monograph series

8

RX:3x/WEEK LAAM

ALTERNATIVE

TO METHADONE

U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE • PUBLIC HEALTH SERVlCE • ALCOHOL, DRUG ABUSE, AND MENTAL HEALTH ADMINISTRATION
PX : 3 X /WEEK LAAM

ALTERNATIVE TO METHADONE

EDITORS

JACK D. BLAINE, M.D.

PIERRE F. RENAULT, M.D.

NIDA Research Monograph 8
The NIDA Research Monograph series is prepared by the

Division of Research of the National Institute on Drug Abuse. Its

primary objective is to provide critical reviews of research problem

areas and techniques, the content of state-of-the-art conferences,

integrative research reviews and significant original research. Its

dual publication emphasis is rapid and targeted dissemination to the

scientific and professional community.

EDITORIAL ADVISORY BOARD

Avram Goldstein, M.D.

Jerome Jaffe, M.D.

Reese T. Jones, M.D.

William McGlothlin, Ph.D.

Jack Mendelson, M.D. Alchohol and Drug abuse Research Center

Havard Medical School

McLean Hospital

Belmont, Massachusettts

Helen Nowlis, Ph.D.

Lee Robins, Ph.D.

Addiction Research Foundation

Palo Alto, California

College of Physicians and Surgeons

Columbia University. New York

Langly Porter Neuropsychiatric Institute

Unversity of California

San Francisco, California

Department of Psychology, UCLA

Los Angeles, California

Office of Drug Education, DHEW

Washington, D.C.

Walhington University School, of Medicine

St. Louis, Missouri

NIDA RESEARCH MONOGRAPH series

Robert DuPont, M.D. DIRECTOR, NIDA

William Pollin, M.D. DIRECTOR, DIVISION OF RESEARCH, NIDA

Robert C. Petersen, Ph.D. EDITOR-IN-CHIEF

Eunice L. Corfman, M.A. EDITOR
Rx :3 /x WEEK LAAM

ALTERNATIVE TO METHADONE

EDITORS

JACK D. BLAINE, M.D.

PIERRE F. RENAULT, M.D.

Division of Research

National Institute on Drug Abuse

July 1976

NIDA Reseach Monograph 8

THE NATlONAL INSTlTUTE ON DRUG ABUSE

5600 Fishers Lane

Rockville. Maryland 20857

U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE

Public Health Service
DHEW Publication No. (ADM)78-347

Formerly DHEW Publication No. (ADM)76-347

Printed 1976 Reprinted 1977

Library of Congress catalog number 76-20257

For sale by the National Technical Information Service

Springfield, Va. 22161

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

iv
FOREWORD

This monograph is a biomedical review and assessment

of LAAM (Levo-alpha acetylmethadol), a new treatment

drug for heroin addiction now undergoing large scale

clinical trials, following several years' intensive

research and development under the auspices of the

National Institute on Drug Abuse (NIDA) and its predecessor, the Special Action Office for Drug Abuse

Prevention (SAODAP).

LAAM was developed as an alternative to methadone.

Over 800 methadone-related deaths per year are being

reported by the Drug Abuse Warning Network (DAWN)

from 24 major cities across the country. Moreover,

heroin use has been increasing nationally since mid1973 and 15 percent of heroin-related deaths (from

1,440 in 1973 to over 2,000 in 1975) reported by

DAWN also involve methadone.

Many of these deaths are directly attributable to

illicit methadone diversion from drug treatment programs to street sale. Because methadone patients

must take their dose daily while simultaneously trying to stabilize their work, school, training, family

and personal lives, they have been allowed take-home

doses to reduce the number of clinic visits they must

make. But this practice has made methadone widely

available, accounting for much illicit diversion and

subsequent painful record of methadone overdose deaths.

In contrast, LAAM dosage is three times a week, it

does not yield a quick high and appears to provide a

level, sustained effect. Animal toxicity studies

and clinical research experience indicate that LAAM

is a safe and effective opiate maintenance drug,

under appropriate medical supervision.

A wide spectrum of treatments is needed for various

degrees of addiction and kinds of dependent persons.

But LAAM seems promising for patients who may need

opiate stabilization to ease the difficult switch

from a drug-hustling street life to a less selfdestructive one. LAAM provides one more choice in

tailoring treatment to each individual's needs.

Robert L. DuPont, M.D.

Director

National Institute on Drug Abuse

v

CONTENTS

Foreword

Robert L. DuPont, M.D.

v

Introduction

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

1

The Chemistry of LAAM

Sydney Archer, Ph.D.

10

PRECLINICAL STUDIES

Pharmacology of LAAM

Sydney Archer, Ph.D.

15

Toxicology of LAAM 29

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

CLINICAL STUDIES

Phase I 39

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

Selected Clinical Studies Synopses

Sumnary of Veterans Administration Phase II Cooperative Study for LAAM and Methadone

Walter Ling, M.D.

V. Charles Chamvastra, M.D.

Samuel C. Kaim, M.D.

C. James Klett, Ph.D.

Summary of SAODAP Phase II Cooperative Study of LAAM vs. Methadone

Walter Ling, M.D.

C. James Klett, Ph.D.

Roderic D. Gillis

Phase III Clinical Study of Levo-Alpha-Acetylmethadol

John A. Whysener, M.D., Ph.D.

The Use of LAAM in Treatment

James Cooper, M.D.

A Clinical Experience with LAAM

Avram Goldstein, M.D.

A LAAM Bibliography

Preclinical

Clinical

52

94

103

109

112

115

118

123

vii
INTRODUCTION

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

MEDICAL DETOXIFICATION

For many years heroin addicted individuals

were "treated" by abrupt or gradual discontinuation of heroin, leading to abstinence.

Resulting withdrawal symptoms were either

untreated or treated palliatively with nonopiate medications including sleeping pills,

tranquilizers, analgesics, antidiarrheals,

and/or antispasmodics. The failure of heroin

withdrawal alone as a treatment with the goal

of long-term continued abstinence has been

voluminously documented.

At best, medically controlled detoxification

has only inmediate and temporary value as a

first step in a comprehensive rehabilitation

program. Thus, regulated detoxification

reduces human suffering and frees the individual from his compulsive search for and use

of the drug, permitting a shift in attention

to other more constructive pursuits. Long

periods of confinement in a hospital, therapeutic commmity, or prison, even with traditional psychotherapeutic intervention have not

significantly altered subsequent relapse to

heroin abuse for the vast majority of addicts.

Further, efforts at treatment by large scale

maintenance of heroin addicts on legally

dispensed heroin appears to be an inadequate

treatment approach due to the practical

problems arising from the need to administer

the drug intravenously several times daily.

METHADONE DETOXIFICATION

During World War II, German chemists at the

I.G. Farbenindustrie developed a synthetic

narcotic analgesic, 6-dimethylamino-4-4-dipheny1-3-heptanone (methadone, dolorphine) as a substitute for morphine. After the war, American

investigators (Isbell et al. 1948) found that

methadone’s pharmacological pmfile was

similar to that of morphine and demonstrated

that methadone could substitute for morphine

in morphine-dependent subjects to relieve the

abstinence symptoms after discontinuation of

morphine. Furthermore, methadone could prevent the appearance of withdrawal signs and

symptoms when substituted for morphine in

equipotent doses. So methadone seemed a

likely candidate to substitute for heroin when

detoxifying heroin addicts.

Methadone has several advantages over morphine

for detoxification of heroin dependent persons.

Methadone is almost as effective orally as

parenterally, thus avoiding problems of intravenous dosage. Also, methadone is metabolized

to inactive substances more slowly than

morphine. These two factors extend the duration of action of methadone to 24 hours which

permits once-a-day &sage and smooths the

time-effect curve. Thus, an oral daily dose of

1
methadone can be substituted for several

times daily intravenous doses of morphine or

heroin. The dose of methadone can then be

lowered gradually until it is completely

withdrawn, producing only a mild abstinence

syndrome.

METHADONE MAINTENANCE

In 1965, Dole and Nyswander (1965) extended

the clinical use of methadone to a medical

maintenance or stablization treatment, used

with a comprehensive program of rehabilitation.

In a clinical research setting, they demonstrated that heroin addicts could be

"stabilized" for many months on a single daily

oral dose of methadone (50-150 mg) achieved

by gradually increasing the dose over a

period of four weeks as tolerance developed

to the dose which relieved the abstinence

syndrome. At the stabilization-maintenance

dose, the medication appears to relieve

narcotic “hunger” or craving, induce

sufficient tolerance to prevent an abstinence

syndrome and block the euphoric effect of

intravenous heroin. The maintenance dose is

not intoxicating itself. Thus methadone

stabilization produces a normal steady functional state rather than the wave-like fluctuating feeling states of euphoric intoxication

("high"), normality ("straight"), and

abstinence ("sick") commonly experienced in

the street heroin addict life style. This

stabilization on methadone appears to free

the patient from heroin-oriented hustling,

allowing participation in the treatment and

rehabilitation program and development of

less destructive interests and activities.

In the ensuing several years, many other

clinical researchers, some with support from

the Division of Narcotic Addiction and Drug

Abuse, National Institute for Mental Health

(DNADA, NIMH) NIDA’s precursor, intensively

evaluated the use of methadone as a maintenance

drug for the treatment and rehabilitation of

heroin addicts. (Jaffe 1972; Goldstein 1971,

1972; Blachly 1972; Zaks and Feldman 1972).

By 1970 a rapid proliferation of methadone

maintenance programs had occurred across the

country, and almost 9,000 heroin addicts were

in treatment (Dole, 3rd Methadone Maintenance

Conference, November 1970). Data from these

patients indicated safety and efficacy of this

form of treatment under good medical supervision.

The concept of methadone maintenance, with

several variations from the original prototype

of Dole and Nyswander, achieved widespread

acceptance. Programs and number of patients

in treatment continued to expand. On December

15, 1972 the Food and Drug Administration,

after an extensive review of the methadone

treatment experience, approved the New Drug

Application for methadone maintenance treatment of heroin or morphine-like drug dependent

persons and published rules and regulations

in the Federal Register controlling its use.

METHADONE DISADVANTAGE

While methadone maintenance had been shown

repeatedly to be the most effective treatment

of opiate addiction available, several

investigators realized in the late sixties

(Jaffe et al. 1970; Blachly 1971) that

significant problems related to the pharmacology of methadone existed. Methadone did

not suppress the narcotic craving for a full

24 hours in many addicts. Very large doses of

methadone were necessary to provide sustained

relief of abstinence of symptoms for 24 hours

for these patients. These doses often produced

unwanted sedation causing the patient to "nod"

for the first several hours after consumption.

Furthermore, the patient was required to

attend a methadone dispensing clinic daily to

consume his medication under staff supervision.

This inconvenient and burdensome time and

travel demand was often draining physically

and emotionally. When the patient was assuming

responsibility and trying to engage in work,

rehabilitation or education programs, or

responsible homemaking, this requirement was

considered by some to be antitherapeutic. A

compromise solution was reached.

After demonstrating satisfactory adherence to the program regulations for at

least 3 months, and showing substantial

progress in rehabilitation by participating actively in the programs’

activities and/or participating in

educational, vocational and homemaking

activities, those patients whose

employment, education, or homemaking

responsibilities would be hindered by

daily attendance may be permitted to

reduce to three times weekly the times

when they must ingest the drug under

observation.

(Federal Register, Vol. 37,

No. 242 page 26790, Dec. 15,

1972).

Take-home doses were dispensed for the

other four days.

Unfortunately, the practice of permitting

take home supplies of methadone for unsupervised self-administration away from the clinic

contributed to new problems (Jaffe et al.

1970; Fink 1973). Accidental ingestion of

methadone by non-tolerant persons, especially

children, led to an alarming increase in

methadone toxic reactions and overdose

2
fatalities. Also, a market developed for

illicit sale and redistribution of methadone

to heroin addict peers suffering from withdrawal or to non-addict drug users seeking a

new euphorient. More recently, the phenomenon

of primary methadone abuse without prior

heroin addiction surfaced. That is the treatment agent was becoming a new source of

addiction. Finally, the patient might skip

or delay a dose of methadone in order to

"shoot up" with heroin after the blockade has

diminished. Thus, the take-home privileges

inadvertently negated much of the usefulness

of random urine monitoring for illicit heroin

use. Furthermore, an adversary system or

game was created in which the patient might

attempt to deceive the staff in order to gain

or retain take-home privileges (Goldstein

and Judson 1974).

Thus, a longer lasting medication would have

many practical therapeutic advantages over

methadone and partially resolve some of these

problems encountered in clinical treatment

programs. Fortunately, chemical and pharmacological data were already available on

optical and structural isomers of methadone

as well as several derivatives (Pohland et

al. 1949; Chen 1948; Eddy et al. 1950,1952;

Speeter et al. 1949; Sung and Way 1954).

This data suggested potential clinical usefulness for L-alpha-acetyl-methadol (LAAM, lmethadyl-acetate) because of its high oral

effectiveness, long duration of action, and

low toxicity.

NEW DRUG DEVELOPMENT

The development of a new drug product is a

long and complex process. The 1962 Kefauver

Harris Amendments to the Federal Food, Drug,

and Comestic Act established investigative

procedures to supply substantial scientific

evidence that a drug is safe and effective.

Before a new drug can be marketed to the

general public, thorough testing must occur

both in animals and humans under carefully

controlled circumstances.

Before a new drug may be tested clinically on

humans, the sponsor, usually a pharmaceutical

company, must provide FDA with information as

specified as a “Notice of Claimed Investigational Exemption for a New Drug" known as an

IND. Among the requirements are:

(1) Complete composition of the drug, its

source and manufacturing data.

(2) Results of all preclinical investigations

demonstrating that there will not be

unreasonable hazard in initiating studies

in humans. The minimmum data required are

the pharmacological profile, acute toxicity and short term (two weeks to three

months) toxicity studies in several animal

species.

(3) A detailed protocol of the planned

investigation.

Following preclinical animal studies indicating

the drugs presumptive safety for humans, the

clinical investigation, consisting of three

phases, accumulates substantial scientific

evidence of safety and effectiveness in man.

This is needed to approve or disapprove the

drug for marketing. The Phase I clinical

investigation involves a small number of healthy

patients to establish baseline data. Pharmacological studies are used to determine drug

action, toxicity, metabolism, absorption,

elimination, preferred route of administration

and safe dosage range. Phase II clinical trials

are conducted on a limited number of diseased

patients to determine safety and effectiveness

of the drug. If Phase II studies indicate that

the drug may be useful and safe in treating

a disease and the long-term animal testing

performed concomitantly indicates no unwarranted

toxicity, Phase III studies may commence. The

Phase III investigation involves extensive,

careful controlled and monitored clinical

trials assessing the drug’s safety, effectiveness and most desirable dosage in treating a

specific disease in a large number of patients.

Phase III study approximates general clinical

use.

Once Phase III is completed and claims of

safety and effectiveness of the drug arc

supported, a New Drug Application (NDA) is

submitted to FDA requesting approval to market

the drug. The NDA contains all the information

available about the drug which has accumulated

from studies in animals and several hundred

to several thousands patients. The FDA reviews

the NDA to determine whether the benefits of

the drug when used properly outweigh the risks.

Once an NDA is approved, the drug can be

marketed to the general public. However, the

manufacturer is still required to report

regularly to FDA on any adverse reactions or

toxicity which occurs. At any stage in this

entire process the FDA may prohibit further

testing or marketing based on unacceptable

toxicity or ineffectiveness.

LEVO-ALPHA ACETYL METHADOL (LAAM)

The early clinical work on LAAM focused on

morphine-like analgesic properties (Keats and

Beecher 1952; David et al. 1956; David and

Semler 1952). However, at the Addiction

Research Center, NIDA, Fraser, Isbell and

coworkers (1952, 1954) demonstrated LAAM’s

ability to relieve and prevent opiate withdrawal symptoms in addicts for long periods of

time, up to 72 hours. They also noted that

abrupt withdrawal from LAAM resulted in a mild

but prolonged abstinence syndrome.

3
Merck Company in the early and mid-sixties

investigated LAAM’s usefulness as an analgesic.

However, the delayed onset of action and prolonged time course limited its clinical usefulness for analgesia. Thus, Merck did not proceed with LAAM beyond the early Investigational

New Drug stage.

Jaffe and co-workers first utilized alphaacetyl-methadol in a clinical narcotic treatment program (Jaffe et al. 1969, 1970). They

substituted D, L-alpha-acetylmethadl (DLAAM)

three times weekly for methadone daily in

a small group of methadone maintenance

patients in 1968. TIhe results of that initial

pilot study corroborated the findings of Fraser

and Isbell that D-LAAM could suppress opiate

withdrawal symptoms for up to 72 hours and

might be a useful agent for the treatment of

heroin addicts.

Eased on the positive results of this pilot

study, Dr. Sidney Cohen, Director, Division

of Narcotic Addiction and Drug Abuse, NIMH,

contracted with Merck Company for production

of four kilograms of LAAM in 1969. DNADA

encouraged further clinical investigation by

DNADA funded clinical research centers in the

early seventies. Research by this group substantiated the comparable usefulness and

safety of LAAM as a maintenance treatment of

heroin addiction (Jaffe et al. 1971, 1972;

Blachly et al. 1972; Zaks et al. 1972; Senay

et al. 1974).

LAAM ADVANTAGES

These researchers found that LAAM offers the

patient, clinician and treatment program

several advantages over methadone. Due to

LAAM’s long duration of action, the frequency

of visits to clinic can be reduced from daily

to three times weekly even for patients just

entering treatment (Levine et al. 1973).

Addicts find participation in treatment more

acceptable and return more regularly,

especially those trying to engage in work,

education or rehabilitation activities outside

of the clinic, because travel time and effort

is greatly reduced.

Some investigators found that LAAM offers the

patient a smoother, sustained drug effect. The

patients appeared more alert and more emotionally level. Oral consumption even during the

period of escalating doses did not produce

excessive sedation or subjective euphoria, i.e.

the patients do not report being "loaded" or

"nodding" (Blachly 1971). This effect is

consistent with phanmacokinetic data on LAAM

and 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 reinforcer

of daily drug taking behavior than methadone.

The three times weekly dosage schedule frees

the patient from the daily necessity of

engaging in drug seeking and drug taking

behavior. This represents an important therapeutic step forward because the destructive,

habitual pattern of behavior associated with

the heroin addict daily life style is broken.

The individual feels less psychologically and

physically dependent when not involved with

daily drug taking. This strengthens the

addict’s identification with the drug free

population and breaks association with the

drug taking culture.

These factors are consistent with the treatment program goal of de-emphasizing of the

mystique of drugs and drug taking while empha

sizing human relationship and alternate

pursuits as sources of gratification. In the

context of treatment, LAAM allows a reduction

of emphasis on chemicals, since the life style

no longer pivots around the consuming

preoccupations associated with taking drugs

several times a day or even once a day at the

treatment clinic. So there can be less talking, seeking, taking and relating around

chemicals. More energy is available for

achievement of psychological, social, educational and vocational goals rather than biological stabilization (Senay and diMenza 1972;

Jaffe et al. 1970).

Also, LAAM offers a practical answer to the

problems related to take-home methadone.

Illicit redistribution can be lessened because

three times weekly LAAM reduces the amount of

take-home medication a clinic must provide

patients for out of clinic administration. If

necessary, a no-take-home policy can be established by a clinic or program where redistribution and accidental overdose is especially

prevalent (Jaffe et al. 1970; Fink 1973).

Further, several pharmacological properties

make LAAM less prone than methadone to abuse.

LAAM itself is one-tenth as active as its

metabolites (Smits 1974; Nickander et al. 1974).

Because metabolism requires time, several

hours pass between taking LAAM and the onset

of psychoactivity (Billings et al. 1974).

Therefore, LAAM is less likely to be a reinforcer of drug taking because substances with

a rapid, immediate onset of euphoric effects

are much more desired by drug users. LAAM has

another unique characteristic which makes it

less desired. Unlike other narcotics? LAAM

is more rapidly effective orally than intravenously, the preferred route of heroin addicts

(Blachly 1971; Fraser 1952).

LAAM may offer treatment programs advantages

over methadone by improving the logistics of

4
drug distribution. Three times weekly dosage

allows for more controlled drug delivery to

increasingly large numbers of patients. By

reducing the required number of clinic visits,

efficiency of treatment may be increased due

to savings of staff dispensing and pharmacy

services (Senay et al. 1972; Blachly 1971).

Thus, conversion from methadone to LAAM can

potentially either reduce the cost of treatment or increase the number of available

treatment slots.

SAODAP UNDERTAKES COORDINATION OF LAAM

DEVELOPMENT

In June 1971, the Special Action Office for

Drug Abuse Prevention (SAODAP) was established

by Executive Order "to focus the comprehensive

resources of the Federal Government.... and

to develop a comprehensive, coordinated, longterm federal strategy to combat drug abuse."

The Drug Abuse Office and Treatment Act of

1972 (Public Law 92-255, Sec. 224, 86 stat.

72, March 21, 1972) mandated the expansion of

research on "long-lasting, non-addictive,

blocking and antagonist drugs or other pharmacological substances for the treatment of

heroin addiciton." Based on the potential

advantages of LAAM over methadone, Dr. Jerome

Jaffe, SAODAP's first director, initiated in

the summer of 1971 a comprehensive review of

the status of LAAM and other long-lasting

blocking drugs utilizing experts from the

various government agencies and the private

sector.

The conclusion of the review was that LAAM was

the most promising compound available at the

time, but that the pharmacological development

of LAAM was not proceeding rapidly enough.

Several problems were found to be delaying

LAAM development. There was little general

interest in or knowledge about LAAM in the

treatment, research or pharmaceutical fields.

No one in Federal Agencies or industry was

promoting the drug. LAAM investigation was

limited to a few research centers. Large

quantities of LAAM necessary for use in treatment were not available from any source, and

only a few kilograms remained from the LAAM

produced for DNADA several years previously.

Furthermore, unlike methadone, which was

marketed as an analgesic prior to its use in

narcotic addiction treatment, LAAM was not

patented or marketed for any indication. LAAM

was not patentable because it had been in the

public domain for many years. Thus, the

pharmaceutical companies were not interested

in spending research and development funds for

a drug without exclusivity and with a limited

market. Also, the pharmaceutical industry

drew attention to the special precautions and

regulatory controls pertaining to development

of controlled, Schedule I, narcotic substances.

Facilities were not available in the industry

for preclinical narcotic testing nor was there

an existing structure to perform the carefully

monitored clinical studies required.

Thus, SAODAP recognized that LAAM was not

proceeding because the pharmaceutical industry

did not want to develop and promote it.

Therefore SAODAP set a high priority on creating and coordinating a governmental mechanism

for developing this type of drug using LAAM

as the prototype. Therapeutic drug development

had previously been the function of the

pharmaceutical industry and not a practic of

government. In fact, the recognized function

of the Federal Government was to regulate the

pharmaceutical industry. This led to the

interesting and potentially anomolous situation

of the government attempting to develop and

also regulate the same compound, the former

at SAODAP and DNADA and the latter at FDA.

Although LAAM was to be developed as rapidly

as possible, it was imperative to avoid the

many problems encountered by methadone due

to inadequate and incomplete study. Federal

Agencies had the assigned responsiblity to

be certain that LAAM was a safe and effective

drug before marketing. Therefore, SAODAP

organized and promoted interagency cooperation

in LAAM development, with DNADA and FDA

playing the leading roles. SAODAP effectively

utilized the expertise in academic and

phamaceutical communities for advice and

monitoring the process. A LAAM Medical

Advisory Panel served this latter purpose.

The amount of LAAM available severely limited

the progress of both animal and clinical

investigation. A larger supply of LAAM was

obtained through the cooperation of the

Penick Pharmaceutical Company in 1972 and

arrangements were made for an additional

supply when needed. The recognition that

further animal studies were needed to establish

intermediate and long-term nontoxicity of

LAAM prompted an agreement between DNADA and

Department of Army’s research facilities at

Edgewcod Arsenal to perform the necessary

studies in December 1971. In the Spring of

1972 an interagency Pharmacology Task Force

was formed of representatives from SAODAP,

the Veterans Administration, Department of the

Army, Food and Drug Administration, FM,

National Academy of Sciences. and the Division

of Narcotic Addiction and Drug Abuse, National

Institute of Mental Health DNADA,(NIMH). This

group reviewed previous and ongoing work on

LAAM and planned and coordinated the subsequent development toward the New Drug Application stage.

Through this coordinated effort, the necessary

animal toxicological and teratological studies

could be phased with the subsequent clinical

5
studies of humans. The animal toxicology

studies done previously by Merck and Company

were utilized for the clinical Phase I

Investigational New Drug studies begun in

June 1972 by DNADA. DNADA initiated extensive

chronic animal studies including a one year

study in dogs and rats to provide required

toxicological data to support safe, prolonged

administration in man.

The existence of these animal and early

clinical studies stimulated clinical interest

in LAAM. Planning began early in 1972 for

larger scale cooperative clinical studies to

test LAAM safety and efficacy which could

follow by 6 to 8 months the chronic animal

studies required to support long term administration to humans. Dr. Samuel Kaim, Director

of the Alcohol and Drug Dependence Service of

the Veterans Administration expressed V.A.‘s

interest to SAODAP. The VA had vast experience

with large scale clinical cooperative studies

of other psychotropic drugs. The administrative mechanism including the data gathering

and analysis section and pharmacy was already

functional at V.A. Hospital, Perry Point,

Maryland, under the direction of James Klett,

Ph.D. Also, the VA had recently established

a network of Drug Dependence Treatment Centers

for returning addicted soldiers.

The planning and initiation of further clinical

studies proceeded cautiously. To protect the

well-being of potential subjects, the Advisory

Committee and Pharmacology Task Force wanted

some data from the long-term animal studies

available before long-term clinical studies

were initiated. By the Spring of 1973

sufficient animal toxicity data was available

from the Edgewood Arsenal study to support the

cautious initiation of Phase II clinical

studies. These studies were to proceed in

successive stages contingent upon continued

evidence of lack of toxicity in animals

indicating probable safety in man.

In April 1973, pilot studies were initiated in

three VA Hospitals to evaluate the safety and

efficacy of LAAM maintenance (80 mg three times

weekly) compared to high (100 mg daily) and

low (50 mg daily) dose methadone maintenance.

The study was conducted double-blind and

utilized a common protocol for random selection

of subjects, induction of street heroin addicts

onto the study drugs, maintenance dosage, and

for evaluating safety and efficacy. In the

summer of 1973 based on the up&ted animal

data, the existing data from the pilot studies

and other available clinical data, the decision

was made to continue tentatively the study for

a total of 40 weeks and to proceed with the

addition of nine more Veterans Administration

Hospitals in the Cooperative Study. The

clinical study was carried out over a 2 year

period, terminating in the Spring of 1975.

Four hundred thirty (430) male heroin addicts

were studied. Of these, 142 received LAAM and

the remainder were equally divided between

high and low dose methadone.

Because of technical inadequacies in the Edgewood Arsenal Study, DNADA initiated additional

acute and chronic rat and dog studies of LAAM

in 1973. At approximately this time, SAODAP

began planning and organizing another larger

cooperative clinical study of LAAM to provide

more patient data. The study was designed

to complement the VA study.

Interested patients were selected from those

already in methadone maintenance programs.

In the major part of the new clinical study,

patients were randomly assigned to the LAAM

study group or the methadone control group.

The study was open rather than double-blind.

Take-home methadone was permitted according

to clinic policy, while all LAAM patients

attended the clinic three times a week. Crossover dose from methadone to LAAM was fixed,

but subsequent dose levels were flexible at the

discretion of the clinic physician. In addition, sub-study was performed to examine

further the use of LAAM on Friday only in

place of weekend methadone.

The SAODAP cooperative study was initiated

in February 1974 when the safety data from

the second animal toxicity study and the

clinical data from the VA Cooperative Study

was adequate to support an additional 40 week

human safety and efficacy study. Sixteen (16)

outpatient drug treatment clinics throughout

the country were chosen for participation in

order to provide widespread experience with

LAAM in local treatment programs in a

controlled, carefully monitored and coordinated

manner. Seven hundred sixty seven (767) male

patients, of whom 383 received LAAM, participated in this study. Of these, 136 patients,

of whom 65 received LAAM, participated in the

LAAM Friday only substudy.

COORDINATION OF LAAM DEVELOPMENT TRANSFERRED

TO NIDA

When SAODAP began to phase out in the Fall

of 1974, the coordination and direction of

the LAAM project, including the Pharmacology

Task Force and Cooperative Studies were

officially transferred to the recently

established Division of Research, National

Institute on Drug Abuse, (NIDA), successor

to DNADA,(NIMH). Shortly thereafter, based on

the available results of the animal and

clinical studies, the Food and Drug Administration permitted the use of LAAM for up to

80 weeks to provide longer comparative toxicity data. Also, the inclusion of women with

no child-bearing potential was permitted.

Accordingly, NIDA extended the SAODAP clinical

6
studies until the Spring of 1976 to perform

additional studies of LAAM.

Thus, by the Fall of 1974 all of the basic

work necessary to initiate Phase III large

scale clinical study of LAAM had been completed

or was in the process of completion. LAAM

appeared to be a safe and efficacious drug

for use in the treatment and rehabilitation of

chronic opioid dependent persons. The staffs

of the Clinical-Behavorial Branch, Division of

Research, NIDA and the Drug Abuse Section,

Division of Neuroharmacology, FDA, began to

plan the Phase III clinical study of LAAM

through the Pharmacology Task Force. A Phase

III clinical study is a full scale clinical

trial of the drug under the conditions of the

use in the general population. Thus, those

groups of heroin addicts excluded from participation in a Phase II study can be included

in Phase III. These Phase III studies can

include subjects with medical and/or

psychiatric illnesses, subjects concurrently

taking other medication and women of childbearing potential.

In the Spring of 1975, NIDA advertised a RFP

to perform the Phase III study under a cost

sharing contract. In return for the costsharing NIDA provides patent-like protection

for the contractor to protect his investment

in LAAM and to assure the marketing of the

drurg in the public’s interest. NIDA agreed

to give the contractor the right to exclusive

possession and use of all data generated in

the performance of this contract which would

be necessary to prepare and file a New Drug

Application on LAAM for eight years pending

satisfactory performance of the contract.

Despite the investment and commitment already

made by Federal Agencies the pharmaceutical

industry did not respond. However, other

competitive bids were received. In July 1975,

a medical consulting firm, Whysner Associates,

was contracted by NIDA to conduct Phase III

Clinical Evaluation of LAAM for the treatment

of chronic opioid dependence and to make

appropriate arrangements for the eventual

filing of the New Drug Application and

marketing of LAAM.

The contract is currently ongoing and arrangements are made to formulate and distribute

LAAM The Phase III Investigational New Drug

Application has been submitted and clinics are

being enlisted to carry out the clinical study.

An estimated 6000 patients, including those

already maintained on methadone and heroin

addicts entering treatment, will be asked to

participate in a 40 week study of safety and

efficacy of LAAM. The open study will be

performed in approximately 50 cooperating

methadone maintenance programs nationwide. A

common protocol for medical monitoring and

evaluation of clinical efficacy will be utilized

to produce uniform data. The study will

require approxmiately two years to complete

after which the New Drug Application for LAAM

can be submitted to FDA to permit its marketing

to interested chronic opioid dependence treatment programs.

Pending successful completion of this Phase III

large scale clinical trial, the project has

accomplished the formidable task of developing

at an accelerated pace a drug which offers

considerable potential benefit to heroin addicts

and treatment programs. The task of developing

a drug the private sector was unwilling or

unable to undertake has been carried out, and

in accordance with stringently applied Federal

Regulations designed both to ensure the kind

of scientific baseline data establishing

LAAM safety and efficacy and to provide a

mechanism that can be a model for future drug

development in the narcotic dependence treatment

field. Conjointly the task has entailed creating the means for cooperation between the many

agencies and individuals involved in a far-flung

and large scale project. This also, is a

legacy for future drug development.

REFERENCES

Billings, R. E., McMhahon, R. E., Blake, D.A.

1-acetylmethadol (LAM) treatment of opiate

dependence: plasma and urine levels of two

pharmacologically active metabolites. Life

Sciences 14:1437-1446, 1974a.

Blachly, Paul., Recent developments in the

Therapy of Addictions. Current Psychiatric

Therapies 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 the

treatment 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. Alphaacetylmethadol (LAM) : comparison of laboratory

findings, electmencephalograms, and Cornell

Medical Index of patients stabilized on LAM

with those on methadone. Proc. of Fourth Natl.

Conf. on Methadone Treatment, San Francisco,

Jan. 1972, pp. 203-205.

Chen, K. K. Pharmacology of methadone and

related compounds. Annals of the New York

Academy of Sciences 51:83-97, 1948.

7
David, N. A., Semler, H. J., Clinical trial of

alpha acetylmethadol (dl-6-dimethylamino-4,

4-diphenyl-3-acetoxy-heptane) as an analgesic.

Journal of Phamcology and Experimental

Therapeutics 106:380, 1952.

David, N. A., Semler, H. J., Burgner, P. R.

Control of chronic pain by dl-alpha-acetylmethadol. Journal of the American Medical

Association 161(7):599-603, 1956.

Dole, U. P., Nyswander, M. A. A medical treatment for diacetylmorphine (heroin) addiction.

Journal of the American Association 193:646-

650, 1965.

Eddy, N. B., May, E. L., Mosettig, E. Chemistry

and pharmacology of the methadols and acetylmethadols. Journal of Organic Chemistry 17(2):

321-326, 1952.

Eddy, N. B., Touchberry, C. F., Lieberman,

J. E., Khazan, N. Synthetic analgesics; methadone isomers and derivatives. Journal of

Pharmacology and Experimental Therapeutics

98:121-137, 1950.

Fraser, H. F., Isbell, H. Actions and addiction liabilities of alpha-acetylmethadols in

man. Journal of Pharmacology and Experimental

Therapeutics 105(4):458-465, 1952.

Fraser, H. F., Nash, T. L., Vanhorn, G. D., and

Isbell, H. Use of miotic effect in evaluating

anagesic drugs in man. Archives Internationales

de Phamacodynamie et de therapie 98:443-451,

1954.

Goldstein, A. Blind controlled dosage comparisons in Two hundred patients. Proceedings of

the Third National Conference on Methadone

Treatment. p. 31. Washington, D.C.: U.S.

Government Printing Office 1971.

Goldstein, A. Heroin Addiction and the role

of methadone in its treatment. Archives of

General Psychiatry 26:291-297, 1972.

Goldstein, A. LAAM and LAAM metabolites: plasma

levels in patients.

1975 (Unpublished)

Summary progress report.

Goldstein, A., and Judson, B. Three critical

issues in the management of methadone programs:

Critical Issue 3: Can the community be protected against the hazards of take-home methadone. Addiction. Peter G. Bourne, ed.

Academic Press, New York, p. 140-148, 1974.

Henderson, G. L., A two-year pharmacokinetic

study of LAAM. Fourth quarter progress report.

1974. (Unpublished)

Henderson, G. L., Two-year pharmacokinetic

study of LAAM. Sixth quarter progress report.

8

1975. (Unpublished)

Henderson, G. L. Two-year pharmacokinetic

study of LAAM.. Seventh quarter progress

report. 1975b. (Unpublished)

Isbell, H., Wickler, A., Eisenman, A. J.,

Daingerfield, M., Frank, E. Liability of

addiction to 6-dimethlamino-4-4-diphenyl-3-

hepatone in man. Archives of Internal Medicine

82:362-392, 1948.

Jaffe, J. H. The maintenance approach to the

management of opiod dependence. In: Zarafonetis, Chris J. D., ed. Drug Abuse: Proceedings of the International Conference. Philadelphia: Lea and Febiger, 1972, pp.161-170.

Jaffe, J. H., Schuster, C. R., Smith, B. B.,

Blachly, P. H. Comparison of acetylmethadol

and methadone in the treatment of long-term

heroin users: A pilot study. Journal of the

American Medical Association 211:1834-1836,

1970.

Jaffe, J. H., Schuster, C. R., Smith, B. B.,

Blachly, P. Comparison of dl alpha-acetyl

methadol and methadone in the treatment of

narcotics addicts.

1969.

Phamacologist 11(2):256,

Jaffe, J. H., Senay, E. C. Methadone and

1-methadyl acetate. Use in managment of

narcotics addicts. Journal of the American

Medical Association 216:1303-1305, 1971.

Jaffe, J. H., Senay, E. C., Rehault, P. F.

A six-month preliminary report of the rehabilitative efficacy of 1-methadyl acetate compared

to methadone. Proc. of Fourth National Conference 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. Methadyl

acetate vs methadone. A double-blind study in

heroin users. Journal of the American Medical

Association 222(4):437-442, 1972.

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

Levomethadyl acetate. Prolonged duration of

opiod effects, including cross tolerance to

heroin, in man. Journal of the American

Medical Association 226(3):316-318, 1973.

Moreton, J. E., Roehrs, T., Khazan, N. Sleepawake activity and self-injection pattern of

rats dependent on morphine, methadone, or

L-alpha-acetyl-methadol (LAAM). Federation

Proceedings 33(3):516, 1974.

Nickander, R., Booher, R., Miles, H. a-l-acetylmethadol and its N-demethylated metabolites

have 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 methadon

Journal of the American Chemical Society 71:

460-462, 1949.

Senay, E. C. and diMenza, S. Methadyl acetate

in the treatment of heroin addiction: A review,

34th Annual Scientific Meeting of the Committee

on Problems of Drug Dependence, 1972, Ann

Arbor, Michigan.

Senay, E. C., Jaffe, J. H., diMenza, S., and

Renault, P. F. A 48-week study of methadone,

methadyl acetate, and minimal services. Chapter

in Fisher, S. and Freedman, A. M., eds., Opiate

Addiction: 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 a

week methadone: A preliminary report of a

control study. Proceedings of the First

National Drug Abuse Conference, 1974. (In Press)

Smits, S. E. The analgesic activity of a-lacetylmethadol and two of its metabolites in

mice. Research Communications in Chemical

Pathology and Pharmacology 8(3): 575-578, 1974.

Speeter, M. E., Byrd, W. M., Cheney, L. C.,

Binkley, S. B. Analgesic carbinols and esters

related to amidone (methadon). Journal of

American Chemistry Society 71:57-60, 1949.

Sung, C. Y., Way, E. L. The fate of the

optical isomers of alpha-acetyl-methadol.

Journal of Pharmacology and Experimental Therapeutics 110:260-270, 1954.

Zaks, A., Feldman, Martin. Private methadone

maintenance: analysis of a program after one

year. Journal of the American Medical Association 222(10):1279-1280, 1972.

Zaks, A., Fink, M., Freedman, A. M. 1-alphaacetylmethadol in maintenance treatment of

opiate dependence. Proc. of Fourth National

Conference on Methadone Treatment, San

Francisco, Jan. 1972, pp. 207-210.

Zaks, A., Fink, M., Freedman, A. M. Levomethadyl in maintenance treatment of opiate

dependence. Journal of the American Medical

Association 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 levoalpha-6-dimethylamino-4, 4-diphenyl-3-heptyl

acetate and is used as its hydrochloride salt.

The chemical structure of LAAM is as follows:

It is a white crystalline compound with a

melting 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). Infrared

absorption conforms to structure in CHCl3

solution and KBr Pellet.

RELATIONSHIP TO OTHER RELATED DRUGS

The compound was first reported by Pohland,

Marshall and Carney (1949)l as a water-soluble

substance with a melting point of 201-202°C

and an observed rotation of 25 D = -59°

(c=0.2 in water).

It was prepared by catalytic reduction of dmethadone (II) to afford 1-alpha-methadol

(III) which on acetylation with acetic anhydride in pyridine furnished LAAM (I).

1 References cited my be found at the conclusion of the monograph in the LAAM Preclinical

Bibliography.

10
Pohland, Marshall and Carney (1949) also performed the same sequence of reactions on 1-

methadone. This yielded d-alpha-acetylmethadol

whose hydrochloride was also water-soluble and

melted at 200-303°C. The optical rotation was

25 D = +57° (c=0.2 in water).

It will be noted that the dextrorotary form of

methadone gave levorotatory acetylmethadol,

whereas the analgetically more active l-methadone gave the dextrorotatory isomer.

It will also be noted that whereas methadone

(II) has only one chiral center (starred carbon) the acetylmethadols have two chiral centers (starred carbons). Two diastereomeric

pairs of isomers are possible. However, catalytic hydrogenation gave only the alpha-series

as reported by Pohland et al. May and Mosettig

(1948) showed that catalytic hydrogenation of

dl-methadone furnished the alpha-series exclusively and Speeter, Byrd, Cheney and Binkley

(1949) found that lithium aluminun hydride

reduction of dl-methadone furnished dlmethadol exclusively also.

On the other hand Eddy, May, Mosettig (1952)

found that sodium propanol reduction of either

racemic or optically active methadone gave the

beta-methadols, as the major but not exclusive

products. These results are summarized in

Chart I.

11
These authors converted the isomers to the

corresponding acetates. Thus, all four possible isometric acetates were synthesized.

In the course of studying the metabolism of

LAAM, two new matabolites were discovered.

These are 1-alpha-6-methylamino-4, 4-diphenyl3-heptyl acetate (V), (Nor-LAAM), and 1-alpha6-amino-4, 4-diphenyl-3-heptyl acetate (VII),

(DiNor-LAAM). Their synthesis was reported

by Booher and Pohland (1975) and is outlined

in Chart II.

LAAM (I) was treated with trichlororthyl

chloroformate to give the amide (IV), which

was reduced with zinc in formic acid to give

Nor-LAAM (V) in 44 percent overall yield from

I. Oxidation with potassium permanganate gave

the nitro ester VI in 24 percent yield. Reduction using Raney nickel gave DiNor-LAAM

(VII) in 72 percent yield.

Chatterjie and Inturissi (1975) were able to

prepare Nor-LAAM from LAAM in one step using

a mercuric acetate demethylation procedure.

The yield was 50 percent and is shorter than

the method of Booher and Pohland (1975).

DESCRIPTION OF DOSAGE FORM AND

QUANTITATIVE COMPOSITION

The dosage form of 1-alpha-acetylmethadol is

a colorless, clear liquid with the odor of

parabens. One ml of concentrate contains:

1-alpha-acetylmethadol 10 mg

methyl paraben 0-18 percent

propyl paraben 0.02 percent

in distilled water.

ASSAY OF LAAM FOR STABILITY

The following procedures were developed by

the United States Public Health Service HSHMA

Supply Service Center, Perry Point, Maryland

(January, 1974), for the assay of samples of

LAAM packaged in 16-ounce amber, polyethylene

bottles and stored at 25°C and 45°C. The

titrimetric procedure which follows is a

modification of the USP XVIII procedure for

Methadone Hydrochloride Injection:

12
Transfer a volume of concentrate equivalent to about 50 mg. of LAAM to a separatory funnel and wash

with 25 Ml. of either. Transfer the aqueous layer quantitatively to the Watkins Continuous Extraction

Apparatus set up for use with ether. Make alkaline with NaOH T.S. and charge the apparatus with ether.

Reflux for 6 hours. Remove the receiving flask, add 20.0 ml. of 0.02 N sulfuric acid, and evaporate

the ether. Cool, add methyl red T.S., and titrate the excess acid with 0.02 N sodium hydroxide. Each

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

Recovery with this method was as follows:

Because of the need for a "stability indicating"

assay method a gas chromatographic method was

developed and is as follows:

Standand Solutions: Prepare two (2) standard solutions of LAAM-HCl in water such that standard solution

#1 contains 11.0 mg. of LAAM-HCL per ml. and standard solution #2 contains 9.0 mg. LAAH-HCl per ml.

Internal Standard: Prepare a solution of Diphenhy dramine Hydrochloride in water at a concentration of

10.0 mg. per ml.

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

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

Transfer 10.0 ml. to a 100.0 ml. volumetric flask. Add 5.0 ml. of internal standard, dilute to volume

with water, and mix. Inject 1 microliter of each solution into the apparatus. Run at least 3 injections

of each standard and the sample. From the chromatograms obtained calculate the ratio of the peak area

of LAAM-CHCl to the peak area of Diphenhydramine HCl. Plot the peak area ratios of the two standard

solutions versus the weight ratios. Read the weight ratio of the sample and calculate the wt. of LAAMHCl in the sample.

Recoveries with this method were as follows:

13

PRECLINICAL STUDIES

PHARMACOLOGY OF LAAM

Sydney Archer, Ph.D.

The synthesis of levo-alpha-acetylmethadol

(LAAM) and early preclinical investigations

into toxic and analgesic properties were

carried out in 1948. The delayed onset and

long duration of action of this compound was

suggestive of the activity of metabolites,

and further studies showed that two metabolites, noracetylmethadol (N-LAAM) and

dinoracetylmethadol (DN-LAAM), were responsible for the unique time-response characteristics of 1-alpha-acetylmethadol. Currently,

research is being carried out into the

pharmacokinetics of 1-alpha-acetylmethadol,

as well as long-term toxicity studies and

studies of the effects of the drugs upon

reproduction.

This chapter is devoted to an account of

LAAM preclinical animal studies and provides

a summary of all pharmacological studies of

LAAM. The following chapter offers an

account of the preclinical toxicology of

LAAM.

PHARMACOLOGICAL SUMMARY OF FINDINGS

The following summary of LAAM preclinical

studies presents a comprehensive overview of

the pharmacological research which had been

conducted with LAAM in animals, through

summer of 1975.

Five areas of LAAM animal pharmacology

research findings are discussed below:

Analgesic Activity of LAAM

and Related compounds

K. K. Chen (1948)1 first reported on the

analgesic activity of 1-alpha-acetylmethadol

(LAAM) and d-alpha-acetylmethadol (DAAM)

LAAM was prepared from d-methadone which is

less active as an analgesic than l-methadone.

The latter is the precursor of DAAM. Chen

found that in rats l-methadone is seven times

as potent as d-methadone but in higher animals the difference in potency is even

greater. The l-isomer is 25 times as active

in dogs and 50 times as active in man. Thus,

it may be expected that the analgesic activity of DAAM will be greater than LAAM. This

proved to be the case. It was found that in

rats using the Haffner technique for determining analgesic activity (F. Haffner,

Deutsch, Med. Wochenschrift 55: 731, 1929)

DAAM was 5.4 times as active as LAAM by the

subcutaneous (s. c.) route of injection and

References cited my be found at the conclusion of the Monograph in the LAAM Preclinical Biography.

15
twice as active as dl-methadone. It was

noted that LAAM had a delayed onset but a

long duration of activity as compared with

the d-isomer.

Smith and Lehman (1953) found that the

analgesic effects of methadone and LAAM in

rats were additive when both were injected

subcutaneously using the D'Armour-Smith test.

Using the pinch test with rats, McCarthy

(1974) found that at 30 minutes after subcutaneous administration, LAAM was about

0.67 (0.53-0.86) times as potent as morphine

sulfate but at peak activity, which occurred

three and one-half hours after drug administration, it was six times as potent as

morphine. The onset of analgesic action was

considerably later than that of morphine or

methadone.

Leimbach and Eddy (1954) determined the

analgesic activity in mice (s.c.) of all

four of the stereoisomers as well as the

LD50 values. Their analgesic results are

summarized in Table I and Table II.

In agreement with K. K. Chen, these authors

found that d-a-acetylmethadol (DAAM) is

about six times as active as an analgesic

than 1-a-acetylmethadol (LAAM). They also

noted a delay in onset and a longer duration

for LAAM as compared with DAAM. However,

these differences tended to disappear when

the durgs were administered orally (Table

II). When the oral route was used, the ED50

doses, the onset, and duration were almost

identical. When compared with dl-methadone,

LAAM was more active orally (ED50 =1.1 vs

9.2) and had a greater duration of action.

The LD50 data for these compounds is

summarized in Table III.

16
LAAM turned out to be the least toxic

stereoisomer whether given orally or subcutaneously and was less toxic than dlmethadone also. It must be emphasized that

these acute toxicities were determined in

nondependent mice and caution must be

observed in extrapolation of these results.

Veatch, Alder, and Way (1964) studied the

nalorphine reversibility of the analgesic

effects of DAAM and LAAM as compared with

l-methadone and d-methadone. The ED values

were obtained by intraventricular injection.

Because of the long duration of action of

LAAM and the relative short duration of

action of nalorphine, the latter (50/mg/kg)

was administered 40 minutes after the dose

of LAAM and doses of the antagonist were

given every hour thereafter for a total of

six hours. The results are summarized in

Table IV.

It is surprising that no nalorphine

reversibility was noted after administration

of LAAM or d-methadone. The results are

self-consistent in the sense that d-methadone

is the precursor of LAAM and l-methadone is

the precursor of DAAM.

Nevertheless, it would be expected that

nalorphine would reverse these morphine-like

effects of all the compounds. In contrast,

Killam (1974) found that in monkeys the

respiratory depressant effects of LAAM were

nalorphine and naloxone reversible.

Analgesic Activity of LAAM Metabolites

When it became known that LAAM was metabolically converted to 1-alpha-noracetylmethadol

(N-LAAM) and 1-alpha-dinoracetylmethadol

(DN-LAAM), Nickander, Booher, and Miles

(1973) compared the analgesic activity of

these three compounds on the guinea pig ileum

preparation. The results are summarized in

Table V.

17
Smits (1974 studied these drugs for analgesic activity in the acetic acid-induced

writhing test in mice. The results are summarized in Table VI.

It was noted that LAAM had a slower onset of

action than its metabolites.

1-alpha-noracetylmethadol (N-LAAM) is more

active than LAAM. The slow onset of the

latter coupled with the high activity of the

metabolite, N-LAAM, is highly suggestive that

LAAM is metabolically transformed to an

active drug which is probably N-LAAM. The

studies of Way using SKF-525A strongly

support this proposition.

Billings, Booher, Smits, Pohland, and

McMahon (1973) found that ED50 of l-alphadinoracetylmethadol (DN-LAAM) in the acetic

acid-induced mouse writhing test for analgesia 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) determined

the physical dependence capacity (PDC) of

some compounds related to LAAM although LAAM

itself was not run. The usual single dose

suppression technique, using morphine-dependIt is clear that in both the in vitro and ent monkeys was employed. The results are

in vivo tests for analgesic activity that summarized in Table VII.

TABLE VII: PHYSICAL DEPENDENCE CAPACITY (PDC) OF CONGENERS OF LAAM

18
Although no studies were reported on LAAM itself, the racemic mixture of its primary metabolite (dl-alpha-noracetylmethadol) was run

as was the d-isomer of alpha-noracetylmethadol. The former had an equivalent dose of

0.75 mg/kg and the latter required a dose of

3.5 mg/kg to suppress signs of morphine abstinence. Thus, it may be concluded that the

l-isomer is more active than the d-isomer in

suppressing abstinence in morphine-dependent

monkeys. Since the 1-isomer is a metabolite

of LAAM it may be concluded that LAAM will

have a high PDC.

During the development of tolerance to

morphine in rabbits, the hyperglycemia produced by regularly spaced injections of the

drug gradually diminished and even turned to

a hypoglycemia as tolerance developed.

Phatak and David (1953) noted that LAAM

produced a hyperglycemia on initial injection in rabbits which gradually diminished

as tolerance developed. Abrupt withdrawal

of the drug produced a hypoglycemic effect.

Moreton, Roehrs, and Khazan (1974) studied

the pattern of self-administration of morphine, methadone, and LAAM in rats. Adult

female albino rats weighing 250-300 g were

made physically dependent on morphine and

intravenous (i.v.) cannulated to permit

self-administration of morphine (10 mg/kg/

injection). EEG and EMG activity was

recorded continuously.

Morphine was available 24 hours per day.

Methadone (2 mg/kg/injection) was substituted for morphine and LAAM (1 mg/kg/injection) was then substituted for methadone.

In the naive rat, administration of morphine

at 10 mg/kg intraperitoneal (i.p.) was

followed by a biphasic pattern of behavioral

stupor and subsequent stimulation. The

depressed phase lasted 60-90 minutes and the

EEG tracings showed the occurrence of highvoltage slow bursts. During the phase of

stimulation, lasting 60-90 minutes, the EEG

revealed desynchronized awake tracings.

Only a few short episodes of behavioral

stupor with EEG slow bursts intervened in

this period. This phase was characterized

by increased locomotor activity, stereotyped

behavior, and episodes of startle reactions.

In the dependent rat, the duration of the

biphasic response after self-injection of

morphine was reduced by about 50 percent.

The behavioral stuporous phase, concomitant

with EEG slow bursts, appeared within a few

minutes and lasted for only 15 to 30 minutes.

The behavioral stimulation and EEG activation

lasted for only 30-60 minutes. Sleep and

REM sleep predominated before the next

injection. Upon methadone substitution,

the sleep-awake distribution within the

interinjection intervals was qualitatively

similar. In the case of LAAM self-administration, EEG slow bursts usually occurred

several minutes after injection and were

followed by brief episodes of sleep and REM

sleep. These few sleep and REM sleep episodes were terminated by the appearance of

wakefulness with EEG slow bursts and then

behavioral arousal which lasted for two to

three hours. The arousal state, as in the

case of morphine and methadone, was followed

by alternating episodes of sleep, REM sleep,

and wakefulness prior to the next injection.

Under these experimental conditions of free

access to the drug, morphine (10 mg/kg/

injection) was self-administered as a single

or multiple injection at intervals of

2.5±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 was

8.8±0.8 hours.

LAAM possessed a relatively slow onset and

long duration of action in dependent rats

having free access to the drug. When low

doses of naloxone were administered intravenously, there was an immediate precipitation of abstinence signs.

Killam (1974) studied the effects of LAAM on

the morphine uptake of morphine-dependent

monkeys. At 2.0 mg/kg intramuscular (i.m.)

three morphine-dependent monkeys exhibited

a slight decrease (2-16 percent) in morphine

uptake, but a fourth showed a significant

increase (40-50 percent). The next day all

monkeys showed a significant increase which

dropped on the second day and returned to

baseline on the third day. At 4.0 mg/kg

there was a 30.6 percent decrease in morphine

uptake followed by an increase of 50-87 percent on the second day. On the third day,

the intake returned to baseline values. At

6.0 mg/kg, both monkeys were depressed and

ataxic. This lasted for 8-16 hours during

which time there was no uptake of morphine.

There was a rebound effect on the second

day and morphine uptake varied for the

following three days.

Other Pharmacological Effects

Henderson (1974a) found that a dose-dependent

acute necrosis of the kidney of rats occurred

following administration of LAAM (2 mg/kg

(0 percent), 5 mg/kg (65 percent), 10 mg/kg

(73 percent)). This effect was also noted

after administration of 50 mg/kg of morphine

sulfate (83 percent). Complete reversal

19
occurred after 32 hours. The fact that naloxone prevented this phenomenon indicated

that it was the result of the pharmacological

action of the analgesics rather than an

intrinsic effect of LAAM.

Maickel (1974) found that at 0-10 minutes

postadministration, LAAM caused a decrease

in spontaneous activity of mice. At doses

of 50 to 100 mg/kg s.c., the activity of the

mice was about 50 percent of that of the

control group and at 200 mg/kg the spontanenous activity decreased to only 60 percent

of control. In comparison, methadone at

15 mg/kg S.C. increased spontaneous activity

to about 200 percent of control. There was

a marked decrease (<50 percent of control)

at 45 mg/kg s.c.

Killam (1974) studied the effects of LAAM

in the monkey. Using doses of 1 to 8 mg/kg

i.m. and 2-6 mg/kg p.o., it was noted that

the drug produced an initial decrease in

hostility and increase in salivation followed by a markedly depressed state with low

muscle tone. Respiratory arrest occurred

which was reversible by nalorphine or naloxone. The EEG changes paralleled the behavioral changes. There was a delayed onset

of action which occurred about 10-12 hours

after oral administration and lasted 38

hours. Drug effects were noticed 40-50

minutes after intramuscular injection and

lasted about 24 hours.

The interaction of LAAM with other drugs was

also examined in the monkey (Killam, 1974).

These were secobarbital, diazepam, ethanol,

amphetamine, and diphenylhydantoin. The

effects of amphetamine and secobarbital were

slightly enhanced; those of ethanol and

diazepam were slightly obtunded, and there

were no effects on diphenylhydantoin.

Inwang et al., (1975) showed that LAAM was

qualitatively similar but differed quantitatively from methadone in its effect on

the rabbit cortex. New Zealand rabbits

which had chronically implanted electrodes in

the optic and posterior sensory motor cortex

were treated by intracortical administration

with 0.5 mg/kg and 1.25 mg/kg of LAAM. At

the lower dose, an initial, facilitatory

effect occurred four minutes postinjection

and lasted 52 minutes. The onset of peak

amplitude of the slow negative wave (SNW)

was delayed, followed by a depression of the

amplitude of the SNW with no recovery in

delay of the SNW. At the higher dose, complete abolition of the SNW occurred without

recovery.

Mice were electroshocked with 140 mV of D.C.

by contacting their eyes with electrical

terminals 10 or 20 minutes after intraperitoneal (i.p.) administration of LAAM

(0.1-2.0 mg/kg); they had prolonged postictal recovery. At 0.21-0.5 mg/kg, the

prolongation was followed by a decrease in

post-ictal recovery.

Gary Henderson has studied the behavioral

effects of LAAM in beagle dogs. One mg/kg

dose was administered intravenously and two

mg/kg doses were administered both intravenously and orally.

One Mg/Kg Intravenously--Immediately after

dosing, dogs started to pant, become

quiet, and lay down. By 30 minutes, three

of four dogs defecated. The females were

coordinated but moved slowly. The males

were slightly ataxic. By one to one and

one-half hours after drug administration,

all dogs were quiet and unwilling to move.

One male had vomited. At two to two and

one-half hours postinjection, all dogs

were laterally recumbent but alert. At

the fourth hours, they were alert and

fairly well-coordinated. At the eighth

hours, they had recovered.

The body temperature fell from 98 degrees

F to 94 degrees F, leveling at two hours

and returning to normal after six hours.

Heart rates decreased from about 65 to

55 and started to return to normal after

six hours. Respiration rose initially

due to panting, but became normal after

two hours. The males seemed to be more

affected with respect to changes in temperature, respiration and heart rate,

whereas the females showed greater degrees

of ataxia, vocalization, and shivering.

Owing to the small number of animals

involved, no firm conclusions about sex

differences can be drawn.

Two Mg/Kg Intravenously--Stimulation or

excitement appeared immediately after drug

administration. There was salivation,

increased motor activity (circling), urination, and defecation. Respiration

increased but temperature and pulse

decreased. This was followed by prolonged

hind limb ataxia, decreased motor

activity, and a sleep-like state. Respiration was only mildly depressed but body

temperature dropped from 101.5 degrees F

to 95 degrees F and returned to normal in

24 hours. The pulse was low and irregular

during the first 24 hours.

Two Mg/Kg Orally--The beagles which

received 2 mg/kg i.v. also received

2 mg/kg perorally (p.o.) after a suitable

recovery period. After 30-45 minutes, the

dogs licked their lips, panted, and salivated. One male vomited. The males were

20
depressed and were in a state of lateral

recumbency, eyes partly closed and pupils

constricted. At one to one and one-half

hours, one female was also depressed.

One male could only be aroused by shaking

and did not respond to audio or visual

stimuli. At two hours, the other female

was depressed and showed hindquarter

weakness. By the third to fourth hours,

the males dragged their hindquarters and

were ataxic. The ataxia in the males

lasted for two hours and about four hours

in the female.

In both the i.v. and p.o. studies, the

males seemed to be more affected than the

females. The only major difference

between the two routes of administration

is that, as expected, the onset of action

by i.v. injection was more rapid.

Behavioral effects of LAAM in monkeys were

also studied by Henderson (1975). Four

naive and one morephine-depent monkey

received 2 mg/kg (i.v.) H

3

 -LAAM. Drug

effects were noted within five minutes postinjection and lasted about one hour. Eyelids drooped or closed completely, pupils

were dilated, and the frequency of eye

blinking was decreased. Some catalepsy,

muscle twitching, and shivering were

observed.

There were little change in respiratory rate.

The heart rate decreased slightly in the

first three hours. The body temperature

fell from 100 degrees F to 96 degrees F.

The pupils and body temperature returned to

normal within four hours.

In one morphine-dependent monkey, 2 mg/kg

i.v. of LAAM had little effect. Papillary

size did not change but there was a slight

decrease in heart rate from 150 b.p.m. to

120 b.p.m. Heart rate was normal in two and

one-half hours.

One naive male monkey was given 5 mg/kg p.o.

of H

3

 -LAAM. After three and one-half hours

he was sedated and cataleptic. After six

hours there was marked sedation, shallow

breathing, and a rapid heart rate. He

expired one hour after drug administration.

The levels of radioactivity were high in the

lung and liver but very high in the bile

which indicated that biliary excretion was

the major pathway of disposal of the drug.

H

3

 -LAAN (2 mg/kg p.o.) was given to four

naive monkeys and one morphine-dependent

monkey. In the naive monkey, there was a

decrease in heart rate and a slight decrease

in respiratory rate beginning about one hour

after drug ingestion which lasted about four

hours. The pupils began to dilate in 30

minutes, reached a maximum in one hour, and

lasted about 12 hours. By the end of the

first hour, the animals were sedated and

showed signs of muscle twitching and shivering. They were alert to external stimuli.

Rectal temperature fell from 100 degrees F

to 96 degrees F and stayed below normal for

eight hours. Two monkeys were anorexic.

Absorption, Distribution, Excretion,

and Metabolism

The first metabolic study on LAAM was carried

out by Sung and Way in 1954. The compound

was determined in tissues by a modification

of Brodie's methyl orange technique. The

sensitivity of this procedure is very poor

when compared to modern methods.

After subcutaneous injection in rats, about

70 percent of the dose (20 mg/kg) was

absorbed from the injection site after one

hour. About 7 percent was recoverable after

13 hours. The rate of disappearance was

much slower after oral administration; about

80 percent of the dose was recovered from the

stomach after one hour and 50 percent of the

dose was recovered after 24 hours. There was

some experimental evidence adduced to suggest that the drug was being secreted into

the stomach, because appreciable amounts of

LAAM were found in the stomach after intravenous and subcutaneous administration.

The tissue levels of LAAM in Long-Evans rats

were compared after administration of 20

mg/kg of the drug. Except for the gastrointestinal tract, levels in all other organs

were higher after subcutaneous than oral

administration. The highest concentrations

were found in the lung. The kidney, spleen,

liver, and fat contained appreciable levels,

whereas very low levels were present in the

heart, blood, and brain. As noted above,

high concentrations were found in the stomach

after oral and even subcutaneous and intravenous administration. A large proportion

of the drug was accounted for in the carcass

(chiefly muscle and bone). Tissue levels of

the drug persisted for at least 24 hours.

Despite the rapid uptake and high tissue

levels noticed after parenteral administration, the morphine-like effects did not

become manifest until four-six hours after

the injection. The effects lasted as long

as 24 hours. Following oral administration,

the tissue levels were lower, but the onset

of action occurred about one hour later. In

view of these results, the authors concluded

that LAAM was being converted to an active

21
metabolite, a process which occurs more

rapidly after oral than parenteral

administration.

Very little (less than 3 percent) of the

original dose was found in the feces and

urine of rats after subcutaneous administration. Bile taken continuously from cannulated bile ducts yielded very small amounts

of LAAM. The low recovery of LAAM supported

the view that the drug was being metabolized.

Sung and Way found that in mice 40-50 percent of the drug was still present after

12 hours. Appreciable amounts were detected

after 24 hours, but by 48-72 hours, LAAM was

barely detectable. In rats, the decline in

tissue levels was more rapid, but the

pharmacological effects were more sustained.

Veatch, Adler, and Way (1964) studied the

effect of prior administration of the metabolic inhibitor SKF-525A. If microsomal

biotransformation is converting LAAM to an

active metabolite, then SKF-525A ought to

interfere with the analgesic effectiveness

of the drug. In preliminary experiments,

they determined that in the Eddy-Leimbach

hot-plate test for analgesia, the ED50 of

LAAM is 3.25 mg/kg with an onset of 135

minutes, a peak effect at 210 minutes, and

a duration of greater than six hours. The

ED90 dose was 21 mg/kg. At this dose the

onset time was reduced to 15 minutes and

the peak was 110 minutes, after injection

of the drug into the right thigh. 50 mg/kg

of SKF-525A was given 20 minutes before the

ED90 dose of LAAM and the mean analgesic

response was recorded as the percentage of

the control dose. After the first hour, the

SKF-525A treated animals responded at 92 percent of the controls, after two hours at

72 percent, after three hours at 67 percent,

after four hours at 59 percent, and after

the fifth and sixth hours at about 28 percent

of controls. Thus, it was clear that SKF525A did decrease the analgesic response of

LAAM.

McMahon, Culp, and Marshall (1965) succeeded

in identifying the major metabolites of

dl-alpha-acetylmethadol "sing radio-labeled

drug. They labeled the N-methyl group and

the O-acetyl group, using the synthetic

methods shown in the following equations.

Note: The starred carbon atoms in equation (1) and (2) are C

14-labeled.

22
The C

14-labeled dl-alpha noracetylmethadols were prepared

according to equation (3) and (4).

For in vivo studies, 150 g male albino rats

(Harlan Industries) were used. Since this

strain was sensitive to the drug, the dose

of dl-alpha-acetylmethadol used was 2.5 mg/

kg. The identity of the metabolites was

secured by the isotope dilution technique.

When C

14 -labeled N-methyl was used, the

rate and extent of expired C14O2 was

measured. Urine samples were assayed

directly in a scintillation counter and feces

were treated by the Schoniger method before

assay.

The in vitro metabolism of dl-alpha-acetylmethadol studied using rat liver homogenates. It was found that the drug was demethylated by microsomal N-demethylase to give

dl-alpha-noracetylmethadol. The latter was

also a substrate for this enzyme and furnished dl-alpha-dinoracetylmethadol but at

a considerably slower rate.

The N-demethylation was studied in vivo by

using N-C14CH3

 dl-alpha-acetylmethadol and

following the respiration of C

14O2

. On

intravenous injection, C

14O2

 formed rapidly.

In five hours, 50 percent of the dose corresponding to complete removal of one N-methyl

group was recovered in the respired air. Excretion continued until nearly 80 percent of

the administered dose was recovered as C

14O2

showing that a second N-methyl group was

coming off. The half-life for the removal of

one N-methyl group was about two hours.

Orally, the initial rate of N-demethylation

was slower, but after 16 hours, it was

almost as great as that following intravenous

injection.

C

14 -acetyl labeled dl-alpha-acetylmethadol

was administered to rats. By following loss

of the acetyl label (due to ester hydrolysis)

it was found that this occurred to the extent of 30 percent following intravenous

(i.v.) injection. About 15 percent of

dl-alpha-noracetylmethadol hydrolyzed in the

first 18 hours.

The tissue levels of radioactivity were

measured following administration of N-methyl

C

14 -labeled dl-alpha-acetylmethadol and

dl-alpha-noracetylmethadol. Following intravenous injection, peak levels of radioactivity were found in lung, muscle, and brain

one to five minutes after injection. Peak

levels in the liver and kidney occurred

later. Plasma levels were low, tended to

drop, and then reached a new maximum at

about eight hours. Orally, much lower tissue

levels were found except for the liver. Peak

levels were observed to occur 0.5 to 1.0

hours postadministration of the drug.

23
At 0.5 hour postinjection, dl-alpha-acetylmethadol predominates over the nor-analog by

a ratio of 2:1 in lung and liver and 6:1 in

the brain. After two hours, the ratios

decreased and at four hours, dl-alpha-noracetylmethadol predominated in the liver and

the radio was about 1:1 in the lung. In the

brain, the isomer ratio shifted from 6:1 to

2:1 in this period of time. No quantitative

studies were carried out because of the low

level radioactivity.

With NC14 methyl dl-alpha-noracetylmethadol,

unmetabolized drug was found in the lung,

liver, and brain at eight hours following

intravenous injection. The drug persisted

in the lung and liver for 24 hours. Radioactivity was detected for 14 days after

administration, but this long-lasting effect

could be due to the fact that some of the

C

14O2

 from the N-C14 methyl. group was being

incorporated into the body pool.

The radioactivity in the urine and feces

foIlowing administration of C

14 labeled

dl-alpha-noracetylmethadol is shown in

Table VIII.

The metabolites from the N-methyl labeled

drug can be either unchanged dl-alpha-noracetylmethadol or dl-alpha-normethadol. The

metabolites from the acetyl-labeled drug can

be unchanged drug, dl-alpha-denoracetylmethadol or a derivative of the latter.

Inspection of the column on urinary excretion shows that the percentages for N-methyl

and adetyl-labeled drug are almost the same.

Thus, unchanged drug is the primary excretion product accompanied by some bisnoracetylmethadol. However, the differences

in the fecal excretion patterns are very

large. The major product in the feces is

dl-alpha-dinoracetylmethadol or some conjugate thereof.

Biliary excretion studies show that the

major metabolic pathway involves retention

of the C

14 -acetyl group and loss of the

C

14 -N-methyl group. About 60 percent of

the administered drug is excreted via the

bile in 24 hours.

Thus, the conclusion of Sung and Way that

biliary excretion is a minor pathway for the

disposition of LAAM requires modification.

It will be recalled that these authors

looked for unchanged LAAM whereas the

material secreted in the bile are metabolites

of the drug.

Billings, Booher, Smits, Pohland, and

McMahon (1973) developed a gas-chromatographic method for the determination of

alpha-noracetylmethadol and alpha-dinoracetylmethadol. They formed the trichloracetyl derivatives of these metabolites.

These were separated on a two-foot siliconized glass colunm containing 3 percent OV 1

on 100-200 mesh Gas Chrom Q at 205 degrees.

A 63 Ni Ec-detector was used. Under these

conditions, alpha-noracetylmethadol had a

retention time of 3.4 minutes and alphadinoracetylmethadol had a retention time of

2.4 minutes. The identity of the metabolites

was confirmed by mass spectrographic analysis.

These authors determined the tissue levels

of dl-alpha-noracetylmethadol after i.p.

administration. The results are summarized

in Table IX.

24
From these data, it is clear that the tissue

build-up of dl-alpha-noracetylmethadol is a

relatively slow process and confirms the

suspicions voiced by Sung and Way (1954)

about twenty years earlier.

Gary Henderson (1975b) is studying the

metabolism and pharmacokinetics of LAAM in

rats, dogs, and monkeys. These studies are

not yet complete. The current Status of

this work is reviewed below.

Rats (Excretion Patterns)--Four male

Sprague-Dawley rats weighing between 204

and 273 g were given 2 mg/kg of H

3

 -LAAM

orally. The rats were constipated for

about 12 hours. About 8 percent of the

radioactivity was recovered from the

urine in 96 hours and about 85 percent was

found in the feces. Most of the urinary

radioactivity was excreted in the first

48 hours and little (about 16 percent)

was excreted in free form. The metabolites were separated on thin-layer chromatography (TLC) and quantitated. A

summary of the findings is given in

Table X.

Preliminary experiments showed that the

recovery of l-alpha-acetylmethadol (LAAM

was 91 percent, l-alpha-noracetylmethadol

(N-LAAM) was 91 percent, alpha-methadol

(MOL) was about 88 percent, nor-alphamethadol (N-MOL) was 90 percent, and

l-alpha-dinoracetylmethadol (DN-LAAM) was

96 percent. The pH had to be kept at 9.5

because at pH 13 acetyl migration

occurred rapidly.

It is clear that N-LAAM and DN-LAAM were

the major metabolites excreted in

unbound form and that most of the urinary

metabolites were excreted as conjugates.

25
Higher doses of LAAM were also studied.

Two male and four female Sprague-Dawley

rats weighting between 212 and 371 g were

given 5 mg/kg of H

3

 -LAAM by gavage.

Food was supplied ad lib and urine and

feces were collected every 24 hours up

through 96 hours. At this dose, the

males exhibited hematuria. At the end of

96 hours, the males had excreted 6.66

percent of the administered radioactivity

in the urine and 87.32 percent in the

feces. The females excreted 13.55 percent in the urine and 59.86 percent in

the feces.

Rats (Tissue Distribution)--Four of the

male rats which received 2 mg/kc H

3

 -LAAM

p.o. were sacrificed after 96 hours and

selected tissues were assayed for radioactivity. No attempt was made to identify the compounds in the tissues. The

results are summerized in Table XI.

In contrast to Sung and Way’s results

(1954), very little material was found in

the stomach. This discrepancy can be

explained by the difference in time

interval between the initial medication

and the subsequent sacrificing. In

Henderson’s case, the sacrificing took

place much later than the original

dosing. Despite the fact that tissues

were examined 96 hours post-dosing, it is

interesting to note that the only organ

which contained more than trace amounts

of LAAM and/or its metabolites was the

liver.

Kinetics of H

3

 -LAAM Elimination In Rat

Bile--In the initial experiments, the

interval between cannulation and dosing

was so long that several rats were too

sick to be used. The remaining animals

were used to determine the nature of the

biliary excretion patterns. Free metabolites were determined and then the

remaining bile was treated with -glucuronidase (Sigma) to deconjugate the

water-soluble fraction. Hydrolysis was

incomplete even after 36 hours incubation

at pH 5.0 at 37 degrees. Thirty percent

of the radioactivity was excreted in the

bile as unbound drug and metabolites. Of

the remaining 70 percent, about 81 percent underwent deconjugation. After

six hours the bile contained detectable

levels of free LAAM, N-LAAM, DN-LAAM,

MOL, and N-acetyl-N-Mol. The major

26

metabolites were DN-LAAM and N-acetyl-NMOL. Following enzymic hydrolysis,

N-acetyl-N-MOL and DN-LAAM proved to be

the major metabolites. In addition,

LAAM, N-LAAM, MOL, and N-MOL were detected. It is difficult to see what sort of

conjugate LAAM itself can form.

The experiment was repeated with a modification which consisted of medication

inmediately after the animals recovered

from the surgery. The rats were given 5

mg/kg of H

3

 -LAAM p.o. Bile was collected every 30-60 minutes up to 96 hours.

This experiment is incomplete; however,

initial results have been reported and

are summarized below.

Biliary excretion appears to follow zeroorder kinetics until 72-96 hours when it

then apparently follows first-order

kinetics. In two male rats, 80-85 percent of the administered radioactivity

was recovered from the bile after 96

hours. The radioactivity appears in the

bile five minutes after dosing and less

than 10 percent of the dose appears in

the feces of bile-cannulated rats. Thus,

greater than 90 percent of LAAM is

absorbed by the oral route. After 96

hours, about 96 percent of the administered radioactivity is eliminated in the

male rats and about 74 percent in the

females. The nature and abundance of

LAAM and its metabolites was the same as
in the previous experiment. In rat urine

DN-LAAM was the major metabolite followed

by N-LAAM, LAAM, and MOL.

Dogs (Blood Levels)--Blood levels peaked

in 30 seconds following a dose of 2 mg/kg

i.v. and about the same time after 1

mg/kg i.v. The levels drowned in 15

minutes and were negligible after 96

hours. After 2 mg/kg p.o., blood levels

peaked one hour postadministration.

Dogs (Excretion)--In dogs given 1 mg/kg

i.v., 79 percent of the radioactivity was

accounted for in the urine and feces after

96 hours. After 2 mg/kg i.v., 89 percent

was accounted for in this time period.

Urinary excretion peaked in the first 24

hours, whereas in the feces, peak excretion occurred at 24-48 hours. After 2

mg/kg p.o., 81 percent of the dose was

excreted in 96 hours by the males and

somewhat less by the females.

The urinary recovery of LAAM and its

metabolites after 2 mg/kg p.o. is shown

in Table XII.

Monkeys (Blood Levels)--After some preliminary dosing, four naive and one morphine-dependent monkey were given 2 mg/kg

(i.v.) of H3 -LAAM. These same animals

were used for the oral studies. The

highest level of radioactivity was noted

one minute after injection. This corresponded to a blood level of LAAM equal

to 0.47 ug/ml. There was a rapid

decrease in 15 minutes followed by a new

peak one hour after injection which corresponded to a drug blood level of 0.35

ug/ml. This was followed by a steady

decline in radioactivity which was negligible after 72 hours.

H

3

 -LAAM (2 mg/kg p.o.) was given to four

naive monkeys and one morphine-dependent

monkey.

The blood levels of radioactivity appeared in 30 minutes, peaked four to eight

hours after drug administration, and were

still detectable after 96 hours.

Monkeys (Excretion)--The urines of three

female monkeys which were given 2 mg/kg

of H

3

 -LAAM i.v. were examined. A total

of 21.55 percent of the radioactivitv

was excreted over a 96-hour period. O f

this, 19.11 percent was in the conjugated

form, and 2.44 percent was free. The

distribution of the radioactivity is

summarized in Table XIII. The morphinedependent monkeys excreted 13.7 percent

of the radioactivity in 96 hours.

27
Approximately 20 percent or less of the A better recovery of the drug was noted

admininistered dose is excreted in the when 2 mg/kg p.o. was given in an apple

urine of rat, dog, and monkey. Of this rather than by stomach tube. About 92

amount, most is excreted as conjugates percent of the radioactivity could be

rather than free drug or metabolites. accounted for in 96 hours. Most of this

In the male monkey, about 65 percent of was in the feces. The distribution of

the drug is excreted in the feces and H

3

 -LAAM and its metabolites in monkey

about 55 percent for the female. urine is summarized in Table XIV.

As usual, the amount of free LAAM and its

metabolites in the urine was very low.

The bulk of the metabolites were excreted

as conjugates.

Sullivan, Due, and McMahon (1973) reported

some preliminary results on the metabolism

of a l-alpha-methadol. They used the 2-C14

labeled derivative having a specific activity

of 14.1 μCi/mg. Bile-cannulated Wistar rats

were given 40 mg/kg s.c. and the urine and

bile were collected for 24 hours. Unconjugated drug and metabolites were extracted

with butyl chloride at pH 9.5. The pH of

the body fluids was adjusted to 3.5 and the

materials were incubated with gluselase to

deconjugate metabolites and these were then

taken up in butyl chloride.

After 24 hours, 10 percent of the administered radioactivity was found in the urine

and 36 percent was found in the bile. The

following were identified in the urine:

Unaltered 1-alpha-methadol

1-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 which

appeared to be a conjugate of 1-alpha-6-acetamido-4, 4-diphenyl-3-heptanol. These

results suggest that the major biliary excretion product of LAAM itself may be a conjugate of 1-alpha-6-acetamido-4, 4-diphenyl-3-

heptyl acetate. However, Henderson (1975b)

found that DN-LAAM readily undergoes OtN

acetyl migration so that the actual metabolite my be DN-LAAM rather than the N-acetyl

derivative.

Kochhar (1975) isolated and identified

metabolites of LAAM after incubation of the

drug with a microsomal supernatant fraction

obtained from liver homogenates of SpragueDawley rats and also from the urine of rats

which were given the drug intraperitoneally.

He identified methadol (MOL), nonnethadol

(N-MOL) 2-ethyl, 1, 5-dimethyl-3, 3-diphenylpyrroline, noracetylmethadol (N-LAAM), and

dinoracetylmethadol (DN-LAAM). The pyrroline

may be an artifact derived from DN-LAAM.

AUTHOR

Sydney Archer, Ph.D., is Research Professor

of Medicinal Chemistry, Chemistry Department,

Rensselaer Polytechnic Institute, Troy, N.Y.,

12181.

28
TOXICOLOGY OF LAAM

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

INTRODUCTION

Before a new drug can be tested in humans,

pre-clinical toxicity studies must be carried

out to demonstrate that there will not be an

unreasonable hazard to subjects to whom the

drug will be administered. Acute and chronic

toxicity studies can also demonstrate whether

the observed toxic effects are such as to

preclude administration of the drug to man

and also to alert the clinician to those

effects which would require particular attention. For these reasons the doses which are

used in toxicity studies are selected so that

some toxic effects will be produced.

Toxicity studies are so designed that information will be obtained about the relationship

of toxic to effective doses. It must be kept

in mind that such studies are not directly

translatable to presumed effects in humans.

The doses used in animals are much higher than

the expected clinical dose. The life spans of

man and the test animals are not comparable so

that an 18 month chronic study in rats means

that the drug is administered for at least

half the life span of that species. There is

usually a rapid increase in rodent mortality

after 12 months so that deaths that occur in

the second year of medication may be due to

aging, the effects of the drug, or both.

The Food and Drug Administration (FDA) guidelines suggest that at least one rodent and

one non-rodent species undergo toxicity tests.

In this case, rats and beagle dogs were utilized. Fats are often used in toxicity studies for their test convenience and in addition

because of their metabolic closeness to humans.

Rabbits and rats are used in reproduction

studies because of their reproductive capacity

and because of their sensitivity to teratogenic agents.

For these chronic toxicity studies, animals

of a given species were divided into four

groups: a control group, and low, medium and

high dosage groups. Hematological and clinical chemistry evaluations on the four groups

were done periodically: e.g.,13 weeks, 26 weeks,

52 weeks, 79 weeks. At the end of each

period, some portion of each group was sacrificed for gross and microscopic pathologic

examination to determine possible effects of

the drug. Postmortem examinations were also

performed on animals which died during the

experiment.

29
An additional complication occurs when the

test drug is one in which drug tolerance occurs. In such a case tolerance is induced in

the medium and high dosage groups by gradually

increasing the dosage to the predetermined

medim and high dosage level, in order to reach

truly toxic levels while avoiding lethal depressant reactions that would occur if such doses

were given to naive animals.

The initial chronic toxicity study on LAAM was

carried out for one year in rats and dogs at

Edgewood Arsenal. Because LAAM was administered for 5 days per week, further studies

were carried out by Industrial Biotest wherein

the drug was given daily to the test animals

for a longer period of time.

ACUTE ORAL TOXICITY OF LAAM

IN RATS (Industrial Biotest)

The acute oral toxicity of LAAM was determined

in naive albino Charles River male and female

rats. The LD50 of LAAM in the males was 28.6

mg/kg and in the females it was 35.0 mg/kg.

The acute toxicity was determined in tolerant

rats also. Rats were made tolerant by starting with a 2.0 mg/kg dose which was increased

at two-week intervals until they were receiving 12.0 mg/kg/day. This dose level was maintained for a 13 week period of medication and

then the LD50 values were determined. The

LD50 in males was 93.0 mg/kg and in females

it was 220.0 mg/kg. Thus prior exposure to

the drug had a considerable effect on the

acute toxicity of LAAM.

CHRONIC TOXICITY STUDIES

One Year Chronic Oral Toxicity

in Rats (Edgewood Arsenal)

In this study Sprague-Dawley albino rats were

used. The drug was administered by gavage at

dose levels of 5.0, 10.0 and 15.0 mg/kg five

days a week for 52 weeks. No induction schedule was employed. After the first 10 weeks

all the rats that died during that time period

were replaced by fresh rats in order to have

a sufficient number of animals for terminal

sacrifice and pathological examination. The

mortality data is summarized in Table 1.

Several rats that died after the first dose of

LAAM were found to have intracellular calcification in the heart, liver and kidney. This

phenomenon was not observed in any of the

animals which died later or in any of the rats

in the replacement groups. This effect was

not observed in a later Industrial Biotest study.

A special study was carried out in an additional group of rats to assess the significance of the intracellular calcification of

the heart, liver and kidney observed in the

rats dying after the first dose of LAAM in the

original study. To this end 75 rats were

given 15.0 mg/kg of the drug for 5 days and at

the end of that time were sacrificed and examined. None of the animals in this group

showed signs of calcification in the previously affected organs. As a result it was concluded that this phenomenon which was noted

once was not drug related.

TABLE 1

Mortality of Rats Medicated With LAAM 5 days/week

Original Group

# deaths/treated

Week of last death

Dose Levels

Control 5.0 mg/kg 10.0 mg/kg 15.0 mg/kg

4/80 3/40 17/40 52/80

36 4 39 47

Replacement Group

# deaths at 2 days/treated

# deaths at 38 weeks/treated

TOTAL

0/12 0/24

0/3 4/12

0/12 4/24

30

14/74

6/33

21/74
All of the test animals on the chronic toxicity study were observed for behavioral reactions and general physical appearance after

each daily dosing and prior to the next dosing. Body weights, food and water consumptian and several clinical parameters, including hematology and blood chemistry were

measured at specific intervals. A special

study was carried out to determine the effect

of hepatic N-demethylase on LAAM in vitro.

In the latter study it was noted that like

meperidine and 1,1-dimethylhydrazine, the two

positive controls used in the experiment,

hepatic microsomes did demethylate LAAM as

evidenced by the production of formaldehyde

in the incubation media.

Food and water consumption in all three groups

on LAAM was decreased when compared to the

control rats but only the decreased food consumption was felt to be dose related. Bloody

eyes, and analgesia, as evidenced by a

decreased response to pinching of the tail,

were observed during the first two weeks of

dosing. After that time sensitivity to tail

pinching appeared to increase. Piloerection,

exophthalmos and the Straub tail phenomenon

were present during the entire period of medication. Hematological and blood chemistry

values were all within normal limits for both

the test and control groups, with the exception of plasma lactic dehydrogenase (LDH)

which was higher in the 10.0 mg/kg and 15.0

mg/kg groups than in the controls at both the

6 month period of sacrifice and at the end of

the year. After 12 months the LDH values

were: 1072 (controls), 1688 (10.0 mg/kg) and

1833 (15.0 mg/kg).

Gross examination of tissues at necropsy and

organ weights showed that with one exception

there were no significant differences between

the treated and control groups. Only the

liver/body weight ratios in the female rats

at all doses were higher than the controls

after completion of medication. Histopathalogical examination of the tissues failed to

reveal any incidence of dose related lesions.

The most frequent finding was inflammation or

congestion of the respiratory tract.

During the first two weeks of exposure to

LAAM there was little if any gain in weight

by the medicated rats. During the course of

the study the rate of gain in weight in the

treated groups was greatly retarded and appeared to be dose related. After the first

two weeks the dosed rats began to show a

weekly cyclic patter” of a large increase in

body weight on the first two or three days of

the week followed by a loss in weight during

the remainder of the week. It is believed

that this pattern was related to the fact that

after the first weeks of medication the rats

became tolerant to and dependent on the drug,

because when medication was omitted over the

weekend the animals showed withdrawal signs.

The most prominent such sign in dependent

rats upon abrupt withdrawal of an opiate-like

drug is a rapid loss in body weight. Usually

this body weight loss can be reversed by

renewed administration of the drug.

One Year Chronic Oral Toxicityin Dogs (Edgewood Arsenal)

Beagle dogs were medicated by capsule 5 days

a week for 52 weeks at dose levels of 2.0,

6.0 and 11.0 mg/kg. Dosing was started at

2.0 mg/kg in all test groups and was then

gradually raised in the medium and high level

groups until by the end of the sixth week the

desired dose levels were achieved. Fourteen

dogs served as controls. There were 12 dogs

at the low and medium levels and 14 at the

high dose.

All of the test animals were examined daily

for clinical signs of systemic toxicity. Body

weights, food consumption and clinical parameters including hematology and blood chemistry

were measured at specific intervals during the

course of the medication. Complete physical

examinations were performed monthly including

electrocardiograms and ophthalmologic exams.

Body weight, food and water consumption decreased for all three test groups. Behavioral reactions were observed at all dose levels and

consisted of depression, hind limb weakness,

emesis, salivation and prostration. The frequency and intensity of some of these signs decreased as the study progressed. Three dogs

died at the high dose level, none at lower levels.

Hematology and blood chemistry values in the

test groups were comparable to those of the

controls. Physical examination revealed the

presence of tachycardia, slower reflexes and

decreased respiration rates but these did

not appear to be dose related. The medicated

dogs had rough coats, appeared to be thin and

presented a generally unkempt appearance as

if they did not do any grooming. Electrocardiogram (EKG) recordings taken immediately

after dosing showed an increase in duration

of the S-T segment usually accompanied by

bradycardia. Seventy-two hours after dosing

the EKG tracings were normal. Reversibility

can be determined since the dogs were not

medicated on the weekend. Other than a large

absolute liver weight in the high dose dogs

when compared to controls, no other significant differences in organ weights were apparant. Histopathological examination of tissues

disclosed no drug related abnormalities. This

was true also for the three dogs which died

spontaneously during the course of the medications.

31
79-Week Chronic Oral Toxicity

in Rats (Industrial Biotest)

Charles River albino rats were used in this

study. The final doses used were 2.0, 6.0

and 12.0 mg/kg administered daily by gavage

throughtout the 79 week period of medication.

The dose schedule is shown in Table 2.

The middle group (T-11) did not reach the 6.0

mg/kg daily dose until the 9th week and the

high dose (12.0 mg/kg) was not reached until

the 21st week.

All of the test animals were examined daily

for behavioral reactions and general physical

appearance including tumor palpation. Body

weights, food consumption and clinical paramaters were determined at specific intervals.

Group

Control

T-I

T-II

T-III

tion period all values were in the normal

range. Blood chemistry values were essentially normal for the test animals except

for some scattered slightly elevated serum

alkaline phosphatase (SAP) readings in medicated males. The females were comparable to

untreated controls. The serum glutamicpyruvic transaminase (SGPT) values were essentially normal but the serum glutamic-oxaloacetic transaminase (SCOT) values were slightly

elevated in the high dose male and female rats.

The albmin/globulin ratios of both male and

female animals in the 6.0 and 12.0 mg/kg

groups showed a moderate decrease at 52 and

78 weeks. All test females showed a moderate

decrease at 52 and 78 weeks. All test females

showed a moderate increase in total protein at

week 52 but this parameter normalized by the

78th week. The remaining blood chemistry

studies were normal.

TABLE 2

Schedule for Administration of LAAM

No. of Animals Dose Level

mg/kg/day

Male Female Week:

1-4 5-8 9-12 13-16 17-20 21-79

110 110 0 0 0 0 0 0

110 110 2 2 2 2 2 2

110 110 2 4 6 6 6 6

110 110 2 4 6 8 10 12

The Body weight gain of all test animals was

reduced significantly with the males showing

a greater initial reduction, but at the end

of the 79th week body weight gain depressions

for both sexes were about the same. During the

period of recovery the surviving animals at

the 6.0 and 12.0 mg/kg dose levels exhibited

body weight gains comparable to the controls.

The test females consumed less food during

the first 27 weeks of the medication period

but thereafter their food consumption was the

same as the controls.

Observations for phammcological and behavioral reactions during the 79-week treatment

period showed that the rats displayed hyperirritability and hyperactivity gradually

shifting to hypoactivity. The males in all

test groups showed greater hyperirritability

than the females. Alopecia and excretion of

loosely formed stools were noted in the medicated groups. Hematological parameters for

the test and control animals were comparable

The rat mortalities which occurred in this

study are shown in Table 3 Also included

are the animals which were deliberately sacrificed at 13, 26 and 52 weeks. There was an

excessive mortality rate in the control animals between weeks 23 and 26. Mortality in

all test groups at the end of week 52 was

moderate, but increased markedly from week

52 to week 79. Mortality was high in the

control group throughout the test period. In

both control and treated groups mortality was

higher in the male rats. The vast majority

(if not all) of the deaths was attributed to

naturally occurring disease characterized by

bronchoneumonia associated with metastatic

infections and polyserositis. None of the

deaths was attributed to the medication but

mortality did appear to be related to the

length of exposure to LAAM.

There was a significant reduction of absolute

except for slight varlatlons in total leuko- organ weights of the livers of the 6.0 mg/kg

cyte 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 body

32
Dose Level

mg/kg

Control

2.0

6.0

12.0

TABLE 3

Rat Mortality in the 79-Week Study

Sex Treatment Time Period (wks)

Accumulated Deaths Recovery

Total Mortality

Number Tested

0-52 53-79

M 37 5 4

F 18 34

M 24 69

F 10 31

M 16 73

F 14 35

M 35 78

F 2 7 54

and organ to brain weight ratios were normal

and in most instances comparable to the controls. Histopathological changes in the

tissue, except for the liver, were judged to

be caused by spontaneous disease and were not

unusual for the strain and age of the rats.

Treatment related changes were observed in

the livers of most of the test animals at all

dose levels of LAAM. These changes were characterized by hypertrophy of hepatocytes due

primarily to an increase in cytoplasmic mass.

The relative extent of the changes could be

correlated with the dose of the drug and duration of treatment. These changes were considered to be an adaptive response of the

hepatocytes to the metabolism of LAAM. A

separate study demonstrated that there was an

increase of microsomal enzyme activity in

rats receiving LAAM. (A similar observation

was made in the Edgewood Arsenal study).

During the recovery period surviving rats

were sacrificed the first and second months

after cessation of medication. Marked but not

complete regression of the hepatocyte hypertrophy was noted.

The remaining organ changes observed at each

sacrifice interval were judged to be related

to naturally occurring diseases or associated

with the age of the animals at autopsy. These

changes were present in the control as well

as medicated groups, The types of tumors

present in all groups were not unusual

for a random population of the strain

of rats used and there were no significant

differences in numbers between test and control groups.

80-87

4 58/110

5 39/110

2 71/110

3 34/110

3 76/110

0 35/110

0 78/110

2 56/110

52-Week Chronic Oral Toxicity

in Dogs (Industrial Biotest)

LAAM was administered orally, via gelatin

capsule at final dose levels of 2.0, 4.0 and

8.0 mg/kg seven days a week for one year

A fourth group served as controls. The medication schedule is shown in Table 4.

An initial dose of 4.0 mg/kg produced severe

reactions, particularly sedation. Gradually

increasing the dose from 0.5 mg/kg to 4.0

ng/kg over a twelve week period resulted in

the production of only slight reactions to

the drug, i.e. tolerance developed. Increased

tolerance to the drug developed at all dose

levels. Only one high (8.0 mg/kg) and one

low (2.0 mg/kg) dose level male died at 26

and 49 weeks respectively. Neither death was

considered to be drug related.

All of the test animals were examined daily

for clinical signs of systemic toxicity, particularly after dosing. Body weight, food

consuption and clinical parameters were

measured at specific intervals during the medication period. Opthalmological examinations

and EKG recordings were made.

Food consumption during the first six months

was similar for both treated and control

groups. In the latter half of the study there

was a noticeable increase in food intake in

the treated groups which was not reflected in

a corresponding increase in body weight. When

the dogs became tolerant to LAAM their weights

were comparable to that of the controls.

33
TABLE 4

Medication Schedule For LAAM in Dogs

Group Dose

(mg/kg/day)

Weeks

at dose level

T-I

T-II

0.5

1.0

2.0

0.5

1.0

2.0

4.0

1-4

5-20

21-52

1-4

5-8

9-12

13-52

T-III 0.5 l-4

1.0 5-8

2.0 9-12

4.0 13-16

6.0 17-20

8.0 21-52

Behavioral reactions were observed in the animals at the 4.0 and 8.0 mg/kg doses. These

consisted of salivation, hyperactivity, vomiting and sedation. Increased tolerance to the

drug occurred at all dose levels. The hematological parameters remained normal throughout

the study. The only change in blood chemistry

was a slight elevation of the serum alkaline

phosphatase (SAP) levels at the 4.0 mg/kg and

8.0 mg/kg dose levels. These returned to

normal during the 4 week recovery period.

Electrocardiogram tracings during the early

stages of the study showed some T-wave and S-T

changes, some tachycardia at the 4.0 mg/kg

dose level. At 8.0 mg/kg QRS complex irregularities were observed and significant S-T

and T wave changes as well as significant rate

and rhythm disturbances were noted. These

changes were present on later tracings but no

further deterioration occurred. The tracings

made during the 4-week recovery period were

considered to be within normal limits. Histopathological examination of cardiac tissue at

necropsy showed no significant abnormalities.

Gross and histopathological examination of

other organs and organ weights disclosed no

significant differences between treated and

control groups.

REPRODUCTIVE STUDIES WITH LAAM

(Industrial Biotest)

Teratogenic Studies

1. Non-tolerant Rabbits

LAAM was administered orally via gelatin capsules to non-tolerant, pregnant, New Zealand

rabbits at doses of 0.2, 0.6 and 2.0 mg/kg

from day 6 through day 18 of gestation. A

slight weight loss occurred during the treatment period but it was comparable to the untreated and thalidomide-treated control groups.

No deaths or unusual reactions occurred. All

dams were sacrificed on day 29 of the gestation period. Fetal examination revealed no

external, internal or skeletal teratogenic

abnormalities among the fetuses of the LAAMtreated rabbits and untreated controls. The

thalidomide controls yielded the expected anomalies. The numbers of resorption sites and live

young per 100 implantation sites was similar

for LAAM and unmedicated controls. Body weights

of fetuses from treated and untreated dams

were comparable also.

2. Tolerant Rabbits

Rabbits were made tolerant to LAAM by administering the drug over a twelve week period

34
starting with 2.0 mg/kg/day and incrementally

increasing the dose until the desired levels

were reached. Then doses of 6.0, 8.0 and

10.0 mg/kg/day of LAAM were given to three

groups of tolerant animals from day 6 to day

18 of gestation. A decrease in body weight

was noted at the two higher dose levels and

some non-dose related deaths occurred. It

is concluded that pre-natal exposure to LAAM

did not alter fetal skeletal development as

compared to unmedicated controls. The number

of implantation sites, resorption sites and

live young were not adversely affected by

LAAM.

3. Tolerant Rats

Rats were made tolerant to LAAM by gradually

escalating the doses from 2 mg/kg/day to 12.0

mg/kg/day over a period of 90 days. The dose

levels of LAAM were 2.0, 6.0 and 12.0 mg/kg/

day administered to day 20 of gestation. The

drug had no effect on the numbers of corpora

lutea, implantation sites, resorption sites

and viable fetuses. There was no effect on

external and internal development but there

was an increased incidence of angulated ribs

among fetuses obtained from dams exposed to

6.0 and 12.0 mg/kg/day. No other skeletal

abnormalities were found.

Perinatal and Lactation Performance

in Albino Rats

0.06, 0.20 and 0.60 mp/kg to non-tolerant

pregnant rats from day 15 of gestation

throughout the period of lactation. A total

of 28 or 29 doses were used. All dams were

allowed to deliver their litters and carry

them through weaning. In the cross-over portion of the study litters from the 0.6 mg/kg/

day test group were exchanged with a control

group with both dams carrying their litters

through weaning.

In the first phase of this study no deaths

occurred and no unusual behavior was observed.

Only the dams at the 0.60 mg/kd/day dose showed a reduction in body weight from day 15 of

gestation through day 4 of lactation. This

dose group retained fewer pups than the controls but the difference did not appear to be

statistically significant. The high dose

group did show a statistically significant

reduction in survival of the pups and reduction in body weight as lactation progressed.

During the cross-over study both groups of

dams exhibited a reduction in the number of

pups surviving to weaning. The groups of pups

exposed to LAAM in utero and reared by control

dams revealed slightly meduced body weights

through day 21. Pups untreated in utero but

reared by treated dams also showed slightly

reduced body weights.

Reproduction and Progeny Cross-over Studies

in Tolerant Rats

Using the same dosing schedule described in

Section A-3 above it was noted that body

weight reductions and hyperirritability occur

red in a dose related manner in both sexes.

Mating experiments showed that there was no

difference in reproductive performance among

treated animals as compared to controls.

Female rats exposed to LAAM showed an increased number of stillbirths. Following delivery

litters from drug treated rats were exchanged

for litters from control rats and the progeny

remained with the foster mothers tnrougnout

the lactation period. Concurrent groups of

progeny delivered by treated and control rats

were retained by their natural mothers. Survival of each group of progeny exposed to

LAAM was reduced during lactation. Progeny

fostered by LAAN-treated rats did not exhibit

as great a reduction in survival as those

pups; exposed to the drug in utero and then

fostered by non-treated rats or those delivered and retained by LAAM-treated mothers.

The body weights of progeny exposed to LAAM

in utero and then fostered by unmedicated

mothers were similar to drug-free controls.

Those not exposed in utero but fostered by

treated mothers showed reductions in body

weight. Progeny delivered and retained by

drug-treated rats showed body weight reductions only on day 1 and 4 of lactation. By

day 12 of lactation only 1 litter was viable

and at weaning these 4 pups displayed weights

equal to that of the untreated controls.

DISCUSSION:

Methadone and LAAM were developed in the

1940’s as analgesics. Although acute toxicological studies had been performed, relatively

little animal toxicological data is available

on subacute or chronic toxicity in the tolerant animal. Therefore, these current studies

were performed because the drugs are now being utilized or proposed for long term, high

dose maintenance in man. Because LAAM is

being developed as an alternative to methadone, it is appropriate to compare the toxicological effects of both drugs in the same

species.

al data for LAAM. (A.S. Keats and

Only one previous study reported toxicologic-

 N.K. Beacher,

Analgesic activity-and toxic effects of acetylmethadol isomers in man, Journal of Pharmacology and Experimental Therapeutics, 105:210-

215. 1952). The authors report that Merck and

Company studies found that racemic-levo- and

dextro-forms of acetylmethadol have a subcutaneous LD50 in mice of about 40 mg/kg. The

levo- form exhibited delayed onset of toxicity.

35
In comparison, the subcutaneous LD50 of racemic methadone (the form used clinically) in

mice is 33-48 mg/kg. (National Research

Council Handbook of Toxicology, 1956, pp.

186-187). Although previous data is not available for LAAM in other animals or by other

routes of administration, several studies have

been performed for methadone. In the mouse,

the following LD50’s have been noted: oral

93.8 mg/kg, i.v., 17.3-9 mg/kg. In the rat,

the following LD50’s are reported: oral

90-95 mg/kg, subcutaneous, 45-48 mg/kg, and

intravenous 9.2-14.6 mg /kg In the monkey

subcutaneous LD50 of 10-20 mg/kg was reported

No studies previously reported evaluated the

LD50 or chronic toxicity for methadone or LAAM

in animals dosed chronically. In the studies

supported by NIDA, Industrial Biotest carried

out similar studies using similar protocols

in the same laboratory simultaneously with

methadone and LAAM. These studies utilized

the oral route of administration which is used

clinically in man.

The LD50 of methadone in non-tolerant male

rats was 94.0 mg/kg and 102-0 mg/kg in females.

The corresponding values for LAAM were 28.6

mg/kg for males and 35.0 mg/kg for females. In

tolerant male rats the methadone LD50 was 102

mg/kg in males and 114 mg/kg for females. The

LAAM values in tolerant rats were 93.0 mg/kg

for males and 220.0 mg/kg for females.

In the case of methadone there was no sex

difference in toxicity in either naive or tolerant rats nor were there significant differences between naive and tolerant rats. In the

case of LAAM there was a slight difference between sexes in the non-tolerant animals but a

much larger difference in the tolerant ones.

Of even greater interest is the fact that tolerant animals of both sexes were less sensitive to the acute toxic effects of LAAM given

orally than naive rats, whereas no such difference occurred with methadone. An explanation for this finding requires further study.

Although LAAM and methadone are structurally

similar there are major differences in their

metabolism and pharmacokinetic behavior. The

major metabolites of LAAM are two N-demethylated derivatives, nor-LAAM and bisnor-LAAM

which persist in the animal for long periods

of time and are almost certainly responsible

for the long duration of the pharmacological

effects of LAAM. In contrast the metabolic

products of methadone do not persist and probably contribute little to its pharmacological

action.

In the Edgewood Arsenal rat and dog chronic

toxicity studies, the animals were medicated

for five rather than seven days a week and the

duration of each study was 52 weeks. Because

the dosage regimen may have influenced the

toxicity findings, and in view of the nonreproducible organ calcifications which appeared after the initial dosing in rats, it was

considered advisable to perform other chronic

toxicity studies, using a seven day dosage

regimen.

A Toxicity panel consisting of outside consultants was constituted to act as advisors to

NIDA, review data and generally oversee the

progress of the new chronic toxicity studies

of LAAM and methadone, run simultaneously in

the same laboratory (Industrial Bio-Test).

An 80-week chronic toxicity study in rats was

carried out using gradually increasing doses

of methadone to reach the final doses of 5,

10 and 15 mg/kg/day of methadone, 7 days a

week. The protocol and design of the study

resembled the LAAM experiment. The mortality

ata for methadone is summarized in Table 5.

The above mortality also includes animals

which were deliberately sacrificed and thus

is comparable with Table 3. The dosages in

both protocols are approximately the same,

there was a greater mortality in males in both

studies and a great number of animals died

after the first year of treatment. In both

studies a large number of animals died and the

cause of death for LAAM, methadone and control

animals was attributed to naturally occurring

respiratory infections and are not drug

related.

On the basis of mortality figures alone, in

tolerant rats LAAM does not appear to be more

toxic than methadone. In both studies the

drugs were administered daily whereas it is

anticipated that in man LAAM will be given

three times a week with an average weekly intake of 180 to 240 mg. The average weekly

intake of methadone is about 350 mg.

Hepatic changes were noted in both the LAAM

and methadone studies. Separate experiments

showed that administration of either drug

induced an increase in N-demethylase activity.

Such a phenomenon is commonly encountered on

chronic administration of many drugs such as

phenobarbital and diazepam which are subject

to hepatic metabolism. In the case of methadone hepatic changes reverted to normal within one month of cessation of treatment.

Recovery was not complete two months after

LAAM treatment was stopped, but definite

signs of normalization were apparent. The

difference in metabolic behavior of the two

drugs may account for this difference.

36
TABLE 5

Frequency and Distribution of Deaths in Rats Treated With

Methadone

Group

and Dose Level

Control

5 mg/kg/day

10 mg/kg/day

15 mg/kg/day

Sex

M

F

M

F

M

F

M

F

Accumulated Deaths

in Treatment Period

52 weeks 80 weeks

33

12

39

15

37

15

58

48

Changes in the electrocardiogrm tracings of

dogs on the middle and high dose levels of

LAAM were noted in the Edgewood Arsenal and

Industrial Bio-Test Studies. Owing to the

medication schedule in the former study the

reversibility of these changes could be observed. This could not be seen in the latter

study, but four weeks after medication the

EKG tracings in the Industrial Bio-Test

experiment were essentially normal. Histopathological examination of cardiac tissue

revealed no drug related abnormalities. However. in view of these findings careful attention was paid to the possibility of cardiotoxic effects of LAAM in the Phase I and

Phase II clinical trials. No evidence of

cardiotoxicity in man has been found to date.

Teratogenic studies were carried out in

naive and tolerant rabbits and in tolerant

rats. The highest dose used in naive rabbits

was 2.0 mg/kg/day but it was possible to go

to 10 mg/kg/day in tolerant rabbits. In both

experiments no embryotoxic or teratogenic efffects were observed. In tolerant rats the

only abnormality noted was an increased incidence of angulated ribs at the middle and

high dose levels.

Reproduction, perinatal and lactation performance studies with progeny cross-over were

carried out in LAAM nontolerant and tolerant

rats. The effects seen in the nontolerant

animals were similar to but of lesser magnitude than those observed in the tolerant

rats.

62

2 9

6 5

3 7

68

30

77

JO

Recovery

6

5

4

1

2

5

1

0

Total Mortality

Total Treated

68/110

34/110

69/110

38/110

70/110

35/110

78/110

70/110

In the studies with tolerant rats the drug

treated group evidenced an increased number

of stillbirths, a decrease in progeny during

lactation, and lower body weight of the progeny, although the weights were within the

normal range. The cross-over studies indicated that in utero exposure to LAAM was the

main cause for the decreased progeny survival.

These findings would appear to be consistent

with the effects of large, repeated doses of

a narcotic drug, resulting in fetal LAAM exposure and neonatal dependence via placental

transer. The decrease in progeny survival

could be related to narcotic withdrawal during the neonatal period. The increase in

number of stillbirths was also found in sinilar studies with methadone. The decrease

in progeny survival and lowered birth weight

is consistent with clinical observations

for infants born to heroin and methadone

dependent women.

On the basis of the toxicological studies

carried out thus far it can be concluded that

when the human dose regimens are taken into

account the toxicity of LAAM and methadone

are comparable in tolerant animals. The

hepatic changes that were found are in all

probability an adaptive response of the hepatocytes to the metabolism of both drugs.

The major difference between the two drugs is

the greater sensitivity of non-tolerant animals to the toxicological and pharmacological

effects of LAAM by the oral route. The difference should be kept in mind when LAAM is

to be administered to humans.

37
REFERENCES AUTHORS

Farrand, R. L., McNamara, B.P., Christensen,

M.K., Toxicological Testing of l-AlphaAcetylmethodol, 1974. (Unpublished).

Prepared at Edgewood Arsenal, Aberdeen

Proving Grounds, Maryland.

Industrial Bio-Test Laboratories, Inc.

One Year Chronic Feeding Study with LAAM

in Beagle Dogs, 1975. (Unpublished).

Prepared under Contract HSM-42-73-178

at Northbrook, Illinois.

Ms. Ann Wolven is associated with the Shell

Chemical Company, 2401 Crow Canyon Road,

San Ramon, Calif., 94022.

Sydney Archer, Ph.D. is Research Professor

of Medicinal Chemistry, Chemistry Department.

Rensselaer Polytechnic Institute, Troy, N.Y.,

12181.

Industrial Bio-Test laboratories, Inc.

Chronic Oral Toxicity Study with LAAM

in Albino Rats for 79 Weeks, 1975.

(Unpublished). Prepared under Contract

HSM-42-73-178 at Northbrook, Illinois.

Industrial Bio-Test Laboratories, Inc.

Teratogenic Study with LAAM in Albino

Rats, 1973. (Unpublished). Prepared

under Contract HSM-42-72-171 at Northbrook, Illinois.

Industrial Bio-Test Laboratories, Inc.

Perinatal and Lactation Performance

Study with LAAM in Albino Rats, 1973.

(Unpublished). Prepared under Contract

HSM-42-72-171 at Northbrook, Illinois.

38
PHASE I

Ralph M. Sollod, M.S.

Marcia G. Goldstein, M.A.

Clinical studies on LAAM were conducted as

early as 1952. Most investigations with the

drug in the 1950’s tested the use of LAAM

as an analgesic. However, in the late 1960's

and early 1970's, an interest developed in

this drug as an alternative to methadone in

the treatment of heroin addiction. These

studies preceded the Phase II clinical trials

on LAAM initiated by SAODAP in 1973. Here

they are grouped as Phase I studies. Table

XVII, provides a list of LAAM Preclinical,

Phase I, and Phase II clinical investigators.

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

FINDINGS

This section provides a comprehensive summary of clinical studies on LAAM exclusive

of the current VA/SAODAP Phase II clinical

trials. The summary has been organized into

the following sections:

Pharmacokinetics

Clinical Pharmacology

Controlled Clinical Studies

Other Clinical Studies

Summary of Toxicity-Safety Findings

and Observations

The sumnary of toxicity-safety findings and

observations covers all clinical studies

prior to Phase II (1952-1974).

Pharmcokinetics

The delayed onset and long duration of action of 1-alpha-acetylmethadol has been attributed to its biotransformation to two

active metabolites, noracetylmethadol (NLAAM) and dinoracetylmethadol (DN-LAAM) (Billings et al. 1974a). Other products of meCLINICAL STUDIES

tabolism are methadol (MOL) and normethadol

(NMOL) which are the result of deacetylation.

LAAM has two methyl groups attached to nitrogen, These are N-demethylated by

N-demethylating enzymes in vivo to 1-alphanoracetylmethadol by the removal of one methyl group and its replacement by hydrogen.

This, in turn, may be converted to a di-nor

form by the enzymatic removal of the second

methyl group and its replacement by hydrogen

(Billings 1974a). The demethylating enzymes

are located in the liver and, hence, account

for the more rapid onset of action of LAAM

when orally administered , and also explain

the delayed onset of effect when LAAM is

administered intravenously, intramuscularly, and subcutaneously (Fraser 1952).

Techniques for identifying and quantitating

plasma and urine levels of acetylmethadol

and its metabolites in human biofluids have

been developed by Kaiko and Inturrisi (1973).

Plasma and urine samples were obtained from

patients receiving maintenance dose of LAAM

(level unspecified) for treatment of heroin

addiction. Peak plasma levels of acetylmethadol were found to occur at four hours

postadministration and had nearly disappeared at 24 hours. N-LAAM plasma levels peaked

in four-eight hours and declined slowly over

the next 40 hours. DN-LAAM levels remained

constant during the dosing interval. The

time cource of pupillary effect was found

to be related to the plasma levels of the

active metabolites. (Kaiko and Inturrisi

1975, in press). Henderson (1974, 1975) has

found the time course of peak plasma levels

of LAAM and its metabolites (N-LAAM and DNLAAM) following acute administration of 60

mg LAAM to be similar to those for racemic

39


acetylmethadol: LAAM, 6 hours; N-LAAM, 2-6

hours; DN-LAAM 2-48 hours. After 90 days, a

dose level of 85 mg of LAAM three times

weekly was attained. LAAM plasma levels

were only slightly higher than initially

while N-LAAM and DN-LAAM levels were 5-10

times higher. Billings et al. (1974) found

that DN-LAAM levels were substantially higher after repeated doses of LAAM, while LAAM

and N-LAAM levels tended to remain the same.

Goldstein (1975 unpublished) found that

plasma levels of LAAM were very low at 72

hours postadministration in patients maintained on LAAM; the plasma levels of N-LAAM

and DN-LAAM, on the other hand, increased

from 24 to 48 hours and were almost as high

at 72 hours as at 48 hours. This is consistent with the proposition that it is the

active metabolites which are responsible

for the long duration of action of LAAM: the

dosage was "holding" at 72 hours when LAAM

plasma levels were practically nonexistent

and N-LAAM and DN-LAAM plasma levels were

still high.

The active metabolites of LAAM play a central role in the profile of action of this

compound. An appreciation of their role is

helpful in understanding the slow onset,

long duration of action, and cumulative

effects which have been observed.

In addition, individual variations in the

rates of formation and elimination of these

compounds have been noted (Billings et al.

1974 a; Kaiko and Inturrisi 1975, in press).

Goldstein (1975 unpublished) has also found

a great deal of variation among individuals

in LAAM plasma levels (from 15 to 170 ng/ml

at 24 hours postadministration). DN-LAAM

levels also varied considerably among patients from undetectable (<30 ng/ml) to 278

ng/ml at 72 hours postadministration.

These individual variations with respect to

the metabolism of LAAM may help to explain

the differences in response which have been

observed among LAAM patients in therapy.

The extent of individual variability in the

metabolism of this compound appears to be

an important factor which should be taken

into consideration in the formulation of

dosage levels and intervals. Several pharmacokinetic studies are currently investigating these clinical issues.

Clinical Pharmacology

LAAM investigational studies on clinical

pharmacology have been summarized below under four areas: (1) analgesic activity, (2)

relief of abstinence syndrome (withdrawal),

(3) opiate effects, and (4) cross tolerance.

(1) Analgesic Activity--Early interest in

the acetylmethadols centered around their

appropriateness for use as analgesics. Clinical trials were undertaken to evaluate the

potential of these compounds as substitutes

for morphine.

David et al. (1952) found that 20-30 mg of

racemic alpha-acetylmethadol, administered

orally and subcutaneously, relieved chronic

pain for four to five hours and bad a cumulative effectiveness which enabled patients

to skip doses in some instances.

Keats and Beecher (1952) in clinical trials

with the levo isomer (LAAM) administered

subcutaneously found it to be less effective

as an analgesic than morphine. LAAM administered subcutaneously in a dose of 20 mg/70

kg produced analgesia within 90 minutes, but

the analgesia was less than that produced

by 10 mg of morphine. By extrapolation they

estimated that 50 mg of LAAM would be needed

to equal 10 mg of morphine in efffectiveness.

They did not find the duration of action of

LAAM to be longer than that of morphine.

Cumulative toxic effects were noted after

administration of LAAM, and coma occurred

in four patients at dose levels below the

estimated equivalent effective dose. They

concluded that the margin of safety of this

drug was too small to encourage its use as

an analgesic.

There were subsequent interest in the analgesic potential of noracetylmethadol. Gruber and Baptisti (1962) found that oral

doses of noracymethadol were three and onefourth times as potent as morphine and also

had fewer undesirable side effects.

Houde et al. (1962) found that noracetylmethadol subcutaneously administered was equivalent to morphine in 8 and 16 mg doses and

had a similar duration of action.

The analgesic potential of the acetylmethadols has not been of interest currently and

the results of the early studies, while of

historical interest do not have particular

relevance to the consideration of LAAM as a

substitute for methadone in the treatment

of heroin addiction. Adverse experiences

and side effects noted in the course of these

clinical investigations will be of interest

in a consideration of the evidence pertinent

to the safety of the drug to follow later

in this summary.

(2) Relief Of Abstinence Syndrome (Withdrawal)--The early clinical investigations

of Fraser and Isbell (1952) with alpha-acetylmethadol included the racemic form of the

compound, as well as both optical isomers.

42
While only dl- and 1-alpha-acetylmethadol

have been of clinical interest as substitutes

for methadone in the treatment of heroin addiction, some findings on the dextro isomer

are discussed herein to provide a perspective of the background of the development

of interest in LAAM.

Fraser and Isbell (1952) investigated the

potential of dl-, l-, and d-acetylmethadol

to relieve withdrawal symptoms after abstinence from morphine. They found that 15-

50 mg doses of dl-acetylmethadol administered subcutaneously between the 28th and

34th hours of abstinence from morphine

brought relief from the abstinence syndrome

within two hours and that relief of symptoms

was complete after a second dose. d-acetylmethadol, on the other hand, was less effective than methadone in relieving abstinence

syndrome. Fifteen-twenty mg doses of d-acetylmethadol administered subcutaneously

at the 28th and 32nd hours of abstinence

brought little relief; with 30-40 mg doses,

relief was marked. Oral administration of

the d-isomer resulted in a less rapid onset

of action and less pronounced effects. Doses of d-alpha-acetylmethadol sufficient

suppress 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. One

mg of LAAM was equivalent to 6-8 mg of methadone. Thirty mg of LAAM administered subcutaneously bad inconsistent results with

respect to relief of abstinence; however,

30-60 mg administered orally completely

abolished all signs of abstinence.

Fraser and Isbell (1952) also found that

withdrawal from LAAM resulted in a mild but

definite abstinence syndrome, similar in

course and intensity to that following withdrawal from methadone. There appeared to

be no significant difference in abstinence

syndrome following either abrupt or gradual

withdrawal from LAAM.

Suppression of abstinence syndrome with LAAM

was of long duration. Sixty mg of LAAM administered orally was shown to be sufficient

to prevent abstinence syndrome for 72 hours.

Mild but definite abstinence symptoms did

not appear until 84 hours postadministration.

Significant withdrawal symptomes were not

manifested until the interval was extended

to 96 hours.

Levine et al. (1973) found that 20-50 mg doses of LAAM resulted in discomfort 48-72

hours posttreatment, 70 mg doses produced

mild abstinence syndrome 60-72 hours posttreatment. and 80 mg doses prevented abstinence syndrome completely for 72 hours.

Subsequent clinical research has confirmed

the ability of LAAM to prevent the development of withdrawal syndrome for long periods.

(3) Opiate Effects--Several investigators

have established data on the onset, peak,

and duration of opiate effects following administration of the acetylmethadols.

Fraser and Isbell (1952) used subjects who

were formerly addicted to morphine and withdrawn ("post-addicts") to evaluate the effects of single doses of racemic acetylmethado1 and both isomers.

dl-alpha-acetylmethadadol produced morphinelike effects which included increased psychomotor activity, somnolence, garrulousness, pupillay constriction, itching,

scratching, nausea, and insomnia. Fifteenforty mg of dl-acetylmethadol administered

subcutaneously produced morphine-like effects

in 30 minutes which persisted for 24 hours.

The d-isomer produced morphine-like effects

which were subjectively pleasing to the patients in 15 minutes following subcutaneous

administration of single 5-20 mg doses. The

duration of action was 24 hours. Twenty mg

doses of d-alpha-acetylmethadol administered

orally bad no effects on any patients tested.

Single ten-thirty mg subcutaneous doses of

1-alpha-acetylmetbadol bad a delay in onset

of action of four-six hours. Effects were

slow to appear (14 hours in some cases) and

were always evident at 24 hours, usually

evident at 48 hours, and occasionally evident

at 72 hours postadministration. Thirty mg

of 1-alpha-acetylmethl administered intravenously bad effects which were the same as

those following subcutaneous administration.

Thirty-forty mg of 1-alpha-acetylmethadol

administered orally had a more rapid onset

of action than that following subcutaneous

or intravenous administration, effects being

evident in one and one-half hours and persisting in all cases for 24 hours and in

some cases for 72 hours.

The time course of miotic effects (decrease

in pupillary diameter) was shown to parallel

that of other drug effects. Following oral

administration of the levo isomer, pupillary

miosis began in 2 hours and was maximal in

4 hours with a return to baseline measures

at 24 hours. Following subcutaneous and intravenous administration of the levo isomer,

pupillary constriction appeared more slowly,

was more intense, and lasted longer (48 hours),

Fraser et al. (1954) confined earlier find43
ings of more rapid onset of action following

oral rather than subcutaneous administration

of LAAM. Miotic effects were observed to

last 72 hours and the time course of these

effects were related to patient subjective

reports of "euphoria." Oral administration

of LAAM produced an earlier, more intense

euphoria which diminished more rapidly than

that following subcutaneous administration.

Miosis correlated with the delay of abstinence until three days postadministration,

but did not correlate well with analgesic

actions of the drug.

In an unpublished study using nonaddicted

subjects, Irwin, Blachly, Marks and Carter

administered .2 mg/kg of LAAM and methadone

orally and observed that the profile of

action following acute administration was

the same for both drugs. Peak effects, measured by the Irwin Comprehensive Humans Assessment Procedures, occurred in four hours

and the duration of action of LAAM was not

significantly longer than that of methadone.

The period of observation was 10 hours. The

only significant difference in effects were

reductions in wakefulness and attentiveness

following administration of LAAM.

In another unpublished study, Irwin, Kinohi,

Cooler and Bottomly (1973) administered .8

mg/kg and .16 mg/kg oral doses of LAAM and

.1 mg/kg and .2 mg/kg oral doses of methadone to nonaddicted subjects. Peak effects

occurred three hours posttreatment with both

drugs. The duration of action of LAAM was

over 24 hours; that of methadone was 12

hours. The higher dose of LAAM produced

effects similar to but less intense than

those produced by the lower dose of methadone. LAAM and methadone produced bi-phasic

effects which were: early activation, elevation of mood, and liking for the drug followed by later depressant effect and dislike of the drug. The effects of LAAM were

primarily activating while those of methadone were generally depressant.

Levine et al. (1973) administered 100 mg

doses of LAAM to heroin-addicted subjects

and evaluated the effects on pupillary

diameter. Twenty mg of LAAM produced maximum miosis in 24 hours. Greater doses of

LAAM produced no further constriction; 30-

50 mg doses sustained maximum constriction

for 48 hours, and 80-90 mg doses sustained

maximun constriction for 72 hours.

(4) Cross Tolerance--The ability of LAAM

to provide blockade to the effects of heroin

and the dose levels necessary for complete

blockade have been studied by several investigators. Irwin, Blachly, Marks, and Carter

(unpublished) studied the development of

cross tolerance to 30 mg morphine sulfate

in LAAM-maintenance subjects. It was found

that most subjects experienced a slight rush

after administration of morphine and could

distinguish morphine from placebo. Responses were unrelated to levels of LAAM doses.

One subject receiving 20 mg of LAAM showed

a marked response to morphine injections,

while subjects receiving 30, 85, and 140 mg

doses 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 postadministration. LAAM was usually, but not always,

effective in suppressing the effects of morphine.

Levine et al. (1973) undertook a study to

determine the dosage of LAAM which is required to provide blockade to 25 mg heroin

using heroin-addicted subjects who were

detoxified and drug free at least seven days

before the experiment. Patients were started on 10 mg of LAAM three times a week and

dosages were increased by 10 mg per week up

to 100 mg. Heroin challenges were performed

at 72 hours after administration of varying

doses of LAAM. At dose levels of 30 mg LAAM,

four of six subjects reported some effects

of heroin and two felt none. At dose levels

of 50 mg, no effect of heroin was perceived

and at dose levels of 70 and 100 mg LAAM

blockade was complete.

Zaks et al. (1972) found that three of four

subjects receiving 30-40 mg doses of LAAM

responded to challenge with 50 mg heroin 24

hours after administration of LAAM with

mile, transient euphoria, while blockade was

complete in the fourth subject. All subjects

receiving 80 mg of LAAM demonstrated complete

blockade to 50 mg of heroin at 24 hours: one

subject was challenged at 48 hours postadministration and demonstrated complete

blockade to heroin.

Controlled Clinical Studies

Clinical trials prior to Phase I have provided some evidence as to the safety and

effectiveness of LAAM as a substitute for

methadone in the treatment of heroin addiction. A review of the studies undertaken

and their results pertinent to the effectiveness of LAAM as a substitute for methadone

will be presented here. Discussion of data

from these studies pertinent to the safety

of LAAM will be presented in the section

titled Summary of Toxicity-Safety Findings

and Observations. A summary of all controlled clinical studies prior to Phase II is

presented in table XVIII, which follows this

page

44
The term "controlled clinical studies" as

used here refers to all studies in which a

control group, i.e., a group of patients

who are taking methadone, is used to provide

a basis for comparison of outcomes with the

LAAM-treated group. The study design may

be open, where the patients are aware of

the medication they are receiving; blind,

where the patients are unaware of the medication they are receiving and are given

placebo in place of active medication on

nondrug days; or double-blind, where the

identity of the medications which patients

receive is not known to patients or the

staff who administer the medication and evaluate the results.

The following section will discuss other clinical studies which likewise may be open or

blind, but in which no control group is used.

The first clinical trial (Jaffe et al. 1970)

was a double blind study of the effectiveness of dl-alpha-acetylmethadadol as a substitute for methadone in the treatment of

21 patients. Doses were administered in

the ratio of 1.2 mg of dl-alpha-acetylmethadol to 1 mg of methadone. At 24 and

48 hours postadministration, there was no

change from baseline measures on the Addiction Research Center Inventory (ARCI) and

a withdrawal symptom checklist. At 72 hours,

there was a slight rise in the opiate withdrawal subscale of the ARCI; however, there

were no complaints on the checklist or in

interviews with experimenters. Ninety-six

hours postadministration there was a sharp

rise in withdrawal symptoms and complaints.

No differences were found between groups

with respect to relief of withdrawal symptoms, illicit drug use or other indicators

of social adjustment. One-third of the

LAAM patients and 11 Percent of methadone

patients dropped out of the study.

In a subsequent double-blind experiment

comparing dl-alpha-acetylmethadol and methadone, 34 patients were studied for 15 weeks

(Jaffe et al. 1972). The withdrawal symptoms of patients taking a mean dose of 36-

80 mg of dl-alpha-acetylmethadol/active

dose three times weekly did not differ from

those of patients taking a mean of 30-90 mg

of methadone daily. There were no significant differences between the two groups for

the following outcome measures: dropout

rate, employment, arrests, percentage of

urines negative for illicit drugs, clinic

attendance and requests for dose level

changes. Twenty-six percent of the dl-alphaacetylmethadol patients and 13 percent of

methadone patients dropped out. The difference was not significant.

A double-blind, controlled study was carried

out with 10 patients to determine if LAAM

could be effectively substituted for methadone on weekends (Jaffe and Senay 1971).

The duration of the study was three weekends

and no differences were found between the

experimental and control groups with respect

to morphine-positive urines, clinic attendance, interviewer observations, self-reports

of symptoms, or requests for change in medication. It was found that LAAM in doses

equivalent to the patient’s usual dose of

methadone were sufficient to prevent abstinence symptoms for 48 hours. Abstinence

syndrome was prevented for 72 hours by doses

of a mean of 1.3 mg of LAAM for every 1 mg

of daily methadone. Mean dose levels were

60 mg of LAAM and 68 mg of methadone. LAAM

was found to be similar in potency to the

racemic compound, not higher as anticipated.

Senay, Jaffe, diMenza and Renault (1974) in

a 48-week, double-blind study started 157

patients on mean doses of 57.8 mg of LAAM

three times weekly, with placebo on alternate days, 40.6 mg of methadone daily (Full

Service Group), or 41.3 mg of methadone daily

(Dispensary Group). Few significant differences were found between the LAAM Full Service group, the Methadone Full Service group,

and a third treatment group (Dispensary) receiving methadone only and no counseling or

other services. There were no significant

differences in total number of weeks accumulated by patients in their original treatment

groups. At the end of 48 weeks, 49 percent

of the Dispensary group, 50 percent of the

LAAM Full Service group, and 29 percent of

the Methadone Full Service group had dropped

out. There were no significant differences

between treatment groups with respect to use

of illicit drugs and employment and arrest

rates. Requests for dose-level changes were

significantly less in the Dispensary group.

Zaks, Fink and Freedman (1972) compared 40

LAAM (30-80mg/three times a week) and methadone (100 mg/day) patients in an open study

of six months duration and found the groups

to be equivalent with respect to patient

acceptance, withdrawal symptoms, response

to heroin challenges, and number of positive

urines tested for morphine. Patients taking

40-50 mg doses of LAAM evidenced withdrawal

symptoms 40-48 hours posttreatment and 80

mg of LAAM completely prevented abstinence

syndrome for 72 hours. Twenty percent of

methadone patients and 11 percent of LAAM

patients dropped out.

In a controlled study with both double-blind

and open comparisons, Lehmann (unpublished)

studied 42 16-21 year olds on LAAM every 72

hours. Some camplaints of mild discomfort

45
after 60 hours were made by patients in the

open group (who knew they were taking LAAM);

however, complaints were not severe enough

to warrant change in dosages or inter-emotional reactions, performance in jobs,

school, athletics, and therapy. Withdrawal

was accomplished from both drugs at the end

of 16 weeks with equal ease.

Savage, Karp and Curran (unpublished) carried out a six-month double-blind crossover

comparison between 99 patients on LAAM (1.3

times their usual methadone dose) and methadone. Treatment groups did not differ in

frequency of positive urines, clinic attendance, and social and emotional adjustment.

Those patients who were induced on LAAM initially dropped out at a significantly higher rate than those who started on methadone

and transferred to LAAM (x2 5.49, p=0.2).

The dropout rate was also higher for LAAM

patients in the second half of the study,

after the crossover, but the difference was

not significant. Fifty-three percent of all

patients taking LAAM dropped out and 35 percent of all patients taking methadone dropped out.

Irwin, Blachly, Marks, Carlson, Loewen and

Reade (1973) in an eight-month open study

of 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 dropouts

from the study were disproportionately males

and tended to occur in the first two months

of the study. There was a higher percentage

of dropouts in the LAAM group (42 percent)

than in the methadone group (23 percent) or

among the nonaddict controls (20 percent).

There were no differences between treatment

groups in social adjustment indicators.

In an open study comparing 65 patients on

LAAM and methadone, Senay, Renault, diMenza,

Collier, Daniels and Dorus (1974, unpublished) found that patients can be maintained on a mean dosage of 44.4 mg of LAAM

three times weekly in comparison with patients maintained on 36.5 mg of methadone

daily. Mean initial dose levels were 44.7

mg of LAAM and 33.5 mg of methadone. No

significant differences in illicit drug use

and employment and arrest records were noted at 14 weeks. LAAM patients tended to

drop out earlier than methadone patients.

The difference was significant at five weeks

but was no longer significant by 14 weeks.

The dropout rate was 32 percent for LAAM

patients and 22 percent for methadone patients.

Goldstein and Judson (1974) compared 44 patients receiving 50 mg of methadone daily

to 14 patients receiving 75 mg of LAAM three

times weekly on a double-blind basis and 16

patients taking 75 mg of LAAM three times

weekly on an open basis. No significant

differences were noted in dropout rates, attendance records, and jailings. Urine tests

for opiate use indicated the LAAM groups

were superior to the methadone group in having less illicit use of narcotics. Methadone group members were superior in reduction of amphetamine and barbiturate use.

Goldstein also investigated the question of

whether complaints of medication not holding

over the weekend were psychological or pharmacological in nature. He increased the

Friday dose of LAAM from 75 mg to 100 mg on

three successive weekends on a limited basis with the expectation that complaints

would decrease if their origin was pharmacological rather than psychological. The effects of this dosage increase were inconsistent, indicating that complaints of withdrawal may well arise out of patients' concern

that their medication will not hold than,

rather than being pharmacological in origin.

The overall results of all controlled clinical studies prior to Phase II reveal few

differences between LAAM and methadone patients on outcome measures such as use of

illicit drugs, illegal activity and arrests,

employment, clinic attendance and dose-level

changes. A large number of studies have

confirmed the initial findings of Fraser

and Isbell that LAAM is capable of suppressing the development of abstinence syndrome

for 72 hours. The dose levels necessary to

achieve this have been shown to vary greatly, and the patient’s attitudes and concerns

about the ability of the medication to hold

him for this period of time are important.

The main differences between treatment groups

appear to be in the percentage of patients

who drop out of the studies. With one exception (Zaks et al. 1972), all studies reported a greater percentage of LAAM patients

dropping out than methadone patients, although the differences between groups were

often not significant.

Dropouts among LAAM patients tended to occur

early in the studies. Goldstein and Judson

(1974) noted a greater number of dropouts

among LAAM patients than among methadone

patients during the stabilization phase.

Savage et al. (unpublished) noted a significantly greater number of dropouts among LAAM

patients in the first half of their crossover study. Dropouts were also greater among

LAAM patients after medications were switched,

but not significantly so.

Senay et al. (1974 unpublished) noted that

the significant difference in percentage of

46

dropouts among LAAM and methadone patients

at the 5th week of their study had disappeared by the end of the 14th week when the

rate of dropouts for methadone patients increased to a level similar to that of LAAM

patients.

Jaffe et al. (1970) noted that the four patients taking dl-alpha-acetylmethadol who

dropped out of his study did so on the first

day. Jaffe et al. (1972) found that the

average stay of patients on dl-alpha-acetylmethadol was 5.8 weeks compared to 10 weeks

for methadone patients.

In summary, investigators have found that

on most outcome measures, LAAM compares favorably with methadone as a substitute drug

in the treatment of heroin addiction. The

dropout rate among LAAM patients has been

shown to be generally higher than that for

methadone patients, although differences

are often not significant. Dropouts among

LAAM patients often occur during the early,

stabilization phase and may be related to

physiological problems in inducing patients

onto a new drug or to psychological concerns

about the taking of an "experimental" drug.

If, as is suspected, the metabolite N-LAAM

is the active agent, there is a lag in

buildup of pharmacologically active blood

levels. During the period when patients

are off methadone and just starting on LAAM,

the blood levels of the desired agent may

be too low and initial discomfort may occur.

Other Clinical Studies

Other clinical investigations have been

carried out with LAAM where a methadone or

other control group was not employed and

have produced findings pertinent to the effectiveness of LAAM in the treatment of

heroin addiction.

Blachly (1971) reported starting 74 patients

on LAAM in an open study. The initial conversion factor of one-sixth the patient’s

usual dose of methadone proved to be inadequate, and all patients suffered withdrawa1.

Twenty-two out of twenty-three patients

started at those dose levels returned to

methadone within a week. Twenty-four of

51 other patients continued on dose levels

equal to their methadone dose. Doses of

LAAM equivalent to the patient’s usual methadone dose were sufficient to prevent abstinence in 18 patients for 48 hours and in

6 for 24 hours.

Wilson, in an unpublished open study, observed 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 having

been maintained on methadone for three

months

Five patients induced directly on LAAM

(60-65 mg Monday and Wednesday and 80-

85 mg on Friday) who had never taken

methadone

Six patients who received methadone

Monday through Thursday, and 80-85 mg

of LAAM on Friday

The dropout rate was identical in both groups

taking only LAMM (40 percent). The group

who had never taken methadone stabilized on

LAAM with less distress and fewer complaints

than the group who had been transferred from

methadone maintenance. The group of patients

taking methadone during the week and LAAM

on the weekends all experienced withdrawal

on the third day after the Friday dose. Twothirds of them dropped out of the study after

five weekend doses; this part of the study

was discontinued after two months.

Summary Of Toxicity-Safety Findings And Observations

When all the research which has been done

with LAAM prior to Phase II is taken into

consideration, it appears that there have

been few unusual reports of toxicity; such

adverse experiences as did occur resembled

those of methadone, and particularly occurred

after excessive dosage. The cumulative nature of the drug effects and the variability

among individuals in the rate at which LAAM

is metabolized necessitate close attention

to dosage levels and intervals. Following

is a summary of clinical experience which

has accumulated as a result of investigations

prior to Phase II and which has relevance

to the safety of the drug. This summary is

organized in the following categories: results of laboratory tests, adverse experiences, and side effects

Results Of Laboratory Tests

Laboratory tests have revealed few differences between LAAM and methadone patients

and most results have been within normal limits, or unchanged from pretreatment values

where pretreatment values were not normal.

Following is a description of those results

which are unusual in any respect.

Blachly et al. (1972) canpared 21 LAAM Patients to a matched sample of 19 methadone

patients on laboratory findings (results of

SMA 12 and SMA 6 screen and automated reagin

tests) and electroencephalograms. The only

48
statistically significant finding (p.025)

for LAAM patients was hyperglycemia (mean

blood glucose 117 percent for LAAM patients

103 percent for methadone patients where

110 is defined as the upper limit of normal).

Sixty-three percent of the methadone patients and 38.5 percent of the LAAM patients

had EEG abnormalities but the difference was

not significant (p 0.1-0.2, chi square=2.44).

Irwin, Blachly, Marks and Carter (unpublished) in another discussion of the same study

also noted a higher incidence of abnormalities in SGOT, albumin, and alkaline

phosphatese determinations in both the LAAM

and the methadone groups, suggesting a

slight impairment in liver function. ‘Ihirty-five and 29 percent of methadone and LAAM

subjects, respectively, also had abnormally

high white blood counts. LAAM subjects’

performance on cognitive tasks involving

memory, learning, speed, and accuracy was

significantly better than was methadone

subject’s performance.

Jaffe, Senay, Schuster, Renault, Smith and

diMenza (1972) in a study of dl-alpha-acetylmethadol noted that only 7 of 66 patients

bad normal results on liver-function tests

upon entry and that profiles remained unchanged at the end of the study. With respect to hematology, most subjects were normal initially and at the end of the study.

In one subject, the hematocrit dropped from

48 percent to 39 percent but hemoglobin

level, RBC, and WBC remained normal. White

blood cell counts decreased in two patients

and increased in one; no symptoms were associated with any of these changes. Thirteen subjects had positive results for VDRL

and PTA tests initially, which were unchanged

at the end of the study, except for one subject whose values reverted to negative.

Wilson (unpublished) noted elevated SGOT

determinations and slightly decreased hemoglobin, hematocrit, and white blood count

in five of six LAAM patients.

Zaks et al. (1972) reported elevated transaminase levels which were sporadic and not

dose-related for both the LAAM and the methadone groups. Results of all other laboratory tests (fasting, blood glucose, blood

urea nitrogen, uric acid, blood cell count,

and urinalysis) were normal.

Irwin, Blachly, Marks, Carlson, Leowen and

Reade (1973) found the incidence of EBG abnormalities among methadone patients was 43

percent upon entry into the study and had

increased to 53 percent at eight months.

Incidence of EEG abnormalities increased

less markedly for 48-hour LAAM patients

(31 percent upon entry to 40 percent at

eight months). There was a statistically

significant increase in incidence of EEG

abnormalities for 24-hour LAAM patients (34

percent upon entry to 100 percent at eight

months) . There was no significant alteration of cognitive performance for LAAM or

methadone patients and EEG abnormalities

did not seem to be reflected in performance

on cognitive tests.

Blood chemistry analysis revealed that both

LAAM and methadone produced elevations in

SGOT determinations and that methadone produced a greater incidence of lowered abnormal T-3 value. Incidence of abnormalities

was sustained for methadone patients and

decreased for LAAM patients over the eightmonth study period. Urine analysis revealed

no abnormalities.

Savage et al. (1974, unpublished) found no

differences in LAAM patients pre- and posttreatment in EEG, blood chemistry analysis,

or hematology. Methadone patients evidenced

significant changes on three of seven hematology measures; the mean values of neutrophiles decreased and the mean values of

lymphocytes and basophiles increased. All

values were still within normal range, however.

Adverse Experiences

There have been several reports of adverse

experiences in the course of investigations

with LAAM prior to Phase II.

Keats and Beecher (1950) noted four incidents of coma among 81 patients receiving

subcutaneous doses of LAAM for relief of

chronic pain. The patients bad received 16

40 mg LAAM twice in 24-34 hours with one to

three 6-10 mg doses of morphine in the same

interval. Coma occurred 12-24 hours after

the last dose of LAAM and lasted an average

of 20 hours.

Blachly (1971) noted four cases of toxicity

to LAAM at dose levels above 100 mg among

74 patients taking LAAM. Two patients had

seizures while on 180 mg and 120 mg LAAM

every 24 hours. A female patient on 110 mg

LAAM every 24 hours lost consciosness, suffered cardiac arrest, and showed EEG abnormalities, and a patient on 220 mg LAAM

per day complained of feeling as though he

were going to have a fit and was returned

to methadone. A fifth patient bad a manic

attack when his dosage was reduced to 35 mg/

48 hours from 55 mg/48 hours during voluntary

withdrawal. He was returned to methadone

(55 mg/day), treated with lithium and thorazine, and subsequently completed withdrawal

49
while on LAAM.

Side Effects

The response of patients on LAAM has been

shown to vary considerably among individuals.

Some patients evidence no side effects or

complaints, while others experience distress

from either withdrawal or side effects.

Billings et al. (1974) observed different

responses in three LAAM subjects studied.

The subject with the highest plasma levels

NAM and NNAM reported only mild sweating

and constipation. The two other subjects,

whose plasma levels of the metabolites were

similar to each other, reported more severe

side effects. One reported anxiety, sweating, and gooseflesh in the early weeks of

the study which disappeared later; the other

reported considerable dysphoria, irritability, muscle weakness, tremors, and paranoia.

Zaks et al. (1972) received no complaints

of side effects from methadone patients except constipation (4 out of 10 patients).

Of the nine LAAM patients, three complained

of irritability, one of anxiety, and two

of involuntary, jerky movements of the

extremities before falling asleep.

Jaffe, Senay, Schuster, Renault, Smith and

diMenza (1972) noted few complaints of side

effects in the 66 subjects in their study,

and no toxic reactions. Two patients complained of impotence and two complained of

jerking and twitching of arms and legs when

at rest.

Withdrawal, irritability, restlessness, gastrointestinal upset, and anxiety were complained of by methadone patients who were

taking LAAM on weekends (Wilson, unpublished). All five patients in the treatment

groups who were transferred to LAAM from

methadone all complained of amphetaminelike effects, irritability, anorexia, constipation, and diminished libido in the

early weeks of the study. Other complaints

were appetite and weight loss. The five

patients in the treatment group who were

induced directly on to LAAM stabilized with

fewer side effects than the group which was

transferred from methadone.

David and Semler (1956) found that side

effects were minimal among patients receiving small doses of LAAN orally and subcutaneously for relief of chronic pain. Twenty-five of seventy-six patients were nauseated or vomited at some time while receiving LAAM. Ten of thirty-one patients treated for longer than 31 days complained of

moderately severe constipation. Six patients

in the total sample complained of dizziness,

thirteen reported feeling lethargic, and two

experienced severe depression attributable

to intolerance to LAAM.

Fraser and Isbell (1952) found that repeated

doses of dl-alpha-acetylmethadol and LAAM

resulted in cumulative toxic effects in

four patients: depression, approaching coma,

nausea, respiratory depression, and mental

confusion.

Reports of loss of sexual desire, constipation, drowsiness, and loss of energy were

received from patients in both LAAM and methadone groups. The mean number of complaints

was 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 proportion to the dose level of nor-acetylmethadol; constipation, headache, nervousness,

and abdominal discomfort were reported as

side effects but were not dose-related.

Itching was volunteered as a complaint often

enough to be added to the list.

Houde et al. (1962) observed that nausea

and drowsiness occurred in some patients at

higher doses of noracetylmethadol (8 and

16 mg) administered subcutaneously, and burning at the site of injection occurred after

25 percent of the 16 mg doses.

Jaffe et al. (1970) reported that four of

twelve patients taking dl-alpha-acetylmethadol dropped out on the first day because

of complaints of anxiety and nervousness.

The d-isomer has been suspected of producing

anxiety and nervousness (Fraser and Isbell

1952) and may be responsible for the side

effects noted in this instance.

In an open study with LAAM, Levine (1973)

noted that three of seven patients reported

loss of appetite and abdominal discomfort

at doses greater than 50 mg; all patients

reported constipation.

Senay et al. (1974) found no instances of

confusion, psychotic symptoms, or unpleasant

subjective states among 157 patients studied.

Anxiety was observed in all treatment groups.

There were two deaths during the course of

the study: a methadone patient committed

suicide and a LAAM patient died of lung cancer .

Senay et al. (1974, in press) reported that

5 of 34 patients taking LAAM experienced

side effects; four suffered from anxiety and

nightmares early in treatment and one patient

5 0
exhibited bizarre behavior of which he had

no recollection. One LAAM patient died as

a result of heroin overdose 48 hours after

his second dose of LAAM.

* * * * * * * *

This chapter has summerized the clinical trials with LAAM which have been conducted prior to Phase II. A sampling of selected abstracts follows.

AUTHORS

Ralph M. Sallod and Marcia G. Goldstein are

associated with Macro Systems, Inc., 1110

Fidler Lane, Silver Spring, Md., 20910.

51
The following synopses were prepared to a

standard format by Macro System, Inc., from

a review of LAAM research, published and unpublished, up to July, 1975.

SELECTED CLINICAL STUDIES SYNOPSES

INDEX

1 Billings, R. E., McMahon, R. E., Blake, D. A.

1-Acetylmethadol (LAM) Treatment Of Opiate

Dependence: Plasma And Urine Levels Of Two

Phamacologically Active Metabolites. 1974

2 Blachly, P. H.

1-Alpha-Acetylmethadol In The Treatment Of

Opiate Addiction: Progress Report, 1971

3 Blachly, P. H., David, N. A., Irwin, S.

1-Alpha-Acetylmethadol (LAM): Comparison

Of Laboratory Findings, Electmencephalograms, And Cornell Medical Index Of Patients

Stabilized On LAM With Those On Methadone.

1972

4 Fraser, H. F., Isbell, H.

Actions And Addiction Liabilities Of AlphaAcetylmethadols In Man. 1952

5 Fraser, H. F., Nash, T. L., Vanhorn, G. D.,

Isbell, H.

Use Of Miotic Effect In Evaluating Analgesic

Drugs In Man. 1954

6 Goldstein, A.

LAAM And LAAM Metabolites: Plasma Levels In

Patients. Summary Progress Report. 1975

(Unpublished)

7 Goldstein, A., Judson, B. A.

Can The Community Be Protected Against The

Hazards Of Take-Home Methadone? 1974

8 Henderson, G. L.

Pharmacodynamics Of LAAM In Man: Plasma

Levels Of LAAM And Its Metabolites Following

Acute 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 Physiologic

Effects Of Long-Term Methadone And Methadyl

Treatment. 1973

10 Irwin, S., Blachly, P., Marks, J.,

Carter, C. C.

Preliminary Observations With Acute And

Chronic Methadone And I-Alpha-Acetylmethadol

Administration In Humans. Unpublished

11 Irwin, S., Kinohi, R. G., Cooler, P. M.,

Bottomly, D. R.

Acute Time-Dose-Response Effects Of Cyclazocine, 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 Methadone

In The Treatment Of Long-Term Heroin Users:

A Pilot Study. 1970

13 Jaffe, J. H., Senay, E. C.

Methadone And 1-Methadyl Acetate: Use In

Management 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 DoubleBlind Study In Heroin Users. 1972

15 Kaiko. R. F., Chatterjie, N.,

Inturrisi, C. E.

Simultaneous Determination Of Acetylmethadol

And Its Active Biotransformation Products

In Human Biofluids. 1975 (In Press)

16 Kaiko, R. F., Inturrisi, C. E.

Disposition Of Acetylmethadol In Relation

To Pharmacological Activity. 1975 (In Press)

17 Lehmann, W. X.

The Use Of 1-Alpha-Acetyl-Methadol (LAAM)

As Compared To Methadone In The Maintenance

And 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, Methadyl

Acetate, And Minimal Services. 1974 (In

Press)

21 Senay, E. C., Renault, P. F., diMenza, S.,

Collier, W. E., Daniels, S. J., Dorus, W.

Three Times A Week LAAM Equals Seven Times

A Week Methadone: A Preliminary Report Of

A Control Study. 1974 (In Press)

22 Zaks, A., Fink, M., Freedman, A. M.

Levomethadyl In Maintenance Treatment Of

Opiate Dependence. 1972

Freedman, A. M.

Levomethadyl Acetate: Prolonged duration

Of Opioid Effects, Including Cross Tolerance

To Heroin, In Man. 1973

53
Methodology

One hundred mg of LAAM was taken orally on

Mondays, Wednesdays, and Fridays. Blood

samples (5-10 ml.) were taken at intervals

in the succeeding 48 hours; total urine

voided was collected for two days. Electron

capture gas chromatography was used to

determine the content of NAM and NNAM.

1

1-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-noracetylmethadol (NAM) and 1-denoracetylmethadol

(NNAM) have been identified and are thought

to explain the characteristic pharmacological

effects of LAAM. (Sung and Way, 1954;

Billings et al., 1973). The determination of

NAMl and NNAM levels in blood and urine of

patients receiving LAAM for treatment of

opiate addiction was undertaken in order to

support the proposition that the activity of

LAAM is due to its conversion to NAM and

NNAM.

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, were

taking 100 mg LAAM three times a week as

volunteers in an experiment comparing LAAM

to methadone and were asked to provide samples of blood and urine.

RESULTS

Plasma Levels

Plasma levels of both metabolites were

established soon after dosing. During the

first day, the levels of NAM were higher

than those of NNAM. As time went on, NAM

levels declined steadily while NNAM levels

remained at peak levels (50-75 ng/ml) up to

the time of the second dose. NHAM levels

were higher after a repeat dose of LAAM than

after the initial dose (100-300 ng/ml). NAM

levels varied in all three subjects.

Urine Levels

Less unmetabolized LAM was excreted than NAM

or NNAM. Excretion levels of all three were

much greater (six to eight times greater)

after repeat dose than after the initial

dose. This is felt to be due to LAAM, NAM,

and NNAM becoming tissue bound easily and

not being excreted until subsequent doses

have saturated the abilitv of the tissues

to bind amines, at which point the rate of

excretion will increase.

Adverse Reactions

The three subjects varied in the side effects

they experienced.

One subject reported only mild excessive

sweating and constipation during the first

week. He had higher plasma and urine

levels of NAM and NNAM than the other two

subjects.

The second subject had difficulty with

amphetamine-like stimulation, anxiety,

sweating, and goose flesh for six weeks.

The third subject evidenced dysphoria,

irritability, muscle weakness, tremors,

and paranoia which decreased during the

first four weeks. He asked to be switched back to methadone at the seventh week

because of discomfort. Significant

plasma levels of NAM and NHAM were still

present seven days after his last dose

of LAM.

54
2

1-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 they

wished, and there would be a transitional

period during which dosages would be

adjusted.

P.H. BLACHLY

INTRODUCTION

Jaffe et al. (1970), demonstrated that dl

alpha-acetylmethadol could be substituted

for methadone and that it suppressed abstinence symptoms for 72-96 hours confirming

the earlier findings of Fraser and Isbell

(1952). In an unreported pilot study by

this investigator using higher doses (mean

106 mg), dl-alpha-acetylmethadol produced

oversedation and gradually increasing toxicity. Further studies have been limited

to the levo isomer which has two features

of interest:

It is more effective orally than

parentera11y.

It is not psychologically addictive.

Methodology

Induction--Conversion from methadone was

initially one-sixth the usual dose of

methadone but was revised to doses of

LAAM equal to the regular methadone dose.

Dose Levels--The mean dose was 89.1 mg

(range 25-140 mg).

Frequency Of Administration--Six patients

received their dose of LAAM every 24

hours; 18 received theirs every 48 hours.

RESULTS

Dropout Rate

Of the 23 patients started on doses of LAAM

equal to one-sixth their methadone dose,

all but one returned to methadone within a

week because of withdrawal symptoms.

Of the 51 patients induced on LAAM in dose

levels equal to their methadone dose, 24

continued on LAAM.

The mean number of days on LAAM of those who

prefer it is 132 (range 18-300).

Reasons For Preference Of LAAM

The following reasons were given for preferring LAAM by the number of persons

indicated:

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 returning to methadone by the number of persons

indicated:

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 reasons

for wanting to return to methadone

Toxicity

There were four cases of toxicity to LAAM,

all occurring in patients for whom high dose

methadone would not prevent abstinence

craving for a full 24 hours; all were receiving daily doses of LAAM in excess of

100 mg. In all cases toxicity developed

between the 8th and 14th day.

Female patient switched to 180 mg LAAM daily

developed panic and “seizures” on the 14th

day which disappeared when dose was lowered

to 110 mg every 48 hours; she also was a

Ritalin addict. EEG was normal.

Female patient switched to 110 mg of LAAM

every 24 hours experienced episodes of depersonalization and loss of contact with

environment on the 9th day. She lost consciousness, suffered cardiac arrest, and

showed EEG abnormalities; she had been a

Doriden abuser with withdrawal seizures in

the past.

Male patient started on 200 mg LAAM every

24 hours from 235 mg methadone. Dose was not

holding him and was raised to 220 mg. On

the 8th day he complained of feeling as

though he were going to have a fit and was

returned to methadone.

Male patient increased from 85 to 120 mg

LAAM had an undocumented "seizure" but did

not lose consciousness. Symptoms disappeared when dose was lowered below 100 mg.

A fifth patient had a manic attack during

withdrawal from LAAM (at 35 mg from previous stabilization dose of 55 mg). He

was placed on regular dose of methadone,

treated with lithium and thorazine. In a

few days when the manic attack disappeared

he returned to LAAM, and accomplished

withdrawal without further difficulty while

on lithium.

56
3

1-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 two

times longer than methadone (Fraser and

Isbell, 1952)

"Smoother" action

Less “nodding”

Oral effectiveness

Less subjective euphoria

Several disadvantages are:

Amphetamine-like effect and dysphoria in

some patients

Occasional complaints of feeling less

"mellow"

Occasional complaints of abdominal cramps

This paper reports on clinical laboratory

studies in patients maintained on LAAM compared to those on methadone.

EXPERIMENTAL DESIGN

Subjects

Twenty--one patients were matched to 19

methadone patients on age, sex, race and

years of opiate use.

Methadone--Mean age 31.4, seven females,

two blacks, mean 10 years opiate use, mean

17 months on methadone program, mea” dose

95 mg (range 35-190 mg)

LAAM--Mean age 32.2, seven females, one

black, one oriental, mean 10 years opiate

use, 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 preference.

Seven patients consumed their doses at

24-hour intervals because it would not

"hold" them 48 hours.

Fourteen consumed theirs at 48-hour

intervals.

Blood and urine samples were collected in

the fasting state and before administration

of regular dose of LAAM and methadone. Blood

analysis was by SMA 12 and SMA 6 screen and

automated reagin tests.

Eight channel EEG's were obtained at one or

six 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 LAAM

patients, 103 percent for methadone patients

where 110 percent is given as the upper limit

of normal.

EEG

Fifty-three percent of all patients had EEG

abnormalities: 63 percent of those on

methadone and 38.5 percent of those on LAAM.

The difference was not statistically significant.

Cornell Medical Index

Those patients with normal EEG's differed

significantly (p <.001) from those with

abnormal EEG's on their total Cornell

Medical Index score. The mean score for

those with normal EEG's was 35.0, for

abnormal EEG's, 69.3.

57
4

ACTIONS AND ADDICTION LIABILITIES OF

ALPHA-ACETYLMETHADOLS IN MAN 1952

Subjects in the single-dose studies were

"post-addicts," previously addicted to

morphine but withdrawn and no longer

tolerant.

H.F. FRASER AND HARRIS ISBELL

INTRODUCTION

The pharmacology and analgesic effects of the

acetylmethadols have been studied in animals

(Chen, 1948; Specter, Byrd, Cheney and

Binkley, 1949; Eddy, Touchberry and

Lieberman, 1950; Eddy, May and Mosettig,

1952); this paper reports on some of the

actions and addiction liabilities of dl-, d-,

and 1-alpha-acetylmethadol in man. The

findings with respect to l-alpha-acetylmethadol will be of primary interest in this

summary.

EXPERIMENTAL DESIGN

Subjects

Subjects were adult white male volunteers.

Subjects in the abstinence-alleviation

studies were addicted to morphine at the

time of the study.

Methodology

Single-Dose Studies (Post-Addict)--

l-alpha-acetylmethadol was administered:

Subcutaneously (10-30 mgm) to 14 postaddicts

Intravenously (30 mgm) to 5 post-addicts

Orally (30-40 mgm) to 7 post-addicts

Pupillary diameters were measured before

and at intervals after oral, subcutaneous,

and intravenous administration of 30 mgm

1-alpha-acetylmethadol.

Subcutaneous (15 mgm) doses were administered twice daily for several days to

six patients.

Relief Of Abstinence From Morphine--

1-alpha-acetylmethadol was administered to

currently addicted subjects:

Subcutaneously (30 mgm) at the 28th and

36th hour of abstinence to two subjects

Orally (30-60 mgm) at the 28th hour of

abstinence to three subjects

Substitution Of 1-Alpha-Acetylmethadol For

Morphine--Seventeen addicts received oral

or subcutaneous doses of l-alpha-acetylmethadol; the administration of morphine

58
was then discontinued. Ten subjects who

received the drug orally remained on it

for fourteen days; the five who received

it subcutaneously and two who received

it orally returned to morphine after two

days on the drug.

The 10 orally dosed subjects were withdrawn abruptly from the drug. Four

additional subjects were withdrawn gradually over five to seven days.

Prolonged Suppression Of Abstinence By

1-Alpha-Acetylmethadol--Five addicted

subjects received 40 mgm orally on a

daily basis for 10 days after which the

dosage was increased to 60 mgm and the

interval was lengthened to 48 hours for

a week, 72 hours-for two weeks, and 96

hours for two weeks.

RESULTS

Single Dose Studies

Single doses of 1-alpha-acetylmethadol produced the following results:

Symptoms of euphoria did not develop

until 4-6 hours after subcutaneous

administration and persisted 48 and

sometimes 72 hours.

Intravenous administration of the drug

produced results similar to subcutaneous

administration.

Following oral administration, morphinelike effects were observed within one

and one-half hours and persisted 24 and

sometimes 72 hours.

Pupillary constriction following oral administration was observed in two hours, peaked

in four hours, and disappeared in 24 hours.

The onset of pupillary constriction was

slower and less intense following subcutaneous or intravenous administration but persisted for 48 hours.

Repeated doses of 1-alpha-acetylmethadol

resulted in the development of cumulative

toxic effects which were depression,

approaching coma; respiratory depression;

severe nausea and vomiting; mental confusion.

Relief Of Abstinence From Morphine

Subcutaneous administration 1-alpha-acetylmethadol had inconsistent effects with

respect to abstinence relief.

Oral administration of the drug abolished

all signs of abstinence.

Substitution Of 1-Alpha-Acetylmethadol For

Morphine

1-alpha-acetylmethadol was substituted for

morphine effectively at a ratio of 1 mgm to

each 6-8 mgm of the subject’s usual dose of

morphine.

Abrupt withdrawal from 1-alpha-acetylmethado1 produced an abstinence syndrome which

was mild and similar to that from methadone.

Gradual withdrawal from the drug produce an

abstinence syndrome that did not differ in

course and intensity from that observed after

abrupt withdrawal.

Prolonged Suppression Of Abstinence By

1-Alpha-Acetylmethadol

Sixty mgm oral doses of 1-alpha-acetylmethado1 successfully prevented development of

significant withdrawal symptoms for 72 hours

in subjects stabilized on 240 mgm morphine

daily.

59
5

USE OF MIOTIC EFFECT IN EVALUATING

ANALGESIC DRUGS IN MAN 1954

Methodology

Predrug measures and observations provided

baseline data; each individual served as his

own control. An individual was studied on

placebo and four to ten analgesics (one per

week) and observed at intervals up to 72

hours.

The following observations were made:

Pulse and respiratory rates

Blood pressures

Temperature

Pupillary size

Respiratory minute volume

Behavioral changes ("euphoria")

Adverse side reactions

RESULTS

Route Of Administration

1-alpha-acetylmethadol induced effects more

rapidly when given orally than subcutaneously.

This difference was statistically significant.

Duration Of Action

H.F. FRASER, T.L. NASH, G.D. VANHORN, H. ISBELL Miotic effects of 1-alpha-acetylmethadol

lasted as long as 72 hours.

INTRODUCTION

The purpose of this report is to show the

extent to which miotic effects of opiatelike drugs correlate with analgesic effects,

side effects, and addiction liability as an

aid to clinical evaluation of these drugs.

Only the results with respect to l-alphaacetylmethadol 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 were

used in each experiment.

Correlation Of Miosis With Fuphoria

The time-course of morphine-like "euphoria"

relates to miotic measurements. l-alphaacetylmethadol administered orally produced

an earlier and more intense euphoria which

diminished more rapidly than that produced

by subcutaneous administration.

Correlation Of Miosis With Relief Of

Abstinence Syndrome

1-alpha-acetylmethadol produced a longlasting papillary constriction which

correlates with the delay of abstinence

symptoms until three days after withdrawal.

Correlation Of Miosis With Toxic Effects

The curves of miotic effect indicate that

toxic effects would persist for long periods

and too short an interval between doses

would result in cumulative toxicity.

Correlation Of Miosis With Relief From Pain

Pupillay miosis does not correlate well

with analgesic properties. 1-alphaacetylmethadol is a potent pupillary constrictor 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 patients

being maintained on LAAM. In a few of these

patients, it was possible to obtain blood at

24, 48, and 72 hours after a LAAM dose. In

most patients, a blood sample could only be

obtained at one or two occasions.

Determinations were carried out by GLC, using

a modification of the customary method for

determining methadone levels in plasma. The

LAAM and its two N-demethylated metabolites--

norxetylmethadol (NAM) and dinoracetylmethado1 (NNAM)--were identified by retention time

on the column, as verified by standards

obtained from Eli Lilly Co. Quantitation is

most accurate for LAAM, less so for NAM and

NNAM, because of their broader peak shapes.

Peak areas rather than heights were used for

this reason.

RESULTS

Plasma Levels

As with methadone plasma levels, the LAAM

plasma levels at any given LAAM dosage are

extremely variable from patient to patient;

at 24 hours, for example, the levels ranged

from 15 to 170 ng/ml. The same is true of

the metabolites, which are considered to be

the active compounds pharmacologically. At

72 hours, NNAM levels varied from undetectable (<30 ng/ml) to 278 ng/ml).

Time Course Of Plasma Levels And Drug Effects

LAAM itself was virtually absent from plasma

72 hours after a dose, but the dose seemed

to "hold" quite well over that period. This

is consistent with the view that the metabolites are primarily responsible for the LAAM

effect, and also with the plasma levels of

the metabolites, which were approximately as

high as 72 hours as at 48 hours, and higher

than at 24 hours.

63
7

CAN THE COMMUNITY BE PROTECTED AGAINST EXPERIMENTAL DESIGN

THE HAZARDS OF TAKE-HOME METHADONE? Subjects

1974 Patients were randomly assigned to one of

five groups of 20 patients each. Females

were subsequently excluded, hence, groups

had fewer than 20 patients.

Methodology

AVRAM GOLDSTEIN AND BARBARA JUDSON

INTRODUCTION

It is desirable to have methadone patients

consume all medication under observation

to eliminate:

Accidental poisonings

Diversion of methadone as a drug of abuse

Adversary nature of routine urine checks

However, seven day a week clinic attendance

is a demand which may interfere with employment . LAAM is a long-acting substitute for

methadone which has shown clinical promise

(Jaffe et al., 1972; Zaks et al., 1972;

Senay et al., 1973). This report covers the

first three months of a clinical trial of

LAAM.

Control Groups--Three groups (M-l, M-2,

M-3) were stabilized on 50 mg of methadone

daily and maintained at that level.

Experimental Groups--LAAM subjects were

started on 30 mg LAAM and increased by

10 mg increments to 75 mg LAAM three times

a week.

One group (L) was "open" and had knowledge that they were on LAAM; they came

to clinic only Mondays, Wednesdays, and

Fridays.

The other group (L-P) was "blind", came

to clinic six days a week but received

quinine placebo on Tuesdays, Thursdays,

Saturdays, and Sundays. Take-home

privileges were given on Sundays and

other placebo days. (Comments by

patients about taste differences have

raised doubts in the minds of the

investigator about the validity of the

“blind” nature of the experiment.)

An additional experiment was carried out

to determine whether Monday morning

sickness was psychological or phannacological. The Friday LAAM dose was

increased from 75 mg to 100 mg on three

alternate Fridays for both LAAM groups

on a "blind" basis.

62
Criteria For Effectiveness--The groups

were compared on the following criteria

of effectiveness:

Weekly urinalysis for opiates, barbiturates and amphetamines

Dropout rates (after a two-week

stabilization phase)

Attendance records

Suspensions for absences

Jailing

Monday morning questionnaire concerning

withdrawal symptoms (“feeling sick”)

experienced on Sunday morning, Sunday

evening, and Monday morning

RESULTS

The results for all five groups at three

months are reproduced in the following

table.

Dropout Rates

During the stabilization phase, dropouts

were as follows:

M-1, (0)

M-2, (0)

M-3, (2)

L , (3)

L-P, (1)

Survivorship was slightly lower in the LAAM

groups but not significantly so.

Attendance Records, Suspensions, And

Jailings

Differences among groups in these dimensions

were variable with neither LAAN nor methadone groups favored.

Urine Testing

Three-quarters of all patients discontinued

heroin use by week 13, and at week 13, no

consistent difference is evident between

LAAM and methadone groups (see table, preceding this page). A running average of

incidence of clean urines for opiates for

the entire quarter was computed which

showed both LAAM groups to be superior to

the methadone groups.

"Feeling Sick"

Methadone groups had large differences

initially in percentage of patients with

complaints; the differences tended to decrease toward the end of the quarter.

The "open" LAAM group (L) showed an increase

in percentage of patients with complaints

from Sunday morning through Sunday evening

to Monday morning. The "blind" LAAM group

(L-P), however, did not show an increase

in percent feeling sick between Sunday

morning and Monday morning.

Increasing the Friday dose has inconsistent

effects in reducing the percent of complaints

in the LAAM groups. Complaints may be more

psychological than pharmacological in origin.

Adverse Experiences

During induction to LAAM when tolerance was

not established, delayed sedative actions of

LAAM were noted (four to six hours). A

problem of additive toxicity could develop

if a patient were to take another drug in

this interval on the assumption that the LAAM

dose was not effective.

63
8

PHARMACODYNAMICS OF LAAM IN MAN: PLASMA

LEVELS OF LAAM AND ITS METABOLITES

FOLLOWING ACUTE AND CHRONIC ADMINISTRATION IN MAN

(FOURTH AND SIXTH QUARTER PROGRESS

REPORTS). 1974-75

GARY L. HENDERSON

Day 3

INTRODUCTION

The purpose of this study was to investigate

the pharmacokinetics of LAAM in man.

EXPERIMENTAL DESIGN

Subjects

Five male patients maintained on methadone

for at least 90 days comprised Group 1.

Addicts with no previous experience with

methadone comprised Group 2.

Methodology

Day 1, Group 1

Patients were hospitalized. A symptom

checklist was completed, blood and urine

were collected, and temperature, pulse,

respiration, blood pressure, and pupil size

were recorded prior to administration of

daily dose of methadone. Group 2 patients

were started directly on 20 mg LAAM. Blood

and urine were collected at six intervals

after 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 after

hospitalization just prior to administration

of 60 mg LAAM (1.2 times the usual methadone

dose). Urine and blood were collected and

the symptom checklist completed at six intervals on Day 2 and every 12 hours afterward

until discharge from the hospital.

Patients were discharged after final blood

and urine sampling and the second dose of

LAAM Weekly blood and urine samples were

collected on an outpatient basis. Groups

1 and 2 received LAAM every three days for

90 days at which point they were rehospitalized, and laboratory and physical examinations were repeated.

Urinalysis

Urine was analyzed for pH, protein, glucose,

ketones, bilirubin, and blood. Drug concentrations were calculated, and recovery

studies for drug and metabolites were conducted at the beginning and end of the

experiment.

Plasma

Plasma was analyzed by standard GLC procedures

64
RESULTS

Urine (Group 1)

Urine excretion patterns for LAAM and N-LAAM

(noracetylmethadol) did not vary much among

patients. Less than 2 percent of the drug

dose was excreted as LAAM and N-LAAM at the

end of the 72 hours.

Plasma

Group 1--Peak plasma levels of LAAM and

its metabolites following acute administration were:

LAAM, 135 ng/ml at 6 hours

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

DN-LAAM (dinoracetylmethadol), 20 ng/ml

at 2-48 or more hours

Plasma levels of LAAM decreased rapidly

after 12 hours; N-LAAM and DN-LAAM

levels remained fairly constant over

a 48-hour period.

Plasma kinetics of methadone appeared to

be altered by subsequent administration

of LAAM; a slight increase in methadone

plasma levels occurred 4-12 hours after

LAAM administration.

Three patients completed 90 days on LAAM.

After 90 days on LAAM, the LAAM plasma

levels were only slightly higher than

after the acute dose, but N-LAAM and

DN-LAAM levels were 5-10 times higher

than after the acute dose. The levels

of DN-LAAM were highest followed by

N-LAAM and LAAM. LAAM and N-LAAM decreased with time, while DN-LAAM levels

remained at a constant high level for

72 hours.

N-MOL (normethadol) could not be detected

in plasma after the first or the last dose

of LAAM.

Group-2--After the initial dose of 20 mg

LAAM, plasma levels of the drug were too

low to quantitate. After 90 days (dose,

85 mg), the peak LAAM plasma levels were

reached two and four hours after the last

dose of LAAM, but the concentration was

the same as that of Group 1.

65
9

THE 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 been

shown to be an effective, longer-acting

substitute for methadone in maintenance

therapy (Chen, 1948; Fraser and Isbell, 1952;

Jaffe et al., 1970; Jaffe and Senay, 1971).

The purpose of this study was to establish

the basic data on the pharmacology, potential

toxicity, and comparative safety of methadone

and 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 heroin

addicts and 15 male and 9 female nonaddicted

controls of similar socioeconomic status.

Methodology

Dosages--Three treatment groups were

established.

Daily methadone (mean stabilization

dose, 50 mg; range 25-115 mg)

Daily LAAM (mean stabilization dose

55 mg; range 30-90 mg)

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

Assessments--Subjects were assessed just

prior to receiving medication and at

four hours afterward (time of peak drug

action) 11-14 days after entry with the

program (0 time) and at l-, 2-, 4-, 8-,

and 16-month intervals by EEG, blood and

urine analysis, Irwin Comprehensive Human

Assessment Procedure, Subjective State

Questionnaire, Adverse Symptom Checklist,

Special Performance tests, social adjustment questionnaire, and oral interview.

Urine was monitored weekly for the

presence of illicit drugs.

RESULTS

Dropouts

Dropouts occurred most in the first two

months of treatment and were disproportionately males, fairly equally divided between

the races and much higher with LAAM (42 percent) than methadone (23 percent) or controls

29 percent).

The 16 LAAM patients who dropped out were

distributed 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 out

were 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 those

receiving 24-hour LAAM than among those

receiving 48-hour LAAM.

Dose Level Changes

Mean daily methadone doses were 50 mg

(range 25-115 mg) after stabilization and

had increased to 90 mg (range 50-170 mg) at

eight months.

Mean daily LAAM doses were 55 mg (range 30-

90 mg) after stabilization and increased to

63 mg (range 35-90) at eight months.

Mean 48-hour LAAM doses were 57 mg (range

20-80 mg) after stabilization and decreased

to 56 mg (10-100 mg) at eight months.

Blood Chemistry Abnormalities

Subjects had a high incidence of abnormalities consisting of lowered T-3 and elevated

SGOT determinations upon entry into the

study. The incidence of abnomality was

sustained over time for methadone patients

but decreased to almost normal values for

LAAM patients by the eighth month.

EEG Abnormalities

There was an increased incidence of EEG

abnormalities over time for all treatment

groups, characterized primarily by diffuse

or focal slowing.

The incidence of abnormalities for 48-hour

LAAM patients was not statistically significant and changed from 31 percent at 0 time

to 29 percent at four months to 40 percent

at eight months.

The increase in abnormalities for methadone

patients was significant (p<0.01) and changed

from 43 percent at 0 time to 41 percent at

four months to 53 percent at eight months.

The incidence of EEG abnormalities for 24-

hour LAAM patients was statistically significant (p<0.01) and illustrated the cumulative

effects of chronic administration. The incidence of abnormalities was 34 percent at

0 time, 75 percent at four months, and 100

percent at eight months.

Cognitive Performance Testing

Data analysis thus far has revealed little or

no depressant effects or neurologic impairment. There was slightly less overall

impairment of cognitive performance and

functioning with LAAM than with methadone.

Overall data, however, show very little

alteration of cognitive performance with

either drug and levels of cognitive performance do not seem to be affected by the

increased incidence of EEG abnormalities.

Subjective State

LAAM patients indicated they felt a slightly

greater intensity of drug effects than did

methadone patients, and tolerance to drug

effects did not develop during the study.

Both drug treatment groups demonstrated

improved affect relative to controls; the

Change was greater for methadone than for

LAAM patients hut not significantly so.

Social Adjustment

No major changes were seen in areas of social

adjustment and only minor differences were

evident between the two groups.

Conformity to law and work adjustment were

increased for both treatment groups; and

sexual performance, and illegal activities

and earnings diminished. A slight but significant decrease in marihuana use was

reported by LAAM patients.

Illicit Drug Use

There were no significant differences in the

incidence of use of illicit narcotic and

non-narcotic drugs between treatment groups.

Side Effects

Most frequent complaints for both drugs

were loss of sexual desire, constipation,

drowsiness, loss of energy, headache, increased or decreased appetite, and nausea.

There were no significant differences

betweem treatment groups in either the nature

of 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 .2

mg/kg oral doses of LAAM and methadone in a

cross-over study with one week between tests.

The Irwin Comprehensive Human Assessment

procedure was used to quantify the timecourse 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 to

determine:

Peak time effects for LAAM and methadone

over 10 hours

Development of cross-tolerance to morphine in LAAM-treated subjects

Possible adverse effects of LAAM and

methadone on:

EEG

Blood chemistry

Hematology

Thyroid function

Urinary function

Cognitive performance

on the psychosocial, physiologic, and cognitive state of the subjects.

Cross-Tolerance Of LAAM-Treated Subjects To

Intravenous Morphine

Nine subjects maintained on LAAM were tested

for cross-tolerance to 30 mg morphine sulfate, administered intravenously 3-54 hours

after their LAAM dose. They were assessed

for cross-tolerance with the procedure of

Dole et al. (1966).

Clinical Laboratory Studies

Twenty methadone maintenance subjects (mean

dose 93.5 mg, range 35-190 mg) were matched

by age, sex, race, and years of opiate use

with 21 LAAM maintenance subjects (mean dose

79.6 mg, range 12-140 mg). LAAM subjects

were on methadone therapy an average of 13.9

months followed by an average of 8 months on

LAAM. Methadone subjects were on methadone

an average of 17.9 months.

They were assessed for electroencephalographic findings, blood chemistry, thyroid

and urinary function, and cognitive performance.

RESULTS

Time Course Of Action

Peak effects with LAAM and methadone occurred

four hours post-treatment and durations of

action were similar with subjects reporting

68
an earlier peak and greater intensity and

duration of effects with LAAM than with

methadone. The only significant differences

were greater reduction of wakefulness and

attentiveness, and a higher incidence of

nausea and vomiting with LAAM than with

methadone.

The duration of action of LAAM was not significantly longer for LAAM than methadone.

Cross-Tolerance Of LAAM-Treated Subjects To

Intravenous Morphine

Subjects experienced a slight rush and could

distinguish morphine from placebo. A

slight "high" was reported, usually soon

(3-8 hours) or long (52-54 hours) after

treatment with LAAM. Responses were not

completely dose related and LAAM was not

invariably effective in suppressing the

effects of morphine.

Clinical Laboratory Studies

Electroencephalograph Findings--Sixtyfive percent of methadone and 33 percent

of LAAM subjects had abnormal EEG

findings (p < .10, two-tailed test), consisting of diffuse slowing (usually in

temporal and occipital regions), low

level of paroxysmal activity and bursts.

All methadone subjects with high Cornell

Medical Index scores on admission had

significant EEG abnormalities (8/8);

none of the LAAM subjects with high

C.M. I. scores did (0/5).

The increase in slow wave activity which

usually follows hyperventilation was

suppressed in both groups with only 19-29

percent showing the expected response.

The "driving" of the EEG which generally

occurs with photic stimulation was likewise suppressed in LAAM and methadone

subjects occurring in only 35 percent

and 5 percent.

Hyperglycemic Response--Both drugs produced a significant hyperglycemic

response; the difference between mean

blood glucose levels for methadone (103

mg percent) and LAAM (117 mg percent) was

significant (p.<0.05). There was also a

significant difference (p.<0.05) between

the number of subjects with abnormally

high blood glucose levels with LAAM (14)

and with methadone (5).

Liver Function Abnormalities--The SGOT,

albumin, and alkaline phosphatase determinations in both groups showed a higher

incidence of abnormalities, suggesting

slight impairment in liver function.

Hematology--Abnormally high white blood

counts occurred in 35 percent of methadone and 29 percent of LAAM subjects.

Thyroid Function And Urine Analysis--No

significant abnormalities were found in

these areas.

Effects On Cognitive Performance

LAAM maintenance subjects' performance on

cognitive tasks was significantly better

than methadone maintenance subjects’ on

tests involving memory, learning, speed, and

accuracy, and did not differ significantly

from the past performance of a control group

of college students.

69
11

ACUTE 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 acute

time-dose-response effects of cyclazocine,

methadone, and 1-alpha-acetylmethadol with

respect to psychosocial, cognitive, and

physiologic functions. The profiles and

durations of action were of particular interest, as were the nature of the differences

between the three drugs. The investigations

and findings with respect to cyclazocine

will not he reported in this summary.

EXPERIMENTAL DESIGN

Subjects

Twenty-eight male, nonaddicted volunteers

21-35 years of age were paid to participate

in the experiment and were screened for

mental and physical health.

Methodology

Subjects received two doses of drug orally

at least one week apart on a randomized,

coded, double-blind basis. Fourteen subjects received placebo. Seven subjects were

used per dose level of drug. Dosages were

.l and .2 mg/kg methadone hydrochloride and

0.8 and .16 mg/kg l-alpha-acetylmethadol.

Trained observers assessed the subjects on a

scale of 0.8 at -60, 20, 80, 160, 220, and

280 minutes before and after treatment using

the Irwin Comprehensive human Assessment

Procedures. A subjective state questionnaire (SSQ) and adverse symptom checklist

(ASC) were completed by the subject at 12

and 24 hours posttreatment. A variety of

special performance tests were also used.

Placebo effects were subtracted from the

scores in reporting data.

RESULTS

Peak, Duration, And Intensity

Peak time effects for all drugs tested

occurred about three hours posttreatment.

The duration of effects with the high dose

of 1-alpha-acetylmethadol was over 24 hours;

for methadone it was 12 hours or less.

With respect to the intensity of drug

effects, the higher dose of 1-alpha-acetylmethadol produces effects similar to hut

somewhat less in intensity than the lower

dose of methadone.

The two modes of assessment, observer rating

and subject's self-reporting, correlate

highly with each other.

70
Profiles Of Action

All drugs produced biphasic effects, most

often an early activation, elevation of

mood, and liking for the drug followed by a

later depressant effect and dislike for the

drug.

The effects of 1-alpha-acetylmethadol were

primarily activating and included:

Slightly increased capacity for functioning

Increased arousal, drives, energy, speed

and durations of movement and expressiveness

Slightly improved mood and emotions

Methadone, on the other hand was generally

depressant and its effects were:

Impairing arousal, focusing, and psychomator activity

Distorted perceptions

Worsened moods and emotions

On several measures, however, 1-alpha-acetylmethadol produced effects similar to the

effects of methadone in reducing:

Impulse control

Memory

Respiratory rate

Pupil size

Facial skin color

and in promoting:

Ataxia

Unusual body sensations

Distorted senses

Light headaches

Itching

As these effects are characteristic of the

effects of narcotics in general, it would

seem that methadone and 1-alpha-acetylmethadol are similar in potency but differ in

their qualitative effects.

71
12

COMPARISON OF ACETYLMETHADOL AND

METHADONE IN THE TREATMENT OF LONGMethodology

Study design

TERM HEROIN USERS: A PILOT STUDY. 1970 The study was a double-blind, controlled

study lasting seven weeks.

JEROME H. JAFFE, CHARLES R. SCHUSTER,

BETH B. SMITH, PAUL H. BUCHLY

Dosages--control groups

INTRODUCTION

dl-alpha-acetylmethadol has been shown to

prevent withdrawal symptoms for more than

72 hours (Fraser and Isbell, 1952). Its

effectiveness as a substitute for methadone

in maintenance treatment of narcotic addicts

was the subject of this study.

The control group received their usual

daily dose of methadone hydrochloride.

The average dose was 37 mg/day (range

20-55 mg).

Criteria for effectiveness

EXPERIMENTAL DESIGN

Subjects

Urines were checked for illicit opiate

use at each clinic visit (three times/

week).

Twentyy-one participants in a methadone The opiate withdrawal subscale of the

maintenance clinic stabilized on 20-90 mg Addiction Research Center Inventory (ARCI)

of methadone per day served as subjects. and a symptom checklist measuring

Twelve were randomly assigned to the experi- intensity of withdrawal were filled out

mental group and nine to the control group. three times weekly.

Patients reported to the clinic three

days per week.

Dosages--experimental group

Dosages were computed initially at 1.2

times the usual methadone dose and

increased slightly in two cases.

Subjects received dl-alpha-acetylmethadol on Mondays, Wednesdays, and Fridays,

and placebo (dextromethorphan hydrobromide added to the usual vehicle) on

alternate days.

The average dose of dl-alpha-acetylmethadol was 50 mg three times weekly

(range 24-66 mg).

72
Open-ended interviews were held with the

staff three times weekly.

Baseline measures were obtained for two

weeks before the new drug was introduced.

Intensity of withdrawal from methadone

and dl-alpha-acetylmethadol was studied

by administering placebo in place of

active medication in six control and six

experimental patients. This was done on

Monday of the seventh week, 48 hours

after the last dose of methadone, and

96 hours after the last dose of dl-alphaacetylmethadol. All patients were provided with a dose of methadone to take

in case of emergency.

RESULTS

Dropout Rate

Four patients in the experimental group

dropped out on the first day complaining of

abdominal pain.

There were eight patients in each group at

the end of the study.

Withdrawal Symptom Reports

There were no significant differences

between the experimental and control groups

on the opiate withdrawal subscale of the

ARCI and the withdrawal symptoms checklist

during the two week baseline period.

Control group

No change was evidenced from baseline

with a 24-hour interval between doses.

of the six patients who experienced a

48-hour interval with placebo, two took

their emergency doses of methadone at

36 hours and the remaining four

experienced intense withdrawal distress

at 48 hours.

Experimental group

No change was evidenced from baseline

at 24- and 48-hour intervals between

doses.

At 72 hours there was a slight rise in

the opiate withdrawal subscale of the

ARCI, but no change in the symptom

checklist or during the interview.

At 96 hours there was a marked rise in

intensity of withdrawal Symptoms as

measured by the test and interviews.

Measures Of General Functioning

Urine analysis showed no difference between

the two groups in illicit drug use.

The two groups also did not differ with

respect to numbers employed, arrest rate, or

admissions of illegal activity.

Adverse Experiences

Side effects of anxiety and nervousness were

perceived as sufficiently troublesome to 4

out of 12 subjects in the experimental group

to 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 out

to determine if 1-alpha-acetylmethadol could

be effectively substituted for methadone on

weekends.

JEROME H. JAFFE AND EDWARD C. SENAY

INTRODUCTION

Racemic methadyl acetate (dl-alpha-acetylnethadol) has been shown to be effective in

suppressing narcotic withdrawal syndrome

for periods up to three days (Jaffe, 1970).

There are substantial differences between

the d- and l-isomers in effectiveness in

suppressing the withdrawal syndrome (Fraser

and Isbell, 1952). In view of the limited

clinical experience with either isomer, the

purposes of this study were:

To gain further clinical experience with

1-alpha-acetylmethadol

To determine if 1-alpha-acetylmethadol

could be used interchangeably with

methadone

Subjects

The subjects were volunteers participating

in a methadone maintenance program, stabilized on a 30-100 mg. dose of methadone per

day for three weeks prior to the experiment.

Experimental Group--The experimental

group consisted of five male patients

taking a mean daily dose of 50 mg. (range,

40-60 mg/day) of methadone.

Control Group--The control group consisted of five male patients taking a

mean daily dose of 68 mg (range, 30-100

mg/day) of methadone.

Methodology

Study Desire

The groups were studied for three

weekends.

Patients were randomly assigned to drug

or control groups; clinical observers

were blind to who was in which group.

The experimental group received 1.2 mg

of 1-alpha-acetylmethadol for every 1 mg

of methadone in his daily dose (a threeday dose); they were given two 30 mg

doses of dextromethorphan hydrobromide

to take home as placebos.

The control group received their usual

dose of methadone at the clinic and two

doses of methadone to take at home.

74
Criteria For Effectiveness

Urine was collected and tested for the

presence of narcotics.

Clinical interviews were held on

Fridays and Mondays.

Symptom checklists were filled out by

the subjects on Fridays and Mondays

prior to receiving their medication.

Clinic attendance was noted.

Requests for increase in medication was

noted.

RESULTS

The frequency of urine specimens positive

for morphine was the same in both groups

(one in each group).

"Blind" experimenters found nothing in the

behavior or reports of subjects to indicate

which medication they had received.

Patients in both groups complained of

sweating; all had reported problems with

sweating prior to the study.

No side effects were reported by either

group.

The rates of clinic attendance did not

differ.

Subjects in both groups complained of their

medication not holding; the conversion

factor was increased in the experimental

group to 1.2 - 1.5 mg (mean 1.3 mg) 1-alpha.

acetylmethadol to 1 mg methadone hydrochloride.

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 a

maintenance program (Jaffe et al., 1970),

confirmed earlier findings of the ability

of this drug to prevent development of abstinence syndrome for 72 hours (Fraser and

Isbell, 1952). The purpose of this study

was to gain further experience with the drug

in more extensive trials.

EXPERIMENTAL DESIGN

Subjects

Subjects were 66 male heroin addicts, age 20

through 50, screened by physical and laboratory examination.

Methodology

The study was carried out under doubleblind conditions and lasted 15 weeks.

Subjects were randomly assigned to one of

four groups in the study design.

Experimental group receiving DLAAM three

times a week and dextromethorphan placebo

on alternate days (19 subjects)

Control group receiving methadone daily

(15 subjects)

Waiting list detoxified with methadone

receiving no further medication (16

subjects)

Treatment group of the patient’s choice

exclusive of the experimental and control

groups in the study (16 subjects)

Adjustments were made in dosage of medication

by patients' requests to the weekly visiting

physician. The program physician was blind

to medications and levels.

All medication was initially taken at the

clinic under observation; take-home doses of

methadone and placebo were later allowed.

Criteria For Effectiveness

The following measures were used to determine

the relative effectiveness of the drugs:

Frequency of illicit drug use as determined by urinalysis

Twice weekly completion of the morphine

and opiate withdrawal subscales of the

Addition Research Center Inventory (ARCI)

and a withdrawal symptom checklist

76
Weekly self-report of illicit drug use,

criminal activity, and legitimate employ

ment

Clinic participation defined as keeping

clinic appointments and group therapy; a

dropout was defined as a person who did

not attend for two consecutive weeks and

was discontinued in the study

Adverse Experiences Looked For

The following tests were taken initially and

at the end of the study as indicators of the

safety of the drug:

CBC

Urinalysis

Liver-function tests

BUN

Serrum uric acid determinations

RESULTS

Data for those subjects in the group assigned

to clinics of their choice will not be

reported; 12 of 16 of these patients did not

report to clinics assigned to them.

Statistical analysis of data was based upon

patients who completed at least eight weeks

of treatment: 15 subjects in the experimental and 15 in the control group.

Dropout Rate

Five (26.3 percent) subjects left the DLAAM

group; two (13.3 percent) left the methadone

control group. This difference was not

statistically significant.

The average length of stay for the dropouts

was 5.8 weeks in the experimental group and

10 weeks in the control group.

Employment

Both groups evidenced increases in employment. The experimental group had 12 (80

percent) employed at the end of the study

and 4 (26.7 percent) employed at the begin

ning; 10 (66.7 percent) of the methadone

control group were employed at the end, 4

(26.7 percent) at the beginning. These

changes were statistically significant.

Arrests

Decreases were observed in arrest rates for

both groups compared to arrest rates in the

two years prior, however, the sample size

was too small for a determination of statistical significance either between groups or

as a result of treatment.

Illicit Drug Use

Seventy-one and one-tenth percent of the

treatment weeks were characterized by

"clean" urines for the control group and 49

percent for the experimental group. The

difference was not statistically significant.

Clinic And Group Therapy Attendance

Clinic attendance was high for both groups

and quite similar (93.3 percent, experimental; 91.8 percent, control). Group

therapy attendance was lower for both groups

(60.5 percent, experimental; 61 percent,

control) and the difference between them was

not significant.

Clinical Observations

There were no differences in the subjective

reports of patients; the "blind" physician

could not distinguish between DLAAM and

methadone groups.

Dose Level Changes

Dosages were 30-80 mg methadone hydrochloride/day and 36-80 mg DLAAM/active dose.

All patients requested increases in the

initial two weeks; an equal number from

each group requested increases thereafter.

Most patients required a higher dose of

DLAAM for the 72-hour (Friday to Monday)

interval than the 48-hour intervals.

Withdrawal Scales

There was no significant difference between

the two groups on any withdrawal scale.

Medical Data And Adverse Experiences

Liver Function--Only seven of the 66

patients had normal results on liverfunction tests upon initial examination;

profiles remained unchanged at the end

of the study

Hematology--Most subjects were normal

initially and at the end of the study.

Four reverted to normal

tie remained the same

Two did not return for reevaluation

In one subject, the hematocrit dropped

from 48 percent to 39 percent but hemoglobin level, RBC, and WBC remained

normal.

White Blood Cell Counts--All were stable

except in three subjects.

77
In one subject, the initial count was

12,800/cu mm and the count at reevaluation was 3,400/cu mm; he had been

treated with trifluoperazine hydrochloride prior to reevaluation.

Changes from 8,500 to 4,000/cu mm and

7,100 to 41,000 cu mm were observed in

two other patients. No symptoms were

associated with any of these changes.

VDRL And Fluorescent Treponemal Antibody

Tests (FTA)--Thirteen subjects had positive results for VDRL and FTA tests

initially; these values were unchanged at

reevaluation except in one subject whose

results reverted to negative.

Side Effects--There were few complaints

of side effects and no toxic reactions.

Complaints of decreased libido came out

in conversations; two patients complained of impotence. Jerking and

twitching of arms and legs when at rest

was complained of by two subjects.

78
15

SIMULTANEOUS DETERMINATION OF ACETYL- quantitation procedures are beyond the

scope of this summary; results will be

METHADOL 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 to

active metabolites.

INTRODUCTION

TION PRODUCTS IN HUMAN BIOFLUIDS. 1975 RESULTS

Plasma

Most plasma samples contained AM, NAM, and

NNAM in concentrations above 0.020 ug/ml.

Concentrations of MOL and NMOL above this

were not observed in any samples obtained.

Urine

A mean of 20 percent of the administered

dose was recovered as AM and biotransfomrmation products in total urine collected 48

hours after dosing; approximately 2 percent

was recovered as AM, 8 percent as NAM, 5

percent as MOL, and 13 percent as NNAM. The

pattern of excretion is the same regardless

of dosage.

Other routes of elimination (the gastrointestinal tract) and other biotransformation

products are likely. Biotransformation is

a prerequisite for the elimination of AM

and N-demethylation is quantitatively more

important than deacetylation in the human.

AM, noracetylmethadol (NAM), methadol (MOL)

normethadol (NMOL) have been identified in

the urine of AM maintenance subjects (Kaiko

and Inturrisi, 1973). Dinoracetylmethadol

(NNAM) was identified by Billings (1973) in

the biofluids of rats given AM and has been

found in plasma and urine of AM maintenance

subjects (Kaiko and Inturrisi, Fed. Proc.,

1974).

This report describes a specific and sensitive method for quantifying AM, NAM, and

NNAM in human plasma and urine. The details

of the extraction, identification, and

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 were

maintained on a mean dose of 50 mg (range

40-60) acetylmethadol three times weekly

for 4-25 weeks. Four others were inpatients,

dosages and history not stated.

Methodology

Plasma--Venous blood samples were

collected just prior to dosing (i.e., 72

hours after last dose) and at 4, 8, 24

and 48 hours from all patients.

Urine--The eight maintenance subjects

provided urine specimens at 0, 24 and

48 hours after administration of acetylmethadol; urine was collected at 0, 4,

8, 24 and 48 hours from the hospitalized

patients.

INTRODUCTION

Acetylmethadol has been shown to have a

72-hour duration of action (Fraser and

Isbell, 1952) which has been attributed to

the biotransformation of acetylmethadol to

active metabolites (McMahon et al., 1965;

Sung and Way, 1954; Veatch et al., 1964).

Acetylmethadol, noractylmethadol and dinoracetylmethadol have been identified in human

Plasma (Kaiko et al., in press; Kaiko and

Inturrisi, 1973; Billings and McMahon, 1974).

Extraction And Estimation--A multistep

solvent extraction procedure (Kaiko et al,

in press) was employed; noractylmethadol

and dinoracetylmethadol were converted to

corresponding amides and measured as

equivalents. Qantitation was achieved

by the addition of an internal standard,

SKF 525-A, prior to extraction.

Measurement Of Pupil Size--Miotic effect

was calculated by subtracting the size

of the pupil (determined photographically) at each blood sampling time from

the baseline (0-hour) size.

This report describes the disposition of

acetylmethadol in maintenance subjects with

particular emphasis on the relationship

between the time course of acetylmethadol

and its biotransformation products in plasma

and the timeaction of pupillary miosis.

Apparent Half-Life, Renal Clearance And

Urinary pH--Regression analysis program

was used to calculate the apparent halflife for elimination of the compounds

from plasma. Renal clearance values were

80
calculated using the average rate of

urinary excretion of each compound for

the four to eight hour collection period

and the corresponding plasma concentration at the midpoint of the collection

period (6 hours). Urinary ph was measured with a Metrohm E-512 pH meter.

RESULTS

Time Course, Mean Plasma Levels and Mean

Pupillary Constriction in the Eight Maintenance Subjects

Acetylmethadol

None present at 0 hour

Peak level 0.060 μg/ml at 4 hours

Rapid decline to 0.013 μg/ml at 24 hours

Undetectable at 48 hours

Noracetylmethadol

0.042 ug/ml at 0 hour

Peak level 0.114 μg/ml at 4 and 8 hours

Slow decline to 0.068 μg/ml at 48 hours

Dinoracetylmethadol

0.052 μg/ml at 0 hour

Peak levels ranged from 0.057-0.123

μg/ml at 4 hours

Levels did not decline during sampling

Pupillary Constriction

Pupillary constriction was greatest at

8 hours, 1.8 mm.

Return to predose value was slower than

rate of disappearance of acetylmethadol

but faster than rate of disappearance

of noracetylmethadol.

Time-action of miotic effect corresponds most closely with noracetylmethadol in plasma.

The effect of dinoracetylmethadol could

not be ascertained since plasma levels

did not decline.

Apparent Half-Life for elimination of

compounds from Plasma

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

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

Dinoracetylmethadol levels did not

decline, therefore, no calculation of

half-life value was possible.

Renal Clearance and Urinary pH--The subject with the lowest urinary pH exhibited

the highest renal clearance of all three

compounds; the subject with the highest

urinary pH exhibited the lowest renal

clearance values.

Correlation Between Plasma Levels and

Drug Effect--Miotic effect is more

closely associated with noracetylmethadol plasma levels (p <0.10) than with

the acetylmethadol dose (p <0.10).

Spearman's correlation coefficient was

used to determine the relationship

between noracetylmethadol plasma levels

and parameters which might influence

its magnitude. High plasma levels of

any one of the compounds tend to be

associated with high levels of the

others.

Noracetylmethadol plasma level is a

more reliable correlate of the effect

of acetylmethadol than is the acetylmethadol dose.

Noracetylmethadol plasma level is more

a function of other factors relating

to its disposition than the acetylmethadol dose.

81
17

THE USE OF 1-ALPHA-ACETYL-METHADOL the heroin detoxification program at Vitam

Center, 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 and

methadone

WALTER X. LEHMANN

INTRODUCTION

The purposes of the study were to:

Compare LAAM with methadone for effectiveness in a short-term, low-dose maintenance program

Determine whether LAAM has potential as a

medication of choice for heroin addicts

Compare LAAM with methadone with respect

to ease of withdrawal and note any clinical problems which might arise

EXPERIMENTAL DESIGN

Subjects

Forty-two male and female heroin addicts

between the ages of 16 and 21, enrolled in

Fourteen patients received 10 mg doses

of LAAM every 72 hours and placebo on

intervening days

Twenty-one patients received methadone

daily in doses sufficient to maintain

a comfortable state

An open study in which the drug and

dosage were know to the patients

Seven patients received LAAM every

third day

No placebo was given on intervening

days

The duration of the study was 16 weeks after

which patients were detoxified; they were

followed up as long as they remained in the

program. Withdrawal was accomplished on an

inpatient basis by lengthening the interval

between doses for a week then stopping the

drug completely.

Criteria For Effectiveness--Patients were

observed daily with respect to the

following:

Physical and emotional reaction

Performance of job functions in the

center

Performance in group and individual

therapy

Atheletic involvement

82
High school and special education

involvement

Community and home involvement

Toxic reaction

Urines were collected and analyzed three

times a week during the first two weeks;

they were collected three times a week but

only analyzed weekly thereafter.

RESULTS

Physical And Emotional Reactions

There were no differences in the physical

condition of the three groups. No side

effects such as nausea, vomiting, constipation, weakness, or fatigue were reported.

Half the patients in the open study complained of mild discomfort 60 hours after

medication which disappeared during the

third week.

Emotional reactions were similar for all

patients with some tension, depression, and

hostility noted initially which dissipated

by the third week.

Performance Of Job Functions

There was no difference between groups; performance improved in all groups during the

third week.

Performance In Groups And Individual Therapy

There was no difference between grows in

either type of therapy; performance &proved

during the fourth week.

Athletic Involvement

Athletic involvement was the same for all

patients; there was no interference with

coordination or ability to perform.

High School And Special Education Involvement

These activities did not start until the

8th and 12th weeks, respectively; there

appeared to be no differences in performance.

Community And Home Improvement

This applied only to those living in; no

differences were noted between groups and

there was improvement after the fourth week.

Toxic Reactions

No toxic reactions were noted; it was not

necessary to terminate treatment in any cases

Urinalysis

There were no urines positive for nonprescribed drugs in either group.

Withdrawal

Withdrawal from LAAM and methadone was

accomplished with equal ease; no clinical

problems were manifested during withdrawal

83
18

LEVOMETHADYL ACETATE: PROLONGED

DURATION OF OPIOID EFFECTS, INCLUDING

EXPERIMENTAL DESIGN

Subjects

CROSS TOLERANCE TO HEROIN, IN MAN.

1973

Seven male volunteers ranging in age from

21-50 years with at least two years of

narcotic abuse and two previous treatment

failures were used as subjects. They were

detoxified and drug free at least seven

days before the experiment.

Methodology

ROBERT LEVINE, ARTHUR ZAKS, MAX FINK,

ALFRED M. FREEDMAN

INTRODUCTION

Levomethadyl acetate (LAAM)has been determined to have an onset of action which is

delayed by four to six hours post-administration and has been demonstrated to have

the ability to prevent the development of

abstinence syndrome in methadone tolerant

patients for 72 hours (Jaffe and Senay, 1971;

Zaks et al., 1972), the purpose of this study

was to determine the dosage of LAAM which is

required to provide blockade to 25 mg of

heroin, to prevent opiate withdrawal symptoms, and to provide maximal opiate effect

for a minimum of 72 hours.

Oral doses of LAAM were administered three

times a week beginning with 10 mg and

increasing 10 mg/week until doses of 100 mg

were reached.

Pupillary diameter was measured prior to

the experiment and at 24, 48, and 72 hours

after the third dose each week. The mean

predrug diameter was 6.7 nun. A symptom

checklist was completed at these times

also.

Heroin challenge of 25 mg was performed at

72 hours following various doses of LAAM.

RESULTS

Adverse Experiences

Three of the seven patients withdrew after

five weeks. Dose levels of 50 mg had been

obtained by that time.

All patients reported constipation throughout their participation in the study.

Three of the seven patients reported loss of

appetite and abdominal discomforts which

later disappeared at dose levels greater

than 40 mg.

84
Abstinence Syndrome

At doses of 20-50 mg, six Out of seven

patients reported discomfort, yawning, lacrimation, and uneasiness, occurring 48-72

hours post-treatment.

At doses under 70 mg, three out of four

remaining patients reported yawning and

uneasiness 60-72 hours post-treatment.

Symptoms were milder and of shorter duration

than at lower doses.

At doses greater than 80 mg, there were no

reports of discomfort.

Heroin Challenges

One patient refused to receive heroin. At

dose levels of 30 mg LAAM, four patients

reported feeling some effects of heroin, two

felt none. The mean change in pupillary

diameter was 0.8 mm.

At dose levels of 50 mg LAAM, no effect of

heroin was perceived. The mean pupillary

diameter was 0.1 mm greater following the

heroin challenges.

At dose levels of 70 and 100 mg LAAM, blockade was complete.

Sustained Opiate Effects

Twentymg of LAAM produced maximum miosis

for 24 hours.

Doses greater than 20 mg produced no further

decrease in pupillary diameter; maximum constriction was sustained for 48 hours at dose

levels of 30-50 mg LAAM and 80-90 mg LAAM

sustained a pupillary diameter of 5.0-5.2 mm

for 72 hours.

85
19

A METHADONE/1-ALPHA-ACETYLMETHADOL

(LAAM) MAINTENANCE STUDY.

CHARLES SAVAGE, ELAINE KARP, STEPHEN CURRABN

INTRODUCTION

LAAM has had clinical success as a substitute

for methadone (Levine et al., 1973; Jaffe and

Senay, 1971; Jaffe et al., 1972). The purpose of this study was to validate past clinical research, to determine the relative

safety and effectiveness of LAAM and methadone, and to identify factors associated with

treatment success and failure.

EXPERIMENTAL DESIGN

Subjects

Subjects were 99 male heroin addicts; they

were, on the average, 28 years old with 11th

grade education! seven years narcotic addiction, four to five arrests, and two treatment failures. Half were employed when they

entered the study.

Prior to treatment the following data were

collected:

Background characteristics

Medical and psychiatric history

Physical examination and chest X-ray

Laboratory examination: EEG, urinalysis,

blood chemistry (BUN, glucose, bilirubin,

total protein, albumin, alkaline phosphatase, and SGOT), hematology (white

blood count, hematocrit and differential)

Cornell Medical Index

Psychological tests: Minnesota Multiphasic Personality Inventory (MMPA),

Personal Orientation Inventory (POI),

Benton Visual Retention Test, Psychological Evaluation Profile (PEP), Wechsler

Adult Intelligence Scale (WAIS)

Methodology

Treatment Groups--Assignment to treatment

groups was random and there were no significant differences between groups in

background characteristics, EEG results,

blood chemistry and hematology measures,

and personality measures. Patients and

staff were blind to the medications.

Group 1, 52 patients, received methadone

daily for three months and then were

switched to LAAM three times a week

with dextromethorphan placebo on other

days.

Group 2, 47 patients started on LAAM

and were switched to methadone at three

months.

Dosages--All Medication was mixed with

Tang and dextromethorphan. Dosage was

86
flexible. LAAM patients received doses

equal to 1.3 times their usual dose of

methadone

Assessments--At the end of three and six

months, the EEG, physical examination,

blood chemistry and hematology tests,

and MMPI were repeated.

Urine was checked one to three times a

week for quinine, morphine, amphetamines,

and barbiturates.

Clinic attendance and changes in social and

occupational status were monitored throughout the study.

RESULTS

Dropout Rates

Sixty percent of the methadone group

(Group 1) completed three months; 31 percent

of the LAAM group (Group 2) completed. This

difference was significant (X2 5.49, p=0.2).

In the crossover phase of the study, 66 percent of the LAAM patients (Group 1) completed the three subsequent months on

methadone; 81 percent of the methadone

patients (Group 2) completed the three subsequent months on LAAM. This difference was

not statistically significant.

With both phases combined, 65 percent of the

patients completed treatment with methadone

and 47 percent with LAAM.

Analysis Of Reasons For termination

Side effects were given as the most frequent

reason for withdrawal regardless of which

drug the patients were on by 31 percent of

LAAN patients and 23 percent of methadone

patients. The difference was not significant.

The specific symptoms reported were the same

for both medications: experiencing withdrawal or feeling over medicated.

Urinalysis

The mean percentages of urines positive for

illicit drugs were 5 and 8 percent for the

methadone and LAAM groups, respectively.

The difference was not significant.

Clinic Attendance

The mean absentee rates were 2 percent and

4 percent for the methadone and LAAM groups,

respectively. The difference was not significant.

Dose levels

There was no difference in the dose levels

of those who completed LAAM treatment and

those who dropped out.

Lower dosage methadone patients dropped out

more frequently than higher dosage patients.

Physiological Assessments

There were no differences between dropouts

and completers in EEG, hematology and blood

chemistry results except for bilirubin

which was, nonetheless, within normal limits

for both groups.

Personality

Dropouts differed from completers in several

personality characteristics being:

More suspicious and distrustful (MMPI,

Pa Scale)

More impulsive (POI Spontaneity Scale)

Less self-accepting (POI, Self-Acceptance

Scale)

More grandiose (PEP, Great Cause Scale)

More easily fatigued, more frequently

feeling ill, and more incapacitated due

to illness (Cornell Fatigue and Frequency

of Illness Scale)

Safety

No deaths or serious illness occurred in

patients on either drug.

Methadone patients

EEG measures did not differ pre- and

post-treatment

Three hematology measures showed significant changes, however, all were

within normal range

Mean value of neutrophiles decreased

Mean values of lumphocytes and

basophiles increased

LAAM patients--there were no differences

in EEG, blood chemistry or hematology

measures pre- and post-treatment.

87
20

A 48-WEEK STUDY OF METHADONE, METHADYL

ACETATE, AND MINIMAL SERVICES. 1974

EDWARD C. SENAY, JEROME H. JAFFE,

SALVATORE DIMENZA, PIERRE F. RENAULT

INTRODUCTION

dl- and 1-alpha-acetylmethadol have been

shown to be capable of suppressing narcotic

withdrawal symptoms for long periods of time

(Fraser and Isbell, 1952). These findings

have been confirmed in pilot comparisons with

methadone (Jaffe et al., 1970; Jaffe and

Senay, 1971; Jaffe et al., 1972). This study

reports investigations into the clinical

acceptability and safety of the levo isomer,

1-alpha-acetylmethadol, (LAAM), and an

evaluation of the role of auxiliary services

in the treatment of heroin addiction.

EXPERIMENTAL DESIGN

Subjects

The subjects were male narcotic addicts

between the ages of 20 and 50, randomly

assigned to one of three groups:

Thirty to methadone with full services

Thirty-one to LAAN with full services

Ninety-six to methadone with no other

services

There were no significant differences in the

background characteristics of the groups

with respect to race, education, employment,

arrests, family stability, and drug use

influences. The Dispensary group was significantly younger than the Methadone Full

Service group but not the LAAM group; the

Methadone Full Service group had used heroin

longer than the LAAM group or the Dispensary

group. The correlation of age with years of

heroin addiction was .81; the difference in

age is thought to account for the difference

in mean number years of addiction.

Methodology

Study Design--The study was a doubleblind, controlled study. The LAAM group

received active medication three times a

week and a 30 mg dextromethorphan placebo

on alternate days; attendance at group

therapy sessions was requested weekly, and

other counseling, vocational, legal and

recreational services were provided. The

Methadone Full Service group received

methadone daily and services as above.

The Dispensary group received methadone

daily for four weeks and then three times

88
weekly with take home doses on alternate

days. No counseling or services were

offered. Dosage modifications were made

during the study. The mean initial administered doses were 57.8 for the LAAM

group, 40.6 mg methadone for the Methadone

Full Service group, and 41.3 mg for the

Dispensary group.

Criteria For Effectiveness--The groups

were compared with respect to the following variables:

Dropout rate

Changes in medication dosages

Use of illicit drugs (as evidenced in

biweekly urine checks)

Employment rate

Self-reports of illegal activity and

arrests

RESULTS

Failure Of Research Design With Respect To

Dispensary

Inpractice, counseling services, and support

could not be withheld from the Dispensary

patients by the clinic staff, so the comparison made by the study was between full

and minimal services rather than between full

and no services as intended.

Methadone with full services appeared to be

superior to LAAM with full services and to

methadone with minimal services.

Dropout Rate

Forty-nine percent of the Dispensary group,

50 percent of the LAAM group, and 29 percent

of the Methadone Full Service group had

dropped out by week 48. There were no significant differences among treatment groups

in total number of weeks of participation in

originally assigned group (Dispensary, 30.5

weeks; LAAM, 29.7 weeks; Methadone Full

Service, 35.3 weeks). Methadone with or

without services had more holding power than

LAAM.

Illicit Drug Use

There was an increase in numbers of urines

negative 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 total

sample (33.3 percent, 33.3 percent, and 38.7

percent, respectively). Differences between

the groups were not significant.

Dosage Changes

Dispensary patients requested significantly

fewer changes (p<0.01) than did patients in

the full services groups (Dispensary: 3

changes/100 ma” weeks of treatment; LAAM: 7

changes/100 man weeks of treatment, Methadone Full Service: 8 changes/100 weeks of

treatment). The mean LAAM dose at 48 weeks

(93.9 mg) was significantly higher than the

mean dose of the Dispensary group (p<0.01;

51.7 mg), or the Methadone Full Service

group (p<0.05; 70.9 mg), but total weekly

dosage was less than that of patients on

methadone.

Employment Rates

There were no differences in employment

rates among the three treatment groups.

Arrests And Illegal Activity

Self-reported illegal activity decreased in

proportion to length of time in treatment

for all groups. There was no significant

difference among groups in self-reports of

arrests (Dispensary: 2.1 arrests/100 man

weeks in treatment; LAAM, 2.3 arrests/100

man weeks; Methadone Full Service, 3.0

arrests/100 man weeks.

Clinical Observations

There were no observations of confusion,

psychotic symptoms, or unpleasant subjective

states in any subjects. Anxiety was observed but was not associated with any

treatment group in particular. Two deaths

occurred, one from suicide and one from lung

cancer.

89
21

THREE 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 of

two 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 substitute for methadone in the treatment of

heroin addiction (Jaffe and Senay, 1971;

Jaffe et al., 1970, 1972; Senay et al., 1973).

Medication is only one part of therapy, however; and the decreased frequency with which

LAAM patients need to visit the clinic may

weaken the influence of the rest of the program, i.e., therapy, vocational rehabilitation, and legal services. This paper reports

an extension of previous studies to determine

whether new LAAM patients attend clinic less

frequently than new methadone patients and

if treatment outcome is influenced by

attendance.

90

Experimental (LAAM) Group--Thirty-four

male patients were included in this

group with the following characteristics:

Average age, 31.1 years

Average education, 11.2 years

Average years narcotic use, 11.7

32.3 percent married

20.6 percent employed

73.3 percent arrested at least once in

two years prior to entrance in study

100 percent black

At least 14 weeks in treatment

Control (Methadone) Group--Thirty-one

male patients were included in this

group 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 employed

70 percent arrested at least once in

two 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 dispense

LAAM and offered group therapy and individual

counseling three times weekly, remaining open

with support staff and recreational facilities Monday through Friday. The other dispensed methadone and was open six days a

week with Sunday medication taken home.

The two groups were compared on the following

criteria:

Dropout rate .

Clinic attendance

Urine negative for illegal drugs

Dosage changes

Employment

Arrest

Side effects

Dose levels were 10 mg higher on Friday for

LAAM patients and dosage in both groups could

be adjusted weekly. No other medications

were prescribed.

RESULTS

Retention Rate And Clinic Attendance

LAAM patients dropped out earlier in treatment; the difference was significant at five

weeks. By the end of the fourteenth week,

‘however, there was no significant difference

between the two groups. The LAAM clinic

retained 23 of 34 subjects. The methadone

clinic retained 23 of 31 subjects.

LAAM patients attended the clinic on 57.6

percent of the days it was open and 94.2

percent of the days on which medication was

dispensed.

Methadone patients attended the clinic on

90.3 percent of the days it was open, medication being dispensed every day.

Urine Negative For Morphine

The two groups were similar in extent of use

of unauthorized drugs. LAAM patients had

urines negative for morphine a” average of

10 out of 14 weeks; methadone patients, 9.8

out of 14 weeks. The early tendency for the

methadone group to have more urines negative

for morphine was reversed after the eighth

week when the LAAM group began to use drugs

less.

Dosage Changes

The initial average LAAM dose was 44.7 mg;

doses were 10 mg higher on Fridays than on

Mondays and Wednesdays. At 14 weeks, the

average LAAM dose was 44.4 mg.

The average initial daily methadone dose was

33.5 mg and was 36.5 mg at 14 weeks.

Dose levels were very stable throughout the

duration of the study.

Employment And Arrests

Employment and arrest measures were identical in both groups:

Two subjects in each group were arrested.

Five of the six patients who had jobs

initially still had them at 14 weeks.

One of the 17 unemployed in each group

found a job.

Side Effects

No side effects attributable to methadone

were reported.

No medical complications developed in either

group.

One LAAM patient died due to heroin overdose

48 hours after his second dose of LAAM.

Five patients experienced side effects in

the LAAM group.

Four patients had anxiety and nightmares,

three in the first month of treatment and

the fourth in the second month.

Dose levels were 30 mg (2) and 50 mg

(2).

Dose levels were lowered 10 mg in two

subjects, one on 30 mg and one on 50 mg.

Symptoms did not persist nor did they

return when dose levels were increased

again.

Dose levels were maintained for the

other two patients and symptoms did not

persist more than one week.

One patient on 50 mg LAAM exhibited

bizarre behavior of which he had no

recollection. Medication was reduced to

40 mg and symptoms persisted. He was

transferred to a methadone clinic. He

subsequently reported having been hospitalized in a mental institution seven

years before the study.

91
22

LEVOMETHADYL IN MAINTENANCE TREATMENT

OF OPIATE DEPENDENCE, 1972

group and ten to the control (methadone)

group. The two groups did not differ from

each other in age, years of drug abuse, or

social class. They were detoxified and drug

free 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 received

medication on Mondays, Wednesdays, and

Fridays. Dose levels were built up as inpatients; the subjects were discharged when

dose levels were attained. Two dose levels

of LAAM were established:

Four patients at low dose, 30-40 mg twice

weekly and 50 mg on Fridays

Five patients at high dose, 80 mg three

times a week

One subject was discontinued because of

of a prior seizure disorder

INTRODUCTION

The 72-hour duration of action of methadyl

acetate has been established in single dose

and controlled clinical studies (Fraser and

Isbell, 1952; Jaffe et al., 1970 and 1971).

The purpose of this study was to investigate

the potential of levomethadyl acetate (LAAM)

in a maintenance program for narcotic addicts

and to define dose levels. duration of

action, secondary effects; and degree of

blockade to heroin.

EXPERIMENTAL DESIGN

Subjects

Subjects were 20 male narcotic addicts age

21 or over with at least a two-year addiction

history and one treatment failure. Ten were

randomly assigned to the experimental (LAAM)

Subjects in the control group were built up

to 100 mg methadone hydrochloride daily in

the hospital and discharged. After the first

month, they attended the clinic twice weekly

and received take-home medication.

Criteria For Effectiveness

Subjects were evaluated for changes in vocational and social rehabilitation on a scale

from 0 (no change) to 2 (marked improvement).

Substance abuse was monitored by twice weekly

urine testing for the presence of morphine,

heroin, barbiturates, and amphetamines.

Cross-tolerance to 25 mg heroin was established while drug free and to 25 and 50 mg

heroin after induction at 24 hours after

treatment for all subjects and 48 hours after

for one high-dose LAAM subject. The quality

92
of the euphoria, voice change, and pupillary

constriction were observed; subjects were

interviewed and completed an Addiction

Research Center Inventory (ARCI) questionnaire.

Adverse Experiences Look For

Laboratory studies of liver function, fasting

blood glucose, blood urea nitrogen, uric

acid, blood cell caunt, and urinalysis were

made prior to and weekly during the study.

RESULTS

Dropouts

One of the nine LAAM subjects dropped out at

three months; two of the ten methadone

patients dropped out, one at two months and

one at four months. Eight LAMM and eight

methadone patients remained in the study at

six months.

Behavioral Change Ratings

Ratings of change in vocational and social

functioning were similar in the two groups;

1.4 for the LAAM group and 1.2 for the methadone group.

Dose Levels

Withdrawal symptoms were experienced by

three of the four low-dose LAAM group, 40-48

hours following their last dose.

At the 80 mg LAAM dose level, no withdrawal

symptoms or craving for heroin were reported.

Cross-Tolerance To Heroin

Three low-dose LAAM subjects responded to

challenge with 50 mg heroin with mild, transient euphoria; blockade was complete in the

fourth subject.

All five high-dose LAAM subjects demonstrated

complete blockade to 50 mg heroin.

The high-dose subject challenged at 48 hours

demonstrated complete blockade to heroin.

All 10 100 mg methadone subjects demonstrated

complete blockade to 50 mg heroin.

Urine Tests

The LAAM group had 8.9 percent positive tests

for morphine compared to 2.0 percent for the

methadone group. High- and low-dose LAAM

subjects had 2.8 percent and 18.9 percent,

respectively.

The LAAM group had 2.0 percent positive

tests for barbiturates and amphetamines compared to 7.9 percent for the methadone

group.

Adverse Experiences And Side Effects

The methadone group did not complain of side

effects; constipation at the beginning of

treatment was acknowledged by four subjects

when asked.

Three of nine LAAM subjects complained of

irritability; one of these also complained

of anxiety. Tranquilizers were prescribed

to two patients.

Two of the LAAM subjects complained of involuntary, jerky movements of the extremities preceding sleep, persisting intermittently throughout the study.

Results of all laboratory tests were normal

for both groups except liver function tests.

All subjects manifested intermittent elevated transaminase levels which were

sporadic and not dose related.

93
This chapter and the following present summaries of the Phase II

clinical studies of LAAM. A8 discussed in the introductory chapter, both

of these studies were initiated by SAODAP to detenmine safety and effectiveness of LAAM. The clinical trials in each of the Phase II studies

were carried out simultaneously in multiple participating clinics utilizing a common protocol. This procedure ensured attainment of adequate

sample sizes within a reasonable time and of a more geographically

representative sample of addicts than possible in a single clinic. Also,

this procedure permits analysie of variation in outcome between different

clinics. Organization, execution, monitoring of both studies and data

compilation, analysis, interpretation and reporting were performed by

C. James Klett, Chief VA Central Neuropsychiatric Research Laboratory

and Cooperative Studies Program Support Center. The following summaries

of the VA and SAODAP Cooperative Studies of LAAM and Methadone were prepared from progress reports submitted by Dr. Klett to FDA as sponsor of

the Phase II IWD.

SUMMARY OF VETERANS ADMINISTRATION PHASE II

COOPERATIVE STUDY FOR LAAM AND METHADONE

Waltor Ling , M.D.

V. Charles Charuvartra, M. D.

Samuel C. Kaim, M.D.

C. James Klett, Ph.D.

Although early studies tend to substantiate

the observation of the clinical usefulness of

acetylmethadol, the number of patients

studied was quite small. The present study

attempted to maximize subject availability by

means of multihospital participation in a

common double blind protocol. The goals of

the study were to evaluate the safety and

toxicity of a fixed dose of acetylmethadol

(80 mg TIW) and to compare its relative efficacy with two doses of methadone, a high

(100 mg) and a low (50 mg) daily dose.

Safety and toxicity were evaluated by a multilayer clinical and laboratory monitoring

system. Relative efficacy was measured in

terms of a number of outcome variables,

including positive urines, clinic attendance,

employment, and social rehabilitation. A

secondary goal of the study was to compare

the two methadone doses with regard to

these same outcome variables, since the

desirability of high dose versus low dose

methadone maintenance remains an issue of

controversy. Originally, Dole and Nyswander

(1) had advocated a rather high methadone

dose. It was felt that this would produce a

physiological "blockade" against the effect

of heroin and would thus discourage further

experimentation with illicit drugs. Others

have questioned the need for this high

(80-120 mg) dosage. Garbutt and Goldstein

(2), for instance, have found an average of

50 mg to be just as effective as 100 mg

with respect to survivorship in the program

and cessation of heroin use.

METHOD

Patients

Patients were eligible for the study if they

met all of the criteria for admission to

methadone maintenance programs as defined by

the FDA and were males between the ages of

18 and 60. Patients were excluded for

incapacitating or life-threatening conditions, disease requiring regular repeated

medication, frankly psychotic states,

epilepsy, current severe alcoholism, and

pending criminal charges. It was further

specified that any addicted spouse or relative in the same household must be under

treatment and that there be a reasonable

expectation that the patient would continue

to reside in the vicinity of the clinic and

be able to attend for the full duration of

the trial. Eligible patients who signed an

informed consent for voluntary participation

in the study were then given a general physical examination with neurologic and

94
psychiatric evaluation and including chest

x-ray, electrocardiogram, urinalysis, and

blood studies. Patients began treatment on

the following Monday.

Drug Administration

Patients were randomly assigned to levoalpha-acetylmethadol or one of two dose

levels of methadone. The two methadone

groups received active medication daily but

the acetylmethadol group received active

medication on Monday, Wednesday, and Friday

with placebo (dextromethorphan plus quinine)

on all other days. Take-home doses (of the

Tuesday, Thursday, Saturday, Sunday doses

only) were permitted at the physicians’

discretion after the twelfth week of treatment. Take-home doses of acetylmethadol were

not permitted; any take-home dose in this

group was placebo. All doses were dispensed

in a masking-diluting liquid such as Tang or

grapefruit juice.

The first dose in all three groups was 30 mg

which was incremented by 10 mg on each succeeding Monday until the patient achieved

his target dose of 50 mg of methadone (M-50),

100 mg of methadone (M-100), or 80 mg of

acetylmethadol (L-80). All doses were dispensed double-blind with the sequence of

dosage increments and placebo doses controlled by bottle number. Duration of

treatment was 40 weeks (280 days).

Psychotrophic drug use was permitted only

for occasional nighttime sedation. All use

of supplemental medication during the trial

was recorded.

Clinical Evaluations

Patients were evaluated immediately before

and every four weeks during their tenure in

the study. The evaluation included a brief

history, a current status record of their

employment activity, legal involvement,

interpersonal relationships and drug use

during the preceding four weeks, a supplementary medication record of all drugs prescribed during the preceding four weeks, and

a symptom-sign checklist. The complete

physical examination was repeated at the

twelfth week and at the end of the study,

with abbreviated physical exams at all other

four week evaluations. Vital signs (blood

pressure, temperature, pulse) and weight were

recorded on these occasions and fluid samples

were obtained for laboratory tests.

In addition, daily entries were required on

a treatment record of each patient’s

adherence to the clinic schedule of visits

and details of medication dispensed. Urine

samples were collected weekly following a

random testing sequence supplied centrally.

Specimens were sent to the clinical laboratory at the Sepulveda VA Hospital where they

were tested for morphine, barbiturates,

amphetamines, and a variety of other substances. Whenever a patient concluded

treatment, an attempt was made to repeat all

evaluations and the staff recorded their

consensus judgment of outcome in a number of

different areas.

RESULTS

Characteristics of Sample

The sample consisted of 430 men whose median

length of addiction to opiates was 7.2

years. They were reasonably young (58% were

below the mean age of 31 years) and reasonably well educated 62% had graduated from

high school and 21% had gone on to do some

college work. Mast had been married at one

time but 37% were still single. Racially,

46% were black, 39% white, and 11% had

Spanish surnames. Other characteristics

were consistent with expectation in an

addict group.

Early Termination

Only 42% of the starting sample completed

the full 40 weeks of the study. If all

reasons 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 difference between the L-80 and M-100 groups is

statistically significant. Not all of these

patients terminated for drug related reasons

but since the nondrug related terminators

should have been equally distributed among

groups except for chance, it has to be concluded that high-dose methadone maintenance

(M-100) was superior in retention to the

L-80 group. It does not necessarily follow

that high-dose methadone is the superior

maintenance drug, however, because there are

other dimensions of outcome that must be

considered.

The average length of stay in the study

before early termination was remarkably

similar for the three groups: 82 days for

the two methadone groups and 81 days for

the L-80 group. Of the 251 early terminations, 45% occurred by the end of the

seventh week (which marked the end of the

induction period for the M-100 group). A

greater number of terminations had occurred

95
in the L-80 group by this time but when the

groups were adjusted for their total number

of dropouts, there was no apparent trend for

patients to drop earlier from one group than

another.

Table 1 presents the number of patients in

each group who terminated early for a

variety of reasons. The only significant

differences between groups for specific

categories of dropout were: a greater

number for side effects in the L-80 group

than in the M-50 group, and a greater number

of "No shows" in the L-80 group than the

M-100 group. (Note: In these and all subsequent analyses, p<.05 was accepted as the

level 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, nor

were there any serious adverse reactions

reported. There were 11 patients terminated

primarily for side effects. Four L-80

patients terminated because of inability to

ejaculate and another L-80 patient who terminated because of swelling of joints listed

decreased sexual interest along with heartburn, nodding, and constipation. The other

L-80 terminators were: a patient who

couldn’t keep medication down (nausea, vomiting); another who complained of being tired

and dizzy with chest and arm pain; and one

who experienced jerking of extremities at

bedtime and some nausea. The three high-dose

methadone patients were terminated because

of: a pruritic maculo-papular rash that

developed on a second day while the patient

was still on 30 mg; abnormally high liver

function tests which were present before

treatment but showed only minor trends toward

stabilization at a lower level; and an

apparent case of hone marrow suppression.

The symptom-sign data were collected by a

research assistant, nurse, or primary

therapist before the Monday dose every week

for the first eight weeks and every four

weeks thereafter. The schedule consisted

of 30 symptom-signs and an "OTHER" category.

Specific symptom-signs were not enumerated,

but when their presence was elicited by

general questioning, their severity was

judged as mild, moderate, or severe.

Initially each symptom-sign was monitored

independently as well as in a priori clusters.

When sufficient data had accumulated, the

schedule was factor analyzed and a three

factor solution accepted as the best representation of the data. The first factor (14

items) is clearly an Underdosing withdrawal factor. It consists of Aching Bones

and Joints, Yawning, Runny Nose, Watery Eyes,

Muscle Cramps, Goose Bumps, Loss of Appetite,

Abdominal Cramps, Nausea and Vomiting,

Diarrhea, Insomnia, Excessive Sweating,

Irritability, and Anxiety (tension, nervousness). The second factor (five items) is an

Overdosing factor which consists of Feeling

High, Nodding, Dizziness on Standing, Poor

Concentration, and Impotence. The remaining

11 items made up a third factor which was

termed Somatic: Heartburn-Gastric Distress,

Constipation,Bad Dreams and Nightmares,

Drowsiness, Blurring of Vision, Urinary

Frequency, Decreased Sexual Interest, Delayed

Ejaculation, Numbers of Hands and Feet,

Involuntary Jerking Movements of Lower Extremities, and Edema of Extremities. These three

factors and their sum which was referred to

as Total Symptomatology were subsequently

monitored along with the individual symptomsigns.

As a general statement, reporting of any

symptom-signs was infrequent and of a low

level of severity when reported. All three

factor scores and total symptomatology had

their highest level in the first week or

two of treatment but rapidly decreased to

nearly absent levels. There were no differences between drugs worth noting. Because

of special interest in several specific

symptom-signs, this analysis was supplemented by another approach which used the

patient as the unit of analysis and examined

individual symptom-signs (rather than dealing with the mean level of a cluster). For

each symptom-sign separately, a patient was

tallied as "severe" if he had even one such

rating at any time during his tenure in the

study. A patient who was never rated as

"severe" but had at least one rating of

"moderate" was tallied in that category and

if 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 those

rated as asymptomatic throughout. In this

particular approach, the pretreatment rating

was ignored completely. To be tallied somewhere in the table, a patient had to have

at least one rating during treatment;

patients who completed the study could have

as many as 16. This approach defines the

highest rating obtained during treatment per

patient as a unit of analysis. Table 2

presents these data for all three drug

regimens combined.

97
TABLE 2

Number and Percent of Patients in Terms of Highest

Severity Rating Obtained During Treatment

N %

Aching bones and joints

Yawning

Runny nose

watery eyes

Musle cramps

Goose bumps

Loss of appetite

Abdominal cramps

Nausea or vomiting

Diarrhea

Insomnia

Excessive sweating

Irritability

Anxiety (tension, nervousness)

Feeling high

Nodding

Dizziness on standing

Poor concentration

Impotence

Heartburn-gastric distress

Constipation

Bad dreams or nightmares

Drowsiness

Blurring of vision

Urinary frequency

Decreased sexual interest

Delayed ejaculation

Numbness of hands or feet

Involuntary jerking movements

of lower extremities

Edema of extremities

Other

None Mild Moderate

N %

152 37

171 42

136 33

160 39

212 52

221 54

117 29

181 45

160 39

288 71

113 28

92 23

124 30

91 22

298 74

260 65

297 74

252 63

297 74

221 54

78 19

205 50

162 40

286 70

244 60

164 40

185 45

231 57

130 32

152 37

163 40

158 39

118 29

106 26

156 38

134 33

141 35

81 20

139 34

111 27

144 35

136 33

74 19

96 24

75 19

107 27

44 11

123 30

129 32

110 27

156 38

84 21

101 25

116 29

98 24

114 28

N %

108 27

75 18

97 24

79 19

60 15

70 17

117 29

76 19

84 21

37 9

129 32

177 44

123 30

150 37

25 6

38 10

24 6

31 8

44 11

54 13

167 41

81 20

83 20

32 8

54 13

97 24

84 21

46 11

180 44 136 33 83 20

335 82 47 12 23 6

253 62 46 11 81 20

The data shown in Table 2 were also generated

separately by drug regimen and differences

between groups evaluated by 2 x 3 chi-square

or Fisher’s exact probability test. For

these tests, rating was dichotomized as NoneMild and Moderate-Severe. In only three

instances was there a significant drug

difference: Aching Bones and Joints for

which the M-50 group had a significantly

higher frequency of moderate-severe ratings

than either of the other groups; and

Severe

N %

18

10

12

11

17

10

18

17

23

2

27

28

17

31

3

6

4

10

15

9

34

12

7

5

9

30

40

16

8

2

27

4

2

3

3

4

2

4

4

6

0

7

7

4

8

1

2

1

2

4

2

8

3

2

1

2

7

10

4

2

0

7

Anxiety for which M-50 significantly exceeded

L-80 in terms of moderate-severe ratings.

98
Although Delayed Ejaculation (and possibly

other problems in sexual function) seemed to

be associated with the L-80 patients in the

early termination data, this was not supported by the symptom-sign data where ratings

of moderate and/or severe on Impotence,

Decreased Sexual Interest, and Delayed Ejaculation are all more frequent (but not significantly so) in the methadone groups.

Irritability is another symptom-sign of

special interest because of observations of

animals on acetylmethadol in the preclinical

studies. In this study, irritability is

represented in higher frequency in the

methadone groups but not significantly so.

The "Other" category included a wide array

of symptom-signs, many of which seem to be

either trivial or clearly nondrug related,

most of which were reported at a single

rating period only rather than persistently

and some of which were elaborations of one

or more of the 30 symptom-signs on the

checklist.

The laboratory studies were conducted before

treatment and every four weeks thereafter.

Hematologic tests consisted of total WBC,

total RBC, neutrophils, lymphocytes, eosinophils, monocytes, basophils, hematocrit, and

hemoglobin. Blood chemistry was the usual

SW-12 panel, specifically calcium, FBS, BUN,

uric acid, total protein, albumin, total

bilirubin, alkaline phosphatase, LDH, and

SGOT. (Globulin was calculated as the

difference between total protein and albumin.) Urinalysis included albumin, sugar,

WBC, and RBC. Vital signs recorded at the

same intervals included blood pressure,

pulse and temperature, plus weight.

The hematologic tests, blood chemistries,

vital signs and weight provided 25 comparisons for each of the 10 test periods (weeks

4, 8, 12, 16, 20, 24, 28, 32, 36, 40)--a

total of 250 analyses of covariance with

initial level as the covariate. Only six of

these were statistically significant. Three

of these occurred on a single variable--

weight. The others represented a difference

between groups at one period only: WBC at

week 20, calcium at week 36, and alkaline

phosphatase at week 16. Sample sizes for

these tests ranged from slightly over 300

cases for the pre- to four-week analyses to

around 160 cases for the 40th week analyses.

Two cohorts of patients were established to

look specifically at changes over time

rather than cross-sectionally. The 24-week

cohort consisted of patients who had a complete set of data on a variable at pretreatment and every test period for the first

24 weeks. Usually this consisted of 60 M-50

patients, 57 M-100 patients, and 45 L-80

patients. The 40-week cohort usually consisted of 39 M-50 patients, 45 M-100

patients and 31 L-80 patients. Although the

statistical testing provided a variety of

information about within-group and betweengroup differences, the primary interest was

in two tests of between-drug regimen difference. One of these was essentially in terms

of the average of all tests periods--the

height of the curve. The other tested the

variation of means across time between drug

groups (the drug by time interaction). In

the analysis of the 25 variables using the

24-week cohort, there was a single significant finding--the interaction of drug and

time on weight. In the analysis of the same

variables using the 40-week cohort, there

was a significant interaction for total WBC,

total RBC, hematocrit, hemoglobin, and

weight. In addition, there was a significant difference between groups for SGOT when

all values were collapsed across time.

In another series of analyses, a cohort of

128 patients from three hospitals who had a

complete set of values over a 20-week

period were used to provide similar but

somewhat different information. In these

analyses, the pretreatment value was

included as a covariate and all subsequent

values were adjusted for initial level.

Hospital was included as a factor in the

design which permitted a comparison of

hospitals and the various interactions of

hospital with drug and time. Both of these

changes in design were introduced to provide greater sensitivity for the analyses

of drug difference, although it was accomplished by reduction in time to 20 weeks, a

reduction of sample size and a restriction

to the three hospitals that had sufficient

data to be included. In these analyses, the

only main effects of treatment that reached

significance were on weight and pulse.

There were significant interactions between

drug and time on hematocrit, hemoglobin, and

SGOT.

A final attempt to gain precision and

extract information about any drug group

changes present in the data consisted of a

series of multivariate analyses of covariance. The following hematologic tests were

analyzed simultaneously: WBC, RBC, neutrophils, lymphocytes, hematocrit, and hernoglobin. The pretreatment values on all six

variables were used as covariates and the

values at each test point were used as

dependent variables. Hospital was included

as a factor, and in each analysis as many

patients and as many hospitals were included

99
as possible. There were no significant

differences involving treatment group in

these analyses. The renal tests (calcium,

BUN, and uric acid) were analyzed in the

same manner and with the same result. In

the analysis of liver function tests (total

bilirubin, alkaline phosphatase, LDH, SGOT

and an index defined as albumin divided by

globulin), there was a significant difference between groups at the 16th week only.

The multivariate test of vital signs and

weight was significant at the 4th week only.

These different analyses each supply somewhat different information and need to be

further examined and integrated. In the

hematologic tests, there is reason to look

closer at WC, RBC, hematocrit, and hemoglobin. In the covariance analyses of WC,

a significant difference between groups was

obtained at week 20. The adjusted means

were M-50 7180, M-100 7720, and L-80 8060.

In addition there were significant differences in unadjusted post means at week 16

and 20. In a total of 30 tests of pre-post

within-groups change (three drug groups

times 10 time periods), only the change from

pre- to week 8 in the L-80 group was significant. Furthermore, all means at all test

points were within the normal range (all

means varied from 7260 to 8020). In both

the 24 and 40-week cohorts, there was significant within-group variation of means

across time in the L-80 group but this

variation represented considerable scatter

in values from one test period to the next

rather than an increasing or decreasing

trend in WBC. The same scatter was present

but not significantly so in the two methadone groups. In the 40-week cohort analysis,

this variation across time was significantly

greater in the L-80 group than in the two

methadone groups (significant interaction)

and there were significant differences

between drugs at week 16, 20 and 28. The

drug by time interaction was not significant

in the 24-week cohort. At each of these test

points (week 16, 20, 28) the L-80 mean was

highest and the M-50 mean was lowest. All

means were in the normal range. There were

no drug differences in the 20-week cohort

analysis. In summary, there is a suggestion

that something might have been happening

with WBC in at least some patients during

the middle weeks but it is difficult to give

clinical meaning to it because it did not

persist, all means are comfortably in the

normal range and a review of individual

patient's data did not identify anything

remarkable about this part of the treatment

period. RBC, hematocrit, and hemoglobin

surfaced as possibly significant (in a

clinical sense) on the cohort analyses only.

The evidence for RBC is not convincing.

There appeared to be a predominately linear

downward trend particularly in the two methadone groups over the first 20 to 24 weeks but

the trend did not continue and in fact

seemed to reverse itself. It may be more

accurate to say that there was some initial

decline which then leveled off. The only

between-groups difference was the drug by

time interaction in the 40-week cohort, and

even in this analysis only at week 8 was

there a significant difference between drugs

(M-100 highest, L-80 lowest, all means within

normal values). It is difficult to conclude

that there is anything clinically significant

in RBC. The situation is much the same for

hematocrit and hemoglobin. The trend analyses suggest an initial decline in all three

groups and then a leveling off after about

the eighth week. There is no clear and consistent separation of groups across time.

Finally, considering also the results of the

multivariate tests that included all of

these variables, it seems reasonable to conclude that the occasional between-groups

differences that did emerge as statistically

significant have no clinical importance. In

no case were the blood changes sufficient to

necessitate termination from the study.

The evaluation of renal and liver function

tests was similarly reassuring from a clinical point of view. SGOT was noteworthy

for the fact that the means of all three drug

groups before and throughout treatment were

well above the usual normal range (from a low

of 56 to 107) and the pretreatment values for

many individual patients were high enough to

be of serious concern in a nonaddict sample.

The main finding for SGOT is that the L-80

curve is at a somewhat higher level at pretreatment and throughout the 40 weeks than

the methadone groups. All three groups show

essentially no change across time on SKIT.

The significant difference between groups at

week 16 in the multivariate analysis of the

liver function tests is paradoxical and not

likely to be of clinical importance because

there is so little supporting evidence of

differences at other weeks either in the

univariate or multivariate tests.

The analysis of vital signs and weight had a

generally low yield, except for weight,

which is clearlv affected bv all three drug

regimens, and particularly acetylmethadol.

There is clearly an upward trend in all

groups, and somewhat more substantially so in

the L-80 group. There was no morbid obesity

reported.

100
Efficacy

This study was not designed to evaluate

efficacy in the usual manner, i.e., there is

no placebo or nontreatment group. However,

acetylmethadol has previously been shown to

be pharmacologically effective in suppressing

the abstinence syndrome and there is abundant evidence in this study that both drugs

will maintain addicted individuals without

their having to resort to supplementary

(illicit) narcotic use to avoid withdrawal.

It seems reasonable to assume efficacy in

this sense and turn to the question of the

relative efficacy of the three drug regimens.

There are a number of variables that individually or collectively could be used to

deal with the issue of relative efficacy.

All of these are imperfect indices. The

amount of discomfort indicated on the Underdosing factor of the Symptom-Sign Record

provides a measure of efficacy but would need

to be evaluated sirmultaneously with illicit

drug use to be unambiguous as an outcome

index. Early termination is obviously

related to efficacy in some complex manner

but is less than ideal as an indicator for

some equally obvious reasons. A patient

who completes 40 weeks of treatment but

tests positive for morphine at every week

cannot be considered more of a treatment

success than a patient who is clean for 32

weeks and then moves to another part of the

country Both kinds of patients are represented in this study. Conformity to scheduled clinic visits is equally ambiguous.

Some patients who faithfully attend clinic

show a heavy illicit drug use pattern. It

is not even safe to assune that missed clinic

visits are accompanied by illicit drug use.

Many other outcome variables are clearly

secondary, i.e., have no direct pharmacological relationship to the drug. Examples

are employment variables, encounters with the

law, and interpersonal relationship variables.

It is the hope and the expectation that

patients being adequately maintained will

show improvement in these areas and it may

be appropriate to use such variables to

evaluate a total program of rehabilitation

including the whole array of supportive

services but it seems unjustified to use

them as criteria of primary drug effect.

They seem, instead, to be contingency

variables. The use of these variables as

outcome indicators of maintenance treatment

is contingent upon achievement of the primary

goal which is to decrease illicit drug use.

Urine test data is considered to be the key

to evaluation of the results of this study.

Unfortunately, even illicit drug use is not

a simple variable. The amount of drug use

is, of course, important but the pattern is

probably even more so. A patient who completed the study with 50% urines positive

for morphine could have been entirely clean

in the first or the last 20 weeks. The

latter seems to be a clearly superior outcame.

An index of illicit morphine use has been

derived which takes into account total use

and pattern of use. With a single exception

to be noted later, this index was developed

completely independent of the study data and

was therefore not biased by knowledge of

drug group outcomes. This index has some

arbitrary features end some defects but

experience with its use has not revealed

serious distortions. The rules are entirely

objective and do not require clinical judgment . The entire operation can be performed

by the computer.

Rule 1: A score cannot be derived for a

patient who is in the study for less than 50

days (seven weeks).

Rule 2: Urine tests Positive for morphine

are given a weight of five if they occur in

the last 8 weeks of a patient’s tenure in the

study, a weight of four if they occur in the

next to last 8 weeks, three if they occur in

the next block of 8 weeks and so on.

Rule 3: A missing urine test result is

handled in exactly the same manner as a

positive urine except that it is not weighed

as heavily. A positive urine in the last

8 weeks would be weighted 5 x 1 = 5; a

missing value would be weighted 5 x .22 =

1.1. The value .22 is not totally arbitrary

but is derived from the data. It represents

the percent of all urine samples collected in

the study that tested positive for morphine

and its use for missing value introduces some

notion of the probability that a missing

value would have been positive.

Rule 4: All scores derived by the rules

above are adjusted to a comparable range of

0 to 120. Patients who have 40 negative

urines would be scored 0; patients with 40

positive urines would be scored 120.

Although the index seems to have the desired

characteristic in an abstract sense, the test

of its value must be in terms of actual data.

Preliminary attempts to establish construct

validity have been encouraging. It was predicted that the drug use index would correspond to staff judgments of outcome made at

the time of termination of a patient’s participation in the study. The patients rated

101
as being better or much better had a mean

urine index of 17.5, the patients rated

unchanged had a mean of 38.3, and the

patients who were worse or much worse had a

man of 39.9. The F was 24.16 (p< 001). A

similar relationship was predicted for

percent clinic attendance. Patients who had

a perfect attendance record had a mean urine

index of 17.7, those patients that had a

near perfect attendance record (96-99.9%)

had an index of 20.5, the patients who

attended 90 to 95.9% of the time had an

index of 33.0 and patients whose attendance

was below 90% had an index of 36.3. The F

was 7.82 (p< .001). A series of more carefully planned analyses will need to be conducted to further define the index. However,

using this index to compare the three drug

regimens gave the following results: 110

M-50 patients had a urine index of 33.3,

111 M-100 patients had an index of 22.6, and

96 L-80 patients had an index of 20.8. The

F was 6.19 (p< .005). The M-50 group is

significantly higher on the urine index than

either M-100 or L-80.

Urine test data were analyzed in other ways

as well. For each patient, the number of

urines positive for morphine was divided by

the number of his specimens tested. This

gave a "percent dirty for morphine" score

for that patient which was then used in a

comparison of groups. A similar score was

calculated for barbiturate positive, amphetamine positive, and "something" positive,

the latter being the number of specimens

positive for either morphine, barbiturates,

amphetamines, or cocaine (tested randomly) at

any one week divided by the total number of

specimens for that patient. The results of

these analyses showed the L-80 group less

likely to use illicit barbiturates than the

M-50 group.

Another kind of outcome index is program

conformity, which was defined as each

patient's number of actual scheduled clinic

visits divided by his total number of

expected scheduled visits for however long

he was in the study. The M-50 group had an

average of 92% attendance, M-100 95%, and

L-80 90%. The difference between M-100 and

L-80 on this clinic visit index was significant. However, since the acetylmethadol

patients only received active medication on

MWF, the analysis was redone comparing the

three groups on percent attendance for those

days only. L-80 still had a lower average

attendance rate than M-50 or M-100 but the

difference is not significant.

Still another evaluation of relative efficacy

was possible using the global rating of

outcome, which was a combined staff judgment

made shortly after a patient's termination,

taking into account all known information

about the patient. This was a five-point

scale: much improved, improved, changed,

worse, and much worse. The M-50 group was

judged to be significantly less improved than

either 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 not

yielded evidence of advantage of any one

group over another but a conclusive summary

of these variables will have to be deferred

until more definitive analyses have been

done. Similarly, there are many other

aspects of the data that will have to await

subsequent publication.

REFERENCES

1.

2.

Dole, V.P. et al: Methadone maintenance.

A report of two years experience. Presented at Annual Conference of National

Research Council Cormittee on Problems

of Drug Dependence, New York, 1966.

National Academy of Sciences,

Washington, D. C.

Garbutt, G.D., Goldstein, A.: Blind

comparison of three methadone maintenance

dosages in 180 patients. Proceedings

of Fourth National Conference on Methadone

Treatment. National Association for

Prevention of Addiction to Narcotics,

New York, 1972, pp. 411-414.

AUTHORS

Affiliation of the authors of this article is

as follows: From the Veterans Administration

Hospitals, Sepulveda, California (Dr. Ling),

Brentwoti, California (Dr. Charuvastra) and

Perry Point, Maryland (Dr. Klett) and from

the National Pharmaceutical Council, Inc.,

Washington, D.C. (Dr. Kaim).

102
SUMMARY OF SAODAP PHASE II COOPERATIVE STUDY

OF LAAM VS. METHADONE

Waltor Ling, M.D.

C. James Klett, Ph.D.

Roderic D. Gillis

The primary purpose of the trial was to

compare the efficacy and safety of LAAM and

methadone for treating heroin addicts in a

maintenance program. The program was

designed to be conducted with uniformity,

supervision and coordination based upon

adherence to three common protocols. Data

were recorded on a uniform set of forms and

submitted to a central data coordinating

center for analysis. Safety was evaluated

by monitoring patients for symptoms, signs

and laboratory evidence of toxicity.

Although the primary endpoint for statistical

evaluation of efficacy was use of illicit

drugs, changes in social adjustment, arrest

rate, employment and retention in treatment

were also considered indications of effectiveness.

METHOD

Patients

Patients were eligible for the study if they

were currently in a methadone maintenance

program as defined by the FDA and were males

ages 18 or older. Patients were excluded

for incapacitating or life-threatening conditions, disease requiring regular repeated

medication, frankly psychotic states,

epilepsy, current severe alcoholism, and

pending criminal charges. It was further

specified that any addicted spouce or relative in the same household must be under

treatment and that there be a reasonable

expectation that the patient would continue

to reside in the vicinity of the clinic and

be able to attend for the full duration of

the trial. Eligible patients who signed an

informed consent for voluntary participation

in the study were then given a general

physical examination with neurologic and

psychiatric evaluation and including chest

x-ray, electrocardiogram, urinalysis, and

blood studies. Patients began treatment on

the following Monday.

Drug Administration

Patients were randomly assigned to LAAM or

methadone. Methadone patients were continued

on their regular daily dosage of methadone,

unless an adjustment was required. Patients

assigned to LAAM received a first dose equal

to their previous methadone dose. After the

initial dose, adjustments could be made but

in no case could the dosage exceed 100 mg

TIW. Psychotropic drug use was discouraged

except for occasional sedation. All use of

supplemental medication during the trial was

recorded.

103
Initially the following three protocols were

used for the study: Protocol 1. Random

assignment to LAAM or methadone. LAAM group

receives LAAM three times a week at the

clinic. Methadone group receives methadone

daily, with take-home privileges as determined by the clinic; Protocol 2. Same as

Protocol 1, but no take-home privileges

for methadone group; Protocol 3. Random

assignment to LAAM or methadone. Methadone

group receives methadone daily. LAAM group

receives methadone MTWTH, LAAM on Friday, no

medication Saturday or Sunday.

Twelve investigators chose Protocol 1, three

close Protocol 2, and three chose Protocol 3

(one investigator chose both 1 and 3).

however, changes in clinic policy and the

resultant small number of subjects in

Protocol 2 led to the combined analysis of

patients in these protocols.

Clinical Evaluations

Evaluation was essentially identical to that

of the VA cooperative study described in the

preceding chapter except that urine testing

was done locally rather than in a central

laboratory.

Characteristics of the Sample

(Protocols 1 and 2)--The sample consisted of

636 men, with 308 maintained on methadone

and 328 maintained on LAAM 61% of the sample had been addicted to opiates for more

than five years. The mean age was 28.8 years

54% of the sample had graduated from high

school and 25% had gone on to college. 61%

of the sample were, or had been, married.

55% of the sample was white, 28% black and

15% had Spanish surnames. Almost two-thirds

of the sample was employed, and 54% worked

full-time. 73% had been in some form of

voluntary treatment program previously, but

only 20% had been in some form of involuntary drug treatment program. There were no

significant differences between the LAAM and

methadone groups.

The sample for Protocol 3 consisted of 136

men, 71 of whom were assigned to methadone

and 65 of whom were assigned to LAAM This

sample was somewhat older (mean age 31.3)

than the sample in Protocols 1 and 2, but

the other demographic characteristics were

similar. There were no significant differences between the LAAM and methadone groups.

Early Termination

(Protocols 1 and 2)--49% of the starting

sample completed the full 40 weeks of the

study. If all reasons for termination are

combined, 61% terminated early from the LAAM

group (N = 200) and 40% from the methadone

group (N = 122). This difference is statistically significant. Not all of these

patients terminated for drug related reasons

but since the nondrug related terminators

should have been equally distributed between

groups except for chance, it has to be concluded that methadone maintenance was superior to LAAM in retention, at least under the

conditions of an open comparison of an

approved and an experimental drug.

There was also a difference between the

length of stay in the study before early

termination. The average drop-out in the

LAAM group occurred after 72 days, whereas

the early terminator in the methadone group

dropped out after 122 days. 43% of the

drop-outs occurred before the ninth week,

with the LAAM group drop-outs occurring

earlier as well as more frequently than methadone group drop-outs.

Protocol 3. The pattern of drop-out was

remarkably similar for Protocol 3, although

there was a higher drop-out rate for both

groups. 44% of the total sample conpleted

the full 40 weeks of the study. 48% (N=34)

of the methadone group and 65% (N=42) of the

LAAM group dropped out early. This difference is statistically significant. The

average drop-out in the LAAM group occurred

after 81 days in the study, whereas the

average methadone drop-out occurred after

141 days.

It should be noted that there was a great

deal of variation in percentage and timing

of drop-outs between clinics, which suggests

that factors other than the drugs themselves

contributed to drop-out rates.

Table 1 presents the number of patients in

each group who terminated early for a variety

of reasons under Protocols 1 and 2. Table 2

presents the same data for Protocol 3.

The major differences between groups for

reasons for early termination were Medication

Not Holding (all three protocols) and Side

Effects, Psychiatric, Medical unrelated,

irritability, detoxification, and did not

like drug (protocols 1 and 2). In each

instance, there were more LAAM drop-outs than

methadone drop-outs.

SAFETY-TOXICITY

Protocols 1 and 2

Laboratory data, vital signs and weight were

obtained before treatment and every four

weeks during treatment. At each of ten test

104
TABLE 1

Reasons for Early Termination

(Protocols 1 and 2)

Reasons M L T

Medication not holding

Jail

Moved from area

Detoxification

Did not like study

Disciplinary discharge

Psychiatric

No show for 14 days

Excessive drug use

Side effects

Medical unrelated

Irritability

Did not like drug

Miscellaneous

Excessive alcohol use

Dose too high

Could not attend clinic

Abnormal laboratory value

Not eligible for inclusion

Death

Total

0 62 62

28 19 47

21 18 39

29 9 38

15 7 22

12 5 17

0 14 14

8 4 12

4 8 12

0 11 11

1 9 10

0 9 10

0 7 7

0 5 5

2 3 5

0 4 4

1 3 4

1 2 3

0 2 2

0 1 1

122 200 322

TABLE 2

Reasons for Early Termination

Protocol 3 (Friday only LAAM)

Reasons

Medication not holding

Detoxification

Jail

Moved from area

Disciplinary discharge

No show for 14 days

Medical unrelated

Excessive alcohol use

Did not like drug

Did not like study

Side effects

Psychiatric

Irritability

0

11

6

6

5

4

1

0

0

1

0

20

5

4

1

1

0

3

3

2

0

1

1

1

20

16

10

7

6

4

4

3

2

1

1

1

1

Total

Meth LAAM

0

0

Total

34 42 76

105
paints differences between the means of the

methadone and acetylmethadol groups were

evaluated by analysis of covariance with

adjustments for pretreatment value. Out of

250 such analyses (25 variables x 10 occasions) there were 35 significant differences

between adjusted means: WBC at week 8; RBC

at weeks 16, 20 and 24; basophils at week 8

and 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, uric

acid at week 32; albumin at weeks 4, 32 end

40; weight at week 4; systolic blood pressure

at weeks 8, 12, 16, 24, 28, 32, 36; diastolic

pressure at weeks 8, 20, 24. and 28. Most

impressive of those are hematocrit and hemoglobin and perhaps RBC end basophils. The

blood pressure results are of less interest

as far as LAAM is concerned because the

changes are essentially all due to increased

blood pressure in the methadone group with

little or no change in LAAM patients. The

other scattered differences between groups

(WBC, RBS, uric acid, albmin and weight) are

probably not of much clinical consequence.

On each of the ten occasions that blood was

drawn during treatment, the LAAM group

showed a statistically significant reduction

in hematocrit compared to their baseline

average. These changes were very small. The

largest average change was a drop of 1.53.

None of the tests of pre-post changes in the

methadone group were significant but except

for one test (week 40) the post mean was

always lower then the pre mean. These

changes were also small. In other words,

both groups showed reduction of hematocrit

values during treatment but the changes were

a little larger in the LAAM group. With

sample sizes of 100-200 in a group for all

tests, even very small differences can be

statistically significant. All of the mean

values of both groups at all times were

within the normal range. The LAAM group

tended to have somewhat higher values at pre

than the methadone group and this could contribute to the observed difference in

adjusted means. The changes across time are

not progressive, i.e., there is no discernable trend for continuing decrease in hematocrit as treatment progresses. Instead

there appeared to be an initial drop in the

first 4-8 weeks of treatment and a restabilization of average hematocrit at a somewhat

lower level then pretreatment. Essentially,

the same things can be said for the differences in hemoglobin.

The decrease in average hematocrit (or

hemoglobin) could be caused either by large

drops in a few patients or by smaller drops

in a larger number of patients. Review of

individual patients records did not identify

patients with dramatic and systematic changes

in these tests but there does seem to be a

pattern of small decreases by a fairly large

number of patients. Similar trends were

noted in both the methadone and LAAM groups

in the VA study. The current speculation

is that the introduction of a new drug

(methadone or LAAM in the VA study or LAAM

but not methadone in the SAODAP study)

causes some initial physiologic disturbance

which then stabilizes. It may be that there

is an association with weight gain i.e.,

fluid retention, or some other simple

explanation. In any case, there is no

corresponding clinical evidence of drug

toxicity and unless additional data (or new

analyses of existing data) are forthcoming,

these changes do not seem to be at all

alarming.

SAFETY-TOXICITY

Protocol 3

In Protocol 3, laboratory values were

obtained only at pre, week 12 and week 40.

Differences between the means of methadone

and acetylmethadol on these tests at week

12 were evaluated by analysis of covariance

with adjustments for pretreatment level

using all patients that had pretreatment

and 12th week values. Differences at week

40 were evaluated in the same manner. Out

of 40 such analyses (20 lab tests x 2

occasions), there were four significant

differences between adjusted means: WBC

at week 40, Random Blood Sugar at week 12,

Globulin at week 12, SGOT at week 12.

Vital signs and weight were obtained at pre

and every four weeks thereafter. These five

variables were analyzed in the same manner

at each of 10 occasions yielding 50 more

analyses of covariance. Only one of these

tests of adjusted means was statistically

significant: weight at week 20. These

variables were also analyzed by trend analysis across the 40 weeks as described in the

summary of the main study. There were no

between groups differences in any of these

analyses that reached a significant level.

SYMPTOM-SIGN RECORD

Protocols 1 and 2

Symptom-signs were examined individually in

a number of ways and in scoring clusters

established by factor analysis. In one

approach to individual evaluation of symptom-signs, the highest rating obtained

during treatment per patient was used as a

unit of analysis as described in the VA

10 6
study. To test differences between drug

groups, rating was dichotomized as None-Mild

andModerate-Severe. The following symptoms

were significantly different between groups.

Yawning

Runny nose

watery eyes

Muscle cramps

Goose bumps

Abdominal cramps

Nausea or vomiting

Insomnia

Excessive sweating

Irritability

Anxiety (tension,

nervousness)

Nodding

Impotence

Drowsiness

None

METH LAAM

181 147

151 126

170 128

169 128

182 150

177 122

186 127

118 73

114 93

134 108

118 86

262 255

255 249

195 191

Mild

METH LAAM

84 110

107 109

95 110

91 112

93 109

80 106

74 102

69 94

85 75

92 84

82 87

35 47

42 52

79 80

Other 203 180 36 40 40 62 29 45

Efficacy

The Discussion of issues involved in establisting eficacy of LAAM in the VA Cooperative Study applies equally well to the

SAODAP Cooperative Study. There are a number

of criteria of efficacy that can be used but

all have certain limitations or defects.

Generalization about efficacy from the VA

study has to be qualified because of the

fixed dose design and the induction schedule

which may have been too slow. In theory,

the SAODAP study does not suffer from this

particular problem because dosage was flexible after the first dose. However, any

suggestion that LAAM is a less effective

maintenance drug then methadone has to

consider how effectively this option to

adjust dose was exercized by the clinicians,

most of whom were initially inexperienced in

the use of LAAM. To the extent that dosage

was not individually optimized, LAAM could

be expected to appear somewhat less effective than methadone which is not only a

more familiar drug but was the drug on which

all patients were stabilized prior to the

study. Furthermore, the price paid in the

design of this study to provide for flexible

dosage was to drop the double-blind control.

Patients and staff were aware of the treatment assignment and this allowed for the

full effect of psychological factors associated with treatment with an unfamiliar

Moderate Severe

METH LAAM METH LAAM

40 58

47 80

40 77

42 75

29 60

44 80

43 82

97 119

92

69

126

105

3 12

3 12

3

6

12

12

4 8

7 19

5 16

24 41

17 33

13 30

87 109 21 45

9 21 2 4

8 21 3 5

29 45 5 11

experimental drug. Even if the effect of

psychological factors is discounted, retention rates on LAAM had to be influenced by

the fact that there was a clinical choice

possible with LAAM patients--they could stay

on LAAM or be switched back to methadone--

but this choice did not exist for methadone

patients--their only choice was to drop out

of maintenance altogether. Because of these

problems, the SAODAP cooperative study provides almost no useful information about

efficacy relative to methadone. The exception may be the urine index as defined in

the VA study. In protocols 1 and 2, 28 methadone patients had a urine index of 15.0

while 227 LAAM patients had an index of 14.9.

In protocol 3, 71 methadone patients had a

urine index of 19.9 while 65 LAAM patients

had an index of 16.2. Thus, in both

instances, LAAM had a slightly better (nonsignificant) index of illicit opiate use.

Another kind of outcome index is program

conformity, which is defined as each

patient's number of actual scheduled clinic

visits divided by his total expected scheduled visits for however long he was in the

study. In Protocols 1 and 2 the percentage

of clinic visits were essentially the same

with averages of 97.75% and 97.71% for the

methadone and LAAM groups, respectively. In

protocol 3, the methadone patients attended

97.24% of their scheduled clinic visits while

the LAAM group attended 97.49% of the time.

107
Still another evaluation of relative efficacy scale: much improved, unchanged, worse and

was possible using the global rating of out- much worse. In protocols 1 and 2, the mean

come, which was a combined staff judgment score for both groups was 2.96. In protocol

made shortly after a patient's termination, 3, the mean scores were 3.00 and 2.90 for

taking into account all known infomation the methadone and LAAM groups, respectively.

about the patient. This was a four point

AUTHORS

Affiliation of the authors of this article is

as follows: From the Veterans Administration

Hospitals, Sepulveda, California (Dr. Ling),

and Perry Point, Maryland (Dr. Klett and

Paderic Gillis).

108
PHASE III CLINICAL STUDY OF

LEVO-ALPHA-ACETYLMETHADOL

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

INTRODUCTION

The purpose of the Phase III trial of levoalpha-acetylmethadol (LAAM) is to establish

efficacy of this medication for the maintenance of persons addicted too opioids.

Also during the course of the Phase III

trials additional data relating to the

safety of LAAM will be obtained. It is the

intended purpose of the Phase III clinical

trials to provide sufficient information

to alllow the FDA to grant a New Drug Appliccation for LAAM.

The administrative stucture which has been

developed for these Phase III clinical trials

is intended to provide for a centralized drug

supply, data collection, and adminstrative

system with a maximun national clinical participation. Whysner Asscciates is the prime

contractor for NIDA and is responsible for

the Coordination of the Study which includes

filing of the IND application, medical supervision, review of results, administration

of all subcontractors, and development of

the final NDA application. Subcontractors

include the Vitarine Company, who will be the

formulator of the liquid concentrate, Friends

Medical Science Research Center, Inc., who

will provide data managemement and analysis

support, and approximately 50 methadone

clinics who will perfom the clinical trials

and provide the data for analysis. A Medical

Advisory Panel has been established which is

responsible for approval of the study protocol, analysis of any adverse reactions, and

review of the conclusions of the study.

The subject population will be approximately

6,000 men and woman over the age of 18 who

meet the current criteria for entrance into

methadone maintenance programs or who are

currently clients of such proqrarm. The

clinical trial will last up to 40 weeks for

each patient. Each clinic will participate

in one of two studies whichcc are being conducted as part of these Phase III trials.

In one study all patients will be put on

LAAM. In a second a random assignment

of patients will be made to LAAM or methadone

providing a comparative analysis of efficacy

and safety measures.

MEASURES OF EFFICACY

The proof of efficacy for maintenance of persons addicted to opioids may be defined as

the relief of abstinence over a prolonged

period of time when the drug is given on a

regular basis. There are three aspects of

the abstinence syndrome: drug seeking behavior, physiological, and psychological

changes. A drug such as LAAM must prevent

the development of abstinence inall three

areas. Therefore, measures of efficacy must

be aimed at measuring the signs and symptoms

of the develpment of abstinence in these

three areas.

The measure of drug seeking behavior can be

attempted through history taking, direct

measurement of illicit drugs in body fluids,

or assessment of the consequences of taking

109
illicit drugs. During the past several years

our ability to measure illicit drugs in body

fluids has been developed to the point where

these methods are both reliable and are a

regulaar part of the methadone program routine. Therefore, in the Phase III studies

this will be the most important measure of

drug seeking. Assessment of the use of illicit drugs through history taking or an independent measure of the consequences of

heroin use such as number of arrests, employment, etc. is not reliable or easy quantitrate.

SAFETY MEASUREMENTS

Physiological signs of abstinence will be

measured through the analysis of a synptomsign checklist. The components of the

checklist are well known parts of the physical abstinence syndrome; for example,

sweating, gooseflesh, and rinorrhea.

For the psychological componence patients may

became anxious, hostile, irritable, require

other drugs such as traquilizers, develop

other patterns Of drug abuse such as polydrug abuse, or adjust poorly to the social

and work environment. Many of these aspects

of psychological abstinence may be difficult

to measure; however, measures will be attempted. The Profile of Mood States will be

used to measure anxiety, hostility, and

irritability. Also questions involving

hours of emp1oyment, number of arrests, and

a global assessment Of client's progress

will be made.

There are no fixed scales against which efficacy can be measured. It is not known

what is an acceptable level of abstinence

or what are acceptable drug seeking, physiolcgical or psychological changes. Therefore, a heavy reliance must be made on comparative measures with a control group.

The only applicable control group for this

study would be persons who are currently on

methadone maintenance therapy. Comparisons

of the efficacy and safety measures will be

made between the methadone and LAAM patients

in part of the Phase III study.

Another determinant of an acceptable level

of abstinence would be the willingness of

the participant to stay on the drug. If one

can make the assumption that remaining on

the drug is the equivalent of efficacy,

dropout rates are very useful. The reason

for dropout and a judgment by the clinic of

wheter such a dropout is drug related will

be determined. Only those dropouts which

are drug related such as side effects, feelings of under medication on weekends,etc.

will be used as efficacy measures. However,

dropping out of the study to attempt detoxificationn would be viewed as a positive

result.

Previous Phase II clinical studies have indicated that for a 40 week period LAAM does

not cause any consistent abnormalities in

the CBS, SMA-12, urine analysis, EKG, or

EEG which would be cause for concern. However, these Phase II studies have only been

accomplisked on 170 males for 40 weeks.

Therefore, it is desirable to test a large

number of males and femailes to determine if

there are any untoward reactions which occur

on a low frequency basis. It is hoped that

the Phase III studies will include approximately 2,000 patients om LAAM for 40 weeks.

This should test enough individuals to give

an estimate of the incidence of adverse reactions to the medication.

Another problem which must be studied during

Phase III is the use of other medication

concurrently with LAAM. It is known that

drug interactions may occur which would

either potentiate or preventthe effective

action of narcotics. me use of both prescription and illicit drugs may have untoward interactions effects. Although it has

been suspected that certain other drugs my

interact favorably, not enough patients have

been studied to gather any quantificable

data. In the Phase III studies the use of

all medications will be documenteds and the

possibility of any drug interactions will be

investigated thoroughly.

OPEN VERSUS BLIND STUDY

The use of any maintenance drug for the

treatment of heroin addiction has a strong

subjective component to its effectiveness

for both the patient and the physician. A

double-blind study is designed to eliminate

the impact of these subjective effects om

the outcome of the study. Double-blind

studies have been used in the past to compare the effectiveness of LAAM to methadone

and the results of these studies have been

described elsewhere. There are several

reasons for which the Phase III study has

been designed as an open rather than a

double-blind study. These are the following:

1. The primary advantage of using LAAM instead of methadone is the need for only

three day a week pickup. If a doubleblind study was done a schedule of

either daily pickup or of three day a

week pickup would be necessary in both

LAAM and methadone groups. This would

negate the scheduling effect of LAAM.

110
2 . The large number of patients needed for

the phase III study and the use of multiple clinic sites makes the logistical

problems associated with such a study

very difficult.

3 . A double-blind study may adversely effect

the efficacy of either methadone or LAAM

in an unpredictable way. The patient

population is very anxious concerning

the medication they are receiving and

about participation in a clinical study.

One of the greatest difficulties encountered in the PhaseII study was that

the efficacy results had a large number

of patients who dropped out because of

the nature of the study rather than the

drug

4. The blind is difficult to keep because

patients and physicians would be able

to break the code due to the subjective

effects of the drug.

USE OF LAAM IN FEMALES

The Phase III study will be the first largescale use of this drug in femles. A small

group of famales was tested before the FDA

restrictions on the use of LAAM. During the

course of the Phase II studies there was a

study of seventeen females of non-childbearing potential. The use of LAAM in females

at this stage is essential,otherwise another

large-scale study in females would need to

be canstructed. It is currently being decided whether or not some females should be

AUTHOR

John A. Whysner, M.D., Ph.D. is president of

John Whysner Assciates, Inc., 2600 Virginia

Avenue, N.W. Suite 209, Washington, D.C.

20037.

given LAAM througout pregnacy or whether

all woman who become pregnant while on LAAM

should be switched to methadone. The arguments on both sides of this question are

valid. The use of LAAM through pregnancy

would mean exposing pregnantfemales and neonates to a new drug with which the medical

community is unfamiliar. However, LAAM may

prove to be a drug with fewer problems in

the pregnant female and the neonate than does

methadone. The long duration of action of

LAAM may make the neonatal withdrawal syndrome less severe.

CURRENT STATUS OF THE STUDY (MARCH, 1976)

The current planning for the Phase III study

of LAAM has been almost completed. The

final study design, forms, data management

system, formulation of the drug, and analysis have all been in progress and should be

completed within a couple of months. It is

anticipated that the Phase III study will

begin in the Spring of 1976 and that induction of these patients will be completed by

the Fall of 1976. An additional 40 week

period will be needed for the follow-up of

the last patients included in the Study and

time will need to be available for the final

data analysis and collection. Therefore, it

is anticipated that the Phase III study will

be completed late in 1977. Hopefully by

that time of the other animal and human

data will be comleted to allow the award of

a NDA for LAAM. Therefore, beginning in

1978 there may be another maintenance treatment modality available for the treatment

of heroin addiction.

111
Dr. Cooper is Special Assistant to the Director of

NIDA's Division of Commmunity Assistance (DCA). He

has been its liason to the Division of Research

during Phase II and III of the LAAM studies. Beyond

Phase III DCA will continue to OVersee NIDA-funded

LAAM treatment programs. Like methadone, LAAM

will be dispensed only through licensed narcotic

maintenance programs. Once LAAM's New Drug Application is approved, responsibility for continous

monitoring of treatment programs will pass from

NIDA's Division of Research to the Division of

Community Assistance.

THE USE OF LAAM IN TREATMENT

James Cooper, M.D.

The purpose of this chapter is to present the

National Institute of Drug Abuse, Division

of Community Assistance’s (DCA), perspective

on the usefulness of LAAM as a maintenance

drug in the treatment and rehabilitation of

opiate addicts. One of the major responsibilities of the DCA is to administer, monitor,

evaluate and establish treatment standards

for all National Institute of Drug Abuse

funded treatment programs. It will become

the Division’s responsibility to oversee

those Federal programs which will administer

and dispense LAAM once the drug has received

a New Drug Application (NDA) and is marketed.

In order to understand our current thinking

regarding the utility of a maintenance drug

in the treatment of narcotic dependence, it

is important to review, from a historical

perspective, methadone maintenance treatment

over the last ten years. Initially, there

was a tendency to view the addict simply as

a person afflicted with a metabolic problem

or disease. Methadone was prescribed to

treat the symptoms of this chronic metabolic

disease. In this model, methadone was

analagous to insulin for diabetes and so

perceived as a life-saving treatment. In the

same model, LAAM would be similar to a longacting form of insulin that relieved the

patient of the need for frequent dosing.

In the early stages of development, the

methadone clinic emphasized the physician/

client relationship and cast the physician

in a primary decision-marking role. The

medication was considered the primary treatment and the understanding of its properties

and actions was deemed of utmost importance

to staff and the client.

However, it was appreciated from the

beginning that although methadone corrected

a biological condition by medically stabilizing the addict, this was only one part

of the treatment. Pharmacological treatment

was only one factor in a program which

should include counseling as well as supportive services such as legal vocational

and educational counseling. These supportive

services were believed necessary to provide

the addict with the skills he may never have

developed or had lost during his addiction.

In the following years there was a rapid

proliferation of methadone maintenance

clinics, due to the heroin epidemic of the

late 60's and the success of this prototype

treatment. Unfortunately, the speed of

proliferation and the great number of addicts

needing treatment overwhelmed the treatment

capacity. The need for supportive services

also outstripped available resources, as a

result, treatment effectiveness declined.

In the last several years more knowledge has

accumulated from treating larger and more

diverse populations of addicts. The model

112
has been made more comprehensive with awareness that individualized treatment is needed

which recognizes the unique psychological

characteristics of each addict. Most clinicians have come to view methadone as a stabilizing treatment tool which can be effectively used to engage the client in broader

rehabilitation. Once this engagement occurs,

an individualized evaluation and provision

of appropriate treatment services can proceed. Many, now believe that these services

are the primary rehabilitative tool for

most clients.

This gradual shift in emphasis was a result

of our better understanding of the diversity

of the people applying for treatment. The

only common trait shared by all is that they

are narcotic users and are dependent upon

opiates. Those who make up this population

have different reasons for initiating drug

use, exhibit different patterns of drug use,

relapse for different reasons and have widely

differing experiences as a result of their

drug using behavior. The Division’s experience has demonstrated that the etiologies of

addiction are diverse and complex. While

under-education, unemployment, racial or

ethnic discrimination and environmental

stress may result in drug-taking behavior

for some, other psychodynamic factors

including excessive dependency needs, a

compulsive desire to escape from reality and

a lack of poor coping mechanisms for stress

play an important role in addiction for

others. Further, total abstinence from

drugs may not be a realistic goal for all

drug abusers. Thus, the objectives of

treatment have become more complicated and

achievement of the goals sometimes become

more elusive.

With the knowledge gained from experience,

DCA is currently encouraging all maintenance

programs to develop the resource capabilities

for treating a diverse population. Such a

heterogeneous group requires a number of

distinct treatment, rehabilitative and

resocialization approaches. Pragmatically

this entails that a program have the capabilities of providing legal, vocational, educational, psychological and medical services

either within the program or through referral

sources.

The diversity in the treatment population

has resulted in wide variation as to the

length of time an individual receives methadone and the intensity of the counseling

intervention. Some patients only want detoxification or short-term maintenance, while

others may need or request long periods of

maintenance and services. The well-run

clinic usually will have some clients who

are receiving methadone and very low-key

programming either because the initial

assessment of the client revealed that they

could not tolerate intensive psycho-social

intervention or because there was no indication of need for such service. However,

many other clients will require varying

degrees of psycho-social and vocational

intervention based on the client’s past and

current behavioral performance.

Each program has been encouraged to view

each patient as a unique individual with

his own personal combination of strengths

and weaknesses which must be continually

assessed in order to tailor a treatment

regimen appropriate for each patient.

The Federal Funding Criteria for Drug Treatment Services was developed in part to

insure that this individualized approach be

incorporated by all Federally-funded programs. One section of the Federal Funding

Criteria requires that an individualized

treatment plan be developed for each patient

and that periodic evaluation of the plan

occur. Such a requirement should provide

the staff with an instrument to insure that

(1) each patient’s strengths and weaknesses

are assessed, (2) a determination is made

of the appropriate types of supportive

services needed (if any) and (3) the extent

of counselor involvement necessary to meet

the objectives of the treatment plan is

ascertained. The ongoing individual evaluative process will provide the staff with a

periodic testing and redefining of the

patient’s progress (or lack of progress)

and encourage the counselor to search for

the contributing dynamics of the patient’s

success or failure.

Although the advent of LAAM may not introduce treatment changes, for some patients

and programs, LAAM may provide some distinct

pharmacologic and therapeutic advantages to

methadone based on existing clinical studies.

The 1975 White Paper on Drug Abuse produced

by the Domestic Council Drug Abuse Task

Force recommends "switching from methadone

to LAAM...in treating opiate-dependent persons as soon as its safety and efficacy

have been determined." This recommendation

is based on the potential benefits to programs and patients of three times a week

dosage. Some of these benefits are: less

drug diversion into illicit channels; more

cost-effective treatment; and less interference with patients’ daily work schedules,

education and rehabilitation efforts or

responsible homemaking.

113
Several other potentially advantageous therapeutic characteristics of LAAM have been

observed. Among them are that LAAM helps

change the individual’s and clinic’s focus

from daily preoccupation with drugs and drugtaking to an emphasis upon human relationships and development of alternative activities, life style and peer group relationships. Furthermore, LAAM’s smoother,

sustained, drug effect apparently allows some

individuals to feel more alert, more emotionally level, less "high", and less habituated.

It’s longer duration of action may allow

LAAM to be used for detoxification from

methadone maintenance or heroin. Clinicians

have noticed that some patients appear to be

able to detoxify from LAAM maintenance

easier than from methadone maintenance. This

Division will watch the Phase III LAAM

Studies closely to determine if these observations/findings are substantiated in the

larger population to be studied in Phase III

large scale clinical trial.

The availability of two maintenance agents

may provide for increased treatment flexibility. For example, Sequential Treatment

Employing Pharmacologic Support (STEPS) has

been proposed by Dr. Avram Goldstein as an

alternative treatment method. STEPS is

characterized by sequential use of a variety

of pharmacologic agents each progressively

decreasing narcotic induced euphoria and

increasing social rehabilitation. The STEP

from daily methadone to three times weekly

LAAM would represent a safe and very stable

opiate dependence with virtually no subjective euphoria and less dependence on the

clinic. This novel approach would naturally

have to be investigated with a limited

number of individuals to determine its

effectiveness but does provide a potential

alternative, particularly for those who have

been unsuccessful in remaining abstinent

following a particular maintenance regime.

The Division of Commmunity Assistance does

not currently anticipate that LAAM implementation will lead to dramatic alteration in

the current Federal opiate addiction treatment policy or philosophy. LAAM appears to

be an alternative to, rather than a replacement for, methadone. Some individuals do

better on one or the other drug, probably

due to either pharmacological, psychological

or social factors not yet understood.

Furthermore, LAAM is not viewed as a pharmacologic panacea for all opiate addicts. No

known drug, including LAAM, can cure or

alleviate psychosocial and economic impoverishment. For some opiate addicts, LAAM, like

methadone, may be the primary treatment.

For others, temporary pharmacotherapeutic

stabilization will act merely as a tool to

engage the narcotic-dependent individual

into participation in a comprehensive

treatment program, concomitantly utilizing

extensive psychological socio-economical and

vocational rehabilitation services. And

others may require no pharmacological support at all. LAAM provides one more choice

in tailoring treatment to each individual’s

needs.

114
The following article is from a transcript

of remarks given by Dr. Avram Goldstein at

NIDA, Rockville, Maryland, May 19, 1976.

A CLINICAL EXPERIENCE WITH LAAM

Avram Goldstein, M. D.

I would like to discuss our clinical experience with LAAM. Several years ago we did a

pilot trial with LAAM in the Santa Clara

County Methadone Program with about 60

patients. Some of them were Put directly onto LAAM, off the street, so we had that

experience; and others crossed over from

methadone to LAAM. Now in the last year we

have put 165 addicts directly off the street

onto LAAM. So that my remarks here are based

on this accumulation of experience.

PHARMACOLOGY

There is the pharmacology issue. That’s

turned out, I think, to be the most interesting part of our experience with LAAM. Let

me start by stating that: I think LAAM is a

better drug than methadone, from a pharmacological point of view. I think patients know

that and understand it too. Let me describe

what I mean.

Now, in pharmacology, quite apart from any

regulatory questions or the issue of diversion,

in the development of any drug, one of the

important objectives is to get a lasting

stable effect. I need only refresh your memory about the history of insulin. As you

know the early insulins had to be admininistered several times a day. It was a very

tricky operation, because when you gave the

insulin, you got too much insulin effect;

then it wore off and you had too little

insulin effect. The problem was to stablize

things so that there would be a lasting effect

of insulin in the patient. Tremendous effort

was directed toward developing a long-acting

insulin which you could give once a day to get

stable coverage. Finally that was achieved.

For almost every drug there is the same problem of developing stability of action, so that

there will not be fluctuation up into the toxic range and then down below the therapeutic

range.

Now, let's look at methadone in those terms.

Methadone is a tremendous improvement over

heroin! which has to be administered four or

five tunes a day, giving continual highs and

lows. That's why methadone was introduced, of

course. Nevertheless, you all know that when

patients come in, in the morning, for their

methadone, many are at the very edge of withdrawal; they feel "icky" (as they say). You

also know that after they take their methadone,

within the next hour or so, they feel it hit

them; they feel a sense of warmth that starts

in the abdomen and spreads through the body.

They're getting partially "loaded" every morning with methadone, and they’re partially

115
"sick" every morning before they get their

methadone. That's not a comfortable condition to be in, but they’re a lot better off

than they were when they were using heroin.

The lasting effect that LAAM produces makes

the patients feel better. Every patient I’ve

spoken to who has been on both methadone and

LAAM remarks on this--how he feels just generally better--more under control, more stable

less of this up and down. And they don’t feel

sick at the end of the period.

Now, if patients have enjoyed the feeling of

methadone relieving an incipient withdrawal!

and if that’s been an important part of their

daily pattern, transferring their getting

high on heroin to getting drug-induced satisfaction once a day on methadone, then they’re

not going to like LAAM; there is no question

about it. Some patients really want that

feeling on methadone, so that in the long run

we're probably not going to just replace

methadone with LAAM. There are going to be

patients who need that feeling and it may take

them a long time before they’re ready to-give

it up. But there are also a lot of patients

who don’t want that. who are really willing

to make the transition and give up that sensation, and those patients much, much prefer

to be on LAAM.

The So-Called "Week-end Problem"

Let me give you an example of a pseudoproblem

that turned out not to exist with LAAM. In

some places LAAM was introduced as "48-hour

methadone". The patients, who are by no means

stupid, immediately thought, "Well, if it’s

a two-day methadone, then how will I get

through the weekend? I’ll be sick on Monday

morning." And they were sick on Monday morning ! But LAAM actually has a very long duration of action, at least over a three- to fourday period. Without going into the complicated pharmacokinetics, that means if you get

the dose of LAAM on Monday you’re in a stable

state when you come in Wednesday morning.

That Monday dose hasn’t disappeared; it is

picked up and carried along by the Wednesday

dose and that is picked up and carried along

by the Friday dose, and on Monday morning the

effect of the Friday dose is still there. In

other words, you’re getting a stable effect.

We have some very interesting data on that.

To have you understand the data, I will have

to tell you the way we control dosage. Dosage is self-controlled by patients, who follow

the same principle we described in that article about patient control of methadone dosage (J. Amer. Med. Ass. 234:734, 1975). The

absolute ceiling is 75 mg. of LAAM on Monday

and Wednesday, 100 mg. on Friday. Now up to

that ceiling patients can set their own dosages. Our rule is that on Friday the patient

is allowed to increase, if he wants to, by

about 30%. Thus, if he is taking 75 he can

increase to 100, if he is on 50 he can raise

it to 65, and so on.

The question is, with that opportunity, do

patients actually do it? Now, obviously, if

they felt sick on Monday morning, they would

raise their Friday dose to try to take care

of that feeling of being sick. The interesting thing we found is that the great majority

of patients do not make any increase in their

Friday dose; in other words, they’re voting

that the LAAM takes care of them over the

weekend. About one-third of the patients do

make a Friday increase of varying degree.

The average increase on Friday is very small,

but some patients do take full advantage of

the opportunity. This result tells us that

the "weekend problem" is largely a non-problem,

as long as anxiety is minimized. If the staff

is worried that LAAM is not going to last

through the weekend, and conveys their anxieties to the patient, then you get this tremendous psychological effect.

Patient Reaction to LAAM

If you ask our patients: "How do you like

LAAM," they vote affirmatively. I have not

known an exception to that. Some of the

patients who have experienced methadone in

the past prefer LAAM; others have never

experienced methadone and have nothing to

compare it to but they feel that it "holds"

them in a stable way. Our experience with

the laboratory data has been the same as in

the Phase II study. We don't find any significant abnormalities in all of the careful

checks that we have been making. Efficacy is

very good, as measured by suppression of

heroin use. It's as good or better than

seen in methadone clinics in our area.

Finally, we have been pleasantly surprised to

to find, at least in some patients, that LAAM

can be discontinued with less discomfort than

we were used to with methadone withdrawal.

There is still the problem of anxiety exacerbating withdrawal problems for some patients,

and there are certainly patients who have the

usual problems with withdrawal (especially

insomnia, as with methadone withdrawal). We

have observed some patients, however, who

simply stopped taking LAAM at a dosage of 50

mg or above, and experienced no withdrawal

symptoms at all. It is possible that the long

duration of action and the long persistence of

the LAAM metabolites in the body produce a

situation in which the drug detoxifies itself

(so to speak), tapering itself over a long

116
enough time to minimize any acute withdrawal

distress. This requires more research, however; we are not now claiming that most

patients can detoxify more easily from LAAM

than 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 outset that takehome just doesn't arrive; it's

not in the cards. We never use any methadone

on the premises--exclusively LAAN consumed

right there. For patients who are to be away

for a while, we have had no difficulty at all

in substituting methadone (e.g., by arrangement at a clinic in another city) and then

resuming LAAM when they return.

There is a remarkable consequence of this

policy. You may not realize how much of the

unpleasantness and hassle in your clinic

operation is related to the issue of takehome

privileges, and how much of the deceit and

gameplaying, manipulation and wasted staff

time and energy and argumentation is related

to that issue of takehome. It corrupts the

urine collection system. As long as takehome

depends on clean urines, you really cannot

trust the urine collection, because it pays

to cheat. It doesn't make any difference if

it’s called an "observed" urine collection

or not. The potential for cheating and corruption is always there. With LAAM, suddenly, all that disappears. There is a quite

incredible change in the whole attitude of

the clinic. There is just no more argumentation about things like that. Patients level

with their counselors about their drug use,

and urines can be believed. I think it’s

fair to say that an awful lot of staff time

and energy is wasted otherwise. This time

and energy can now be devoted to patient

welfare and to effective counseling, once

you eliminate the takehome business and

everything that goes with it. Unfortunately,

I don’t know how to measure these effects;

they are major effects; everybody on our

staff is convinced of that, but I don’t know

how to produce objective data to prove it,

so I can only report it anecdotally to you.

I think it is one of the major advantages

of LAAM.

AUTHOR

Dr. Avram Goldstein is Director of the

Addiction Research Foundation, 701 Welsh

Road, Palo Alto, California, 94304.

117
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