-ally level, less "high", and less habituated.It’s longer duration of action may allowLAAM to be used for detoxification frommethadone maintenance or heroin. Clinicianshave noticed that some patients appear to beable to detoxify from LAAM maintenanceeasier than from methadone maintenance. ThisDivision will watch the Phase III LAAMStudies closely to determine if these obser-vations/findings are substantiated in thelarger population to be studied in Phase IIIlarge scale clinical trial.

The availability of two maintenance agentsmay provide for increased treatment flexi-bility. For example, Sequential TreatmentEmploying Pharmacologic Support (STEPS) hasbeen proposed by Dr. Avram Goldstein as analternative treatment method. STEPS ischaracterized by sequential use of a varietyof pharmacologic agents each progressivelydecreasing narcotic induced euphoria andincreasing social rehabilitation. The STEPfrom daily methadone to three times weeklyLAAM would represent a safe and very stableopiate dependence with virtually no subjec-

tive euphoria and less dependence on theclinic. This novel approach would naturallyhave to be investigated with a limitednumber of individuals to determine itseffectiveness but does provide a potentialalternative, particularly for those who havebeen unsuccessful in remaining abstinentfollowing a particular maintenance regime.

The Division of Commmunity Assistance doesnot currently anticipate that LAAM implemen-tation will lead to dramatic alteration inthe current Federal opiate addiction treat-ment policy or philosophy. LAAM appears tobe an alternative to, rather than a replace-ment for, methadone. Some individuals dobetter on one or the other drug, probablydue to either pharmacological, psychologicalor social factors not yet understood.Furthermore, LAAM is not viewed as a pharma-cologic panacea for all opiate addicts. Noknown drug, including LAAM, can cure oralleviate psychosocial and economic impover-ishment. For some opiate addicts, LAAM, likemethadone, may be the primary treatment.For others, temporary pharmacotherapeuticstabilization will act merely as a tool toengage the narcotic-dependent individualinto participation in a comprehensivetreatment program, concomitantly utilizingextensive psychological socio-economical andvocational rehabilitation services. Andothers may require no pharmacological sup-port at all. LAAM provides one more choicein tailoring treatment to each individual’sneeds.

114

The following article is from a transcriptof remarks given by Dr. Avram Goldstein atNIDA, Rockville, Maryland, May 19, 1976.

A CLINICAL EXPERIENCE WITH LAAM

Avram Goldstein, M. D.

I would like to discuss our clinical experi-ence with LAAM. Several years ago we did apilot trial with LAAM in the Santa ClaraCounty Methadone Program with about 60patients. Some of them were Put directly on-to LAAM, off the street, so we had thatexperience; and others crossed over frommethadone to LAAM. Now in the last year wehave put 165 addicts directly off the streetonto LAAM. So that my remarks here are basedon this accumulation of experience.

PHARMACOLOGY

There is the pharmacology issue. That’sturned out, I think, to be the most inter-esting part of our experience with LAAM. Letme start by stating that: I think LAAM is abetter drug than methadone, from a pharmaco-logical point of view. I think patients knowthat and understand it too. Let me describewhat I mean.

Now, in pharmacology, quite apart from anyregulatory questions or the issue of diversion,in the development of any drug, one of theimportant objectives is to get a lastingstable effect. I need only refresh your mem-ory about the history of insulin. As youknow the early insulins had to be admininis-tered several times a day. It was a very

tricky operation, because when you gave theinsulin, you got too much insulin effect;then it wore off and you had too littleinsulin effect. The problem was to stablizethings so that there would be a lasting effectof insulin in the patient. Tremendous effortwas directed toward developing a long-actinginsulin which you could give once a day to getstable coverage. Finally that was achieved.For almost every drug there is the same prob-lem of developing stability of action, so thatthere will not be fluctuation up into the tox-ic range and then down below the therapeuticrange.

Now, let's look at methadone in those terms.Methadone is a tremendous improvement overheroin! which has to be administered four orfive tunes a day, giving continual highs andlows. That's why methadone was introduced, ofcourse. Nevertheless, you all know that whenpatients come in, in the morning, for theirmethadone, many are at the very edge of with-drawal; they feel "icky" (as they say). Youalso know that after they take their methadone,within the next hour or so, they feel it hitthem; they feel a sense of warmth that startsin the abdomen and spreads through the body.They're getting partially "loaded" every morn-ing with methadone, and they’re partially

115

"sick" every morning before they get theirmethadone. That's not a comfortable condi-tion to be in, but they’re a lot better offthan they were when they were using heroin.

The lasting effect that LAAM produces makesthe patients feel better. Every patient I’vespoken to who has been on both methadone andLAAM remarks on this--how he feels just gen-erally better--more under control, more stableless of this up and down. And they don’t feelsick at the end of the period.

Now, if patients have enjoyed the feeling ofmethadone relieving an incipient withdrawal!and if that’s been an important part of theirdaily pattern, transferring their gettinghigh on heroin to getting drug-induced satis-faction once a day on methadone, then they’renot going to like LAAM; there is no questionabout it. Some patients really want thatfeeling on methadone, so that in the long runwe're probably not going to just replacemethadone with LAAM. There are going to bepatients who need that feeling and it may takethem a long time before they’re ready to-giveit up. But there are also a lot of patientswho don’t want that. who are really willingto make the transition and give up that sen-sation, and those patients much, much preferto be on LAAM.

The So-Called "Week-end Problem"

Let me give you an example of a pseudoproblemthat turned out not to exist with LAAM. Insome places LAAM was introduced as "48-hourmethadone". The patients, who are by no meansstupid, immediately thought, "Well, if it’sa two-day methadone, then how will I getthrough the weekend? I’ll be sick on Mondaymorning." And they were sick on Monday morn-ing ! But LAAM actually has a very long dura-tion of action, at least over a three- to four-day period. Without going into the compli-cated pharmacokinetics, that means if you getthe dose of LAAM on Monday you’re in a stablestate when you come in Wednesday morning.That Monday dose hasn’t disappeared; it ispicked up and carried along by the Wednesdaydose and that is picked up and carried alongby the Friday dose, and on Monday morning theeffect of the Friday dose is still there. Inother words, you’re getting a stable effect.We have some very interesting data on that.

To have you understand the data, I will haveto tell you the way we control dosage. Dos-age is self-controlled by patients, who followthe same principle we described in that art-icle about patient control of methadone dos-age (J. Amer. Med. Ass. 234:734, 1975). Theabsolute ceiling is 75 mg. of LAAM on Mondayand Wednesday, 100 mg. on Friday. Now up to

that ceiling patients can set their own dos-ages. Our rule is that on Friday the patientis allowed to increase, if he wants to, byabout 30%. Thus, if he is taking 75 he canincrease to 100, if he is on 50 he can raiseit to 65, and so on.

The question is, with that opportunity, dopatients actually do it? Now, obviously, ifthey felt sick on Monday morning, they wouldraise their Friday dose to try to take careof that feeling of being sick. The interest-ing thing we found is that the great majorityof patients do not make any increase in theirFriday dose; in other words, they’re votingthat the LAAM takes care of them over theweekend. About one-third of the patients domake a Friday increase of varying degree.The average increase on Friday is very small,but some patients do take full advantage ofthe opportunity. This result tells us thatthe "weekend problem" is largely a non-problem,as long as anxiety is minimized. If the staffis worried that LAAM is not going to lastthrough the weekend, and conveys their anxie-ties to the patient, then you get this tre-mendous psychological effect.

Patient Reaction to LAAM

If you ask our patients: "How do you likeLAAM," they vote affirmatively. I have notknown an exception to that. Some of thepatients who have experienced methadone inthe past prefer LAAM; others have neverexperienced methadone and have nothing tocompare it to but they feel that it "holds"them in a stable way. Our experience withthe laboratory data has been the same as inthe Phase II study. We don't find any signif-icant abnormalities in all of the carefulchecks that we have been making. Efficacy isvery good, as measured by suppression ofheroin use. It's as good or better thanseen in methadone clinics in our area.

Finally, we have been pleasantly surprised toto find, at least in some patients, that LAAMcan be discontinued with less discomfort thanwe were used to with methadone withdrawal.There is still the problem of anxiety exacer-bating withdrawal problems for some patients,and there are certainly patients who have theusual problems with withdrawal (especiallyinsomnia, as with methadone withdrawal). Wehave observed some patients, however, whosimply stopped taking LAAM at a dosage of 50mg or above, and experienced no withdrawalsymptoms at all. It is possible that the longduration of action and the long persistence ofthe LAAM metabolites in the body produce asituation in which the drug detoxifies itself(so to speak), tapering itself over a long

116

enough time to minimize any acute withdrawaldistress. This requires more research, how-ever; we are not now claiming that mostpatients can detoxify more easily from LAAMthan from methadone.

TAKE-HOME POLICY

The third point is a very significant one.In our clinic we, of course, have no takehome-- ever. Patients understand from the out-set that takehome just doesn't arrive; it'snot in the cards. We never use any methadoneon the premises--exclusively LAAN consumedright there. For patients who are to be awayfor a while, we have had no difficulty at allin substituting methadone (e.g., by arrange-ment at a clinic in another city) and thenresuming LAAM when they return.

There is a remarkable consequence of thispolicy. You may not realize how much of theunpleasantness and hassle in your clinicoperation is related to the issue of takehomeprivileges, and how much of the deceit andgameplaying, manipulation and wasted staff

time and energy and argumentation is relatedto that issue of takehome. It corrupts theurine collection system. As long as takehomedepends on clean urines, you really cannottrust the urine collection, because it paysto cheat. It doesn't make any difference ifit’s called an "observed" urine collectionor not. The potential for cheating and cor-ruption is always there. With LAAM, sud-denly, all that disappears. There is a quiteincredible change in the whole attitude ofthe clinic. There is just no more argumenta-tion about things like that. Patients levelwith their counselors about their drug use,and urines can be believed. I think it’sfair to say that an awful lot of staff timeand energy is wasted otherwise. This timeand energy can now be devoted to patientwelfare and to effective counseling, onceyou eliminate the takehome business andeverything that goes with it. Unfortunately,I don’t know how to measure these effects;they are major effects; everybody on ourstaff is convinced of that, but I don’t knowhow to produce objective data to prove it,so I can only report it anecdotally to you.I think it is one of the major advantagesof LAAM.

AUTHOR

Dr. Avram Goldstein is Director of theAddiction Research Foundation, 701 WelshRoad, Palo Alto, California, 94304.

117

PRECLINICAL

Adler, F.L. Excerpts from LAAM-relevant re-search. 1975. (Unpublished) publicHealth Research Institute of the City ofNew York, Inc.

Billings, R.E., Booher, R., Smits, S., Poh-land, A., McMahon, R.E. Metabolism ofacetylmethadol. A sensitive assay fornoracetylmethadol and the identificationof a new active metabolite. Journal ofMedical Chemistry, 16:305-306, 1973.

Billings, Q.E., McMahon, R.E. The metabo-lism of acetylmethadol in the rat: a sen-sitive assay for nor-acetylmethadol andthe identification of a new active meta-bolite. Federation Proceedings, 32:764Abs, 1973.

Booher, R., Pohland, A. Synthesis of a newmetabolite of acetylmethadol. Journal ofMedical Chemistry, 18:266-268, 1975.

Casy, A.F., Hassan, M.M.A. Configurationalinfluences in methadol and nonnethadolanalgesics. Journal of Medicinal Chemis-try, 11:3, p. 601-603, 1968.

Chatterjie, N., Inturrisi, C.E. Synthesisof alpha-1-noracetylmethadol. A facileN-demethylation of alpha-1-acetylmethadol.Journal of Medicinal Chemistry, 18(6):630-631, 1975.

Chen, K.K. Pharmacology of methadone andrelated compounds. Annals of the New YorkAcademy of Sciences, 51:83-97, 1948.

Deneau, G.A., Seevers, M.H. Annual reporton drug evaluation. Committee on DrugAddiction and Narcotics and The Committeeon Problems of Drug Dependence, NationalResearch Council, Division of MedicalSciences. 21st Meet., Addendum 1, 1960.(Unpublished) State of New York Narcotic

LAAM BIBLIOGRAPHY

Addiction Control Commission, Brooklyn,New York.

------. Annual report on studies in themonkey (Macacca mulatta) designed to de-termine the value of this animal for ore-dieting addiction liability to the newersynthetic analgesics. Committee on DrugAddiction and Narcotics and The Cammitteeon Problems of Drug Dependence, NationalResearch Council, Division of MedicalSciences. 15th Meet., App. K, p. 1150,1955. (Unpublished) State of New YorkNarcotic Addiction Control Commission,Brooklyn, New York.

------. Evaluation of morphine-like physicaldependence in the Rhesus monkey (Macaccamulatta). Committee on Drug Addictionand Narcotics and The Committee on Prob-lems of Drug Dependence, National ResearchCouncil, Division of Medical Sciences,24th Meet., Addendum 2, 1962. (Unpublish-ed) State of New York Narcotic AddictionControl Commission, Brooklyn, New York.

Eddy, N.B., May, E.L., Mosettig, E. Chemis-try and pharmacology of the methadols andacetylmethadols. Journal of Organic Che-mistry, 17(2):321-326, 1952.

Eddy, N.B., Touchberry, C.F., Lieberman, J.E.,Khazan, N. Synthetic analgesics; metha-done isomers and derivatives. Journal ofPharmacology and Experimental Therapeutics98:121-137, 1950.

Farrand, R.L., McNamara, B.P., Christensen,M.K. Final report. Toxicological testingof 1-alpha-acetylmethadol. 1974. (Unpub-lished) Prepared at Edgewood Arsenal, A-berdeen Prooving Ground, Maryland.

118

Henderson, G.L. Third-quarter progress re-port. Two-year pharmacokinetic studyof LAAM. 1974a. (Unpublished) Preparedunder Contract HSM 42-73-211 at the Uni-versity of California at Davis.

Fourth quarter 1974b.

Fifth quarter 1974c.

Sixth quarter 1975a.

Seventh quarter 1975b.

Eighth quarter 1975c .

Ninth and final quarter 1975d.

Henderson, G.L., Westkaemper, R. Stereotypyfollowing acute administration of l-alpha-acetyl-methadol (LAAM) in the rat. Pro-ceedings of the Western Pharmacologicalsociety, 18:204-207, 1975.

3Henderson, G.L. Biological fate of H-LAAM

in rat, dog and monkeys. Proceedings ofthe National Drug Abuse Conference, NewYork, March 28, 1976.

Industrial Biotest. Report to National In-stitute on Drug Abuse. One-year chronicoral toxicity study with LAAM in beagledogs. 1975. (Unpublished) Preparedunder Contract HSM-42-73-178 at North-brook, Illinois.

Industrial Biotest. Report to the NationalInstitute of Mental Health. Perinataland lactation performance study with LAAMin albino rats. 1973. (Unpublished)Prepared under Contract HSM-42-72-171 atNorthbrook, Illinois.

Teratogenic study with LAAM in al-bino rabbits. 1973. (Unpublished) Pre-pared under Contract HSU-42-72-171 atNorthbrook, Illnois.

Industrial Biotest. Report to NationalInstitute on Drug Abuse. Acute oraltoxicity study with LAAM in albino rats.1975. (Unpublished) Prepared underContract HSM-42-72-171 at Northbrook,Illinois.

42-day pilot study with LAAM infemale albino rabbits. 1975. (Unpub-lished) Prepared under Contract HSM-42-72-171 at Northbrook, Illinois.

Inturrisi, C.E., Kaiko, R.F. The role ofactive metabolites in the duration of ac-tion of acetylmethadol in man. Proceed-ings of the Naional Drug Abuse Conference

New York, March 28, 1976.

Iwang, E.E., Primm, B.J., Bath, P.E. Evi-dence for the stimulant and depressantcentral effects of L-a-acetylmethadol.Experientia, 31:203-205, 1975.

Kaufman, J.J., Koski, W.S., Benson, D.W.,Semo, N.M. Measurement of the pka's,partition and drug distribution coefi-cients of narcotics and narcotic antago-nists, their PH and temperature dependenceand their significance in clinical prac-tice . Problems of Drug Dependence, 435-452, 1975.

Kepler, J.A., Sparacino, C.M., Wall, M.E.Synthesis of labeled narcotics and nar-cotic antagonists. Quarterly Report No.2,1974a. (Unpublished) Prepared underContract HSM-42-73-184 (ND) at ResearchTriangle Institute, Research Triangle park,North Carolina.

Synthesis of labeled narcotics andnarcotic antagonists. Quarterly ReportNo. 3, 1974b.

Synthesis of labeled narcotics andnarcotic antagonists. Annual Report,1974c.

Synthesis of labeled narcotic andnarcotic antagonists. Combined 5th Quarterly Report and 6th Quarterly Report,1975.

Khazan, N. Progress report. Narcotic anta-gonists methadone and morphine addiction.(Unpublished) Prepared under Grant DA00461 at New York State Narcotic AddictionControl Commission, Brooklyn, New York.

Killam, K. Cumulative report. Interactionstudies on narcotics and narcotic anta-gonists in animals. 1974. (Unpublished)Prepared under Contract HSM-42-73-263 atUniversity of California at Davis.

Progress report. Interaction stu-dies in morphine-dependent monkeys. 1975.

Comparison of the effect of 1-alpha-acetylmethadol (LAAM) and methadone inmacaca mulatta. Proceedings of the West-ern Pharmacological Society, 17:519-561,1974.

Kochhar, M. Isolation and identificationof metabolites of alpha-l-acetylmethadol.Summary report. 1975. (Unpublished)Auburn University, Auburn, Alabama.

119

Leimbach, D.G., Eddy, N.B. Synthetic anal-gesics: III. Methadols, isomethadols,and their acyl derivatives. Journal ofPharmacology and Ezperimental Therapeu-tics, 110(2):135-147, 1954.

Levine, W.G. Letter report on l-alpha-ace-tylmethadol (LAAM). 1975. (Unpublished)Albert Einstein Medical College, Bronx,New York.

Maickel, R. Progress reports for contractnumber PHS HSM 42-73-226. Excerpts aboutLAAM from: quarterly progress reports#4, #5 and #6. 1974. (Unpublished)Indiana University, Bloomington, Indiana.

May, E.L. The methadone story. Aldrichimi-ca Acta, 5:38-40, 1972.

May, E.L., Eddy, N.B. The isomethadols andtheir acetyl derivatives. Journal ofOrganic Chemistry, 17(2):1210-1215, 1952.

May, E.L., Mosetting, E. Some reactions ofamidone. Journal of Organic Chemistry,13:459-464, 1948.

------. Some reactions of isoamidone. Jour-nal of Organic Chemistry, 13:663-665,1948.

May, E.L., Perrine, T.D. Wagner rearrange-ment of a-dl-6-dimethyl-amino-4, 4-di-phenyl-3-heptanol (a-dl-methadol). Jour-nal of Organic Chemistry, l8:1572-1577,1953.

McCarthy, D.A. Preclinical toxicity andpharmacology testing of narcotic anta-gonists. #46, l-d-acetylmethadol: anti-nociceptive studies in rats. 1974a.(Unpublished) Prepared under ContractHSM-42-72-167 at Parke, Davis, and Com-pany, Ann Arbor, Michigan.

Preclinical toxicity and pharma-cology testing of narcotic antagonists.#40: Sixth quarterly report. 1973.

Preclinical toxicity and pharma-cology testing of narcotic antagonists.#47: Seventh quarterly report. 1974a.

McIntyre, J.A., Armandi, A.E., Risen, L.P.,Ling, W., Harberfelde, G.C. This-largechromatography and enzyme inmunassy of1-alpha-acetyl-methadol and methadonemetabolites in urine. Clinical Chemistry(Winston-Salem, N.C.) 21(1):109-112, 1975.

McMahon, R.E., Culp, H.W., Marshall, F.J.The metabolism of -dl-acetylmethadol inthe rat: the identification of the

probable active metabolite. Journal ofPhamracology and Experimental Therapeutics149(3):436-445, 1965.

Merck Institute. MK-790 preclinical evalu-ation. 1965. (Unpublished) Merck andCo., Inc., West Point, Pennsylvania.

Misra, A.L., Bloch, R., Mule, S.J. Estima-tion of (2-3H) l -acetylmethadol inbiological materials and its separationfrom some metabolites and congeners onglass fibre sheets. Journal of Chroma-tography, 106(1):184-187, 1975.

Misra, A.L., Vadlamani, N.L., Mula, S.J.Chromatographic Separation of methadone,some of its metabolites and congeners.Journal of Chromatography, 67(2):379-381,1972.

Misra, A.L., Vardy, J., Block, R. Pharmaco-kinetics, metabolism of (3 H) LAAM in themontez and disposition of (3H) naltrexonein the CNS of the rat. Proceedings ofthe National Drug Abuse Conference, NewYork, March 28, 1976.

Moreton, .J.E., Roehrs, T., and Khazan, N.Patterns of drug self-administration andsleep-awake activity during the state ofdependence on morphine, methadone and 1-alpha-acetyl-methadol (LAAM) in the rat.Proc. Comm. Drug Dependence 36th Meet.,National Academy of Sciences, NationalResearch Council, 1008-1016, (1974).

Sleep-awake activity and self-in-jection pattern of rats dependent on mor-phine, methadone, or L-alpha-acetyl-me-thadol (LAAM). Federation Proceedings,33(3):516, 1974.

Nakamura, J., Henderson, G.L., Winters, W.D.Behavioral and EEG electroenceohalographyeffects of 1-alpha-acetylmethadol(LAAM)in the rat. Proceedings of the WesternPharmacological Society, 17:155-158, 1974.

Nickander, R., Booher, R., Miles, H. -1-acetylmethadol and its N-demethylated me-tabolites have potent opoiate action inthe guinea pig isolated ileum. Life Sci-ences, 14:2011-2017, 1974.

Morphine-like agonist effects ofa-acetylmethadol, d-methadone and theirmetabolites on the-guinea pig isolatedileum. Federation Proceedings, 32:764Abs,1973.

North-Root, H., Kuttab, S.H., Henderson, G.L.Biological disposition and transformationof 1-a-acetylmethadol in the monkey, dog,

120

and rat. Problems of Drug Dependence,645-657, National Research Council,National Academy of Sciences. 37th Annu-al Scientific Meeting, 1975.

Biliary metabolism and excretionof 3H LAAM in the rat. Problems of DrugDependence, 1012-1017. 37th Annual Sci-entific Meeting, 1975.

Perrine, T.D., May, E.L. Synthesis of 6-dimethylamino-4, 4-dinhenyl-heptane andother compounds related to methadone.Journal of Organic Chemistry, 19:773-779,1954.

Phatak, N.M., David, N.A. Addiction poten-tialities of some methadone analgesicsand alpha acetylmethadol as determinedby their hyperglycemic responses in rab-bits. Current Research in Anesthesia andAnalgesia, 32:242-249, 1953.

Pohland, A., Marshall, F.J., Carney, T.P.optically active compounds related tomethadon. Journal of the American Chemi-cal Society, 71:460-462, 1949.

Portaghese, P.S., Williams, D.A. Stereo-chemistry of methadol diastereomers.Journal of Phamacological Science, 55:990-991 , 1966.

Rosenkranz, R.P., Henderson, G.L. Renaltoxicity of 1-aloha-acetylmethadol (LAAM)in the rat. Proceedings of the WesternPharmacological Society, 18:284-287,1975.

SAODAP. Background information on the useo f l-alpha-acetylmethadol (LAAM) andmethadone as maintenance drugs duringthe rehabilitation of heroin addicts.(Unpublished) (Office disbanded; dutiesassumed by NIDA).

Seevers, M.H. Summary of data on Wy-401.Committee on Drug Addiction and Narcoticsand The Committee on Problems of DrugDependence, National Research Council,Division of Medical Sciences. 13th Meet.,App. K, p. 936, 1954. (Unpublished)University of Michigan Medical Center.

Sherrod, T.R., Kaiser, R., Santos-Martinez,J., Pfeiffer, C.C. Methadone derivativesof pharmacological interest. FederationProceedings, 7:255, 1948.

Smith, C.C., Lehman, E.G. Effects of anal-gesic combinations on reaction time inrats. Journal of Pharmacology and Expeperi-mental Therapeutics, 108:336-339, 1953.

Smits, S.E. The analgesic activity of -l-acetylmethadol and two of its metabolitesin mice. Research Communications in Che-mical Pathology and Pharmacology, 8(3):575-578, 1974.

Speeter, M.E., Byrd, W.M., Cheney, L.C.,Binkley, S.B. Analgesic carbinols andesters related to amidone (methadon).Journal of American Chemistry Society,71:57-60, 1949.

Stickney, J.L. L-alpha-acetylmethadol(LAAM)cardiovascular effects. Summary state-ment, 1974. (Unpublished) Michigan StateUniversity, East Lansing, Michigan.

Sullivan, H.Q., Due, S.L., McMahon, R.E.Enzymatic reduction. An important path-way in the biotransformation of metha-done in man and rat. Federation Pro-ceedings, 32:764Abs, 1973.

Metabolism of -l- -methadol. N-ace-tylation, a new metabolic oathway. Re-search Communications in Chemical Patho-logy and Pharmacology, 6(3):1073-1078,1973.

Sung, C.Y., Way, E.L. The fate of the opti-cal isomers of alpha-acetylmethadol.Journal of Pharmacology and ExpeperimentalTherapeutics, 110:260-270, 1954.

Van Arsdel III, W.C., David, N.A. Modification-tion of morphine, l-isomethadone, dl-al-pha-acetylmethadol, and n-allylnormor-phine constipation by hydergine. Journalof the American Pharmaceutical Associa-tion, 45:645-649, 1956.

Veatch, R.M., Adler, T.K., Way, E.L. Theimportance of steric configuration incertain morphine-mimetic actions of syn-thetic analgesics. Journal of Pharmaco-logy and Experimental Therapeutics, 145:11-19, 1964.

Venkateswaran, N., Cholewa, R. Final reporton research Contract No. HSM 42-72-124.1973. (Unpublished) Regis Chemical Com-pany, Morton Grove, Illinois.

Way, E.L., Adler, T.K. The biological dis-position of morphine and its surrogates.III. Synthetic surrogates of morphine.Bulletin of the World Health Organization(Geneva), 26(2):261-284, 1962.

The biological disposition of mor-phine and its surrogates--2. Bulletinof the World Health Organization, 26:51-66, 1962.

121

The pharmacologic implications ofthe fate of morphine and its surrogates.Pharmacological review, 12:383-446, 1960.

Welling, P.G. Pharmacokinetic studies onL-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 the38th Annual Scientific Meeting of theCommittee on Problems of Drug Dependence,Richmond, Va., June 7-9, 1976. NationalAcademy of Sciences, 1976.

12 2

LAAM BIBLIOGRAPHY

CLINICAL

Anonymous. Methadone and acetylmethadolmaintenance. (Editorial) Journal ofthe American Medical Association, 211(11) :1847-1848, 1970.

Beecher, H.K. Analgesic power and thequestion of "acute tolerance" to narco-tics in man. Journal of Pharmacologyand Experimental Therapeutics, 108: 158-167, 1953.

Billings, R.E., McMhahon, R.E., Blake, D.A.l-acetylmethadol (LAAM) treatment ofopiate dependence: plasma and urinelevels of two pharmacologically activemetabolites. Life Sciences, 14: 1437-1446, 1974a.

l-acetylmethadol treatment ofopiate dependence: the crucial roleof active metabolites. FederationProceedings ,33(3):473,1974b .

Fink, M., Levomethadyl (LAAM): A long-act-ing substitute for methadone maintenancetherapy of opiate dependence. CurrentPsychiatric Therapies, XIII:151-155, 1973.

Blachly, P.H. L-alpha-acetylmethadol inthe treatment of opiate addiction:Progress Report, 1971. Methadone, 1971Workshop Proceedings, P.H. Blachly, Ed.,ACEB Books, Corvallis, Oregon, 1971.p. 23-25.

Blachly, P.H., David, N.A., Irwin, S. Al-pha-acetylmethadol (LAM): comparisonof laboratory findings, electroencepha-lograms, and Cornell Medical Indexof patients stabilized on LAM with thoseon methadone. proc. of Fourth Natl.Conf. on Methadone Treatment, San Fran-cisco, Jan. 1972, pp. 203-205.

Fraser, H.F., Isbell, H. Actions and addic-tion liabilities of alpha-acetylmethadolsin man. Journal of Pharmacology andExperimental Therapeutics, 105(4): 458-465, 1952.

Fraser, H.F., Nash, T.L., Vanhorn, G.D.,and Isbell, H. Use of miotic effect inevaluating analgesic drugs in man. Ar-chives Internationales de Pharmacodyna-mie et de Therapie, 98:443-451, 1954.

Goldstein, A. LAAM and LAAM metabolites:plasma levels in patients. Sumnary progress report. 1975. (Unpublished)Stanford University, Stanford, California.

Blaine, J.D., Renault, P.F. NIDA's rolein the development of LAAM. Proceedingsof the National Drug Abuse Conference,New York, March 28, 1976.

Goldstein, A., and Judson, B. Three criti-cal issues in the management of metha-done programs: Critical Issue 3: Canthe community be protected against thehazards of take-home methadone. Addic-tion. Peter G. Bourne, Ed. AcademicPress, New York, p. 140-148, 1974.

David, N.A., Semler, H.J. Clinical trialof alpha-acetylmethadol (dl-6-dimethy-lamino-4, 4-diphenyl-3.acetoxy-heptane)

Goldstein, A., On the Role of Chemotherapyin the Treatment of Heroin Addiction.The Amer. Journal of Drug and Alcohol

as an analgesic. Journal of Pharmaco- Abuse 2:3 and 4 279-288, 1975.123

logy and Experimental Therapeutics, 106:380, 1952.

David, N.A., Semler, H.J., Burgner, P.R.Control of chronic pain by dl-alpha-ace-tylmethadol. Journal of the AmericanMedical Association, 161 (7):599-603,1956.

Dorus, W., Senay, E. LAAM as a maintenancedrug. Proceedings of the National DrugAbuse Conference, New York, March 28,1976.

Goldstein, A., Heroin Addiction - SequentialTreatment Employing Pharmacological Sup-ports. Arch. Gen. Psychiatry 33:135 3-358,1976.

Grevert, P., Manover, B. A controlled studyof the effects of methadone and LAAMmaintenance on memory. Proceedings ofthe National Drug Abuse Conference, NewYork, March 28, 1976.

Gruber, C.M., Jr., and Babtisti, A., Jr.Estimating the acceptability of morphineof noracetylmethadol in postpartum pa-tients. Clinical Pharmacology and Thera-peutics, 4(2):172-181, 1962.

Henderson, G.L. A two-year pharmacokineticstudy of LAAM. Fourth quarter progressreport. 1974. (Unpublished) Preparedunder Contract HSM-42-73-211 at theUniversity of California at Davis.

Sixth quarter progress report, 1975.

Seventh quarter progress report,1975b.

Houde, R.W., Murphy, T.W., Wallenstein, S.L.Clinical studies of narcotics at MemorialSloan-Kettering Cancer Center: A. Rela-tive analgesic potencies of (1) noracy-methadol (dl-a-3-acetoxy-6-methylamino-4, 4-diphenylheptane) and morphine; (2)dextropropoxyphene and pethidine; (3) Ro-4-1778/1 (1- [p-chlorophenethyij -6, 7-di-methoxy-2-methyl-1,2,3,4-tetrahydroiso-quinoline) and codeine; (4) oral codeineand morphine. B. Relative respiratorydepressant potencies of piminodine (ethyl4-phenyl-l-[3-phenylamino-propyl]-4-pi-peridine carboxylate) and morphine. Com-mittee on Drug Addiction and Narcoticsand the Committee on Problems of DrugDependence. National Research Council.Division of Medical Sciences. 24th Meet.,App. 14, p. 2852, 1962. (Unpublished)Sloan-Kettering Cancer Center, New York,New York.

Howe, S., Primm, B.J., Drew, J. A compara-tive analysis of LAAM patients in theinner city and in the suburbs. Proceed-ings of the National Drug Abuse Confer-ence, New York, March 28, 1976.

Irwin, S. Effects of long-ten drug depen-dence. Summary progress report, 1973.(Unpublished) Prepared under Grant RO1-DA-00084 at University of Oregon MedicalSchool, Portland, Oregon.

Irwin, S., Blachly, P.H., Marks, J., Carlson,E., Loewen, J. and Reade, N. Preliminaryresults of methadone and methadyl main-tenance therapy. Proc. Comm. Prob. DrugDependence 35th Meet. National Academyof Sciences, National Research Council(1973).

The behavioral, cognitive and phy-siologic effects of long term methadoneand methadyl treatment. 1973b. (Unpub-lished) University of Oregon MedicalSchool, Portland, Oregon.

Irwin, S., Blachly, P., Marks, J., Carter,C. Preliminary observations with acuteand chronic methadone and l-alpha-ace-tylmethadol administration in humans.(Unpublished) University of Oregon Medi-cal School, Portland, Oregon.

Irwin, S., Kinohi, R., Cooler, P., Bottomly,D. Acute time-dose-response effects ofcyclazocine, methadone, and methadyl inman, (Unpublished) prepared under NIMHContract ND-72-115 at University of Ore-gon Medical School, Portland, Oregon.

Isbell, H. Addiction liability of theacetylmethadols. Committee on DrugAddiction and Narcotics and The Commit-tee on Problems of Drug Dependence, Na-tional Research Council, Division of Me-dical Sciences. 7th Meet., App. C, p.161, 1951. (Unpublished) USPHS Hospital,Lexington, Kentucky.

Isbell, H., Eisemnan, A.J. The addictionliability of some drugs of the methadoneseries and 6-methyldihydromorphine. Com-mittee on Drug Addiction and Narcoticsand The Committee on Problems of DrugDependence, National Research Council,Division of Medical Sciences. 2nd Meet.,App., p. 28, 1948. (Unpublished) USPHSHospital, Lexington, Kentucky.

Isbell, H., Fraser, H.F. Addictive proper-ties of methadone derivatives. Journalof Pharmacology and Experimental Thera-py, 13:369-370, 1954.

Jaffe, J.H., Schuster, C.R., Smith, B.B.,Blachly, P.H. Comparison of acetyl-methadol and methadone in the treatmentof long-term heroin users: A pilot study.Journal of the American Medical Associa-tion, 211:1834-1836, 1970.

Comparison dl-alpha-acetylmetha-dol and methadone in the treatment ofnarcotics addicts. Pharmacologist,11(2):256, 1969.

124

Jaffe, J.H., Senay, E.C. Methadone andl-methadylacetate. Use in managementof narcotics addicts. Journal of theAmerican Medical Association, 216: 1303-1305, 1971.

Jaffe, J.H., Senay, E.C., Renault, P.F. Asix-month preliminary report of the re-habilitative efficacy of l-methadyl ace-tate compared to methadone. Proc. ofFourth Natioral Conference on MethadoneTreatment, San Francisco, Jan. 1972, Pp.199-201.

Jaffe, J.H., Senay, E.C., Schuster, C.R.,Renault, P.F., Smith, B., DiMenza, S.Methadyl acetate vs methadone. A double-blind study in heroin users. Journal ofthe American Medical Association, 222(4):437-442, 1972.

Kaiko, R.P., Chatterjie, N., Inturrisi, C.E.Simultaneous determination of acetyl-methadol and its active biotransformationproducts in human biofluids. Jounnal ofChromatography, 109(2):847-858, 1975.

Kaiko, R.F., Inturrisi, C.E. A gas-liquidchromatographic method for the quantita-tive determination of acetylmethadol andits metabolites in human urine. Journalof Chromatography, 82(2):315-321, 1973.

Disposition of acetylmethadol inrelation to the pharmacological activity.Clinical Pharmacology and Therapeutics,18(1):96-103, 1975.

Identification of some biotrans-formation products of acetylmethadol inhuman urine. Federation Proceedings, 32:764Abs, 1973.

Time course of plasma levels ofacetvlmethadol and biotransformationproducts in relation to pharmacologicalactivity in man. Federation Proceedings,33(3):473, 1974.

Keats, A.S., Beecher, H.K. Analgesic acti-vity and toxic effects of acetylmethadolisomers in man. Journal of Pharmacologyand Experimental Thempeutics, 105:210-215, 1952.

Klett, C.J. VA-SAODAP cooperative study ofl-alpha-acetylmethl vs methadone. Re-port.. 1975. (Unpublished) CentralNeuropsvchiatric Research Laboratory.Veterans Administration Hospital, PerryPoint, Maryland.

SAODAP cooperative study of levo-alpha-acetylmethadol vs methadone. Finalreport 1976. (Unpublished). NIDA GrantNo. DA01383, Friends Medical ScienceResearch Center, Baltimore, Maryland.

Lehmann, W.X. The use of l-alpha-acetylme-thadol (LAAM) as compared to methadonein the maintenance and detoxification ofyoung heroin addicts. 1973. (Unpub-lished) Vitam Center, Norwalk, Connec-ticut.

Levine, R., Zaks, A. Duration of action(cross-tolerance) of levomethadyl. 1972.(Unpublished) New York Medical College,New York, New York.

Levine, R., Zaks, A., Fink, M., Freedman,A.M. Levomethadyl acetate. Prolongedduration of opioid effects, includingcross tolerance to heroin, in man. Jour-nal of the American Medical Association,226(3):316-318, 1973.

Ling, w., Charuvastra, V., Klett, J.C.Current status of the evaluation ofLAAM as a maintenance drug for heroinaddicts. NIDA Narcotic Antagonist Clinical Research Conference, Seattle, Wash-ington, 1974. (Unpublished) VA Hospi-tal, Sepulveda, California.

Ling, W., V.C. Charuvastra, and C.J. Klett:Current Status of the Evaluation of LAAM asa Maintenance Drug for Heroin Addicts.The Amer. Journal of Drug and AlcoholAbuse, 2:3 and 4 307-319, 1975.

Ling, W., Charuvastra, V.C., Kaim, S.C.,Klett, C.J. Acetylmethadol and metha-done as maintenance treatments for heroinaddicts. A Veterans Administration Co-operative Study. Archives of GeneralPsychiatry, 1976.

Ling, W., Klett, G.J. Clinical safety andefficacy of LAAM - the collective V.A.,and SAODAP-NIDA experience. Proceedingsof the National Drug Abuse Conference,New York, March 28, 1976.

Mendelson, J.H., Inturrisi, C.E., Renault,P., and Senay, E.C. Effects of acetyl-methadol on plasma testosterone. Clini-cal Pharmacology and Therapeutics, 19(3) :371-374, 1976.

Misra, A.L. and S.J. Mule: l-a-Acetylmethadol(LAAM) Pharmacokinetics and Metabolism:Current status. The Amer. Journal of Drugand Alcohol Abuse, 2:3 and 4 301-306, 1975.

125

Newmann, M.C., C.J. Klett, and R. Stillman:Implementing a National Study of a NewMaintenance Drug. The Amer. Journal ofDrug and Alcohol Abuse. 2:3 and 4 289-300. 1975.

Parwatikar, S., J. Crawford, and C. Unverdi:WULM (l -a-Acetylmethadol) Study in St.Louis. The Amer. Journal of Drug andAlcohol Abuse, 2:3 and 4 341-352, 1975.

Resnick, R., Orlin, L., Geyer, G., Schuyten,E., Kestenbaum, R., Freedman, A.M. l-alpha-acetylmethadol (LAAM): Prognosticconsiderations. Presented at the 128thAnnual Meeting of the American Psychia-tric Association, 1975. (Unpublished)New York Medical College Hospital, NewYork, New York.

SAODAP. Background information on the useof l-alpha-acetylmethadol (LAAM) andmethadone as maintenance drugs duringthe rehabilitation of heroin addicts.(Unpublished) (Office disbanded; dutiesassumed by NIDA).

Savage, C., Karp, E., Curran, S. A metha-done/l-alpha-acetylmethadol (LAAM) main-tenance study. Comprehensive Psychiatry,1976. (In press)

Schecter, A., Kauders, F. Patient deathsin a narcotic antagonist and long-actingmethadone program. NIDA Narcotic Anta-gonist Clinical Research Conference,Seattle, Washington, 1974. (Unpublished)Kings County Hospital, Brooklyn, NewYork.

Schecter, A., and F. Kauders: Methadone andl-a-Acetylmethadol in a Treatment Programin Brooklyn. The Amer. Journal of Drugand Alcohol Abuse, 2:3 and 4 331-340, 1975.

Schecter, A. Historical perspectives onthe use of LAAM in rehabilitating opiatedependent persons. Proceedings of theNational Drug Abuse Conference, NewYork, March 28, 1976.

Senay, E.C. and diMenza, S. Methadyl ace-tate in the treatment of heroin addic-tion: A review, 34th Annual ScientificMeeting of the Committee on Problemsof Drug Dependence, 1972, Ann Arbor,Michigan.

Senay, E.C. A 48-week study of methadone,methadyl acetate, and minimal services.Psychopharmacology Bulletin, 9(4) :37,1973.

Senay, E.C., Jaffe, J.H., diMenza, S., andRenault, P.F. A 48-week study of metha-done, methadyl acetate, and minimal ser-

vices. Chapter in Fisher, S. and Freed-man, A.M., eds. opiate Addiction: Ori-gins and Treatment, V.H. Winston Sons,1974.

Senay, E.C., Renault, P.F., diMenza, S.,Collier, W.E., Daniels, S.J., and Dorus,W. Three times a week LAAM equals seventimes a week methadone: A preliminaryreport of a control study. Problems ofDrug Dependence, 543-550, 1975.

Sullivan, H.R., Due, S.L., McMahon, R.E.Enzymatic reduction. An important path-way in the biotransformation of methadonein man and rat.32:764Abs, 1973.

Federation Proceedings,

Metabolism of a-l-methadol. N-acetylation, a new metabolic pathway.Res. Comm. in Chem. Path. and Pharm.,6(3):1073-1078, 1973.

Taintor, Z., G. Hough, M. Plumb, B.F. Murphy,and C. D'Amanda: l-a-Acetylmethado1 andMethadone in Buffalo: Safety and Efficacy.The Amer. Journal of Drug and Alcohol Abuse,2:3 and 4 317-330, 1975.

Whysner, J., Current progress in the plan-ning of phase III levo-alpha-acetylmetha.dol studies. Proceedings of the Nation-al Drug Abuse Conference, New York,March 28, 1976.

Wilson, B.K. Research report of clinicaleffects of l-alpha-acetylmethadol onman observed during pharmacokinetic stu-dies. (Unpublished) Yolo County MentalHealth Service, Broderick, California.

Wilson, T.G.G., Goldstein, A. Fran heroinaddiction to abstinence, by stages, usingLAAM and naltrexone. Proceedings of theNational Drug Abuse Conference, New York,March 28 1976.

Zaks, A., Derman, R. Comparison of main-tenance with high- and low-dose l-alpha-acetylmethadol. 1972. (Unpublished)New York Medical College, New York, NewYork.

Zaks, A., Fink, M., Freedman, A.M. 1-alpha-acetylmethadol in maintenance treatmentof opiate dependence. proc. of FourthNational Conference on Methadone Treat-ment, San Francisco, Jan. 1972, pp. 207-210.

Levomethadol in maintenance treat-ment of opiate dependence. Journal ofthe American Medical Association, 220(6):811-813, 1972.

126U.S. GOVERNMENT PRINTING OFFICE : 1978 253-105/1937

DEPARTMENT OFHEALTH, EDUCATION, AND WELFARE

PUBLIC HEALTH SERVICE

ALCOHOL, DRUG ABUSE, ANDMENTAL HEALTH ADMINISTRATION

5600 FISHERS LANEROCKVILLE, MARYLAND 20857

OFFICIAL BUSINESSPenalty for private use, $300

DHEW Publication No. (ADM)78-347Formerly DHEW Publication No. (ADM)76-347Printed 1976 Reprinted 1977