NARCOTIC

ANTAGONISTS:

NALTREXONE

PROGRESS REPORT

Editors

Demetrios Julius M.D.

Pierre Renault, M.D.

Division of Research

National Institute on Drug Abuse

September 1976

NIDA Research Monograph 9

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

Public Health Service

Alcohol, Drug Abuse and Mental Health Administration
areas and techniques, the content of state-of-the-art conferences,

integrative research reviews and significant oriainal research. Its

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

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.

Helen Nowlis, Ph.D.

Lee Robins, Ph.D.

Addiction Research Foundation

Palo Alto, California

College of Physicians and Surgeons

Columbia University, New York

Langley Porter Neuropsychiatric Institute

Unversity of California

San Francisco, California

Department of Psychology, UCLA

Los Angeles, California

Alcohol and Drug Abuse Research Center

Harvard Medical School

McLean Hospital

Belmont, Massachusetts

Office of Drug Education, DHEW

W ashington, D.C.

Washington 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

Rockwall Building 11400 Rockville Pike Rockville, Maryland, 20852
NARCOTIC

ANTAGONISTS:

NALTREXONE

PROGRESS REPORT
ACKNOWLEDGMENTS

The editors wish to thank the National Academy of Sciences’

Committee on Problems of Drug Dependence for graciously encouraging the inclusion of a Satellite Conference on Naltrexone into its 38th Annual Scientific Meeting held in

Richmond, Virginia on June 7th to 9th, 1976. They would

like to thank Mr. Alex Bradford and his staff at Biometric

Research Institute for masterfully organizing the successful naltrexone conference. It was from this conference,

and the enthusiastic response and well conceived papers of

the participants, that this research monograph was derived.

DHEW publication number (ADM) 76-387

Library of Congress catalog card number 76-40692

This document is for sale by National Technical Information Service

Springfield, Va. 22161

Order number: PB 255 833. Papercopy: $7.50; Microfiche: $2.25

i v
FOREWORD

The Conference on naltrexone reported here represents another step in a

carefully designed plan to develop better treatment methods for opioid

dependence. The early theoretical foundations for the use of antagonists

were laid down by Abraham Wikler in 1955, when he postulated that physical

dependence on opioids provided a continually recurring “synthetic” need

that was readily satisfied by the use of opioids, that withdrawal phenomena could be conditioned to environmental stimuli, and that such conditioning played an important role in relapse to drug use long after drug

withdrawal was completed.

A decade elapsed before these views on the role ofopioids in the reinforcement of drug seeking behavior and of conditioning could be applied to

treatment in a practical way. In a series of papers, beginning in 1965,

William Martin and his co-workers at the Addiction Research Center at

Lexington, Kentucky, presented the clinical pharmacology of cyclazocine,

a long-acting, orally effective narcotic antagonist, and suggested the ways

in which drugs like cyclazocine might be used in treatment. In essence,

Martin and his colleagues pointed out that cyclazocine would block the

effects of acutely administered opioids, that when cyclazocine was given

daily even chronicopioiduse would not produce physical dependence, that

tolerance did not develop to the antagonistic effects of cyclazocine,

and that cyclazocine itself (while not as aversive as nalorphine), was not

a drug likely to be abused. Thus, chronically administered cyclazocine

had the potential of 1) blocking the positive reinforcement of drug seeking behavior permitting extinction to occur; 2) preventing the development

of physical dependence, thereby eliminating relief of withdrawal as a

source of reinforcement; and 3) preventing readdiction, permitting the

phenomena associated with protracted withdrawal to undergo a gradual resolution. Lastly, the use of antagonists might prevent death from narcotic

overdosage even if it did not eliminate drug seeking behavior.

The question of whether opioid addicts would voluntarily accept treatment

with a drug like cyclazocine, which promised nothing other than to prevent

them from feeling the effects ofopioiddrugs, was quickly answered. Jaffe

and Brill in 1966 and Freedman et al. in 1967, reported their experiences

with heroin addicts who volunteered to participate in treatment programs

centered around the use of cyclazocine. It was apparent that there did

exist a group ofopioid dependent individuals who, at some point, were

motivated to become totally independent of the need for opioid drugs.

v
However, several problems became apparent in these early clinical studiesproblems which are not yet entirely resolved, but which led directly to

this conference and to our present state of knowledge. First, most of

the subjects who volunteered for treatment with cyclazocine frequently

neglected to take the drug on a regular basis; most dropped out of treatment within a few months, and by the time they were contacted many had

relapsed to regular opioid use (usually heroin). Second, many addicts

discontinued treatment complaining of the unpleasant side effects that

cyclazocine produced. While such complaints often seemed to the investigators to be rationalizations, from a practical point of view it was difficult to persuade patients to continue with treatment. In order to test the

conditioning theory and to determine if antagonists could play a useful

role in treatment, better antagonists were needed, i.e., drugs that were

freer of side effects and drugs that would have such a long duration of

action that daily ingestion would be unnecessary. It was apparent that this

was primarily a technological problem, and one that given time and money

could be solved.

Thus, by 1967 the basic strategy that would be required to test the utility

of narcotic antagonists in the treatment of opiate dependence was largely

shaped. Although Freedman and Fink and their co-workers continued to

explore the possibilities of using high doses of oral naloxone, a relatively

pure antagonist, most investigators felt that its short duration of action

and relative ineffectiveness by mouth limited its usefulness. In that

same year, 1967, Blumberg and his colleagues reported on the effects in

animals of a new oxymorphone-derived antagonist, EN-1639A, later to be

called naltrexone. Naltrexone seemed to be the sought after antagonist--

relatively free of agonistic activity, and with a longer duration of action

than noloxone. Although the formal archival publications did not appear

until 1973, at the 1971 meeting of the NAS/NRC Committee on Problems of

Drug Dependence Martin, Jasinski and their co-workers reported that in

post-addicts naltrexone was orally effective, long-acting and relatively

free of side effects.

The effort to move naltrexone from these preliminary observations on a

few patients at the Addiction Research Center at Lexington to the hands of

clinical investigators where its efficacy might eventually be tested was

given sudden acceleration when President Nixon created the Special Action

Office for Drug Abuse Prevention (SAODAP) on June 17, 1971. Along with

this office, established within the Executive Office of the President,

came both the economic resources and the influence needed to speed up the

development of narcotic antagonists. As the first director of SAODAP, I

regarded the development of naltrexone as one of my high priorities.

However, even if I had not felt that the development of naltrexone was

worthwhile, I would have felt obliged nevertheless to bend every effort

toward its clinical development. Influential members of Congress had

become enthusiastic about the possibility of a non-dependence producing

pharmacological alternative to the use of methadone. The Congress included

in the legislation creating SAODAP a section on the development of antagonists along with appropriations to be used specifically for such development.

v i
There have been numerous stumbling blocks along the way. Some of them

related to supplies of thebaine, the precursor used in the manufacture

of naltrexone, and the limited production of the drug. In addition, not

wanting to place all bets on a single drug, SAODAP initiated research

with other antagonists; and recognizing that eventually even the two to

three day duration of action of naltrexone would prove to be too short,

SAODAP also initiated the effort to develop long-acting depot preparations.

Ultimately, money, people and experimental designs were combined in a

manner required to produce the products and the data.

At various times over the past decade, as the effort to test the utility

of antagonists progressed, I pointed out that despite their great theoretical promise, antagonists might prove to be of value for only a limited

subgroup within the opioid using population. Yet, each of those times

there seemed to be little alternative to getting on with the effort to

subject antagonists to careful clinical testing and the resultant data to

rigorous and objective analysis. Some of the results of this long term

effort are presented here.

Jerome Jaffe, M.D.

College of Physicians and Surgeons

Columbia University, New York

vii

CONTENTS

31

5

12

16

2 7

v

1

THE FEDERAL ROLE IN NALTREXONE DEVELOPMENT

NIDA'S NALTREXONE RESEARCH PROGRAM

Demetrios Julius, M.D.

REQUIREMENTS FOR DRUG DEVELOPMENT

Edward C. Tocus, Ph.D.

PRECLINICAL TOXICITY STUDIES OF NALTREXONE

Monique C. Braude, Ph.D. and J. Michael Morrison, M.S.

THE EFFECTS OF NALTREXONE IN THE CHRONIC SPINAL DOG AND ACUTE SPINAL CAT; POSSIBLE

INTERACTION WITH NATURALLY - OCCURRING MORPHINE-LIKE ANTAGONISTS

William Martin, M.D., James Bell, Ph.D., Paul Gilbert, Ph.D., Jewell Sloan, B.S.,

James Thompson

INTRODUCTION

Pierre Renault, M.D.

Foreword

Jerome Jaffe

THE DEVELOPMENT OF SUSTAINED ACTION PREPARATIONS OF NARCOTIC ANTAGONISTS

Robert E. Willette, Ph.D.

THE NAS DOUBLE-BLIND STUDY

67

70

74

77

EVOLUTION OF THE NATIONAL ACADEMY OF SCIENCES STUDY OF NALTREXONE

Samuel C. Kaim, M.D. 37

PHILOSOPHY AND STATUS OF THE NAS CENA STUDIES

Leo E. Hollister, M.D. 45

VARYING CLINICAL CONTEXTS FOR ADMINISTERING NALTREXONE

Marc Hurzeler, M.D., David Gewirtz, M.S., Herbert Kleber, M.D. 48

PATIENT RESPONSE TO NALTREXONE: ISSUES OF ACCEPTANCE, TREATMENT EFFECTS AND FREQUENCY

OF ADMINISTRATION

Stephen Curran, M.A., and Charles Savage, M.D.

NALTREXONE IN METHANE MAINTENANCE PATIENTS ELECTING TO BECOME "DRUG FREE"

Neil Haas, M.D., Walter Ling, M.D., Elaine Holmes, Ph.D., Mara Blakis, M.D.,

Margaret Litaker, MSW

COMMENTS AND FINDINGS FROM A NALTREXONE DOUBLE-BLIND STUDY

John Keegan, M.A., Carol Lavenduski, A.C.S.W., Kenneth Schoof, M.D.

FACTORS INFLUENCING SUCCESS IN AN ANTAGONIST TREATMENT PROGRAM

Sadashiv Parwatikar, M.D., FRCP (C), James Crawford, M.S., John V. Nelkupa,

Chona DeGracia, M.D.

ix
THE NIDA CLINICAL STUDIES

A POINT OF VIEW CONCERNING TREATMENT APPROACHES WITH NARCOTIC ANTAGONISTS

Richard B. Resnick, M.D., and Elaine Schuyten-Resnick, M.S.W.

CLINICAL EXPERIENCE WITH NALTREXONE IN 370 DETOXIFIED ADDICTS

Muriel Thomas R.N., Frank Kauders, M.D., Marcel Harris, Judy Cooperstein, R.N.,

Gordon Hough, Ph.D., Richard Resnick, M.D.

NARCOTIC ANTAGONIST TREATMENT OF THE CRIMINAL JUSTICE PATIENT - INSTITUTIONAL VS

OUTPATIENT - INCLUDING A 24-HOUR DETOX NALTREXONE INDUCTION REGIMEN WITH ORAL MEDICATION

Leonard Brahen, Ph.D., M.D., Victoria Wiechert, MPS, Thomas Capone, Ph.D.

USE OF NARCOTIC ANTAGONISTS (NALTREXONE) IN AN ADDICTION TREATMENT PROGRAM

David Lewis, M.D., Ronald Hersch, Ph.D., Rebecca Black, Ph.D.,

Joseph Mayer, Ph.D.

AN ANALYSIS OF NALTREXONE USE - ITS EFFICACY, SAFETY AND POTENTIAL

Ralph Landsberg, D.O., Zebulon Taintor, M.D., Marjorie Plumb, Ph.D.

Leonard Amico, B.A., Nancy Wicks, B.S.

CLINICAL EFFICACY OF NALTREXONE: A ONE YEAR FOLLOW-UP

Richard Resnick, M.D., Michael Aronoff, M.D., Greta Lonborg, M.A.,

Richard Kestenbaum, Ph.D., Frank Kauders, M.D., Arnold Washton, Ph.D.

Gordon Hough, Ph.D.

THE NIDA BEHAVIORAL STUDIES

THE THEORETICAL BASIS OF NARCOTIC ADDICTION TREATMENT WITH NARCOTIC ANTAGONISTS

Abraham Wikler, M.D.

LIMITATIONS OF AN EXTINCTION APPROACH TO NARCOTIC ANTAGONIST TREATMENT

Roger E. Meyer, M.D., Mary Randall, M.S., Cecily Barrington, B.A.,

Steven M. Mirin, M.D., Isaac Greenberg, Ph.D.

NALTREXONE IN A BEHAVIORAL TREATMENT PROGRAM

Charles P. O'Brien, M.D., Ph.D., and Robert Greenstein, M.D.

CLINICAL EXPERIENCE WITH NALTREXONE IN A BEHAVIORAL RESEARCH STUDY

Robert Greenstein, M.D., Charles O'Brien, M.D., Ph.D., Jim Mintz, Ph.D.,

George E. Woody, M.D., Nancy Hanna, B.A.

COMPARISON OF TWO NALTREXONE TREATMENT PROGRAMS: NALTREXONE ALONE VERSUS NALTREXONE

PLUS BEHAVIOR THERAPY

Edward Callahan, Ph.D., Richard Rawson, Ph.D., Michael Glazer, M.A.,

Beverly McCleave, B.A., Richard Arias, B.A.

NALTREXONE IN THE MANAGEMENT OF HEROIN ADDICTION: CRITIQUE OF THE RATIONALE

Avram Goldstein, M.D.

CURRENT STATUS OF NALTREXONE SAFETY DATA

84

88

93

99

106

114

120

123

136

141

150

158

INTERIM REPORT ON CLINIC INTAKE AND SAFETY DATA COLLECTED FROM 17 NIDA-FUNDED NALTREXONE

STUDIES 163

H. Alex Bradford; M.S., Frank L. Hurley, Ph.D., Oksana Golondzowski,

Catharine Dorrier

AGENDA - NAS - NIDA SATELLITE CONFERENCE ON NALTREXONE 172

NALTREXONE BIBLIOGRAPHY 176

I S 180

x
INTRODUCTION

Pierre F . Renault, M.D.

With the end of Phase II clinical testing of

naltrexone in sight and the planning for

Phase III underway, this seems an appropriate

time to take stock, review our accomplishmerits, and re-evaluate our theories and preconceptions. Obviously, this cannot be done

completely in only one volume. The full

promise of naltrexone will only be realized

after years of clinical innovation and careful observation. The purpose of this volume

is to inform, act as a reference for clinical

procedures, encourage interest and possibly

stimulate further innovation and research

with this important new drug.

The volume contains a series of five papers

recounting the history of the political and

bureaucratic processes necessary to have

gotten us this far in the development of naltrexone. Dr. Julius gives a comprehensive

statement of the interest of the Federal government in making a narcotic antagonist available for use in the treatment of chronic opioid

dependence. Dr. Kaim details the decisions

which led to the formation of the CENA committee and the National Academy of Sciences

study. Dr. Tocus outlines the procedures that

the Food and Drug Administration has developed

to assure us of the safety and efficacy of all

the drugs marketed in this country. This is a

particularly helpful paper because it catalogs a process that most clinicians and

scientists find bewildering. Braude and Morrison summarize the preclinical animal toxicity

studies, a crucial and difficult step in the

process of drug development. Dr. Hollister

gives a candid portrayal of many underlying

pressures that, fueledbysimplistic thinking

and unrealistic expectation, complicated the

beginning of naltrexone’s development. Dr.

Hollister’s paper highlights a tension which

is evident in other papers in this volume, a

tension between the wish to respond to society’s

demand that a solution be found for the problem of heroin abuse and the wish to develop

effective treatment for afflicted individuals

without exposing volunteer subjects to undue

risk. While it is true that political pressure

was important in overcoming the inertia and

getting naltrexone development underway, the

pace of development has been in step with the

pace of development of safety data and the

requirements of the FDA. The paper by Dr.

Willette on long-acting preparations

points us toward the future. Many questions

remain unanswered. What place will a sustained

release preparation have in future treatment?

Will it provide protection against the impulse

with gradual extinction, or will it simply be

another “sentence” removing responsibility from

the patient and only delaying the eventual confrontation with heroin availability? How can

these preparations be overridden when analgesia

is necessary?

Although much of our primary concern has been

the development of naltrexone as a clinically

useful medication, the paper by Martin, et al,

on the possible interaction of naltrexone with

“naturally occurring morphine-like agonists”

1
indicates the importance of research on naltrexone in the development of knowledge about

the basic processes of opioid action and physical dependence. “‘Pure” antagonists have no

known effect on normal organisms, but they

may have important effects in organisms whose

endogenous morphine-like substance (endorphin)

system has been disequilibriated by chronic

administration of opioid drugs. This possibility relates directly to Dr. Wikler’s paper

and his interest in a possible “satiating”

effect of naltrexone in addicts. Later in the

volume Thomas, et al, and Landsberg? et al,

give clinical examples of such “satiation,”

and Goldstein supports the likelihood of this

interaction.

In his paper Dr. Wikler continues his tradition of provocative theorizing about the

addiction process and innovation in treatment

methods. He reviews the concept of extinction

which formed the basis for the use of narcotic

antagonists in treatment. Convinced that extinction is the process which must occur for

complete recovery from compulsive opioid use,

Dr. Wikler suggests new ways of overcoming

the failure of extinction to generalize beyond

the therapeutic setting. Meyer, et al, have

done extensive testing of the extinction theory

under controlled conditions. They found that

extinction achieved in a controlled inpatient

setting did not generalize. Those patients

who did well were those who continued to take

their naltrexone after discharge and who made

major lifestyle changes. This group of investigations has extended our understanding of

human heroin taking by making systematic

observations of heroin self-administration by

individuals who did not know whether they were

blocked by naltrexone or not blocked by placebo.

It took longest for extinction to occur in

those individuals with the longest history of

heroin use. They have also demonstrated that

interpersonal factors outweigh pharmacological

factors in determining continued heroin use.

They also advance the concept that taking

naltrexone creates the “stimulus state” that

signals heroin is “unavailable” and that

therefore, addicts treated with naltrexone

must eventually face the day when treatment

ceases and heroin again becomes available.

This concept resonates with the clinical concepts, later in the volume, of Lewis and Resnick, who feel that dropping out and returning

to treatment are part of a process of gaining

control over this state of facing heroin

availability.

O’Brien, et al, review their procedures for

outpatient extinction trials. Callahan, et

al, while agreeing that change in lifestyle

must be the ultimate goal of naltrexone treatment, find that naltrexone aids the cooperation of patients in their behavior therapy

techniques aimed at lifestyle change.

Three investigators, Lewis, Resnick, et al,

and Goldstein present clinical ideas on improving the efficacy of naltrexone. Lewis

feels that a “permissive” attitude on the

part of clinic staff is helpful in allowing

patients to make full use of naltrexone. The

goal of treatment is “internalization of control.” Missing doses and clinic appointments

can be seen as effortstointemalize the protection against the impulse to take heroin

which naltrexone provides. Resnick, et al, in

their followup study give data to support this

“permissive” attitude by pointing out that

subsequent treatment periods, after relapses,

tend to increase in duration, that duration of

naltrexone treatment is correlated with eventual success, and that a decision to take

naltrexone is a “responsible” decision not to

take heroin. They feel that the clinic staff

must develop the trust of the client, so that

he will transfer his reliance from drugs to

his counselor.

Each of the investigators involved in the

clinical trials of naltrexone was asked to

summarize his experiences and to describe

actual clinical procedures to provide a reference source of clinical experience for other

investigators who plan to do clinical research

with this drug. A wide variety of experience

is represented in these papers. Among the

participants in the NAS Cooperative Study,

Parwatikar, et al, treated street addicts.

Hurzeler, et al, and Curran, et al, treated

primarily patients from the criminal justice

system who were not currently physically

dependent. Haas, et al, and Schoof, et al,

inducted patients from methadone maintenance

who required detoxification. Among the NIDA

Clinical Study participants, Thomas, et al,

have had the most extensive experience with

naltrexone in a general clinic population.

Greenstein, et al, have also treated a substantial number of patients and they give a

very detailed description of the clinic procedures. Brahen, et al, also give details of

a unique and important application of antagonist treatment within the criminal justice

system.

All the clinical papers fulfilled our request

for detailed information on clinic procedures.

Their impressions and results are consonant on

several issues:

1. Naltrexone is safe in the population tested,

otherwise healthy male heroin addicts

requesting treatment.

2. The major side effect is in the gastrointestinal system. The major symptoms are

2
3.

4.

5.

6.

7.

8.

9.

10.

anorexia, nausea and vomiting, and abdominal cramping.

They are unanimous in their agreement that

naltrexone, at the equivalent of 50 mg/day,

completely blocks euphoria and the development of physical dependence from street

heroin.

The induction procedures currently employed

are satisfactory.

The greatest problem with retention

occurred during the detoxification process.

Patients either could not complete detoxification or upon completion decided they

did not need further medication.

The study itself, especially the doubleblind study, was a factor in causing a low

retention rate.

Retention in treatment is not an adequate

measure of outcome.

Naltrexone is a drug for the highly

motivated.

The goal of treatment should be focused on

change of lifestyle.

The patient maintained on naltrexone must

eventually face a crisis when he attempts

to maintain control in the absence of naltrexone and heroin is again available.

Bradford has compiled an interim report on the

combined safety data collected in 17 separate

clinics involving 883 subjects who took study

medication. Review of this data confirms

clinical impressions presented earlier. There

is no evidence of naltrexone being toxic.

Specific symptoms: loss of appetite, nausea

and vomiting, abdominal cramps and constipation did occur at a slightly higher frequency

among naltrexone patients.

Broader questions also remain. Who are the

patients likely to benefit from narcotic

antagonist treatment? Are there any lowincidence side effects of naltrexone? Is

naltrexone the “ideal” antagonist? Naltrexone

was chosen because of its lack of agonistic

properties, which in the case of cyclazocine

were experienced as side effects; but would

an antagonist with some reinforcing agonistic

properties be more acceptable to patients and

therefore effective in a larger propertion of

patients? Does a pure antagonist such as naltrexone have a healing action on the disequilibriated “endorphin” system? What are

the effects of naltrexone on protracted abstinence? Is naltrexone best viewed as a

maintenance or a crisis drug?

It is our intent that this volume mark a point

in time when we begin the final developmental

phase. Our accomplishments consist of a body

of thought and data on opioid dependence and

strategies of intervention with naltrexone.

Naltrexone is thus far safe and efficacious.

Its usefulness is limited to a minority of

patients characterized by their motivation.

Perhaps naltrexone is not Dr. Hollister’s

“new magic bullet” for heroin addiction, but

it has stimulated the imagination of researchers in this field and its promise seems to

change and grow as our knowledge and understanding of basic processes increases.

The papers have been grouped roughly in the

same fashion as they were presented at the

National Academy of Science’s Satellite Naltrexone Conference, held June 6 and 7, 1976,

in Richmond, Virginia. The first set of

papers describes the Federal role in the

development of naltrexone. The second group

of papers describes the conceptual basis and

the results of the double-blind study of naltrexone’s clinical safety and efficacy conducted by the National Academy of Science’s

Committee on the Evaluation of Narcotic Antagonists (CENA) . The third group of papers deals

with the NIDA open clinical studies of naltrexone safety and efficacy. The fourth group

of papers includes theoretical discussion and

the clinical testing of behavioral hypotheses

concerning the treatment of opiate addiction

with narcotic antagonists. The last paper is

a current assessment of the data collected on

naltrexone safety to date.

AUTHOR

Pierre Renault, M.D.

National Institute on Drug Abuse

Division of Research

3
THE FEDERAL ROLE IN NALTREXONE DEVELOPMENT
NIDA’S NALTREXONE

RESEARCH PROGRAM

Demetrios Julius, M.D.

The current naltrexone research program sup

ported by the National Institute on Drug

Abuse can be traced developmentally to its

embryonic beginnings in the mid-1960’s. At

that time Dr. William Martin and his coworkers at the Addiction Research Center in

Lexington, Kentucky initiated a series of

studies into the use of narcotic antagonists

for the treatment of opioid dependence (Martin et al. , 1966). The studies were a practical outgrowth of the theoretical formulations elaborated by Dr. Abraham Wikler over

the preceding years (Wikler, 1948 and 1965).

The results of the studies showed that a

narcotic antagonist could be effectively used

to block the euphorigenic and dependenceproducing properties of opioids in man. Furthermore, this chemotherapeutic agent would

produce neither physical dependence nor abuse

liability in the treated individual. This

was important because previous treatment drugs

had the liability of producing their own

degree of addiction.

These early clinical studies into the therapeutic use of narcotic antagonists might have

faded into textbook obscurity had it not been

for a number of concurrent social and political events that were rapidly developing. In

the years following the tragedy of President

Kennedy’s assassination on November 22, 1963,

our nation was quickly pulled into social

turmoil at home and military turmoil abroad.

By the late 1960’s this multi-determined

chaotic national scene had led hundreds of

thousands of individuals to seek multiple

avenues of relief. Many chose to seek refuge

in what was felt to be the blissful escape

provided by illicit drugs. This could be

viewed sociologically as a massive attempt at

self-medication. For many individuals, one

dead-end to which these pharmacological

avenues led was heroin addiction. Consequently by 1970 the use of heroin both at

home and among our military personnel abroad

had reached epidemic proportions. Among

national authorities, apocalyptic visions of

opioid-dependent armed United States soldiers,

as well as similarly afflicted anti-war, antiAmerican anarchists roaming the streets looking for a “fix,” provided necessary impetus

to both the Executive and Legislative Branches

of the Government to authorize funding for

expanded research and treatment of opioid

dependence.

On June 17, 1971, President Nixon signed into

creation the Special Action Office for Drug

Abuse Prevention (SAODAP), to coordinate the

various resources of the cederal Government

necessary to check the continuing spread of

illicit drug abuse. These resources for drug

abuse research, prevention, and treatment had

been previously scattered across more than

fourteen different agencies. In 1972, the

Congress passed the Drug Abuse Office and

Treatment Act which was signed into Public Law

92-255, Section 224, 86 statement 72 on March

21, 1972. Among the numerous provisions of

the Law was a substantial financial support

for the expansion of research on “long-lasting,

non-addictive. blocking and antagonist drugs or

5
other pharmacological substances for the

treatment of heroin addiction.” With these

substantial mandates, SAODAP’s first director,

Dr. Jerome Jaffe, set the development of a

safe and effective narcotic antagonist as one

of the highest priorities for this new agency.

THEORETICAL BASIS OF NARCOTIC

ANTAGONIST THERAPY

Pharmacologically, a narcotic antagonist is a

substance which has the ability to block the

euphorigenic and dependence-producing properties of opioids (Martin, 1967). At the

present time, it is theorized that this type

of drug accomplishes this feat because of its

structural similarity to narcotics themselves.

Thus, antagonists have the ability to occupy

the same presumed opiate receptor sites in

the body as the narcotics do, and thereby

produce competitive inhibition of narcotics.

Different narcotic antagonist drugs also have

differential abilities to produce both antagonistic and agonistic action. These differential properties are, of course, important

in choosing the proper narcotic antagonist

for this type of therapeutic use. It should

be noted that a pure narcotic antagonist

differs greatly from a drug such as disulfuram

(Antabuse (R) ) . When alcohol is ingested, by

an individual taking the latter medication, a

violent physical reaction ensues that can have

life-threatening consequences. When heroin is

injected in a dose which is blocked by the

dose of the former medication being taken by

an individual, no physical reaction ensues.

Of course, an individual may attempt to overcome the blockade with too great an amount of

heroin and fatally overdose himself.

This unique class of antagonist drugs thus

formed the basis of a potential treatment

modality as outlined by Wikler (1948, 1965)

and Martin, et al. (1966). They postulated

that operant conditioning plays an important

role in initiating and perpetuating heroin

use. Initially, the euphorigenic properties

of narcotics probably act as strong reinforcers of what was conceptualized as “drugseeking behavior” in the opioid-dependent

individual. Thereafter, tolerance to the

narcotic develops and slowly reduces the

euphoric effects. In addition to the pursuit

of pleasure (the euphoric effects), there is

now within the individual a growing awareness

of the need to avoid pain (the abstinence

syndrome) . Therefore, the avoidance of the

discomforting opiate abstinence syndrome also

perpetuates the “drug-seeking behavior.”

Finally, a hypothesized “conditioned abstinence syndrome” may apparently be precipitated

by environmental stimuli that have been associated with opiate dependence in the past.

Occasionally after opiate detoxification,

dependent individuals have described the onset of withdrawal symptoms by merely coming

into contact with their previous environment.

This conditioned abstinence syndrome may be

characterized by increased reactivity to

stimuli, prolonged abnormal autonomic responses, feelings of dysphoria, and often an

intense “craving.”

Quite logically, it was theorized, the narcotic antagonist could be used to control

these various determinants of drug-seeking

behavior. Since the antagonist would block

the euphoria and the dependence produced by

the opiates, the reinforcement for drugseeking behavior provided by these two critical determinants of opioid dependence would

gradually be attenuated. Furthermore, the

antagonist would protect the detoxified individual against the conditioned abstinence

syndrome. Thus, with the absence of these

reinforcers would come the gradual extinction

of the drug-seeking behavior itself.

The protection afforded by the antagonist

would then give the needed time to aid the

detoxified individual in altering his life’s

course. In the context of a close and humane

psychotherapeutic milieu, the individual could

learn to regain control over his own destiny.

That is to say, he could begin to develop

greater internal controls and greater independence and begin to extricate himself from the

sticky external web of drugs and environmental

pressures that had ruled his life until then.

DEVELOPMENT OF AN OPTIMAL

NARCOTIC ANTAGONIST

In light of the above-described socio-political milieu and the enticing theoretical

notions concerning the antagonists, we can

easily understand why the development of a

safe, effective antagonist was of the highest

priority for SAODAP in 1971. SAODAP directors

also recognized that the selection and development of such an antagonist was of no burning

interest to the private pharmaceutical industry. The projected spending of research and

development funds and time seemed to outweigh

projected returns from what appeared to be a

limited market. This projected spending was

high because the development of a new drug is

a complicated and time-consuming affair.

By law, any new drug must pass through rigorous and controlled testing in several animal

species as well as in humans before it can be

marketed. The testing is divided into a preclinical phase and three clinical phases. In

the pre-clinical phase, the gamut of toxicity

studies should be carried out on at least two

different animal species. Provided the drug

proves to have a sufficient margin of safety

6
in these toxicity studies, it may then be

introduced into man for the purpose of gathering safety and efficacy data. Phase I of the

clinical studies deals with the basic clinical

pharmacology of the drug in man. This covers

such areas as dosing levels, absorption rates,

metabolites, and so on.

limited and quite controlled clinical trials

Phase II represents

intended to demonstrate the safety and relative efficacy of the drug. For reliable

results! it is desirable that these studies

be carried out within a double-blind placebo

design. That is, neither patient nor administering staff know which patients are on the

drug and which on a placebo. Phase III then

represents both controlled as well as uncontrolled clinical investigation in a much larger group of patients. The successful completion of this phase with a demonstration of

drug efficacy is the final step before a New

Drug Application (NDA) is submitted to the

Food and Drug Administration (FDA). With

approval of the NDA, the drug then is eligible

for marketing to the general public, Of

course, there is a constant financial risk

involved in this process, for drug development

may be halted at any point, based on unacceptable toxicity or disproven efficacy.

It was with this long and complex procedure

ahead that the Federal Government, through

the Special Action Office for Drug Abuse Prevention (SAODAP) and the Division of Narcotic

Addiction and Drug Abuse (DNADA, NIMH), undertook the development of a safe, effective

narcotic antagonist. A research plan was

initiated by DNADA in September, 1971 to help

organize such an efficient development. In

this plan were outlined the necessary preclinical research, the procedures for clinical

testing, and the cost and personnel estimates.

Additionally the optimal characteristics of

narcotic antagonists were described. These

were as follows:

1. Ability to antagonize the euphoric high

of opiates.

2. Absent or low-agonistic effects,

especially unpleasant ones.

3. Does not cause physical dependence.

4. Does not exhibit increasing tolerance

to its antagonistic actions.

5. Absence of serious side effects and

toxicity even in chronic use.

6. Easily administered, i.e., no surgery or

painful procedure involved.

7. Long-lasting or moderate duration of

antagonist effects.

8. Absent or low abuse potential.

9. Reversible effects in case of medical

emergency.

10. High potency to allow administration of

small amounts in a biodegradable vehicle,

11. Easily available and inexpensive.

12. Therapeutic efficacy in treatment of

narcotic addiction.

By early 1972 there were several antagonists

in existence at various stages of development.

The purest antagonist was naloxone. It seemed

to be a potent antagonist and showed almost no

agonist action of its own. Its main drawbacks

as a therapeutic agent in opioid dependence

were its high cost, the difficulty in synthesizing it, its very poor oral absorption rate,

and especially its short duration of action in

the body. Naloxone had been approved by the

FDA for short-term use in humans as an antidote for opiate overdose. In spite of its

drawbacks, naloxone had met with limited success as an adjunct to treatment by several

investigators. This seemed encouraging for

narcotic antagonist treatment in general.

Concurrently being developed was another promising and potent antagonist called cyclazocine

(Jaffe, 1967; Resnick, et al., 1970 and 1971).

This drug demonstrated a longer duration of

action of up to 24 hours with 4 milligrams of

the substance. However, its drawbacks were

also recognized. These consisted of strong

agonist properties when administered rapidly

to individuals. These properties included

quite unpleasant feelings described as dysphoria and psychotomimetic effects. Despite

the tolerance that develops to these effects,

cyclazocine was not well received by the

addict volunteers and soon acquired a bad

street reputation. However, it was successful

in the treatment of some individuals, and these

individuals are still, in fact, being treated

with cyclazocine in certain clinics in New

York City.

Additionally, three other compounds, designated

as M-5050, BC-2605, and EN-1639A, wereinearly

animal and human testing at the time. One of

these, EN-1639A, seemed to be a potent antagonist and also did not show the dysphoric and

unpleasant side effects of cyclazocine (Blumberg and Dayton, 1973). It had a good duration, in that 50 mg seemed able to block narcotic action for 24 hours. By late 1972,

there was a substantial supply available for

testing of this drug, which came to be known

as naltrexone. By mid-1973 it became evident

that this drug fulfilled the criteria of an

optimal narcotic antagonist to a greater degree than any of the other available substances

(Martin, et al., 1973a and 1973b; Resnick,

et al., 1974a, 1974b, and 1974c).

Besides the research progress being made,

there were also administrative changes occurring within the Government. In 1973, the

Division on Narcotic Addiction and Drug Abuse

7
was separated out from NIGH and expanded into

the National Institute on Drug Abuse. Thus,

from 1973 to 1974, NIDA and SAODAP shared the

responsibility for the ongoing development of

the narcotic antagonists in general and of

naltrexone in particular. By mid-1974, as

SAODAP began to phase out of existence, the

entire direction and monitoring of the naltrexone research program fell to the Division

of Research, NIDA.

NIDA-SUPPORTED NALTREXONE RESEARCH

From 1973 to 1974, NIDA supported 26 various

grants and contracts in pre-clinical and

clinical studies directly related to narcotic

antagonists. This support totalled over five

million dollars. Approximately seventeen of

these grants and contracts dealt with the use

of naltrexone in clinical situations, and

they fit together into a rather loosely knit

naltrexone research program. Five of these

research clinics were selected to participate

in the double-blind placebo study of naltrexone that was, and still is, being conducted

by the National Academy of Science (NAS). It

was planned that such a study would satisfy

in an elegant manner the Phase II requirements for new drug development and would

demonstrate the safety and relative efficacy

of naltrexone when compared to placebo. The

five NAS clinics in the double-blind studv

had a standardized group of three research

protocols which they had to follow. The

differences in the three protocols derived

from the fact that each used a different type

of opiate-dependent individual. The Baltimore and New Haven Clinics could use only

“post-addicts” in their research. The Detroit

and Sepulveda Clinics could use only “methadone maintenance addicts” And the St. Louis

Clinic could use only “street addicts.”

By contrast, the remainder of the grants and

contracts consisted of a variety of controlled

and uncontrolled clinical trials with naltrexone (Brahen, et. al., 1974; Brahen, 1975;

Brahen, et al., 1976; Lewis, 1975; Meyer, et

al., 1976; O’Brien, et al., 1975; Schecter,

1975; and Taintor, et al., 1975). Researchers in this group were free to use different

protocols, to use different treatment settings,

to treat different types of dependent individuals, and to pursue any variety of different research questions. This group of grants

and contracts were called the NIDA clinics,

for want of a better title. These NIDA clinics were later divided into a group of “open

clinical naltrexone studies” and a group of

“behavioral naltrexone studies,” in an effort

to bring greater order and specificity to the

overall naltrexone program. In the former

category were classed those studies which

tested naltrexone within a variety of clinical

contexts, whereas in the latter category were

gathered those studies which specifically

attempted to test out the original behavioral

formulations discussed above.

All of the studies underway by 1974 were conceived by NIDA to represent Phase II testing

of naltrexone. That is to say, naltrexone was

receiving exposure in limited clinical populations. In Phase II, one of the chief responsibilities of NIDA was providing a watchful

eye over the safety aspects of this drug when

it was administered to humans. Consequently,

a tight monitoring system had to be devised

if the limited staff at NIDA was to function

properly in detecting any ill effects of the

drug. We therefore decided to establish the

same kind of monitoring of all the NIDA

research clinics that existed for the five

clinics in the National Academy of Science’s

study. Biometric Research Institute (BRI) of

Washington, D.C., was providing the monitoring

and statistical capabilities for the NAS study

and had developed a number of forms in conjunction with the NAS-CENA committee to carry

this out. We therefore arranged for BRI to

provide a similar monitoring function for the

NIDA clinics. This consisted of gathering

information on the monthly laboratory records

(NAS-5a), monthly physical and psychiatric

summaries (NAS-5b) , weekly symptom check lists

(NAS-7), and the daily treatment records (NAS9 and 9a) from the various open clinical and

behavioral NIDA studies. Thus, by early 1975,

we were able to gather a large quantity of

both safety and efficacy information into the

central data bank of Biometric Research Institute and were able to keep constant and close

watch over any potentially unpleasant or harm

ful effects of the drug.

Up to the present time, we have not seen any

dysphoria or other psychic ill effects from

naltrexone. The question arose in the past

whether naltrexone caused an increase in blood

pressure. According to the collective data,

there seems to be a small (2-3 millimeters of

mercury), but not statistically significant,

rise in both systolic and diastolic pressure

after initial administration of naltrexone.

However, by four to six weeks, there is a

return to baseline and in many cases a 2-3

millimeter decrease in both systolic and diastolic pressures (Brahen, et al., 1975;

Resnick, personal communication). The only

occasional side effect with some subjects

seems to be an abdominal and gastrointestinal

discomfort. When this was found at the beginning stages of treatment, it was attributed to

minor withdrawal symptoms, because opiates

were presumably still in the addict’s system.

However, these symptoms have been reported

later on in treatment as well. Some researchers have found that these symptoms are some8
times relieved by antacids or by administering naltrexone to the addict after he has

eaten. So it may be that naltrexone acts as

a gastric irritant for some addicts.

An intriguing scientific question, however,

is: what interaction could naltrexone be

having with the endogenously occurring opiatelike compound that has recently been isolated

by researchers? Could, in fact, these abdominal symptoms be related to such an interaction? If an individual who is being maintained on naltrexone has a quantity of this

endogenous substance secreted into his system

and it is, in fact, opioid in nature, is it

not possible to assume that some of the same

symptomatology might occur as if an external

opiate were entering this individual’s system

in a sufficient amount to cause such physical

effects? This symptomatology might therefore

include minor withdrawal symptoms characterized by the abdominal discomfort described.

All of these minor side effects notwithstanding, we have seen no serious lasting side

effects directly attributable to the ingestion

of naltrexone. This antagonist appears to be

a rather safe chemotherapeutic agent for the

treatment of opioid dependence.

NALTREXONE PROGRAM-THE FUTURE

The NIDA naltrexone program currently consists

of the NAS-CENA studies, the behavioral naltrexone studies, the open clinical naltrexone

studies, and a number of studies at the NAS

clinics which are essentially continuation

studies of naltrexone safety and efficacy

without the double-blind protocol. The NASCENA studies, which began intake in mid-1974,

are now in the process of gathering follow-up

data on the patients who have participated in

the study. The double-blind has not yet been

officially lifted for the investigators, and

the existing data are now being tabulated and

analyzed by BRI. These results will be forwarded to NAS-CENA committee which will issue

its final report of this particular study by

the end of 1976. Approximatelv 190 subjects

have taken at least one dose of study medication, about half on placebo, half on naltrexone. The results are not in yet, but it seems

that naltrexone was of benefit to a certain

percentage of subjects in this study.

Aside from the NAS-CENA study, over 690 individuals have taken at least one dose of naltrexone in the other NIDA-sponsored clinics.

This means that the total number of individuals who have at least one-time ingestion of

the drug is therefore over 775. From a numbers standpoint, this would seem to be a more

than adequate figure for satisfying Phase II

requirements for clinical testing. We therefore consider the naltrexone program to be

entering into the late stages of Phase II

testing and are preparing the data collected

to be submitted to the FDA by early 1977.

As this phase of naltrexone development winds

down to conclusion before shifting into Phase

III, so too does type and method of support

provided by NIDA. The program began, as was

described above, with an Executive and Legislative mandate for the development of a safe,

effective antagonist. This mandate carried

with it strong financial support in the form

of contract monies. However, as Phase II

winds down, so too do these contract funds.

We have therefore increasingly encouraged

interested researchers to seek grant support

for proposed naltrexone research. So far,

this seems to be working well, and basic

clinical research continues with naltrexone.

As for Phase III of the drug’s development, we

are currently exploring the possibility that

Endo Laboratories, a pharmaceutical firm and

the owner of the patent for naltrexone, will

be interested in carrying out that phase of

ewanded controlled and uncontrolled clinical

investigation. Although naltrexone safety

seems to be well supported by the Phase II

data, further monitoring of the safety will

be carried out during Phase III, as well as

the all-important testing of the efficacy

claims for this drug.

Naltrexone has proved to be an interesting

agent--almost a non-drug drug because of the

lack of discernible effects other than its

opiate-blocking capacity. This lack of other

pharmacologic action may well prove to be one

of the most attractive features of the drug.

If the sentiment against the dependenceproducing properties of other therapeutic

modalities such as methadone and LAAM begins

to expand, we may well be turning to a therapeutic program which includes naltrexone as a

pivotal feature. This “anti-dependence” sentiment is current in two areas of the country,

California and Massachusetts. Since these

regions often herald what is to come for the

rest of the country, we may find a receptive

atmosphere for naltrexone as it is being prepared for expanded therapeutic use.

As it has been used to date, therefore, naltrexone seems to be a safe drug and an efficacious one in some addicts. However, further

testing of its efficacy needs to be carried

out in new and innovative techniques of administration. The question arises of how naltrexone’s efficacy can best be maximized.

Should we think of this drug as another longterm maintenance chemotherapy? Or would it be

more effective when used in conjunction with

short-term crisis-intervention techniques; or

9
in conjunction with various behavioral techniques; or in a contingency manner, so that

the addict could ask to be put on naltrexone

when he felt the need arise? Furthermore,

the pre-clinical research into the use of

implantable long-acting preparations continues

unabated. These, however, raise-y ethical

questions, besides questions concerning the

efficacy of this mode of drug delivery. From

another angle also, what factors such as

attitudinal, environmental, and socio-cultural

variables both in the clinic personnel and in

the addicts treated are crucial for the

effective use of this drug? Finally, are

there intrapsychic or personality variables

in addicts that make some appropriate for one

kind of treatment and others appropriate for

another kind of treatment? (Goldstein, 1975

and 1976; Martin, 1975; Willette, 1976).

The papers that follow in this monograph begin

to touch on many of these intriguing research

questions as well as describing with great

clarity and detail many of the research discoveries and conclusions to date dealing with

naltrexone as a therapeutic agent. It is our

hope that further research will continue to

reveal solutions to these questions, and we

will be able to place naltrexone therapy most

productively into the overall treatment

approach to opioid dependence.

REFERENCES

Blumberg, H.; Dayton, H.B.: Naloxone,

naltrexone, and related noroxymorphones.

In: Narcotic Antagonists. (Braude, M.

C.; Harris, L.S.; May, E.L.; Smith, J.P.;

Villarreal, J.E., eds.), New York: Raven

Press, Publishers, pp. 33-44, 1973.

Brahen, L.S.; Weichert, V.; Babinski,

R.M.: The first narcotic antagonist jail

work-release program for addicted inmates.

In: Developments in the Field of Drug

Abuse. (Senay, E.; Short, V.; Alslene,

H., eds.), Schenkman Publishing Company,

Inc., Cambridge, Mass., 1974, page 769.

Brahen, L.S.: Naltrexone study guidelines: good vehicle--wrong destination.

Amer. J. Drug & Alc. Abuse, 2:451-455,

1975.

Brahen, L.S.; Capone, T.; Weichert, V.;

Babinski, A.: Effects of naltrexone on

blood pressure and electrocardiogram.

Presented to Committee on Problems of

Drug Dependence, National Research Council, Washington, D.C., May, 1975.

1 0

Brahen, L.S.; Capone, T.; Weichert, V.;

Babinski, A.; Desiderio, D.: A comparison

of controlled clinical and laboratory

studies of the narcotic antagonists cyclazocine and naltrexone. Presented at the

Third National Drug Abuse Conference, at

New York, March, 1976.

Goldstein, A.: On the role of chemotherapy in the treatment of heroin addiction. Amer. J. Drug & Alc. Abuse, 2:279-

288, 1975.

Goldstein, A.: Heroin addiction, sequential treatment employing pharmacologic

supports. Arch. Gen. Psychiat., 33:353-

358, 1976.

Jaffee, J.: Cyclazocine in the treatment

of narcotic addiction. Current Psychiatric Therapies, Vol. VII, Grune and

Stratton, Inc., 1967.

Lewis, D.C.: The clinical usefulness of

narcotic antagonists: preliminary findings

of the use of naltrexone. Amer. J. Drug

& Alc. Abuse, 2:03-415, 1975.

Martin, W. R.; Gorodetzky, C. W.; McClane,

T.K.: An experimental study in the treatment of narcotic addicts with cyclazocine.

Clin. Pharm. Therap., 7:455-465, 1966.

Martin, W. R.: Opioid antagonists.

Pharm. Rev., Vol.. 19, No. 4, 1967.

Martin, W.R.; Jasinski, D.R.: Characterization of EN-1639A. Clin. Pharm. Therap.,

14:142, 1973.a.

Martin, W.R.; Jasinski, D.R.; Mansky, P.A.:

Naltrexone, an antagonist for the treatment of heroin dependence effects in man.

Arch. Gen. Psychiat., 28-784-791, 1973.b.

Martin, W. R.: Realistic goals for antagonist therapy. Amer. J. Drug & Alc. Abuse,

2:353-356, 1975.

Meyer, R.E.; Mirin, S.M.; Altman, J.:

McNamee, H.B.: A behavioral paradigm for

the evaluation of narcotic antagonists.

Arch. Gen. Psychiat., 33:371-377, 1976.

O'Brien, C.P.; Greenstein, R.A.; Mintz, J.;

Woody, G.E.: Clinical experience with

naltrexone. Amer. J. Drug & Alc. Abuse,

2:365-377, 1975.

Resnick, R.; Fink, M.; Freedman, A.: A

cyclazocine typology in opiate dependence.

Amer. J. Psychiat., 126:9, March, 1970.
Resnick, R.; Fink, M.; Freedman, A.:

Cyclazocine treatment of opiate dependence: a progress report. Comp. Psychi.,

Vol. 12, No. 6, November, 1971.

Resnick, R.; Volavka, J.; Freedman, A.M.;

Thomas, M.: Studies of EN-1639A (naltrexone): a new narcotic antagonist.

Amer. J. Psychiat., 131:646-650, 1974.a.

Resnick, R; Volavka, J.; Freedman, A.M.:

Short-term effects of naltrexone: a

progress report. Proceedings of the

Committee on Problems of Drug Dependence

of the National Academy of Sciences,

pp. 250-263, 1974.b.

Resnick, R.; Volavka, J.; Gaztanaga, P.;

Freedman, A.M.: Clinical pharmacology

of naltrexone. Presented to 9th Congress

of the Collegium Internationale Neuropsychopharmacologicum, Paris, July, 1974.

c.

Schecter, A.: Clinical use of naltrexone (EN-1639A). Part II: Experience

with the first 50 patients in a New York

City treatment clinic. Amer. J. Drug &

Alc. Abuse, 2:433-442, 1975.

Taintor, Z.; Landsberg, R.; Wicks, N.;

Plumb, M.; D'Amanda, C.; Greenwood, J.:

Experiences with naltrexone in Buffalo.

Amer. J. Drug & Alc. Abuse, 2:391-401,

1975.

Wikler, A.: Recent progress in research

on the neurophysiologic basis of morphine

addiction. Amer. J. Psychiat., 105:329-

338, 1948.

Wikler, A.: Conditioning factors in

opiate addiction and release. In:

Narcotics. (Wilner, D.I.; Kossebaum,

G.G., eds.), McGraw, Hill, New York,

pp. 85-100, 1965.

Wikler, A.: Dynamics of drug dependence:

implications of a conditioning theory

for research and treatment. Opiate

Addiction: Origins and Treatment.

V.H. Winston and Sons, Washington, D.C.,

1973.

Willette, R. (ed.): Narcotic Antagonists: The Search for Long-Acting Preparations. NIDA Research Monograph 5.

U.S. Government Printing Office, Washington, D.C., 1976. Stock No. 017-024-00488-0.

AUTHOR

Demetrios Julius, M.D.

National Institute on Drug Abuse

Division of Research

1 1
REQUIREMENTS FOR DRUG

DEVELOPMENT

Edward C. Tocus, Ph.D.

The development of a drug for marketiny is a

topic which could constitute an entire series

of lectures. During the next twenty minutes

we will only be able to cover a limited part

of the topic relating to drug development.

Specifically, we will be concerned with those

parts of the development of a drug relative

to the regulations, and requirements of the

Food and Drug Administration.

The Food and Drug Administration, or FDA, has

the responsibility for seeing that drugs which

appear in interstate commerce are both safe

and effective for the claims for which they

are being promoted and sold.

The Food, Drug, and Cosmetic Act in Section

505 says that no person shall introduce, or

deliver, into interstate commerce any new

drug unless approval of an application is on

file with respect to that drug. It also says

that any person may file with the Secretary

an application for any drug which is intended

for use in interstate commerce. This application must contain full reports of the

scientific investigations which have been

made to show whether or not the drug is safe

as indicated and whether or not the drug is

effective as indicated. It also must include

a full list of the articles which are used as

components of such a drug, a full statement

of the composition of such a drug; also a

full description of the methods used and the

facilities and the controls used for the

manufacture, the processing and the packing

of such drugs. It must also contain samples

of the drug and the articles used as components.

These are the items that are required in

order to introduce a new drug into interstate commerce. Let's look for the remainder of our time at the requirement for full

reports of investigations to show whether

or not a drug is safe for use and effective

for use.

These investigations are generally performed

under the investigational new drug regulations, or the IND regulations. SUCh drugs

may be shipped across state lines for purposes of study and they must bear the label

1 2
for investigational use only. It is necessary that the sponsor of an investigational

drug demonstrate a pharmacologic effect of

his product, either in an animal model or in

an in vitro model before exposing humans to

the drug.

There are exceptions to this policy, such as

situations where the pharmacological effect

is observed in humans who are receiving the

drug for some other indication; it's possible there are other rare exceptions.

In addition to the pharmacologic effect in

animals, it is necessary that the sponsor

study the toxic effects of the drug in animals in order to determine whether any

organs of the living organism may be irreversibly damaged because of the drug.

The design of the animal toxicity studies

may vary with the type of drug under investigation. Generally, however, a determination of the median lethal dose, that is,

LD50 dose, by several routes of administration in several species of animals is performed to estimate the lethal toxic potential of the drug. Thereafter, toxicity

studies are performed on a multiple dose

basis by the route proposed for clinical

investigation. Animals from these studies

are killed and their organs examined for

possible toxic effects. For further use in

man, chronic animal toxicity studies must be

performed. These are done in at least two

species, and the drug is given to animals for

an extended period of time by the proposed

route of administration in man.

For certain drugs, it may be necessary to do

additional chronic toxicity studies to determine the carcinogenic potential of the drug

in animals.

Before a drug is given to women of childbearing potential, reproduction studies are performed in animals. Segment 1 reproduction

studies involve administering the drug prior

to mating and determining the effects of the

drug on reproductive performance. Segment 2

studies involve administering the drug to

pregnant female animals during the period of

gestation and determining the effects on the

development of the fetus by performing cesarean sections and examining the fetuses for

abnormal morphological effects. Segment 3

reproduction studies involve administering

the drug prior to delivery and during lactation to determine the effects on the delivery

process and on development of the young animal. Although such studies are performed,

the safety in humans is only obtained through

very cautious and careful observation of the

human experience.

When sufficient animal toxicity studies have

been performed, indicating it is safe to administer the drug to human volunteers and

the chemistry of the drug has been delineated to the extent that the material proposed for human administration is well characterized chemically, then clinical studies

may be performed initially in humans.

Clinical studies may be divided into three

phases.

Phase I, Clinical Pharmacoloqy is intended to

include the initial introduction of a druq

into man. It may be in the usual normal volunteer subjects to determine levels of tolerance, which will be followed by early doseranging studies for safety and in some cases

early efficacy in patients. Alternatively,

with some new drugs the initial introduction

into man may, ethically or scientifically,

more properly be done in selected patients.

When normal volunteers are the initial recipients of a drug, the very early trials in

patients which follow are also considered

part of Phase I.

The number of subjects and patients in Phase

I will, of course, vary with the drug but may

generally be stated to be in the range of

20-80 on drug. Drug dynamic and'metabolic

studies, in whichever stage of investigation

they are performed, are considered to be Phase

I clinical pharmacologic studies. While some.

such as absorption studies, are performed in

the early stages, others, such as efforts to

identify metabolites, may not be performed

until later in the investigations.

Phase II, Clinical Investigation is intended

to include early controlled clinical trials

designed to demonstrate effectiveness and

relative safety. Normally, these are performed on closely monitored patients of limited

number and scope. Seldom will this phase go

beyond the 100-200 patients on drug, all under

rigidly controlled protocols.

Phase III, Clinical Trials are tne expanded

controlled and uncontrolled trials. These are

performed after effectiveness has been basically established, at least to a certain degree, and are intended to gather additional

evidence of effectiveness, plus further evidence of safety, tolerance and definition of

adverse effects.

The following principles have been developed

over a period of years and are recognized by

the scientific community as the essentials

of adequate and well-controlled clinical investigations.

The plan or protocol for the study and the

13
report of the results of the effectiveness

study must include the following:

1. A clear statement of the objectives

of the study.

2. A method of selection of the subjects that (a) Provides adequate

assurance that they are suitable

for the purposes of the study, diagnostic criteria of the condition to

be treated or diagnosed, confirmatory laboratory tests where appropriate, and, in the case of prophylactic agents, evidence of susceptibility and exposure to the condition

against which prophylaxis is desired.

(b)

(c)

Assigns the subjects to test

groups in such a way as to minimize bias.

Assures comparability of pertinent variables, such as age, sex,

severity, or duratian of disease,

and use of drugs other than the

test drug in test and control

groups.

3. Explains the methods of observation

and recording of results, including

the variables measured, quantitation,

assessment of any subjects response,

and steps to minimize bias on the

part of the subject and observer.

4. Provides a comparison of the results

of treatment or diagnosis with a control in such a fashion as to permit

quantitative evaluation. The precise nature of the control must be

stated and an explanation given of

the methods used to minimize bias on

the part of the observers and the

analysts of the data. Level and

methods of "blinding," if used, are

to be documented. Generally, four

types of comparisons are recognized:

a.

b.

c .

No treatment: Where objective

measurements of effectiveness are

available and placebo effect is

negligible, comparison of the objective results in comparable

groups of treated and untreated

patients.

Placebo control: Comparison of

the results of use of the new drug

entity with an inactive preparation designed to resemble the test

drug as far as possible.

Active treatment control: An effective regimen of therapy may be

d.

used for comparison, e.g., wnere

the condition treated is such that

no treatment or administration of

a placebo would be contrary to the

interest of the patient.

Historical control: In certain

circumstances, such as those involving diseases with high and

predictable mortality (acute leukemia of childhood), with signs

and symptoms of predictable duration or severity (fever in certain

infections), or in case of prophylaxis, where morbidity is predictable, the results of use of a new

drug entity may be compared quantitatively with prior experience historically derived from the adequately documented natural history of the

disease or condition in comparable

patients or populations with no

treatment or with a regimen (therapeutic, diagnostic, prophylactic)

the effectiveness of which is established.

5. A summary of the methods of analysis and

an evaluation of data derived from the

study, including any appropriate statistical methods.

a. For such an investigation to be considered adequate for approval of a

new drug, it is required that the

test drug be standardized as to its

identity, strength, quality, purity,

and dosage form to give significance

to the results of the investigation.

b . Uncontrolled studies or partially

controlled studies are not acceptable as the sole basis for the approval of claims of effectiveness.

Such studies, carefully conducted

and documented, may provide corroborative support of well-controlled

studies regarding efficacy and may

yield valuable data regarding safety

of the test drug. Such studies will

be considered on their merits in the

light of the principles listed here,

with the exception of the requirement for the comparison of the treated subjects with controls. Isolated case reports, random experience, and reports lacking

the details which permit scientific evaluation will not be

considered.

When results of all studies have been reported to the drug sponsor, analyzed, summarized

and tabulated in an orderly and appropriate

1 4
manner, they are submitted in the form of a AUTHOR

New Drug Application in support of a therapeutic claim. If the FDA concludes the submission presents evidence for the proposed Edward C. TOCUS, Ph.D.

condition, it is approved for interstate com- Food and Drug Administration

merce. If the submission is lacking such

evidence, it is declared non-approvable and

the reason for the decision is given to the

sponsor. If the deficiencies are corrected

the application may be approvable and finally

approved.

15
PRECLINICAL TOXICITY STUDIES

OF NALTREXONE

Monique C. Braude, Ph.D. and J. Michael Morrison, M.S.

INTRODUCTION

Toxicity studies of a new drug are carried

out on animals prior to clinical trials.

Acute and chronic toxicity studies can show

whether observed toxic effects should preclude administration of the drug to man and

can also alert the clinician to effects requiring particular attention. For these

reasons the doses used are large enough so

that some toxic effects will be produced,

and will range upwards so that lethal doses

can be determined.

Toxicity studies are designed to reveal the

relation of toxic to effective doses. But

the studies are not directly translatable to

presumed effects in humans. The doses used

in animals are much higher than expected

clinical doses. The life spans of man and

test animals are not comparable, so that, for

example, there is usually a rapid increase in

rodent mortality after 12 months or so and

deaths during a 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

monkeys were used.

PRECLINICAL TOXICITY STUDIES

OF NALTREXONE

Naltrexone is a white crystalline solid,

soluble in water, with a melting point of

about 275°C. It is(-)-17-(cyclopropylmethyl)-4,5

aloha-enoxv-3.14-dehvdroxvmornhinan-6-one

hyirochloride; (C20 H23 NO4•HCl). Naltrexone

was first investigated by Endo Laboratories

for its acute toxicity in rats, guinea pigs

and dogs. It was found to be relatively nontoxic acutely. In mice the intravenous (i.v.)

LD50 was 180 ± 24 mg/kg, the subcutaneous

(s.c.) LD50 was 570 ± 19 mg/kg and the oral

LD50, 1100 ± 96 mg/kg. In rats, the s.c.

LD50 was 1930 ± 338 mg/kg and it was 1450 ±

265 mg/kg orally. In dogs, the s.c. LD50

was about 200 mg/kg and the oral lethal dose

was approximated to be greater than 130 mg/kg.

The acute oral toxicity study in dogs was

confounded by the fact that the drug causes

emesis.

In all of these studies the deaths occurred

after tonic-clonic convulsions. This was

usually preceded by restlessness, tremor,

depression, salivation and/or retching and

emesis. Peak effects were seen 30 to 60 minutes after s.c. administration. Signs of

toxicity were usually gone after 2-4 hours

and there was no delayed lethality.

16
In a series of studies carried out by

Industrial Bio-Test under a NIDA contract, a

small number (2 males and 2 females) of

adult monkeys was given naltrexone in logarithmically increasing doses. By the s.c.

route, some weight loss was seen at 100 mg/kg

and prostration, convulsions and death were

seen in 4 of 4 animals at 300 mg/kg. Naltrexone given orally in capsules produced

hypoactivity, salivation and emesis at 1000

mg/kg and one of 4 animals convulsed and

died at 3000 mg/kg.

SUBACUTE TOXICITY STUDIES IN RATS

Naltrexone was administered orally by gavage

for 90 dose-days to 3 groups of 50 rats (25

males and 25 females) receiving 35, 70 and

560 mg/kg of body weight 6 days/week. An

additional group of 25 animals served as controls and were dosed with distilled water.

The dose levels in this experiment were

approximately 35, 70 and 560 times the clinical dose of 1 mg/kg/day of naltrexone in

humans. Except for salivation which occurred

in the high dose animals during most of the

study, and which became in part a conditioned

response, the appearance and behavior of all

the animals on test were essentially normal.

Body weight gain and food consumption were

comparable to control values, as were measured parameters in hematology and blood

chemistry, with the possible exception of an

unconfirmed elevated SGPT in one high level

rat. Except for a slight increase in ketone

in some of the high level animals. all urine

analysis values examined were normal, Although some organs in the high level animals

showed a slight trend toward increased absolute weight and percent of body weight, the

changes are small and showed no definite dose

relationship. There was no mortality that

could be attributed to the drug, but one male

rat in the high dose group was killed in an

apparent dosing accident. All gross examinations at necropsy and subsequent microscopic

examinations of fixed tissues were essentially

normal. There were no findings of any significance that could be attributed to the action

of the drug.

A 30 day subacute toxicity study by the s.c.

route at doses of 3, 15 and 300 mg/kg showed

similar results. There was no lethality and

only at the high dose were mild excitation

and conditioned salivation seen. High dose

males had slightly subnormal weight gain but

no hematological, pathological or clinical

chemistry changes that could be attributed to

the drug were seen.

SUBACUTE TOXICITY STUDIES IN DOGS

Naltrexone was administered orally by capsule

for 90 days to 3 groups of dogs, consisting

of 3 males and 3 females per group, receiving 20, 40 and 100 mg/kg of naltrexone 6

days/week. The high dose was originally 130

mg/kg but was reduced after a few days due

to continued emesis. An additional group of

6 animals served as controls.

Appearance and behavior in most of the dogs

throughout the dosing period were essentially

normal. There was some evidence of slight

depression in two dogs at the low dose and

three dogs at the mid dose during the first

few days of dosing, which subsequently disappeared. Tremor, salivation and emesis

occurred in most dogs when the high dose of

130 mg/kg was given, but decreased markedly

when the dose was decreased to 100 mg/kg.

Conditioned salivation, emesis and intermittent slight depression and hind limb stiffness and tremor continued to occur, but with

decreasing frequency as the study progressed.

Physical, neurological and ophthalmological

examinations, food consumption and weight

gain were essentially normal. At termination,

measured parameters in hematology, blood

chemistry, urine analysis and physical and

neurological examination were comparable

between controls and experimental animals,

and equivalent to pretest levels. Although

there was a slight increase in a few absolute organ weights and/or percent of body

weight ratios, these changes showed no dose

relationship to the drug administration. The

only gross findings present in a majority of

the experimental animals and in two of the

controls at necropsy were minor abnormalities

in the lungs and congestion of the stomach

and duodenum. Both of these are believed to

be associated, at least in part, with the

prolonged feeding of capsules, and with the

salivation and emesis that occurred in many

of the high level and a few of the mid level

dogs. Histologically, the lungs showed evidence of mild to moderate chronic bronchitis

and focal bronchial pneumonitis. The stomachs

and duodenums were essentially normal. The

mammary tissue from all the female animals on

test, including the controls, showed varying

degrees of duct and ductal proliferation and

distention. A few cases of slight hyperplasia

were also noted at both high and low levels.

For the most part, the histological picture

of the mammary tissue resembled a lactating

breast , Sections of liver from a number of

animals, both experimental and control,

showed minor changes that included mild central phlebitis, focal necrotizing granulomas

and congestion. Because roundworms were

found in one dog, and eosinophilic granulomas

17
were noted in mesenteric lymph nodes from a

number of dogs, the possibility exists that

some of the changes in the liver were associated with a parasitic infection. In the

opinion of the pathologist, none of the microscopic changes appeared to be drug-related.

A 30-day subacute toxicity study was also

carried out in dogs, using the s.c. route,

at doses of 2, 10 and 50 mg/kg given 6 days/

week. At the high dose, mild toxic signs

such as lacrimation, salivation, emesis,

hind limb weakness and tremors were seen

during the first week, but all signs gradually diminished and none were seen during

the third week or at any time thereafter.

No changes occurred in any clinical parameters or on physical and neurologic examination and no pathological lesions that could

be attributed to the drug were found.

TERATOLOGY & REPRODUCTION STUDIES

Naltrexone was administered orally to rats

at doses of 10, 30 and 100 mg/kg/day and to

rabbits at 20, 60 and 200 mg/kg/day according to standard protocols for study of reproduction and teratology. These studies indicate that naltrexone had no effect on fertility and reproduction in rats and was not

teratogenic in rats or rabbits.

TWO YEAR CHRONIC ORAL TOXICITY

IN RATS

Study Design

This study was carried out under NIDA contract by Industrial Bio-Test Inc., in

Northbrook. Illinois. It was begun on

9/6/73 according to the following dosing

schedule:

Group Dose Males Females

Control 0 mg/kg 90 90

T-I 10 mg/kg 90 90

T-II 30 mg/kg 90 90

T-III 100 mg/kg 90 90

Animals received these doses from the first

day on the test.

Naltrexone was given by gavage in 0.1 to 0.2

ml distilled water. Rats were dosed at the

same time each day seven days/week. Animals

were housed individually and given ad libitum

access to food and water. Ten animals of

each sex per group were sacrificed after

collection of urine and blood samples after

13 and 26 weeks of testing, and subject to a

battery of hematologic, urinalysis and clinical blood chemistry tests. Gross and histopathologic examinations were also performed

on all of these animals. At the 52, 78 and

104 week periods, fewer animals were sacrificed because of high mortality and gross and

histopathology observations were made on some

recently dead postmortem animals. Blood and

urine samples were taken from 10 animals/sex/

group through the 78th week and on 10 females/

group, and on all surviving males at 104 weeks.

Mortality

The mortality data are presented in Figures

1 and 2, which show weekly cumulative deaths

in each group. These figures do not include

animals that were sacrificed or that were

killed in dosing accidents. As can be seen,

the spontaneous rate of mortality was rather

high, so that at the end of the study the

numbers of survivors were quite small. Among

males, survivors were: 1 control, 2 in the

10 mg/kg group, 2 at 30 mg/kg and 2 at 100

mg/kg; among females the survivors numbered

14, 9, 14 and 5 in the same groups. At only

a few points, however, are there statistically significant (Chi-square test) increases,

and at some points decreases in mortality in

any test group, and these differences are

clearly not dose related.

Gross and histopathologic examination was

conducted on tissues from representative

animals that died from week 27 through the

end of the treatment period. The cause of

death in most animals examined was found to

be inflammatory lesions of the respiratory

system due to chronic murine pneumonia and

acute bronchopneumonia which resulted in

respiratory failure.

Reactions

Hyperirritability, expressed as shyness, resistance to handling and dosing and by some

vocalization during dosing, was seen in some

animals in all test groups. Hyperirritability

was roughly dose related and became apparent

at from 3 to 5 weeks. It was maximal from

the 9th to the 12th week during which for

males, 36% at 30 mg/kg and 95% at 100 mg/kg

were affected and for females, 25% at 30 mg/

kg and 95% at 100 mg/kg, were affected.

Irritability declined to 5% or less by 20

weeks and remained there throughout the test

period. The significance of these observations is somewhat obscure since no rieorous

rating scale was used, and observations were

made only once each week. At any rate, the

effect was transient, indicating the possible

development of tolerance.

Alopecia was seen in some test animals, beginning with 2.5% of females in the 100 mg/kg

group at the 14th week and was maximal for

this group in week 26, with about 20% affected.

18
FIGURE 1

NALTREXONE CHRONIC ORAL TOXICITY STUDY

MORTALITY OF MALE RATS (cumulated for each five week period)
FIGURE 2

NALTREXONE CHRONIC ORAL TOXICITY STUDY

MORTALITY OF FEMALE RATS (cumulated for each five week period)
The females in the 30 mg/kg group had about

15% affected at week 26. The incidence of

in females in the 30 mg/kg and/or 100 mg/kg

grouos for adrenals at 13 and 26 weeks. for

alopecia thereafter decreased to less than liver at 26 and 52 weeks and for kidneys at

5% in all groups from the 52nd week to the 52 weeks. These changes were not in any

end of the test. Males had no significant case associated with gross or histopathologic

loss of fur. changes,

No other abnormal reactions were observed in

any of the groups throughout the test.

Body Weight Gain

Mean body weights for each group are shown

in Figures 3 and 4. These show that body

weight gain among all test males were comparable to controls throughout the first 18

months of the test. The variations seen

thereafter are not dose related and can be

attributed to the small number of animals in

each group, leading to a large change in

mean values when a few animals die.

Both sacrificed and postmortem animals showed

lesions of chronic murine pneumonia. In some

of these animals, there were concurrent inflammatory lesions in the lung consisting of

a rather severe bronchopneumonia and pleuritis

which were superimposed on pre-existing

lesions of chronic murine pneumonia. Some

animals had acute inflammatory lesions in

other organs which were probably due to

hematogenous dissemination of the infection

from the lungs.

A depression in body weight gain in all the

treated groups of females is evident from

about 8 or 12 weeks to the conclusion of the

test. There were no dose related differences

among these treated groups, however, and the

differences between treated groups and controls were rather small.

The cause of death in most animals that died

on this test was attributed to inflammatory

lesions of the respiratory tract due to this

murine pneumonia.

Tumor findings were not different among test

and control animals and were of types that

are not unusual for a random population of

adult albino rats of this strain.

Conclusion

Total average food consumption was not different from control in any of the test groups.

Hematology, Clinical Chemistry and Urinalysis

The results of the hematologic studies showed

statistically significant increases in prothrombin time for males in the 30 and 100 mg/

kg groups at 52 and 104 weeks and in females

in all test groups at 104 weeks. However,

these values fall within the normal range

for this parameter as measured in rats of

this age and strain. The results in males,

furthermore, are based on a small number of

animals due to the high mortality. The results obtained in all other hematologic

parameters throughout the study were within

the normal range for rats of this strain,

although some values were occasionally statistically different from control. Except

for an elevated BUN in the few males surviving at 104 weeks, which was neither

statistically significant nor dose related,

results of clinical chemistry and urinalysis

studies failed to show any values outside

the normal range or any dose related effects.

No toxic signs that could be attributed to

the test drug were found in this 2 year

chronic oral toxicity study in rats dosed

daily with 10, 30 or 100 mg/kg of naltrexone.

ONE YEAR CHRONIC ORAL TOXICITY

STUDIES IN MONKEYS

Study Design

This study was carried out under a NIDA contract with Industrial Bio-Test, Northbrook,

Illinois, and the performance site was their

Decatur, Illinois laboratory. In order to

determine the appropriate dose range for the

one year study, a pilot study was undertaken.

In this study, three large older adult (5-

6.5 kg) female monkeys that had been in the

laboratory for a long time, but which had

been drug free for at least 8 months, were

used. These animals were given naltrexone

orally, by capsule, using a balling gun,

according to the following schedule,

Pathology

Gross and histopathologic observations of

sacrificed rats or post mortem animals examined at each interval and at termination

were similar for controls and test groups

in all cases. Organ to body weight and

organ to brain weight ratios were elevated

Test Day Dose (mg/kg)

0-7 72

8-10 90

11-13 108

14-16 126

17-20 144

21-23 126

7 1
FIGURE 3

NALTREXONE CHRONIC TOXICITY STUDY

MEAN BODY WEIGHT OF MALE RATS
FIGURE 4

NALTREXONE CHRONIC ORAL TOXICITY STUDY

MEAH BODY WEIGHT OF FEMALE RATS
When the dose reached 144 mg/kg, there was a

decrease in food intake which disappeared

when the dose was reduced to 126 mg/kg.

There were no other toxic signs in any of

the three monkeys.

The animals used in the one year toxicity

study were obtained from a primate importer

who had held them for 8 weeks in quarantine

to certify them free of serious diseases before release into this country. After these

monkeys were obtained by the contractor,

they were acclimated to his laboratory for 8

weeks and certified to be free of parasites

and of tuberculosis. These young (3-4 kg)

adult Rhesus monkeys could not be shown to

be markedly different from those usually

supplied and used in the contractor’s toxicity studies.

In this study, monkeys were given naltrexone

powder daily by capsule with a balling gun

and controls were given a capsule, empty

during the first few months of treatment,

then filled with lactose powder. Animals

were weighed and dosed at the same time of

day and in the same order and observations

of behavior and reactions were made daily 7

days/week.

The dosing schedule given is as follows:

Group Dose No. Males No. Females

Control 0 8 8

T-I 6 mg/kg 8 8

T-II 12 mg/kg 8 8

T-III 24 mg/kg 8 8

T-IV 72 mg/kg 8 8

Note: The T-II group was begun three months

after initiation of the study and gradually

induced to the full 12 mg/kg dose in 3 mg/kg

increments every two weeks beginning with

3 mg/kg. All other animals were begun immediately on the full dose of naltrexone.

Results

Toxic signs characterized as a “reaction

syndrome” were observed in a total of 41 of

the 80 animals on naltrexone. The occurrence

of the “reaction syndrome” and of mortality

is given in Table 1. This syndrome always

had the same symptoms and sequalae with first

an inappetence that resulted in a sharp decrease or halt in food consumption. This

was followed by subsequent continuing weight

loss throughout the course of the syndrome.

The second sign, seen 2-3 days later, was

mucoid rhinitis, and in a few cases, hemorrhagic colitis, which was often followed by

other signs of respiratory infections including cervical lymphadenitis. Death followed

in from 2 to 10 days after the first loss of

appetite and occurred in all animals where

the drug was not reduced or withdrawn.

As it was felt that it was essential to have

some living monkeys at the end of a year for

pathological analysis and in order to determine the limits of safety, it was decided

that animals would be removed from the drug

when they showed the reaction syndrome.

These animals would then be allowed to recover and then be brought back to their original dose level by induction in 3 mg/kg

increments at one-week intervals. In some

of the sick animals the dose was reduced to a

lower level and then brought back to the

normal level after recovery. The whole 72

mg/kg group was removed from the study 18

days after dosing began, and the 24 mg/kg

group was reduced to 18 mg/kg after 36 weeks

on the study, and another group was added at

12 mg/kg. The 12 mg/kg group was induced to

this dose from 3 mg/kg in 3 mg/kg increments

at 2-week intervals.

The histopathological analysis of animals

that died on this study gave no consistent

drug related findings but did show both

pneumonia and/or throat infections that could

be related to dosing in 7 of 12 of these

animals.

After the time (March 1974) that the reaction

syndrome and deaths occurred and the study

was redesigned, there were no further incidents of sickness in any of the animals on

the study. One animal died as the result of

a dosing accident just prior to sacrifice at

52 weeks. No withdrawal signs were seen

when dosage was discontinued.

Hematology, clinical chemistry and urinalysis

were performed at 0, 4, 13, 26, 39, 48 and

52 weeks of testing on surviving animals.

The only change seen was an elevation of

platelets for T-III females at 52 weeks,

where all 3 survivors had counts of over one

million. There were also no significant abnormalities found after ophthalmologic examinations or in blood pressure, EKG and respiratory rate measured at 0, 13 and 26 weeks of

the study.

Gross and histopathological examination of

all animals sacrificed at 26 and 52 weeks

showed no evidence of drug-related pathological changes.

Conclusions

The results of this study are confounded by

the reduction and stopping of dosing that

occurred at the onset of the reaction syndrome. The study does show that it is possible

24
TABLE I

Figures in parentheses indicate, for each individual animal, the weeks during which

the reactions syndrome occurred; whether the animal died and the week of death.
to chronically administer 12 mg/kg with no

adverse effects provided the dose is reached

in gradual increments. No incidence of the

raction syndrome occurred at 3 mg/kg but was

seen with all higher doses. The reaction

syndrome appeared to be associated with a

loss of the normal defenses against infection,

but whether this is a direct effect or is

secondary to anorexia or other toxic effects

causing the drop in food consumption, is not

known.

SECOND ONE YEAR ORAL TOXICITY

STUDY IN MONKEYS

Due to the confounding of the results of the

one year toxicity study carried out at

Industrial Bio-Test, another one year study

in monkeys is now being carried out by Mason

Research Institute.

Study Design

The study design is as follows:

Dose Males Females

0 5 5

1 mg/kg 5 5

5 mg/kg 5 5

10 mg/kg 5 5

20 mg/kg 5 5

Naltrexone is administered in distilled

water with solutions adjusted so that 1 ml/kg

is delivered using a Nelton catheter and each

dose is followed by 4 ml of distilled water.

During the first month of treatment, final

drug doses were achieved in a step-wise

manner by increasing the dose at weekly intervals from 1 to 5 to 10 to 20 mg/kg. The full

dose was reached in August 1975 and treatment

will be terminated in August 1976. One animal/sex/group was sacrificed at 6 months and

one/sex/group will be observed for a 2 month

recovery period. Animals are dosed daily

seven days/week.

Results

In general, no consistent drug-related behavioral or physiological toxic signs have

been seen except for a dose-related penile

erection that occurred in the earlier weeks.

General health, nutrient intake, all hematological and clinical chemistry parameters

and urinalysis have been normal. The rates

of growth have been intermittently slowed for

some animals but are not related to dose or

food intake. Bodv weight losses in the sixth

month among females could not be definitively

related to circulating drug levels because of

meager data on the latter. In animals sacrificed at 6 months, no drug-related gross or

histopathological cnanges were observed. Absolute and relative organ weights conformed

to those of controls. No monkeys spontaneously died or exhibited morbidity during the

study.

GENERAL CONCLUSIONS

From the studies reported here, it is evident

that naltrexone is not toxic in any species

at doses of at least 20 mg/kg, which is 20

times greater than the recommended clinical

dose of 1 mg/kg. The data from rats and dogs

would indicate than an even larger margin of

safety is possible.

Based on these preclinical studies, the

following parameters should be carefully

monitored in clinical studies with this drug:

Anorexia

Irritability

Nausea and vomiting

Hematology and Blood Chemistry Parameters

Prothrombin time

Platelets

Blood Urea Nitrogen

BIBLIOGRAPHY

1.

2.

3.

4.

Naltrexone Hydrochloride (EN-1639A):

Toxicological Investigations; Research

Report - Endo Laboratories, Inc.,

October 12, 1972.

Chronic Oral Toxicity Study with Naltrexone (EW1639A) in Rhesus Monkeys; Final

Report to the National Institute on Drug

Abuse -Contract # HSM-42-73-262.

Industrial Bio-Test, Inc., July 18, 1975.

Chronic Oral Toxicity Study with Naltrexone (EN-1639A) in Albino Rats; Final

Report to the National Institute on Drug

Abuse - Contract # HSM-42-73-262, Industrial Bio-Test, Inc., February 9, 1976.

The Toxicity of Naltrexone HCl Orally

Administered to Rhesus Monkeys for Six

Months; National Institute on Drug Abuse

Contract # HSM-42-71-79, Mason Research

Institute, May 28, 1976.

AUTHORS

Monique C. Braude, Ph.D. and

J. Michael Morrison, M.S.

National Institute on Drug Abuse

Division of Research

26
THE EFFECTS OF NALTREXONE

IN THE CHRONIC SPINAL DOG

AND ACUTE SPINAL CAT;

POSSIBLE INTERACTION WITH

NATURALLY-OCCURRING MORPHINE –

LIKE AGONISTS

William Martin, M.D., James Bell, Ph.D., Paul Gilbert, Ph.D.,

Jewell Sloan, B.S., James Thompson

Over the last few years our work with the

pharmacology of the narcotic antagonist has

changed rapidly. Following our studies in

which we demonstrated that the narcotic antagonists cyclazocine and nalorphine had agonistic actions and produced a type of physical

dependence that differed from that produced by

morphine, we postulated that they had agonistic actions at a nalorphine receptor, acting

as either partial or strong agonists and

were competitive antagonists at the morphine

receptor (Martin et al., 1965; Martin and

Gorodetzky, 1965; Martin, 1967). It was these

observations that led us to the first practical application of the narcotic antagonists

in the treatment of narcotic addiction because

we had demonstrated: (1) Although tolerance

developed to the agonistic actions of these

drugs, it did not develop to their antagonistic actions, and (2) cyclazocine had a long

duration of action when administered orally

and parenterally in man.

We proposed that the antagonists might help

those patients who wish to remain abstinent

from becoming victims of their own impulsive

drug-seeking behavior in times of stress,

provide a circumstance whereby conditioned

abstinence and drug-seeking behavior would

be psychologically extinguished, and assist

in the physiologic extinction of protracted

abstinence (Martin et al., 1966; Martin and

Corodetzky, 1967; Martin, 1968). It was our

good fortune to study naloxone for its abuse

potentiality and we found that it had neither

agonistic actions of the morphine nor nalorphine type (Jasinski et al., 1967).

In these studies we aiso explored the possible

utility of naloxone as an alternative to cyclazocine for use in antagonist therapy but found

its duration of action too short and its oral

potency too small. This study, however, led

to our investigation of the N-methylcyclopropyl

congener of naloxone, naltrexone, as an orally

27
effective long-acting pure antagonist (Martin

et al., 1971, 1973). Naloxone, we thought,

clearly decided the issue as to whether morphine was an agonist or not and favored viewing morphine as an agonist, a concept that had

not been clearly articulated at that time

(Martin, 1967). We also speculated about the

possibility of the existence of a naturally

occurring agonist and pointed out that the

effects of nalorphine on the EEG, the ipsilateral extensor thrust and respiratory

functions in certain species would be consistent with that formulation. Since naloxone

did not produce hyperalgesia, pupillary dilation, respiratory stimulation or hypophoria in

most preparations, we felt that there was no

natural agonist involved in these functions.

When Hughes (1975) first reported the existence

of a polypeptide that shared actions with morphine on the guinea pig ileum in common with

morphine, we again began to consider critically

the problem of a natural agonist and recalled

our experiments (McClane and Martin, 1967) in

which we demonstrated that naloxone had a

facilitatory action on the flexor reflex. This

facilitation was thought to be “a nonspecific

stimulant action” of naloxone and related to

naloxone’s convulsant action. Naltrexone also

facilitates the flexor reflex of the chronic

spinal dog (Martin et al., in press).

Recent observations suggesting that there are

three closely related receptors in the brain,

the μ, and receptors, which are thought to

be respectively responsible for the euphoric,

sedative and hallucinatory effects of morphineand nalorphine-like drugs, have led to a

reformulation of the role of a morphine-related

natural agonist in brain function. In recent

studies, Dr. Bell has found that both naloxone

and naltrexone facilitate both the C-fiber and

a nociceptive ventral root reflex in the acute

spinal cat. In contrast to earlier observations in the chronic spinal dog, this facilitatory effect increased with dose and was clearly

apparent with minute doses of both naloxone and

naltrexone. Further, Bell and Martin (in preparation) observed that nalorphine which is a

partial agonist of the and type and a competitive antagonist of the μ type-also

facilitated the C-fiber reflex in the acute

spinal cat. In the chronic spinal dog, the

predominant action of nalorphine is to

depress the flexor reflex because of its

agonistic effects. Bell and Martin (in preparation) confirmed the observations of Koll

et al. (1963) showing that morphine depressed

the C-fiber reflex. WIN 35,1972, a pure

agonist that does not appear to occupy the

morphine receptor, also depresses the C-fiber

reflex. Naloxone and naltrexone antagonize

the effects of both morphine and WIN 35,1972

but six times as much naloxone and naltrexone

are needed to antagonize WIN 35,1972 as is

necessary to antagonize morphine. These

findings are similar to those of Kosterlitz

et al. (1974) in the guinea pig ileum and to

those made by Gilbert and Martin (in press)

in the morphine- and cyclazocine-dependent

animal. Cyclazocine is both a potent and

agonist.

These latter observations clearly indicate

that the spinal cord of the cat like that of

the dog has both μ and receptors and that

naloxone and naltrexone although acting as

competitive antagonists at both receptors

have a higher affinity for the μ than the

receptor. The experiments with nalorphine

would also argue that there is a naturally

occurring μ agonist in the spinal cord.

Considering that nalorphine is a partial

agonist of the type, it must be further

postulated that the level of μ tone in the

spinal cord must be larger than nalorphine’s

depressant agonistic activity and when the

μ depressant activity is antagonized by

nalorphine, the resultant dysinhibition predominates. To explain the high potency of

naloxone and naltrexone in facilitating the

flexor reflex of the acute spinal cat but

their relative inactivity in facilitating

the flexor reflex of the chronic spinal dog,

we have postulated that there are μ pathways descending from the brain stem that are

inhibitory to the C-fiber and flexor reflex

(Bell and Martin, in preparation). There

are also intraspinal inhibitory neurones

in the acute spinal cat. The descending

inhibitory μ pathways must have considerable activity below the level of transection, hence accounting for the high

potency of naloxone and naltrexone in facilitating these reflexes. In the chronic spinal

dog, however, these descending pathways have

presumably degenerated leaving only the

intraspinal pathways which have a relatively low level of activity (see Figure 1).

It still remains to be demonstrated that

naloxone and naltrexone have hypoalgesic

effects in the intact animal and we must

assume at this time that in all

probability their activity in the awake rat,

mouse and dog is quite low; however, if one

assumes that one of the roles of the

agonistic system in the dog is the production

of sleep and the inhibition of certain types

of convulsive activity, then the convulsant

activity of naloxone and naltrexone and the

sedative action of WIN 35,197-2 and ketocyclazocine can be readily explained.

As has been previously mentioned, the experiments of Gilbert and Martin (in press) strongly

suggest that morphine is both a μ and

agonist. We have thus initiated experiments

to determine if we can identify the morphine

8
and the receptors in vitro. In homogenates

of the brain which have been incubated with

tritiated naloxone, morphine, levorphanol and

WIN 35,197-2 prevent the binding of naloxone

to receptor sites in rat brain homogenates.

The inhibition of naloxone binding to these

drugs is dose-related; however, a ceiling

effect is encountered by all three drugs. The

fact that WIN 35,197-2 does displace naloxone

clearly indicates that there are receptors

in the rat brain homogenates.

FIGURE 1

Figure 1. Hypothetical role of μ and agonists

in spinal cord function.

The right half of this diagram illustrates the

situation obtaining in the acute and the left

side in the chronic spinal animal. Long axon

neurones are illustrated arising in the brain

stem and projecting down the spinal cord to a

lumbosacral pathway. It is hypothesized that

these long neurones liberate a μ agonist which

is inhibitory to the flexor and C-fiber refflex.

Also illustrated are intraspinal short axon

neurones which are postulated to liberate a

agonist which also is inhibitory to the flexor

and C-fiber reflex.

REFERENCES

Bell, J. A., W. R. Martin: The effect of the

narcotic antagonists naloxone, naltrexone

and nalorphine on spinal cord C-fiber

reflexes evoked by electrical stimulation or

radiant heat. In preparation.

Gilbert, P. E., W. R. Martin: The effects of

morphine- and nalorphine-like drugs in the

nondependent, morphine-dependent and

cyclazocine-dependent chronic spinal dog.

J. Pharmacol. exp. Ther., in press.

Hughes, J.: Search for the endogenous ligand

of the opiate receptor. Neurosciences Res.

Prog. Bull., 13:55-58, 1975.

Jasinski, D. R., W. R. Martin, C. A. Haertzen:

The human pharmacology and abuse potential of

N-allylnoroxymorphone (naloxone) . J.

Pharmacol. exp. Ther., 157:420-426, 1967.

Koll, W., J. Haase, R. M. Schütz, B. Mühlberg:

The predilective action of small doses of

morphine on nociceptive spinal reflexes of low

spinal cats. Int. J. Neuropharmacol., 2:

57-65, 1963.

Kosterlitz, H. W., A. A. Waterfield, V.

Berthoud: Assessment of the agonist and antagonist properties of narcotic analgesic drugs by

their actions on the morphine receptor in the

guinea pig ileum. In: Narcotic Antagonists,

Advances in Biochemical Pharmacology, Vol. 8,

pp. 319-334, eds. M. C. Braude, L. S. Harris,

E. L. May, J. P. Smith, J. E. Villarreal,

Raven Press, New York, 1974.

McClane, T. K., W. R. Martin: Effects of morphine , nalorphine , cyclazocine and naloxone on

the flexor reflex. Int. J. Neuropharmacol.,

6:89-98, 1967.

Martin, W. R.: Opioid antagonists. Pharmacol.

Rev., 19:463-521, 1967.

Martin, W. R.: The basis and possible utility

of the use of opiate antagonists in the

ambulatory treatment of the addict. In: The

Addictive States, Ass. Res. Nerv. Ment. Dis.,

Vol. 46, pp. 367-377, ed. A. Wikler, Williams

and Wilkins, Baltimore, 1968.

29
Martin, W. R., C. W. Gorodetzky: Demonstration

of tolerance to and physical dependence on

N-allylnoxmorphine (nalorphine). J. Phumacol.

exp. Ther., 150:437-442, 1965.

Martin, W. R., C. W. Gorodetzky: Cyclazocine,

an adjunct in the treatment of narcotic

addiction. Int. J. Addict., 2:85-93, 1967.

Martin, W. R., H. F. Fraser, C. W, Gorodetzky,

D. E. Rosenberg: Studies of the dependenceproducing potential of the narcotic antagonist 2-cyclopropylmethyl-2’-hydroxy-5,9-

dimethyl-6,7-benzomorphan (cyclazocine, WIN

20,740; ARC II-C-3). J. Pharmacol. exp.

Ther., 150:426-436, 1965.

Martin, W. R., C. W. Gorodetzky, T. K.

McClane: An experimental study in the treatment of narcotic addicts with cyclazocine.

Clin. Pharmacol. Ther., 7:455-465, 1966.

Martin, W. R., D. R. Jasinski, P. A. Mansky:

Characteristics of the blocking effects of

EN-1639A (N-cyclopropylmethyl-7,8-dihydro-14-

hydroxynormorphinone HCl). Presented to

Committee on Problems of Drug Dependence,

National Research Council, Toronto, 1971.

Martin, W. R., D. R. Jasinski, P. A. Mansky:

Naltrexone, an antagonist for the treatment

of heroin dependence. Arch. Gen. Psychiat.,

28:784-791, 1973.

Martin, W. R., C. G. Eades, J. A. Thompson,

R. E. Huppler, P. E. Gilbert: The effects of

morphine- and nalorphine-like drugs in the

nondependent and morphine-dependent chronic

spinal dog. J. Pharmacol. exp. Ther., in

press.

AUTHORS

William R. Martin, M.D., James A. Bell, Ph.D.,

Paul E. Gilbert, Ph.D., Jewell W. Sloan, B.S.,

James A. Thompson.

NIDA Addiction Research Center

Lexington, Kentucky

30
THE DEVELOPMENT OF

SUSTAINED ACTION

PREPARATIONS OF NARCOTIC

ANTAGONISTS

Robert E. Willette, Ph.D.

INTRODUCTION

The use of narcotic antagonists in the

treatment of opiate addiction is based on

the concept of a pharmaceutical agent

capable of blocking the reinforcing properties of a dose of opiate taken during an

addicts rehabilitation. The rationale for

use is that the antagonist blocks the opiate

“high” and makes it pleasureless, thus removing the addict’s incentive for continued

use. Earlier successful therapy with

cyclazocine and naloxone prompted the fullscale development of new and superior antagonists. Presently naltrexone is the drug

under the most intensive clinical evaluation

and appears to be a promising antagonist

candidate.

It was felt from the outset that a most

desirable component of antagonist therapy

would be long-acting drug, so that the need

for an addict to decide to take his medication would be minimized. Naltrexone in oral

doses of 70 mg. will provide adequate blocking protection for at least 48 hours, or

perhaps 72 hours in certain individuals.

This is not felt to be a long enough interval between dosages to aid the addict in becoming dissociated from his drug-taking behavior .

It was recognized very early that in order

to achieve the desired one week, one month

or longer duration between dosages, it

would be necessary to develop a long-acting

drug delivery system or a sustained-release

preparation of an acceptable but shortacting antagonist. A “drug-delivery system”

is the unwieldy but currently favored expression describing any pharmaceutical preparation capable of providing a sustained or

long-acting antagonistic effect. This effect

may be achieved mechanically (e.g., by implanted discs with timed release capacity) or

chemically (e.g., microcapsules, tubes, solid

balls, gelatinous masses injected intramuscularly). Distinct from the problem not considered here, of finding an optimum antagonist, is the problem of inventing suitable

carriers for the antagonist, releasing it

uniformly bit by bit over a period of time.

Efforts to achieve satisfactory drug deliv31
ery systems were launched in the early 1970’s

by the City of New York Public Health Department and by the NIMH Division of Narcotic

Addiction and Drug Abuse, now the National

Institute on Drug Abuse (NIDA).

During this early period, the pioneering efforts of Dr. Seymour Yolles, University of

Delaware, demonstrated for the first time

that a sustained-release of an antagonist

could be obtained from a biodegradable polymer, i.e., polylactic acid. This success

generated expanded and intensified efforts, a

summary of which is the topic of this article.

At the present time, the program supported

by NIDA includes six contracts that are concerned with the development of new delivery

systems and three contracts that have the responsibility of evaluating them for potential

clinical trials. The program is now narrowing down on those candidates that appear

to have the best combination of essential

properties to assure a successful clinical

trial.

SYSTEM DESIGN

SPECIFICATIONS

There are several properties and features

that are important characteristics in the

design and development of a clinically acceptable and useful delivery system. Some

of these are:

1. Adequate and smooth drug release rate;

2. Ease of insertion or injection;

3. Consideration for the difficulty of

removal by the patient versus the

desirability of possible removal by

the physician;

4. Biocompatability or lack of adverse

tissue reaction or pain upon injection;

5 .

6..

Ease and expense of manufacture;

Stability to sterilization;

7. Stability and storage characteristics;

8. Patient and physician acceptability.

Each of these considerations has a different

relative importance and it is the task of the

development team to select the optimal compromise of suitable specifications in order

to bring a candidate preparation into clinical trial. It is recognized that the first

trial preparation may not be the ideal

system and that additional refinement may

be necessary before a system could be introduced into wide clinical usage.

DEVELOPMENT PLAN

In the Spring of 1973, a new program for the

development of a long-acting narcotic antagonist was initiated. It consisted of two

contracts and two grants directed at the

design and preparation of candidate delivery

systems. Each group was also responsible for

carrying out preliminary screening of the

systems by in vitro and in vivo tests to

select those that had the most promising release properties. This group included work

on polylactide microcapsules, polylactidepolyglycolide beads, polyglyceride pellets

and an insoluble salt complex, the later

three having been originated under the

earlier program supported by New York City.

In addition to these projects, three contracts

were let to carryout in centrallized facilities the evaluation of all promising candidates emerging from the developers. These

consist of a multiple level pharmacological

and pharmacokinetic testing schedule as well

as a range of toxicological measures. The

overall scheme was designed in a pyrimidal

fashion with more rigorous criteria required

to pass from one level to the next.

At the heart of this plan was the recognition

that an advisory group composed of scientists

from several relevant areas was essential to

assist in monitoring progress and making the

difficult decisions about which leads to pursue. Their dedication and loyalty to the

program has played a critical role in its

success. The group has consisted of for

more or less of the length of the program:

Drs. Sidney Archer, William L. Dewey, James

T. Doluisio. Fred A. Kincl. Fred Leonard. and

James L. Olsen. Others, including Drs.

Joseph Borzelleca, Douglas R. Flanagan,

Stanley Kurtz, Grant Wilkinson and Ann Wolven,

have also provided important input. Valuable advice and sharing of information has

come from Drs. Gabrial Bialy and Henry

Gablenick from the Center of Population Research, NICHHD, where a similar Program for

long-acting antifertility agents is being

supported.

At the present time the program has narrowed

down to concentrate on four systems that have

demonstrated the most promise. These will be

described next.

CANDIDATE DELIVERY

SYSTEMS

Polypeptide Tubes

32
Arthur D. Little, Inc.

In order to minimize the amount of animal

testing required to receive FDA approval for

an early clinical trial, it was felt desirable to select a system that is capable of

being removed at the end of a month, but

would eventually be able to be left implanted.

A preparation that meets these and the other

criteria is a tiny hollow tube of a synthetic

polypeptide composed of a 35/65 copolymer of

glutamic acid and leucine. Slowly biodegradable, these 2 mm by 10 to 20 mm tubes are

filled with a solid core of naltrexone free

base, which diffuses out through the tube

wall. Rates of release may be adjusted by

varying the wall thickness.

The tubes are manufactured in a fashion

similar to candles, with a fine glass mandrel being dipped at a controlled rate into a

heated solution of the polymer. The tubes

are removed, filled with a little saline, a

solid rod of 90% naltrexone bound in polymer,

and sealed with a ca Sterilization is

readily achieved with autoclaving.

Samples of these tubes have demonstrated up

to 60 day sustained release. Current devices

are releasing 10 to 30 micrograms of naltrexone per hour, which may be low for human

needs. Devices capable of delivering higher

amounts are being tested. Work on variations

in polymer structure is being carried out in

order to achieve a faster rate of biodegradation.

This work is under the general supervision

of Mr. Kenneth Sidman.

Polylactic/glycolic Acid Beads

Dynatech Corporation

Potentially removable by a surgeon, these

1/16 inch beads of 90/10 polylactic and glycolic acid copolymer offer flexibility in

dose administration. Implantable by means

of a trocar, the 70% naltrexone free base

loaded beads have shown continuous release

for more than a month. Samples of beads

have been periodically removed from injection sites and examined for biodegradation.

They gradually soften, grow smaller or

crumble, and eventually become undetectable.

Problems that remain to be overcome are

sterilization, production scale-up and reproducibility of polymer synthesis. The

latter still presents some difficulties because of the desire to produce polymers

without metal catalysts.

This work has been directed by Dr. Donald

Wise.

33

Polylactic Acid Microcapsules

Washington University

Two major advantages of a microcapsule approach to drug delivery is their potential

for zero-order release rates and injectability. To date microcapsules of less than

180 microns of micronized particles of naltrexone pamoate coated with dl-polylactic

acid have shown sustained release for more

than forty days. They have been injected to

date as a suspension in 2% aluminum monostearate gel in peanut oil. Other vehicles

are being tried.

Additional work is still underway on perfecting capsules of naltrexone free base,

which is more desirable as higher payloads

of drug may be achieved and less toxicology

would be required. A suitable sterilization

procedure has not been worked out as yet.

Several methods are being tested and advanced testing will be initiated as soon as

these are ready.

These systems have been developed by Dr.

Kurt Thies.

Naltrexone Aluminum Tannate

IITRI

Based on older formulation approaches, this

insoluble aluminum tannate complex of naltrexone, when injected intramuscularly in a

suspension of 2% aluminum monostearate peanut

oil gel, gives a sustained release of over

thirty days. The complex is readily prepared and easy to sterilize.

In preliminary studies on tissue compatibility, relatively little reaction was seen. It

is known, however, that peanut oil suspensions are prone to cause occasional reactions.

This preparation would require an extensive

amount of toxicological testing in order to

undergo human trials.

This preparation was developed by Dr. Allan

Gray.

EVALUATION PROCEDURES

Preliminary Screening

Each developer was responsible for carrying

out screening of trial preparations by in

vivo and in vitro methods. The test used by

all groups was the mouse tail flick method

of Dewey and Harris. Animals were injected

or implanted with the preparation and at

various intervals, different groups were injected with morphine and their analgetic response measured for continued antagonism.
Some variations in in vitro tests were used,

with the primary purpose of being to establish

a correlation with the animal tests. Eventually, only the in vitro methods became

necessary for general screening. As a

follow-up to the animal testing, injection

sites were examined for gross pathological

reactions. Usually if nothing is observed by

eye, little is found upon histology.

Advanced Pharmacological Evaluation

At Ohio State University under the direction

of Dr. Richard Reuning, all candidate systems

selected from preliminary screening were

tested in the mouse tail flick test under

standard conditions. Those systems showing

unusual promise were then tested in rats

using radiolabeled drug and the pharmacokinetics of release were studied.

In the course of developing suitable test

procedures, considerable work was done on the

metabolism and pharmacokinetics of naltrexone.

This was essential for the calculation of

actual release rates of the systems themselves.

Advanced Toxicological Evaluation

As candidate systems pass on through the

pharmacological testing, they were evaluated

in parallel at Industrial Bio-Test by Mr.

Carmen Mastri. Depending on the dosage form

being tested, the systems were implanted or

injected into mice, rats and intramuscularly

in rabbits. The last is the classical U.S.P.

irritation test. When possible suitable

positive and negative control materials were

run concurrently.

Final Animal Evaluations

The most promising candidates eventually find

there way into the most rigorous evaluation.

The pharmacological test is carried out in

monkeys that are trained to self-administer

morphine. Developed at Parke, Davis and

Company by Dr. Duncan McCarthy the suppression

of morphine administration is an indication

of how long the system delivers an effective

level of naltrexone. At the same time,

samples of plasma are obtained at various intervals and analyzed by the Ohio State group

to determine the exact amount of drug released. Correlation of this data with

pharmacokinetic measures of naltrexone in the

same animals has given a thorough characterization of the candidate systems.

One of these candidates will soon be started

in a detailed toxicological evaluation also

at Parke-Davis. This will involve three

species at three dose levels. Periodic

sacrifices will be made to obtain a detailed

pathological evaluation. The protocol will

be designed so as to assure an early clinical

trial based on the idea of removing the test

system at the end of one month.

SUMMARY

After several years of tedious and often

frustrating efforts, a few promising systems

are now near final evaluation with the intention of conducting a human trial in the

near future.

AUTHOR

Robert E. Willette, Ph.D.

National Institute on Drug Abuse

Division of Research

34
THE NAS DOUBLE-BLIND STUDY

35

EVOLUTION OF THE NATIONAL

ACADEMY OF SCIENCES

STUDY OF NALTREXONE

Samuel C. Kaim, M.D

The 1972 legislation establishing the

White House Special Action Office for

Drug Abuse Prevention (SAODAP) contained a provision encouraging its

Director to promote research programs

to create, develop and test three

classes of drugs:

1) non addictive synthetic analgesics

to replace opium and its derivatives in medical use;

2) detoxification agents to ease the

physical effects of withdrawal

from heroin addiction; and

3) long-lasting, non addictive narcotic antagonists for treatment of

heroin addiction.

In surveying the status of treatment

modalities then in use for opiate

addicts, SAODAP found methadone maintenance the most widely used and the

most effective method for their management. However, it had a number of

drawbacks, including:

1) it substitutes one addiction for

another,

2) the side effects from the agonist

properties of methadone,

3) the logistic problems in providing

a daily treatment,

4) the dangerous diversion of methadone

to the illicit market, and,

5) the negative image of methadone as a

method of social control of minority

groups.

As the above objections to methadone

appeared to be mounting, SAODAP began a

search for new approaches to treatment,

concentrating largely on a pharmacologic

approach involving opiate antagonists.

It was felt that addicts willing to try

this modality would become “immunized” to

the rewarding effects of opiates, even37
tually being deconditioned to their use.

The SAODAP was aware that antagonist

therapy required cooperative, motivated

subjects, so that it might be acceptable

to a limited segment of the addict population.

However, as current treatments also

appeared effective only for segments

of the affected population, SAODAP felt

it was worthwhile to explore any modality

which appeared promising and offered certain advantages over the older methods.

In fact, SAODAP considered a full exploration of the antagonist modality a matter of the utmost urgency. To expedite

its study it was felt necessary to:

1) do it thru a nongovernmental agency

(There are many constraints within

government, including a ban at the

time on the hiring of new employees.).

2) avoid the time lag of putting a contract to open bidding, such as would

be required if the assistance of a

university, research institution,

pharmaceutical company or independent

treatment.

These potential clinical uses were

based on use of an antagonist which

would be essentially free of agonist

qualities, and would be effective for

at least 24 hours after a single oral

dose. The SAODAP had previouslv initiated a major effort,’ in collaboration

with the pharmaceutical industry and

the research community, to develop new

opiate antagonists. Several compounds

were in various stages of developmental

testing: some had undergone toxicity

testing in animals, others were still

being so tested, some had already

undergone Phase I testing in man,

others were in early Phase II testing.

In a preliminary effort to determine

the efficacy of opiate antagonists,

SAODAP had recently initiated a Phase

II testing program in some ten clinics.

Dr. Philip Handler, President of the

National Academy of Sciences, was then

approached as to the feasibility of the

Academy’s involvement in this proposal.

Dr. Handler expressed his own serious

priety of the choice would be raised.

drug testing laboratory were solicited.

3) to seek a sole source contractor of

such eminence that no auestion of proThe SAODAP contacted the NAS/NRC Committee on Problems of Drug Dependence as a

possible contractor, because:

1) the prestige of the NAS would assure

the feasibility of a sole source contract;

2) the CPDD was the oldest body continually concerned with drug abuse and

addiction (over 40 years of existence);

3) the CPDD had several members involved

in the development and examination of

opiate antagonists.

At the first meeting between SAODAP and

the CPDD. Dr. Jerome Jaffe the first

Director of SAODAP, suggesfed that a

narcotic antagonist might have potential value in several clinical situations:

not soon be demonstrated that drug abuse

concern over the drug abuse problem,

could be managed with some success by

which was then much in the public eye,

medical means. Although the Academy

was usually averse to entering into

voicing a fear that extraordinary

“direct operations” of research propolice measures minht ensue if it could

jects, Dr. Handler felt that the urgency

of the problem and the unique attributes

of the Academy combined to dictate an

exception be made. However, he felt

that the huge effort required would be

beyond the capacity of the CPDD, and suggested that a special arrangement be made

for the large endeavor which would have

to be mounted quickly. Subsequent negotiations between SAODAP and the Academy

eventuated in a contract calling for

establishment of a specially selected

committee (with appropriate staff) within the NRC’s Division of Medical Sciences

to perform the following functions:

1) for addicts following withdrawal

from methadone maintenance;

2) for addicts not interested in methadone maintenance treatment, and

3) for young or early users inappropriate for methadone maintenance

38

A. Recommend for testing, from among the

candidate agents, those that should

be used in clinical trials aimed at

determing the efficacy of these

agents in various clinical settings,

and also recommend the various types

of therapeutic programs and various

types of patients in which the drugs

should be tested.

B. Design:
C.

D.

E.

F.

G.

H.

I.

J.

1. Preliminary protocols;

2. Mechanisms and procedures for data

collection; and

3. Criteria and mechanisms for evaluating the performance of the research and its products.

Develop guidelines for use in selecting clinics to participate in a

pilot study, and assist and advise

SAODAP in identifying the clinics

and investigators suitable to the

purpose of the study.

Receive comments, developed by invesitgators in clinics chosen by SAODAP

to participate in the pilot study,

concerning the protocols, criteria,

mechanisms and procedures defined in

“B” above and make appropriate revisions thereof.

On a periodic basis to be defined by

the Committee, receive, analyze and

evaluate progress reports made by the

clinics participating in the pilot

study , to assess appropriate adherence

to and suitability of the protocols,

mechanisms, criteria and procedures

and to determine whether changes

therein are desirable,

At an approprate time during the

course of the pilot studies, appraise

the results obtained and the procedures, mechanisms and criteria used.

Develop recommendations and, if appropriate, revise protocols, etc., for

full-scale clinical studies.

Advise and assist SAODAP in identifying the clinics and investigators

suitable to the purpose of the fullscale study.

Receive, analyze and evaluate progress reports made by the clinics participating in the full-scale studies.

Receive and analyze reports on followup studies on patients who participated in the pilot and full-scale

trials.

Prepare written reports as required

by SAODAP and a final report at the

completion of the study, evaluating

the efficacy of the antagonists

tested and identifying promising

additional study approaches to the

treatment or prevention of narcotic

addiction.

The next step was the formation of the

CENA Committee. The Chairman of the

CPDD Committee, Dr. Leo Hollister, was

asked to help nominate members from the

CPDD to a small ad hoc Committee, which

would later be augmented by appropriate

additional members covering the disciplines which were relevant to the purposes of CENA. Four members of CPDD

were then appointed to serve, under Dr.

Hollister as Chairman. on the CENA Committee. Subsequently; four outside

members (not from CPDD) were appointed,

bringing the final number to nine.

NARCOTIC ANTAGONIST

REVIEW

The SAODAP had previously discussed the

development and testing of antagonists

with several agencies, including the

NIMH, the FDA, the DOD and the VA.

As Director of the Alcohol and Drug

Dependence Service of the VA, I had discussed the potential usefulness of opiate antagonists with Dr. Jaffe and had

surveyed the literature to attempt to

determine which of the compounds might

be the best choice for a large-scale

multi-clinic study of safety, efficacy

and acceptability.

Nalorphine had been earlier considered

for clinical trial in the treatment of

opiate dependence, but was felt to be

impracticable for this use because of

its short duration of action and the

frequency of agonistic effects (Fink

1971).

CYCLAZOCINE

In 1959 cyclazocine, a benzomorphan

derivative, was found to be an active

analgesic which was effective in blocking the effects of opiates in stabilized addicts. In 1966 Jaffe and Brill

and Martin et al. reported clinical

trials with cyclazocine in the treatment of opiate dependence.

Although cyclazocine also had the agonistic side effects of opiates, it was

shown to have a fairly long duration of

narcotic antagonism, to be effective

orally, and appeared to be an effective

modality of treatment of opiate dependence.

39
Since those first trials, other investigators have reported varying degrees

of success in this use of cyclazocine.

Martin and Sloan (1968) have reported

that cyclazocine can produce analgesia,

respiratory depression, miosis, constipation, sedation, irritability, “racing

thoughts, “delusions and hallucinations.

Tolerance develops to these effects, but

not to its antagonistic properties.

They reported that slow induction on cyclazocine allowed tolerance to the side

effects to develop. They started their

six subjects with 0.1 mg orally b.i.d.

and reached a final dose of 2 mg b.i.d.

after a period of 13 to 33 days. At a

4 mg daily dose, it required 6 - 10 times

as much narcotic to produce the same

effects as it did in the same subjects

when they were not receiving cyclazocine.

They also reported a mild abstinence syndrome when cyclazocine is withdrawn from

subjects who have received it chronically. It did not lead to drug-seeking

behavior. An early symptom of abstinence was found to be a feeling of lightheadedness characterized by patients as

“electric shocks.”

Jaffe and Brill (1966) started a cyclazocine trial with a small group of

addicts who, roughly, fell into one of

several categories:

1)

2)

3)

subjects originally interested in

receiving a narcotic as maintenance

therapy;

patients who heard of cyclazocine

from others, and were opposed to

receiving methadone;

others who wish treatment and are

willing to accept whatever is offered.

Their patients were admitted to a medical

ward for physical examinations and laboratory studies. Those physically dependent on opiates were stabilized on methadone and then withdrawn over 3 to 6

days. Forty-eight hours after the last

dose of methadone, patients were tested

with 7 mg of nalorphine. If they had no

discomfort, cyclazocine was started at a

dose of 0.25 mg orally, 8 hours after

the nalorphine. The total daily dose

was (on average) increased by 0.25 mg

every other day.

Side effects noted included: slowing of

thinking, drowsiness, difficulty in

focusing their eyes, masklike faces,

episodes of depersonalization accompanied

by anxiety and depression, insomnia, and

occasionally an increased sense of

energy. Tolerance developed to these

effects.

Thirteen of 15 subjects stayed in

treatment over the short period of

several months at the time of the

report. The patients were atypical:

older, middle class, with little previous contact with the law, and with

few previous attempts at hospital

treatment. Group therapy was utilized,

the patients forming a cohesive group

and enthusiastically seeking to convert others to the new drug therapy.

In a subsequent paper, Brill, Jaffe

and Laskowitz (1967) reported on the

original 15 plus 72 new patients

treated with cyclazocine. The average

hospital stay was 2 weeks, followed by

once weekly outpatient visits. Sixteen were still in treatment at the

time of the second report and 5 who

discontinued cyclazocine still maintained contact with the therapists.

Most of these patients continued to

use drugs, but on a more intermittent

basis.

Ladewig (1971) reported on the treatment

of 12 “motivated” opiate addicts with

cyclazocine. Ten patients remained in

treatment over one year. Seven of those

10 had no relapses, 3 returned to opiate

use.

Petursson and Preble (1970) reported on

the treatment of opiate addicts committed to the Manhattan State Hospital

Drug Addiction Unit for 9 months of inpatient plus 27 months of outpatient

treatment. Sixty-two male addicts

were treated with cyclazocine: 53

achieved a maintenance dose of 8 mg

daily, 9 reached a 12 mg dose level.

Thirty-six of these patients completed

the inpatient program; 13 eloped from

the hospital; 11 eloped from after-care.

Seventy-five percent of these addicts

had been labeled personality disorders.

The authors considered cyclazocine treatment effective in the “motivated” cases.

Resnick, Fink and Freedman (1971)

reported two series of male addicts

treated with cyclazocine in a special

unit at the Metropolitan Hospital Mental Health Center. Patients were primary opiate addicts, over 18 years of

age, and voluntary.

40
Patients were offered the choice of

detoxification only, methadone maintenance or cyclazocine. Induction to

cyclazocine started with 1 mg daily,

increasing to 4 mg daily after an average of 4 days. Naloxone was available

to patients on request, during induction,

as an antidote to the side effects of

cyclazocine.

Cyclazocine was dispensed at the Clinic

or by a responsible person living with

the patient. Of 62 patients, 60 completed the 4-day induction; 38 requested

naloxone during induction, 3 beyond induction (up to 14 days).

Twenty-one patients from an earlier study,

who had been receiving cyclazocine 1-4

years, were all working or in school.

Four patients who discontinued cyclazozine at their own request, had not been

re-addicted. Six patients dropped out

after 7 months to 3 1/2 years on cyclazocine.

In a subsequent study, 59 patients who

requested cyclazocine were inducted to

the drug. (In the previous study

patients merely had to accept cyclazocine.) Twenty-two of the new group

dropped out of the trial. Marital status

and work or school attendance were significant prognostic factors.

NALOXONE

N-ally1 noroxymorphone hydrochloride

(Naloxone) was reported by Blumberg et

al. (1961) to have narcotic antagonist

properties. Jasinski et al. (1967)

found naloxone five to eight times as

potent as nalorphine in precipitating

abstinence in morphine dependent subjects. In contrast to nalorphine and

cyclazocine, naloxone was found not

to produce physical dependence, nor

to have significant agonistic activity.

As in the cases of nalorphine and cyclazocine, tolerance to the antagonistic property of naloxone does not

develop during chronic administration.

Zaks et al. (1969) felt that its relative

absence of agonistic activity and side

effects would make naloxone prefer able

to cyclazocine in the long term treatment of opiate dependence. They found a

daily oral dose of 200 mg afforded six

hour protection against a challenge of

25 mg of heroin. 400 mg of naloxone

afforded blockade of 50 mg of heroin for

6 hours. 800 to 1250 mg of naloxone was

necessary to protect against 50 mg of

heroin for 18 hours. These authors were

unable to achieve 24 hour blockade with

1500 mg of naloxone.

Kurland et al. (1973) reported a double

blind study of the use of naloxone in 119

male addict parolees over a period of 9

months. Subjects were randomly assigned

to one of three groups: a) concurrent

controls were assigned to a weekly program

of group psychotherapy and urine monitoring; b) the naloxone group received

the drug on a fiexible dosage schedule of 200 - 800 mg daily, depending on the results of the urine

tests; c) the third group received

only placebo pills ranging in number from two to eight daily depending on the results of the urine

monitoring. All three groups participated in the weekly group psychotherapy program.

Only 25% of the control group completed the program, contrasted with

44% of the naloxone group and 51%

of the placebo group. The naloxone

group performed better in respect

to incidence of positive urines:

11% vs. 30% for the placebo group.

The authors speculate that these

results may reflect a negative

relationship between effectiveness

and acceptability of naloxone in

these addict parolees: the less

motivated placebo subject may have

realized he could experience his

customary “high” and still remain

marginally involved in the program,

while the less motivated naloxone

subject may have left the program

when he no longer obtained gratification from narcotic drug taking

behavior.

NALTREXONE

Naltrexone Hcl was synthesized by

Blumberg, Pachter and Matossian

of Endo Laboratories (1972). It

is derived by substitution of a

cyclopropylmethyl group for the

methyl group on the nitrogen atom

of oxymorphone, a narcotic analgesic. It is thus chemically

related to naloxone, an almost

pure narcotic antagonist.

Naltrexone shows slight agonist

activity in animals. It is a

very potent antagonist in animals,

about 8 times as active (orally)

as naloxone, and longer acting.

Naltrexone has had acute, subacute

41
Thirteen of the 37 patients reported

symptoms during the first 2 days on naltrexone: some felt tired or sluggish,

nervous or irritable, some had difficulty cation being dispensed for selffalling asleep. These side effects were administration on weekends.

mild or moderate, subsiding within a few

Three patients discontinued naltrexone before completing induction on the drug, but one of

these continued treatment without

medication. Of 20 patients discharged to the outpatient clinic,

17 continued on the program, receiving naltrexone daily, the mediNaltrexone was administered as a single

daily oral dose. Initial subjects

started at 20 mg/daily. This starting

dose was later increased to 30, 40 and

50 mg/day. Daily dose increments were

10 mg/day and later 20 mg/day.

The patients were first detoxified from

opiates and received a complete physical

examination, chest x-ray, SMA-6, SMA-12,

CBC, reticulocyte count, platelet count,

ESR and urinalysis. These exams were

repeated prior to discharge from the hos

pital. The subjects were then maintained on naltrexone at daily dosages of

120 to 200 mg.

Twenty-seven subjects were challenged with 25 mg heroin i.v. Three

of three had complete blockade 24

hours after 50 mg oral naltrexone.

Six of six experienced complete

blockage 48 hours after 120 mg oral

naltrexone. Four of nine reported

blockade 72 hours after a dose of

200 mg naltrexone. One subject

required 200 mg/day naltrexone to

achieve complete blockade at 24

hours.

Resnick et a1.(1973) studied the use of

naltrexone in 37 addict patients during

the period of January through April

1973. Some of these subjects volunteered for this experimental treatment

following a period on a methadone maintenance program.

The authors felt that naltrexone has

definite advantages over naloxone because of its greater potency and longer

duration of effectiveness. They also

felt that naltrexone had the advantage

over cyclazocine in its relative lack

of agonis tic effects.

The Lexington group found 50 mg of naltrexone orally produced a level of narcotic antagonism comparable to that produced by 4 mg of cyclazocine. There

were no withdrawal symptoms when naltrexone was discontinued after chronic

oral administration at either the 30 or

50 mg daily dose level.

Five patients complained of intermittent crampy abdominal pain, sometimes

associated with mild nausea. Headache was a fairly common transient

symptom. Most of these symptoms subsided spontaneously or were relieved

by diazepam 10-20 mg daily.

Blood pressure was not significantly

changed, but there was a trend toward

narrowed pulse pressure. Heart rate

and temperature fluctuated unrelated

to naltrexone dosage. No significant

changes were noted in laboratory

determinations.

Eight of 10 subjects abruptly withdrawn from 200 mg/day naltrexone

experienced no abstinence effects.

One subject complained of headaches,

fatigue and malaise; another had

chills and abdominal pains on the

first withdrawal day.

Martin, Jasinski and Mansky (1971) After the first four days of naltrexone

tested naltrexone in volunteering induction, 22 of 34 patients experienced

prisoner post-addicts. On oral ad- no symptoms during the period of increasministration, most subjects reported ing doses to the 1.26 to 200 mg daily

no symptoms, excepting two who be- level. There was no consistent differcame sleepy. Diastolic blood pres - ence in the incidence or intensity of

sure increased slightly, body tem- symptoms which appeared at 20 mg/day inperature decreased slightly, pupils crements compared with 10 mg/day increwere slightly constricted. ments.

and 90-day toxicity studies in

animals. With oral administration,

it produces only mild toxic effects

at 100 mg/kg/day, which is 30 times

the probable maximum clinical dose

of 200/mg/60 kg/day.

in dose. No subject reported these

symptoms following stabilization on a

fixed daily dose. The authors felt that

these symptoms resulted from precipitated

abstinence.

days, usually despite further increments

42
The authors found naltrexone to fulfill the criteria for clinical usefulness in treating opiate dependence: a) oral effectiveness, b) non

addicting, c) providing blockage to

heroin for 24 hours or more following a single dose.

SUBSEQUENT PROGRESS

After retiring from the VA and subsequently joining the NRC as Director

of the CENA staff, I circulated my

literature survey among the members

of the CENA Committee.

Although other newer opiate antagonists were becoming available (e.g.

BC 2605. M5050), none had reached

a stage’of study which would have

permitted large scale human studies in

the near future.

Of the three chief contenders, naltrexone

appeared the closest to fulfilling the

criteria for an antagonist suitable for

use as part of a long-term regimen for

the treatment of opiate addicts:

1) it is orally effective for 24-72 hours,

depending on dose;

2) it is not addicting;

3) it appeared to be relatively nontoxic, and

4) its side effects were fairly minor

and well tolerated.

In contrast, cyclazocine had many disagreeable agonistic effects and naloxone

has a short duration of action, even in

large doses.

The difficulty with naltrexone lay in its

rather short history of human trials.

However, animal and human studies were

still under way. The Committee decided

that if the latter should prove the drug

safe for chronic administration, naltrexone would be selected for the study.

At the first meeting of the Committee,

September 21, 1973, the Chairman appointed

a Subcommittee to decide on preliminary

protocols for the CENA pilot studies. and

another subcommittee to develop the instruments necessary for the purpose of the

studies. Dr. Hollister also stressed the

need to select the clinics for participation in the studies on the basis of good

medical and laboratory support and staff

oriented toward evaluating results.

At the February 1974 Committee meeting it

was decided to pretest the proposed measurement instruments in six VA Hospitals,

and also to survey prospective study

clinics as to availability of appropriate

subjects and as to attitudes of staff and

patients toward withdrawal from methadone

maintenance and toward use of a narcotic

antagonist.

Following several meetings of the subcommittees, measurement instruments and three

study protocols were adopted by the full

committee.

Clinics which met the committee’s criteria

were site visited by CENA staff, and then

selected to participate in the studies,

one assigned to the “street addict”, two

to the “post-addict” and the remaining two

to the methadone maintenance protocol:

NAS. with the authorization of SAODAP.

entered into subcontracts with Educational Testing Service for standardization of the instruments, and with

Biometric Research Institute for collection, collation and analysis of

the data to be gathered in the trials.

Training visits were then made by

staff of CENA and BRI to the five

participating clinics and to two VA

hospitals which agreed to complete

sets of study forms for use by ETS

in its standardization effort.

The PHS pharmacy in Perry Point,

Maryland, which had prepared the

study medication, released it in

mid-1974 and the clinics began

to process subjects for entrance

into the trials.

REFERENCES

Blumberg, H., Dayton, H.B., Rapaport,

G.M. and Rapaport, D.N. (1961) N-Allylnoroxmorphone: a potent narcotic antagonist. :311.

Brill, L., Jaffe, J.H. and Laskowitz,

D. (1967) Pharmaceutical Approaches

to the Treatment of Narcotics Addiction: Patterns of Response. Presented at 29th Annual Meeting of NAS/

NRC Committee on Problems of Drug

Dependence, Lexington, Ky.

Fink, M. (1971) A Rational Therapy of

Opiate Dependence: Narcotic Antagonists.

43
Jaffe, J.H. and Brill, L. (1966)

Cyclazocine, a long-acting narcotic

antagonist. Presented at 28th Annual

Meeting of Committee on Problems of

Drug Dependence, NAS/NRC, New York.

Jasinski, D.R., Martin, W.R. and Haertzen, C.A. (1967) The Human Pharmacology

and Abuse Potential of N-Allylnoroxymorphone (Naloxone). Presented at 29th

Annual Meeting of NAS/NRC CPDD, Lexington, Ky.

Kurland, A.A., Hanlon, R.E. and McCabe,

L. (1973) Naloxone and The Narcotic

Abuser: A Controlled Study of Partial

Blockade. Presented at 35th Annual

Meeting of NAS/NRC Committee on Problems of Drug Dependence, Chapel Hill,

N.C.

Ladewig, D. (1971) Die Klinische Behandlung Drogen Abhangiger.

Mart.in, W.R., Gorodetzky C.W., Kay,

D.C.. McClane. T.K.. and Jasinski. D.R.

(1966) Activities of the Addiction

Research Center during 1965. Presented

at 28th Annual Meeting of Committee on

Problems of Drug Dependence, NAS/NRC,

New York.

Martin, W.R., Jasinski, D.R. and Mansky,

P.A. (1971) The Effects of EN 1639A in

Man, An Antagonist for the Treatment of

Heroin Dependence. Presented at 33rd

Annual Meeting of NAS/NRC CPDD, Toronto, Ontario.

Martin, W.R. and Sloan, J.W. (1968)

The Pathophysiology of Morphine Dependence and its Treatment with Opioid

Antagonists.

Medical Division, Endo Laboratories

(1972) Naltrexone HCL (EN1639A)

Petursson, E.S. and Preble, E. (1970)

Use of Cyclazocine in the Treatment of

Heroin Addicts.

Resnick, R.B., Fink, M. and Freedman,

A.M. (1971) Cyclazocine Treatment of

Opiate Dependence: A Progress Report.

Resnick, R.B., Volavka, J., Freedman,

A.M., Jones, T. and Thomas, M. (1973)

Studies of EN 1639A (Naltrexone) -- A

New Narcotic Antagonist. Presented at

Annual Meeting of Am. Psychiat. Assn.,

Honolulu.

Zaks, A., Fink, M. and Freedman, A.M.

(1969) Naloxone in the Treatment of

Opiate Dependence. A Progress Report.

Presented at 31st Annual Meeting of

NAS/NRC Committee on Problems of Drug

Dependence, Palo Alto, Calif.

AUTHOR

Samuel C. Kaim, M.D.

National Pharmaceutical

Council, Inc.

1030 15th Street NW

Washington, D.C. 20005

44
PHILOSOPHY AND STATUS OF

NAS CENA STUDY

Leo E. Hollister, M.D.

Narcotic antagonists as potential treatments

for opiate addiction provided a classic

example of how medical science often gets

involved in politics. Despite some indication of a temporary decrease in the rate of

addiction in the United States, political

pressures were still high in 1973 to "do

something" about the opiate problem. Narcotic

antagonists seemed, at least to the politicians, as a new magic bullet which might

quickly and cheaply solve the problem. What

could be simpler than to block completely the

action of narcotics and thus make their use

unrewarding? And what could be simpler than

allocating a great deal of money to get these

magic bullets into the patients?

So great was the rush that ordinary administrative procedures were not considered adequate. One could not take time to await

grant applications for the study of narcotic

antagonists, nor even to solicit ordinary

contracts. A contractor of such high scientific esteem had to be obtained which would

qualify as a "sole source" so that studies

could be started right away. The National

Academy of Sciences, through its Committee on

Problems of Drug Dependence (CPDD), was a

natural contractor. Accordingly, the first

overture from the Special Action Office for

Drug Abuse Prevention (SAODAP) was to the NAS

Committee on Problems of Drug Dependence.

For reasons still not entirely clear, the

internal administration of the NAS decided

that the CPDD was not the proper vehicle for

doing this study, but rather that a special

committee, the Committee on Evaluation of

Narcotic Antagonists (CENA), be set up. The

chairman of CENA was also the chairman of the

CPDD and several members were recruited from

CPDD, but administratively the committees were

separate. Additional members were recruited

from outstanding people in fields not heavily

represented on the CPDD, but thought to be

useful for doing an evaluative study.

During the preliminary negotiations, a fire

line had to be drawn between 'operational" and

"advisory" functions. The NAS was quite sticky

about its role only as an advisor and did not

want to run the study. To some extent, this

attitude frustrated the hope of SAODAP that the

CENA might operate as a true sole source contractor. CENA did, in fact, become an advisory committee and SAODAP was forced to contract

with those clinics selected to do the study.

The contract was signed on the very last day

of the fiscal year in which the money had been

appropriated, a situation not too uncommon in

the government.

45
With its role clearly delimited, the task of

the CENA was to select the drug or drugs to be

studied, to advise on the suitability of the

clinics proposed for the study, to devise an

experimental protocol and data collection

procedure, to oversee the independent contractor doing the statistical handling of the data,

and to prepare a summary report of the study

when it was completed, All this was to be

done in three years.

The major task of CENA was the preparation

of the protocol and the data collection procedure. We decided that a controlled comparison of the narcotic antagonist, in this

case naltrexone, was to be made against a

placebo. This decision was made because we

felt that one should at least try to ascertain the feasibility of doing such a study,

none ever having been done with methadone.

Some of our wildest hopes were that such a

study would not only be feasible but also

that it might provide some preliminary

support for the efficacy of naltrexone.

Another reason for using the placebo control

was that it would provide a control against

questions of toxicity to the drug, whether

these be clinical side effects or abnormal

laboratory values.

In devising the data collection procedure,

we made the Universal error in any such

large-scale formal study, especially of a

new drug or a new area of clinical research.

We collected far more data than we could

possibly use, and much that in retrospect

proved to be useless. Inefficiency of this

sort is unavoidable, and probably necessary,

as it provides a future basis for efficient

and pertinent data collection.

We had hoped to explore simultaneously protocols concerned with three types of opiate

addict: a) those who had been recently detoxified coming directly off the street; b)

those who were at high risk of relapse even

though currently drug-free, such as patients

returning to the street after a term in prison, in which a condition of parole would be

the entry into some treatment program, and

c) those who were detoxified after a long

course of methadone maintenance treatment.

These goals were worthy, but as things turned

out, they were not very feasible for a number

of reasons.

We anticipated that many patients would be

potential candidates for treatment and that

it would be important not only to know what

sort of patients entered treatment but also

what sort did not. A high refusal rate was

expected, but even with the most liberal

projections, we never fully anticipated the

small yield of patients eventually attained.

We also expected that of those actually

entering treatment, a high dropout rate would

be encountered. Here, too, our advance estimates, even though realistically high, were

far short of the actual experience,

There was some concern that patients

assigned to placebo might overdose by experimenting to see whether or not they were on

the antagonist or on the placebo. This

concern was not substantial, for we felt

that no one would be likely to use an initially large dose Until a smaller one had

first failed, in which case they might try

to overshoot the antagonist. Both at the

time the study began, and for most of its

duration, heroin of considerable potency was

simply not available on the street. We,

expected an amount of experimentation which

might make the "blind" aspect of the study

only relative.

So we embarked on a phase III study on a

drug still Undergoing phase II trials. When

politicians want answers, they want them

fast. Or if they don't get answers, at

least they want fast action. The conditions

Under which this study was inaugurated were

certainly far removed from those which would

ordinarily be done by deliberate, thoughtful clinical scientists.

Well, where do we stand almost three years

later? Was the entire CENA study a monumental waste of time, effort and money, one

of those vast cost over-runs which hasty

expediency in governmental affairs breeds?

The answers are partly "yes" and partly "no".

The CENA study demonstrated the feasibility

of doing a controlled study of narcotic

antagonists. Naltrexone was successfully

compared against a placebo, and were one

given enough sample size possibly significant

differences might be shown. Still, this

comparison is made at an enormous cost, and

with such a high rate of attrition as to

leave the results obtained, whatever they may

be, somewhat questionable. The extraordinarily small sample of all potential candidates for the study represented by those

groups which completed treatment for any

appreciable period of time creates an enormous negative bias. One must assume that

only the most highly motivated patients were

ones who entered and stayed, and these would

be quite naturally those who least needed

any specific assistance. Thus, should we show

a statistically significant difference between

those treated with naltrexone and those

treated with placebo in regard to staying in

the study or in their use of opiates while

in the study it would have been accomplished

against this negative bias. Should we fail

to show any such differences, we shall not

be sure that we have truly failed to find a

difference between the two treatments. Even

46
under the best of circumstances, a no-difference result proves little, but in this

situation it would prove nothing.

The CENA study has culled out a lot of information that for one reason or another seemed

to be worth gathering, so that it might now

be possible to arrange for a data collection

system for future studies which would be far

more efficient and pertinent. Unfortunately,

we did not take the time to test the reliability

of the data we collected. When dealing with

such unreliable sources as addicts themselves,

such reliability studies are a major concern.

The CENA study has probably been most valuable in proving that naltrexone can be given

in the rather liberal dosage schedules postulated with a great deal of safety. Without

the inclusion of the placebo control, several

issues concerning its safety would have been

raised. The placebo control provided reassurance that the drug was acceptably safe,

regardless of how efficacious it may ultimately be found to be. Other uncontrolled

clinical trials run concurrently with the

CENA study confirm the safety of the drug.

So where are we now? Data collection has

been concluded and the data analysis and

summary report should be completed before

the end of the year. It is most unlikely

that the CENA study will prove the efficacy

of naltrexone as a treatment for opiate

addiction. Rather, it will point out in a

most forceable way that oral naltrexone

will be an acceptable, and probably highly

effective, treatment only for patients

whose desire to rid themselves of the

opiate habit is so great that the contribution of the drug as compared with placebo is extremely hard to assess. One

will be able to say that this sort of

treatment can be offered patients with

some assurance that they will not deliberately overdose in an attempt to overshoot the blockade of the drug and with

some assurance that for moderately longterm treatment the drug is safe. Future

studies evaluating treatment of opiate addiction will have available a standard set of

pertinent data to assess the results of

treatment.

And so naltrexone remains a paradox.

Clearly, this treatment could make the

use of opiates totally unrewarding. It

seems unlikely, if not impossible, that

many addicts could obtain enough heroin to

overshoot the blockade produced bv these

doses of naltrexone. Thus, from a

pharmacologic viewpoint, the drug is an

assured success. The paradox is-that it

can't be delivered. When offered as an

intermittent oral dosage schedule to suitable candidates for treatment, it is acceptable only to a small minority, only a few

of whom persist in taking the drug for any

period of time. The paradox is that we

have a good drug which we can't give away.

But this paradox may not be unsolvable. One

can hope that other delivery forms of

naltrexone may mitigate these problems and

that it might still live up to the promise

which only a short time ago made its study

such a matter of high priority.

AUTHOR

Leo E. Hollister, M.D.

V.A. Hospital, Palo Alto, CA

47
VARYING CLINICAL CONTEXTS

FOR ADMINISTERING

NALTREXONE

Marc Hurzeler, M.D., David Gerwirtz, M.S.,

Herbert Kleber, M.D.

The employment of narcotic antagonists in

the treatment of opiate dependent individuals is a subject of growing importance

and attention. The by-now traditionally

accepted modalities of methadone maintenance and therapeutic communities both

have their various disadvantages which do

not require reiteration here. It is

sufficient to recognize that alternatives

to existing treatments for opiate dependence would be highly welcome.

While the existence of narcotic antagonists has been known as long ago as 1915

(Jaffe, 1975), actual work in applying

narcotic antagonists to the problems of

opiate dependent patients in a systematic

clinical way has spanned perhaps a decade

at most of recent history. Much of the

work that has been done so far has been

predicated on the concepts of experimental

extinction of both classical and operant

conditionings of drug seeking behavior as

described by Wikler (1964). Work has been

done with Cyclazocine and with Naloxone

(Jaffe 1975) which has established these

agents as effective but limited modalities.

Cyclazocine is recognized as having long

duration but unpleasant side effects for

some patients, while Naloxone exhibits a

short duration with minimal side effects.

When Naltrexone was synthesized (1965)

it was soon recognized as partaking of the

best qualities of both Cyclazocine and

Naloxone and as such, seemed to be an

outstanding candidate for the further

exploration of the possibilities of narcotic antagonist therapy. Naltrexone

was found to have little or no side effects

and a duration sufficiently long so that a

single oral dose could be given to block

euphoriant effects of heroin for 24, 48, or

even 72 hours if the dose were sufficiently

large (Resnick, 1974).

Naltrexone has thus become the subject of a

number of investigators who are studying the

safety and efficacy of antagonist therapy.

As these questions have been dealt with

(namely, safety and efficacy), a third dimension of Naltrexone's usefulness, which might

48
be called its applicability, has increasingly

become the object of attention. Granted that

Naltrexone works, for whom will it work best

and longest? Put another way, who will be

willing to take this substance which is not

addicting like Methadone and not confining

like a residential program? Naltrexone is a

cure in search of an audience. Thus, three

questions have to be asked about this substanceis it safe, is it efficacious, and is it

applicable?

At this time the first two questions have

been sufficiently answered by other researchers (Resnick et al. 1974, Martin et al. 1973)

as well as the research conducted at this

clinic (which is described below). The third

question remains unanswered and is the primary

focus of this paper. In a detailed fashion,

varying clinical contexts for administering

Naltrexone are described and used as a medium

through which the investigators believe some

clarification concerning this question can be

sought. In the following sections, the programs

are first described and then the results of

these programs will be given under three

headings: Medical Observations, Program Retention and Attrition, and Other Relevant Findings (about factors associated with programmatic success). After this, some brief

conclusions are offered and a glossary of

the abbreviations used in this paper is given.

Naltrexone has been under clinical investigation in the Drug Dependence Unit of the

Connecticut Mental Health Center since 1973.

The process has not been a continuous one,

and the breaks in time have served to

divide the work into three phases which we

will call Naltrexone I, Naltrexone II, and

Naltrexone III (in the figures these phases

have also been called Naltrexone First Series,

Naltrexone Second Series, and Naltrexone Third

Series).

Before the programs under these titles are

discussed a summary is given of the Low

Intervention Program and the patients treated

in the clinic.

PROGRAM FORMAT

The Low Intervention Program is a component of

the Drug Dependence Unit of the Connecticut

Mental Health Center. In this facility, narcotic addicts are treated with twice a week

group therapy (two 90-minute sessions, in the

evenings, of a modified encounter type) and

individual counselling on an as-needed basis.

The patients are also required to void three

urines per week on a random basis, and ingest

narcotic antagonist medication according to

schedules dictated by the research protocols

employed. At that point in the program in

which an individual's narcotic antagonist

therapy is terminated he continues to be

treated with the basic modalities of the program, i.e. group therapy and urine testing,

until such time as he is deemed ready for

discharge by the staff. This judgment is

made only after deliberation by the staff

and involves an assessment of the individual's

programmatic adjustment as well as his overall life adjustment. The general time model

employed in making these judgments has been

about one year for those individuals who

stayed with the program. Concretely, in

the Low Intervention Program the typical

experience for a patient has been to go

about his business of being either a worker

or student during the day and then to attend

group therapy two evenings a week and to

void three urines per week according to a

randomized schedule. During this time he has

had the two official contacts with group

therapy, as well as a number of informal contacts with both counsellors and nurses incidental to his voiding urines, taking medications and undergoing medical testing, In

addition, as mentioned earlier, the patient

has also been subject to individual counselling when this was felt to be needed. It will

be noted that there has been a stress on the

function of the patient above and beyond his

managing to come to the program. This will be

further elaborated on in the discussion of

the patients. The staff has consisted of a

director, three ex-addict counsellors, two

nurses, a research associate, a secretary

(all of the above on a full time basis) and

a part time internist as well as consultants

on a limited basis. The same approximate

staffing pattern has been maintained throughout, although there have been some variations

largely with respect to the number of clinical

personnel whose number was in turn determined

by the census of the clinic.

Patient Population

The patient population studied in the three

phases of Naltrexone research, has been defined,

first of all, by the criteria of inclusion/exclusion which have been used throughout. Where

there have been changes in the criteria which

in fact have always been minor, these changes

will be noted in passing. The criteria of

inclusion have been maleness, age of 18 to 45,

and a verifiable history of opiate dependence

(at first a rigid criterion of two years of

opiate dependence was called for; by the time

of the Third Naltrexone Study, which was done

under the aegis of NAS, this requirement had

been changed to any period of verified opiate

dependence with a lower limit set at about

six months - in fact, most patients admitted

to the program had longer drug histories

than this lower limit and the average was

49
greater than two years). Patients to be

excluded were essentially those suffering

from mental and/or physical illness sufficient to either (a) cause absence from the

program or (b) necessitate continuing medication (which might cause unknown reactions

with the experimental drug employed in the

study and/or confound the evaluation of physiological and subjective side effects).

Besides the change in stipulated length of

prior opiate usage, there was also a change

made in pre-program drug status requirement.

At the beginning of the NAS (Naltrexone III)

Study, it was stipulated that only currently

non-addicted patients would be accepted

(currently addicted patients were being

studied in other NAS-sponsored research).

This was felt practicable at the time in anticipation of intake of freshly discharged

prison inmates. What eventuated was that

the predominant referral to the program was

not a fresh prison discharge, but a person

who had already been on the street for some

time, often using drugs right up to a level

of being readdicted. After several months

then, the admission criterion was changed

back to one which was used in earlier

studies, i.e. men verified through history, physical and urine tests as currently

addicted were given a preliminary Methadone

detoxification. The other descriptions of

our population derive not from program criteria but from demographic factors which

describe our patients, in the average case,

as young (mean age 24.69 years) adult males,

almost equally black (54%) and white

(46%) who come from urban addresses, and

are of generally low or moderate educational

(mean 11.3 years of school) and socio-economic

status and who typically have been in one

or more programs before their referral to

us. In addition, a standard of the Low

Interventfon Program (which was designed

to make rational the application of the

low intervention structure to an addict

population), i.e. the holding of a job or

a place in a full time educational or skill

program and/or demonstration of social stability by maintaining a household or relationship - was imposed but not with the

utmost of consistency. For one thing, the

uncertain employment situation of the last

few years precluded the rigid enforcement

of the employment requirement: for another,

the judgment of social adequacy, while clear,

in some cases, could not be made with certainty in others. In the long run, the LIP

criteria of vocational and social stability

were used as guidelines but not as definitive

or rigid standards.

Overall then, our population has been a fairly

Experience with Naltrexone at the Low Intervention Program (Three Series)

The three programs which have employed Naltrexone at the Low Intervention Program will

now be described briefly, in chronological order, before the results are presented in a

later section.

The first series was initiated in June 1973 and

had an intake phase which ran until September

of that year. The program was started on an

inpatient basis in order to provide close monitoring of physical and psychological functions

in this early phase of Naltrexone research.

The research protocol called for inpatient

treatment of the first ten patients. Twelve

patients were actually accepted into this phase;

of these twelve, ten completed the inpatient

phase. One of the patients showed signs of

acute hepatitis and was withdrawn from the

study; another patient was quite uncooperative

shortly after being brought into the hospital

and kept referring to his need to take time off

in order to attend to personal business. This

patient was induced twice and still drifted

away after these two experiences and was then

discontinued. He was heard from at a later

time when he applied for Methadone maintenance

in another state, and he was then again heard

from at still a later time when he was eventually treated with Methadone again, in this

area.

The ten inpatients were kept for an approximate

inpatient stay of 28 days (some were actually

discharged a bit sooner than this). This 28 day

period was in keeping with the floor policy at

the Connecticut Mental Health Center where the

work was started. Following their inpatient

stay, the patients were converted over to outpatient treatment at the Low Intervention

Program. After these patients had been transferred over, another five patients were enrolled,

and these individuals started as outpatients

from the very start. Thus, there was a total of

17 patients who were ever on Naltrexone in this

first series and of these, 15 were on it for at

least a substantial period of time. These

patients were all inducted onto the drug by ten

mgm. daily increments up to a level of 50 mgms/

day and they were then treated for 7 days a

week with 50 mgms on each day. This treatment

was continued for 90 days and then, in accordance

with the protocol, medication was stopped. The

individuals were then kept on the program, as

has already been described before, for an

average duration of about one year. It might

be noted in passing that not only did about

2/3 of the patients begin in an inpatient

atmosphere, but they also began in a general

ambience of optimism and enthusiasm which was

homogeneous group consisting largely of males of shared by patients and staff alike. The

low educational and socioeconomic status and advent of Naltrexone as a modality had been

considerable treatment experience. preceded by very favorable publicity, and

50
this publicity was perhaps all the more

favorable by virtue of being gained at

the expense of the outgoing Cyclazocine

project which had acquired a reputation

for offering an unappealing and unpalatable

substance. A number of patients were

heard to remark that they felt surprisingly

good and cheerful and were happy tp discover that there were very few side effects

associated with the drug. All patients

were given physical and neurological examinations. CBC, LJA and SMA-12 were done

weekly for the first month and then on a

monthly basis.

Second Naltrexone Series

As already stated the intake on the first

series of Naltrexone patients was begun

in June 1973 and continued until September

1973. At that point, further intake into

the study was halted by a directive of

the Food and Drug Administration and thus

no new referrals could be taken. At this

point, new referrals were largely diverted

away from the Low Intervention Program

to other components of the Drug Dependence

Unit. Nonetheless, some patients were

still referred to Low Intervention because

it was felt by personnel at the screening

unit that these individuals were particularly suited to a low intervention

system. These individuals who were eventually to number 15 in all, were taken

into the Low Intervention Program and'

treated essentially with the same programmatic structure as had been applied to

their predecessors. These patients were

now treated with the antagonist drug

Naloxone, with a dosage of 800 mgm/day.

This dosage was, of course, not a 24-hour

blocking dosage. The medication was given

in the late afternoon in an attempt to

deal, hopefully, with the higher risk

thought to be associated with the evening

period of each day (Kurland et al. 1973).

During this period of accumulation of 15

patients, the individuals were treated

as the patients had been in the earlier

series except for Naltrexone and then,

when the ban on Naltrexone induction was

lifted by the FDA, these individuals were

converted over to Naltrexone with the same

kind of induction and the same kind of

maintenance schedule as had already been

employed. The program duration was now set

at a 6 month period in accordance with the

FDA regulations of that time. In all other

respects, the treatment program and philosophy was identical with that accorded the

first group. As will be seen later in the

discussion of results, this series happens

to have included a larger than average

proportion of atypical outcomes. The reason

might be that the favorable publicity

attached to the first series had caused a

reaction among the screening personnel

such that they responded to requests on

the part of some individuals to be sent

to a low intervention program where the

excellent new drug could be obtained.

This may have attracted some individuals

who were perhaps at this point responding

to something of a fantasied quality

believed to be associated with Naltrexone.

Medical testing indentical to the first

series was carried out on this group

except for the dropping of the EEG.

Third Naltrexone Series

The intake for this second series occupied the first few months of 1974. During this time period a series of discussions

was held with the NAS-NRC (National Academy of

Sciences- National Research Council) with

a view toward undertaking a new protocol

for studying Naltrexone. The Committee

on Clinical Evaluation of Narcotic Antagonists

at NAS had conceived a double-blind drug

vs. placebo design which would test out as

searchingly as possible the true impact of

Naltrexone in the areas of both subjective

and objective effects. This protocol also

would have the effect of maximizing the

potential for individuals' motivation in

wanting to test out the effect of their

medication insofar as the very nature of the

program could very well arouse curiosity in

the patient's mind as to whether he was indeed

blocked against the effect of narcotic drugs.

The provisions of the NAS study included a

very thorough medical evaluation of each

individual. Among other tests, the protocol

called for a slit lamp examination of each

patientls eyes (the earlier series had

called for EEG examination of the patients,

but this requirement had been dropped by

the time of the NAS study). Physical examinations and neurological examinations were

done at baseline (and also repeated every

3 months). Chest films were done at baseline

and termination. CBC, UA and SMA-12 were

done monthly. Australia antigen, VDRL and

special hematology were done at baseline and

termination from program.

Since, by this time, the feasibility of giving

Naltrexone on a three-day a week basis had

already been well established, the NAS

protocol called for dosages of 100 mgm on

Monday and Wednesday and 150 mgm on Friday.

This schedule followed an induction done by

10 mgm increments up to the 50 mgm level.

The 100 mgm and 150 mgm dosages for 2 and

3 day periods had been proven effective by

Resnick (Resnick, 1974).

The NAS Naltrexone study then began in

August of 1974 and continued intake until

51
July 31st, 1975. In this 11 month period

a total of 73 patients were logged, but just

54 patients actually ingested drug one or

more times. In the early phase of the

study, a number of patients were logged in

and assigned bottles of study medication

who actually did not show up after a single

initial contact. This included ineligible

and uninterested patients. It was then

decided not to assign an NAS number until

the patient had completed certain preliminaries and was almost ready for medication.

This sharply reduced the number of "No

Starts". The findings of this study, which

has been called Naltrexone III, will

be given along with the other

results in the following section.

Results I - Medical Observations

One fundamental aspect of exploring the usefulness of Naltrexone is the area of medical

safety. This new substance had been used

with laboratory animals and a limited number

of human volunteers (Martin, Jasinsky & Mansky

1973) but was still in an early phase of

scientific knowledge when first used in our

programs. Accordingly a comprehensive set

of medical and neurological evaluations was

carried out in each of the three Naltrexone

phases. As a matter of fact, the examinations

required were identical in Naltrexone First

Series and Naltrexone Second Series, and

almost the same in the Third Series.

The tests called for in the First and Second

Series were the following, done at baseline: (1) chest film, (2) Tuberculin test,

(3) EKG, (4) EEG, (5) urinalysis (with

microscopic, (6) CBC with differential,

(7) FBS, (8) BUN, (9) Uric acid, (1) Liver

function tests - total protein, albumin,

bilirubin, alkaline phosphatase, SGOT and

LDH and, (11) Serum testosterone.

Following this, certain tests were done

weekly: 1) CBC 2) urinalysis 3) BUN

4) Blood uric acid 5) liver function tests

(as above).

Finally, certain tests were done monthly

and at termination: 1) EKG, serum

electrolytes, testosterone and EEG.

In the Naltrexone II Series, all tests

were done exactly the same except for

omission of the EEG and serum testosterone tests.

In Naltrexone Third Series, the following

tests were done at baseline, monthly and

at termination: (1) CBC with differential,

(2) SMA 12-60 including FBS, BUN, uric acid,

inorganic phosphorous, calcium, cholesterol

and liver function tests including total

protein, albumin, bilirubin, alkaline

phosphatase, SGOT and LDH, and urinalysis.

The following tests were done at baseline,

third month and termination: (1) Reticulocyte count (2) platelet count (3) prothrombin time (4) chest x-ray (5) slit lamp

examination and (6) EKG.

Certain physical measurements were done

regularly: (1) blood pressure was taken

weekly and weight was taken also on a

weekly basis.

Physical examinations, psychiatric interview and neurological examination were

done at baseline, third month and termination.

The results can be dealt with in various

ways but are perhaps most easily dealt with

by categories, first for Naltrexone First

and Second Series and then for Naltrexone

Third Series.

With respect to the first and second Naltrexone

Series, the following can be said: 1) No

changes were seen in chest film. There were

a few instances of mild fibrotic changes and

increased hilar markings, 2) The only

positive Tuberculin tests seen were worked

up further with no evidence of active disease.

3) There were no EKG changes attributable

to Naltrexone! one individual was seen with

PVC's and treated with quinidine with good

result: he had been mildly symptomatic for

years and felt better when treated. 4) There

were no EEG changes before, during, or after

Naltrexone. The only changes seen, of a

very minor degree, were in a beneficial

direction. 5) Urinalysis in this group

(as with the later group) not uncommonly

showed WBC's and other evidence of urinary

tract infections - these were followed,

cultured and treated by the internist. There

was one instance of possible albuminuria

which did not prove out on 24 hour studies

to be significant. 6) The only CBC changes

noted were attributable to familiar sources of

pathology - e.g. viral infections. There

were no prolonged or inexplicable changes of

red or white cells. 7) FBS was normal

throughout; some seeming irregularities found

were due to non-fasting condition of patients

who, on retest, turned out normal. 8) BUN

was almost uniformly normal: where abnormal

it was only slightly elevated and did not

change in the study. 9) Uric acid elevations

were seen in several individuals - these were

of mild degree and did not change with

Naltrexone administration. 10) Liver function

tests showed by far the greatest percentage of

abnormality - for example, only 4 of the 17

patients in Naltrexone First Series showed

consistently normal SGOT levels and of these

4, two were teetotalers. Almost all patients

52
in this and later series used alcohol, many

quite heavily, also, many had positive

histories for hepatitis. It was noted that

several patients had gradual reductions of

SGOT levels (and also, of LDH, bilirubin and

alkaline phosphatase levels) when they were

hospitalized (which gave them an alcohol-free

rest). Similar reductions were seen during

outpatient alcohol abstinence reported by the

patients. Episodes of acute hepatitis were

not uncommon: one in Naltrexone I Series exempted the patient from this series and this

was repeated in Naltrexone Series II. Serum

testosterone levels varied considerably but

all within a normal range and this test was

later dropped from the battery.

In the Naltrexone Third Series, the results were

comparable to those seen earlier. Thus, changes

in the white blood count and differential, while

common, were always transient and associated

with identifiable pathology. The SMA-12

battery results were generally unremarkable

except for (again) a very high percentage

of abnormal liver function tests - most commonly, elevated SGOT's and altered plasma

proteins, usually elevation of gamma globulins

and serum immunoproteins. (IgM, IgA, and IgG).

These elevations were again related to our

patients' histories of alcohol use and/or

bouts of hepatitis. Very often, a curve could

be traced in the more sensitive liver function

tests, such as SGOT, in which the blood chemistries would reflect quite accurately the rising and falling rate of alcohol intake as described by the patient. As in the earlier

series, there were several instances of acute

hepatic pathology accompanied by clinical

manifestations of liver disease - in such

episodes, the program internist made a clinical judgment about the patient as to whether to

continue or discontinue his medication. In

several instances, medication was stopped

because it was felt that it would be improper

to continue experimental medication in the

face of acute illness. One such individual

left our study under the heading of "Nonresponsible drop-out"; another, who had completed 150 days on the program, was called a

successful terminator. Medication was always

stopped if the liver function tests became

worse without alcohol ingestion. In all, 5094

laboratory examinations were performed on the

Naltrexone Series III patients. Of these, 436

or 8.5% were abnormal. Of this number, 277 or

63% related to liver function and another

99 or 23% related to urinalysis findings

(typically, WBC in urine). This left 60 (13%)

abnormal findings scattered over a total

of 54 patients: none of these was associated

with demonstrable pathology.

One test that caused a moment of concern

was the slit lamp examination. By May of

1976 only two completers of medication had

had this final slit lamp examination. At

this time, both showed retinal pathology

(retinal holes in one case, a horse-shoe

shaped retinal tear in the other) that

had not been seen at baseline. Although a

remote possibility, it seemed necessary to

at least entertain the idea of Naltrexone's

association with retinal pathology. The

double-blind code was broken for these two

individuals. The patient with the most

pronounced pathology was on placebo drug;

the other patient was on an active drug.

When the next 20 patients had their final

eye examinations without significant observable change it was then possible to

make an estimate of the incidence of retinal

pathology in this sample and compare it with

a general population - they were found to

be comparable and this placed our findings

in the region of normal expectancy. Consultation

with our own ophthalmological consultant as well

as the scientists monitoring toxicology studies,

and an extensive literature review all confirmed

the proposition that there is no evidence of

direct effects of opiate antagonist

on the retinas of the various species studied,

including man.

No other areas of medical testing yielded any

significant abnormalities. Throughout, the

physical and neurological examinations were

remarkably constant, with the changes noted

above. Changes of psychiatric status were, in

this population of young adult male addicts of

varied backgrounds (including, frequently

broken homes, years of crime and incarceration,

and of course, the usual crises of early

adult life) not uncommon but there were no

changes seen that were not anticipated in

their pre-Naltrexone histories.

Symptom Side Effects

The area of symptom side effects deserves a

more detailed discussion but can be covered

superficially at this time simply by stating

that, in general, Naltrexone was well tolerated

and accepted. Most subjective complaints were

mild and even absent in some individuals. The

one recurring complaint heard with some regularity was that of abdominal discomfort. This

was usually a sense of either constriction or

heaviness in the epigastric and/or lower

abdominal area. It rarely went as far as producing either cramps or pain. There were

three individuals, however, who were discontinued

on drug due to abdominal complaints. The

first patient, L.W. (NAS 016) was found to be

suffering from a viral syndrome and moderate

hypertension soon after starting the program,

and he began to complain of nausea and vomiting

while suffering from the virus. After the virus

cleared up, he still had repeated nausea and

vomiting. He was started and stopped twice on

53
Naltrexone; each time, resumption of medication

caused recurrence of nausea end vomiting. He

was then stopped on medication with cessation

of symptoms and carried on the program, He was

receiving treatment for his hypertension throughout with very gradual response. L.W, dropped

out about a month after this - he was heard to

have returned to drugs but a more recent

follow up showed him to be drug free,

Another patient, F.T. (NAS 028) complained of

chronic abdominal discomfort, sometimes progressing to nausea and vomiting: at other times,

crampy (but not diarrheic) bowel movements.

He also complained of green bowel movements

(which indeed were green by inspection - laboratory analysis failed to disclose any

unusual findings) . He was taken off medication,

felt better, returned to medication with

recurrence of symptoms and then stopped (whereupon he again felt well). Evaluation of his

case has always remained slightly unsettled

because F.T. is an admitted heavy consumer

of alcohol who also felt better when he reduced his drinking. His medication had to

be discontinued, however, when it seemed that

the combination of alcohol and Naltrexone

was, for F.T., an unworkable combination.

Two other individuals, K.A. (030) and W.H.

(067) complained of moderate but persistent

abdominal discomfort and spontaneously

asked to be put back on 6 day-per-week

Naltrexone, rather than 3 day-per-week Naltrexone

regime. It should be understood that the

total weekly dosage is the same in these

two systems but that the 6 day system involves smaller doses and was felt by these two

individuals to be more tolerable. This

would appear to verify that Naltrexone is,

at least for some patients, a gastrointestinal

irritant but it can also be noted in passing

that the two individuals in question

are somewhat more dependent than some of their

colleagues and may conceivably have also been

desiring more frequent clinical contact. This

latter possibility is really mentioned for

the sake of completeness; it is believed

that the two patients were registering

genuine abdominal discomfort (since it was also

mentioned by others) and that these two

responses may indicate some limitation in

Naltrexone dosage for at least some individuals.

Both patients said they had always had

“nervous stomachs” which had been treated

conservatively by their doctors. Still

another patient also requested the 6 day system,

in fact, he asked for a 7 day medication

regime. This man, R.G. (NAS 071) had by

age 23, an 8 year history of “nervous stomach”.

When his gastric symptoms grew so severe

as to require suspension of medication and

a GI series (one of many in his life), the

double-blind code was broken for another

reason, and he was found to be on placebo.

This case certainly underscores the highly

suggestible character not only of this particular patient but probably of many patients

with functional disorders of the intestinal

tract, including the case mentioned earlier.

There were no other frequently or systematically

mentioned symptom side effects noted in our

population.

Results II - Program Retention and Attrition

The results for the first Naltrexone series

are shown graphically in Figure 1. In

this figure, as in later figures, it will

be seen that three categories of program

outcome are given for our patients. First

category is “Split” or “Responsible Dropout”, in which the individual leaves the

program prematurely and of his own volition

or apparently of his own volition. The

next category is “Graduation or Termination

in Good Standing”, and this title should

be self explanatory. It indicates a

successful outcome. The last category applied

is “Obligatory or Non-responsible Drop-out” and

this indicates individuals who are removed from

the study due to some extraneous and apparently

uncontrollable reasons such as having a

medical problem, or relocating outside

our clinic area, etc. In Figure 1 it can

be seen that the first 4 patients in this

series are classified as “Self-responsible

Drop-outs or Splits” and this is 20% of

the base number (the base number is the

total minus the non-responsible drop-outs).

The next 10 patients successfully completed

the drug phase of the program (this is in

distinction to the post-drug clinical phase

of the program), and this represents 71% of

the base number 14. The last three patients

are called “Non-responsible Drop-outs” and

are 3 of 17, or 17% of the total N. It can

be seen that the number of non-responsible

drop-outs has been subtracted in this and subsequent totals in order to make a more

rational base - by definition, the non-responsible drop-outs are those who leave drug

and/or program for reasons not obviously

attributable to their own volition, e.g.:

intercurrent illness, etc. Patients in

Naltrexone I who went on to successfully

graduate from the program (which involved a

considerably longer period of time than the

90 days devoted to Naltrexone) were relatively

few in number (three in all). Here, as in

subsequent series, it has developed that there

can be a large disparity between completed time

on drug and completed time on program. (It

can also be seen here, however, that the disparity was maximized in the First Series and

this is probably due to the simple fact that

in the first study, medication could only be

54
given for three months while the program

duration was for 12 months, and during this

time a number of individuals began to relapse

into their pre-program habits). At this point

it was believed that the relative brevity of

antagonist administration was responsible for

this disappointing decline after an excellent

beginning.

In summary it can be said that retention was

high for a short period for a group which had

predominantly an inpatient beginning and a

daily medication schedule. This was also a

group existing in an atmosphere of optimism

and enthusiasm about a new modality which had

received favorable advance publicity.

In Figure 2 the results of the Second Series,

called "Naltrexone II", can be seen. It will

be recalled that this group of patients followed the initial series when intake was

resumed for the Naltrexone project. The

results of this series, which is shown in

Figure 2, does, to a certain extent, defy

conventional analysis, As has already been

mentioned earlier, the number of atypical outcomes provided a temptation to construct a

larger number of categories than the three

we have been using in this presentation. It

was decided to resist this temptation, however, and explain the unusual outcomes as

follows: (1) Patient Number 1, M.S., left

the program after his court case had been

adjudicated. At this point he revealed that

he had really been masquerading as an addict

to camouflage his real identity as a dealer

in drugs (primarily) and only a moderately

heavy, but not addicted, user of heroin

(secondarily), (2) Patient number 6, J.M.,

deliberately challenged Naltrexone in such a

frontal and reckless way that it was debated

at great length as to whether it was wise to

restart him on the drug. He was, however,

after due deliberation, returned to Naltrexone usage, but he then became increasingly

erratic in his attendance in the clinic and

his ingestion of narcotic antagonist, He

eventually had to be discontinued from LIP

and was transferred to a Methadone program.

(3) Patient 12, S.B., took a near-fatal

overdose of barbituates after an argument

with his girlfriend. He was then transferred

to a state hospital and from the state hospital to a residential program. (4) and (5)

involve patients 13 and 14. Both of these

patients showed increasing disorganization

after being on Naltrexone. This developed

rapidly with Patient 14, who became catatonic

and paranoid and had to be treated with

phenothiazines, and eventually, in addition

to his individual therapy, required transfer

to a Methadone maintenance program. With

individual 13, loss of organization took

place in a more gradual way, but was marked

by clinical signs of increasing depression

FIGURE 1

and dependence which caused him to spend

long hours at the clinic in which he would

seek out the companionship of the clinic

staff. He began to periodically use amphetamines, which he described as the "only antidepressant that allows me to socialize." This

resort to amphetamines took place after he

had declared a trial of both Elavil and

Triavil to be ineffectual. It is true that

both of these patients, number 13 and number

14, did have a previous psychiatric history,

but at the time of admission, they seemed

fairly well integrated, and it did not seem

that they would be unworkable in the study.

It may have been the loss of the tranquilizing

properties of their narcotics that caused

these two individuals to lose their state of

adjustment. There was no reason to suspect

that Naltrexone was productive of their

psychic distress, especially in view of their

FIGURE 2

55
prior histories. (6) Patient number 15 relocated

to a distant part of the state which was

beyond commuting range. Overall, we have

ended up classifying 4 of these 6 atypical

cases as "Non-responsible Drop-outs" for the

reasons given. This relatively high loading

of 4 cases out of 15, or 26% of the total

group, is somewhat high for this category

(in the other 2 series, corresponding proportions of the non-responsible drop-outs were

17% and 13%) and this high percentage had

the effect, of course, of reducing the percentages scored by the other 2 groups. In

any case, the percentage of successful medication completions was considerably less than

in the first series, at 45%, and the percentage of splits, or self-responsible drop-outs,

rose to 54%, which is slightly more than half

the sample.

In summary, then, 15 patients, of whom 10 had

been on Naloxone at the start, were treated

with Naltrexone for 6 months on an out-patient

basis. The series was marked by a number of

atypical developments. The results of 54%

drop-out, 45% completion of medication, and

26% non-responsible drop-outs seem not as

representative of our population in this

series as they have been in others even

though they were ostensibly drawn from the

same pool of patients. The reader should

note that two patients admitted to challenge.

The results of the Third Naltrexone Series

are shown in Figure 3. It should be pointed

out now before the table itself is inspected

that about 1/3 of this group of individuals

did end up testing or challenging the drug or

the program in which the drug was offered.

(The program was a double-blind, active drug

vs. placebo study). This phenomenon will be

discussed again later on, but is mentioned

at this point because of its importance. In

Figure 3 it can be seen that the total N in

- this series was 54, and that 7 of the 54, or

13%, were characterized as being non-responsible drop-outs. The remaining base number

of 47 (54-7) thus yields percentages of 68%

split and 32% satisfactory completion, including three patients who were allowed to

stop medication early due to extraneous reasons judged acceptable by the staff. These

patients are marked by an asterisk in Figure

3. One patient was taken off drug at the internist's advice, due to abdominal problems,

one patient left the program, with approval,

for a full time day job and full time night

school and one patient was encouraged to

leave by his parole officer. All of these

patients had been proceeding normally, with

good performance at time of medication stoppage. All three kept regular contact with

the program.

FIGURE 3

It would be tempting to speculate that the

lower percentage of satisfactory completions

was due to a linear negative relationship between length of program and rate of retention,

which is graphically depicted in Figure 4,

where there is an almost straight line decline

from the first through the third program as

these programs become longer in their drug

ingestion period. It should be borne in

mind, however, that the qualitatively different

nature of the third series, which was a

double-blind study, makes it difficult, if

not impossible, to make this kind of quantitative comparison. It can be seen, for instance, that when the same material is also

looked at, first in Tables 1, 2, and 3 with

raw numbers, and then in Figures 5,6, and 7

with percentages, that it become: even more

unclear as to whether there really is a linear

56
FIGURE 4

relationship between time on program and

number of attritions even though this can be

roughly identified in the figures. In the

same figures it can also be seen that there is

in the first 2 studies, which employed an open

approach to the drug, an eventual decline to

a zero degree of attrition so that it might then

be argued that the unusual table in this series

is the third table which is a double-blind

experiment. In other words, it is conceivable

that if the third series had involved an

open plan for administering Naltrexone, a zero

rate of program attrition might also have

achieved, but could not be achieved because

the knowledge of the patients about the placebo

vs. active drug plan provided a constant

provocation for further challenge which led

to eventual readdiction and discharge. It

might also be noted at this point that the

peak seen in Figure 7 at the 150 day mark

which is underlain by a dotted line representing

another hypothetical outcome, is probably an

artifact due simply to the fact that three individuals violated program rules around the

150th day in the program, This particular

rule was concerned with the carrying of

weapons in the program, and the 2 individuals

who refused to obey the regulation of the

program were discharged and the third individual

who had complicity in the affair was also

discharged at the same time. This was an

unusual and atypical event which produced the

attrition peak at the 150 day mark and probably

would not recur soon again in a similar

series.

To continue this discussion of attritions one

more step, it can also be argued that the decline between the first and second series

while again possibly related to the temporal

increase of 90 days to 180 days of drug nonethe less also seems to have involved a qualitative shift from an "average" group of patients

to an unusual group of patients as has already

been described above. If this was the case

then there might not have been as evident a

decline and the seeming slope which can be

imagined in Figure 4 may really be an artifact.

The phenomenon designated as challenge has

already been mentioned - it is illustrated in

Figure 8 and in Tables 4, 5, and 6. First, it

should be explained that "challenge" originally

designated any opiate usage by any patient during a time that he either was on Naltrexone or

was supposed to be on Naltrexone - obviously,

different kinds of situations. The overall

results are in Table 4. At first, it was

TABLE 1

Frequency Distribution of Responsible Drop-outs in

First Naltrexone Series, N = 14

TABLE 2

Frequency Distribution of Responsible Drop-outs in

Second Naltrexone Series, N = 11

TABLE 3

Frequency Distribution of Responsible Drop-outs in

Third (Double Blind) Naltrexone Series, N = 47

57
thought that there would be few instances

of unwarranted absence from antagonist. This

turned out not to be the case. In Tables 4,

5 and 6 there is a column called "miss med"

which shows the number of missed medications.

Only one patient in 19 did not miss medication

at least once, and the overall average was 10

missed medications, providing more than enough

opportunity to use opiates while still in the

program. Accordingly, data was then collected

under two headings--"direct challenge" referred

to opiate usage within 24 hours of Naltrexone

ingestion (or 48 or 72 hours after correspondingly larger doses) and "indirect challenge"

referred to opiate usage in a Naltrexone free

state. Results are shown in Tables 5 and 6.

So-called "indirect challenge" could perhaps

be better called Naltrexone avoidance, or propam challenqe, or even a refusal to challenge.

Challenges were spotted through urine testing

(opiate, quinine and missed urines), combined

with clinical anecdotes reported to the staff

or elicited by the staff. This questioning

was done with circumspection to avoid false

positives due to boasting. Each anecdote was

judged by an experienced staff including exaddict counsellors. Since only 6 of 19

patients showed morphine urines, considerable

judgment was needed to accept the circumstantial

evidence in the other cases. Probably, any

errors have been made on the conservative

side in estimating the problem. Many patients

told of challenging only near termination when

it was "safe" to reveal their story. Typically,

the patient would say that he "had to know"

whether he was on active drug. Interestingly,

some patients who said they were sure that

they were on placebo did go on to eventual readdiction (NAS 009, NAS 019) while others said

that they knew their drug was placebo but they

would not persist in taking advantage of it

(NAS 023, 072).

Figure 5: First Naltrexone Series, N=14

FIGURE 6

In Figure 8 it is seen that outcome percentages

of Naltrexone III challengers as a whole and

total group were about the same. This seems

to say that challenge of itself does not lead

to unsuccessful outcome. This leaves unexplained

the fact that retention hit a new low in this

series which had a 32% overall challenge rate

FIGURE 5

(40% if one excludes the non-responsible drop- Figure 6: Second Naltrexone Series, N=1

outs). The rates are 22% and 25% for the direct

challengers.

In Table 5, the direct challengers show up as

a rather stable and long-lived group, with the "direct" and "indirect" groups seen by

average time on drug of 176 and average pro- inspection is supported by the Mann-Whitney

gram duration of 201. By contrast, the "in- U-test for significance of median differences

direct" challengers in Table 6, who are really (p. 01). Thus, one is left with the impression

Naltrexone nonchallengers, showed average drug that patients who challenge antagonist showed

duration of 66 days and program duration of a fairly good outcome. At the same time it is

71 days. It seems that the patients in Table true that retention rate hit a new low in this

6 first avoided the antagonist and then avoided program with its considerable challenge

the program. The large discrepancy between behavior.

58
FIGURE 7

Figure 7: Third (Double Blind)

Naltrexone Series, N=47

FIGURE 8

Figure 8: Relative percentages of Outcomes (Splits,

Completers and Obligatory Drops-outs) for Third Naltrexone

Series as a whole (N=54) and Challengers within the Third

Naltrexone Series (N=19)

Results III - Other Relevant Findings

In all clinical research determining what

form of treatment is best suited for a

particular patient or group is an important

question. When these factors or conditions

are known a clinician can be discriminating

as to whom he treats, thereby making his

treatment more effective and efficient.

This is particularly important for programs

that must depend upon foundations or government grants for their monies, In New Haven,

for the past three years an earnest effort

has been made to relate the above question to

antagonist therapy. As a result of this

research we believe we may have: (1) eliminated

a sizeable number of factors that are often

associated with the question as to what type

of addict will benefit most from a narcotic

antagonist program, and (2) identified one

or two variables that are significantly related to this issue. The manner in which

these results were ascertained is important,

and hence a detailed discussion of our methodology is now presented. To define our many

variables here would be distracting to the

reader: therefore a glossary containing our

variable set is found in Appendix A.

Our approach to this problem would be best

considered intuitive/empirical. No formal

standards were applied to the variable

selection process. The researchers primarily

relied upon data from experimental studies

and their own intuitive feeling when selecting

a variable for inclusion in the data set.

This process yielded a total of thirty-five

variables that could be grouped in these

divisions: (1) Program Performance, (2) Demographic Data, (3) Drug History.

The distribution within each group in approximately equal; and variables found within each

division respectively are: (1) Division OneElapsed Time on Medication (ETOM), Elapsed

Time on Program (ETOP), Required Urines

(REQURIN), Number of Missed Urines (NUMISS),

Number of Urines Positive for Opiate Drugs

(COPIATE), Number of Urines Positive for

Barbiturates and Amphetamine Drugs (CBAD),

Number of Urines Positive for Other Illicit

Drugs (POILLD), Completion of Drug (COMPD),

Membership in Naltrexone Series I,II, or III

(SAMPLE), Type of Patient Outcome in Study

(GROUP), Completion of Program (COMPP),

Follow-up Status (FOLLSTAT), and Challenge

(CHALLENG). (2) Division two - Age (AGE),

Race (RACE), Number of Prior Drug Treatment

Programs (PRDRUGTRT), Number of Months in

Prior Drug Treatment Programs (NUMINTRT),

Number of Arrests (NUMARRST), Months of

Incarceration (MOINCAR), Stable Living

Arrangement (STABLIV), Years of Education

(YRED), and Delinquent Record (DELREC);

and (3) Division three - Age of Onset of

Opiate Use(OPIATEAGE), Years of Opiate

Drug Use (OPYRS), Age of Onset of Barbiturate Use (BARBAGE), Years of Barbiturate

Drug Use (BARBYRS), Age of Onset of Amphetamine Use (AMPHETAGE), Years of Amphetamine

Drug Use (AMPHETYRS), Age of Onset of Marijuana Use (MARJAGE), Years of Marijuana

Use (MARJYRS), Age of Onset of Cocaine Use

(COCAGE), Years of Cocaine Use (COCYRS),

and Age of Onset of Alcohol Use (LIQUAGE),

Years of Alcohol Use (LIQYRS).

59
TABLE 4

Total Patients Who Challenged Naltrexone, Directly (+) or Indirectly (-) (Naltrexone III)

URINE TEST

NAS

No.

Quinine

on Nal.

009

019

020

023

024

029

032

040

047

050

054

056

058

066

067

070

071

072

073

TOTALS

MEANS

Patient

B.C.

M.C.

L.F.

S.C.

P.G.

H.S.

R.M.

DoHo

E.S.

RiSp

S.P.

DaHi

G.D.R.

P.S.

W.H.

R.N.

R.G.

A.M.

N.H.

19

Term Drug Miss

Date Days Med

11/14/75 7 2 1 3

11/14/75 8 9 1 4

2/21/75 123 1 5

12/5/75 235 4

3/20/75 123 1 2

8/29/75 265 2

6/28/75 205 25

3/7/75 43 2

3/7/75 1 1 1

3/24/75 37 9

1/19/75 218 1 7

5/3/75 1 2 1 0

4/25/75 4 0

1/9/76 173 1 2

270 2

10/25/75 121 10

5/7/76 239 39

270 4

8/7/75 8 3

2498 194

131 10

Prog .

Days

89

90

130

235

154

266

125

97

31

59

227

31

7

184

279

134

295

350

51

2838

149

20 20

21 4

12 5

3 0

154 2 7

14 3

2 1

9 2 1 8

119 7

89 52

165 42

118 2

1 1

335 238

70 12

Req. Misses

24 9

51 1 7

63 16

144 8

78 5

165 1

Opiate

on Nal.

0

0

0

3

5

0

0

0

1

0

0

0

0

11

0

0

2

2

1

24

—

Opiate

off Nal.

0

0

0

0

4

0

0

0

0

0

0

0

0

0

0

0

0

0

4

—

Other

1 3

1

7

4

2

2

1

2

2

1

4

2

0

19

0

0

3

3

0

6 6

—

0

0

1

0

1

0

20

0

1

0

7

0

0

11

6

15

1

0

63

—

Dir.

Chall.

12+

Anecdotal

Report

yes

yes

yes

yes

yes

?

yes x 2

yes x 3

yes

yes

yes x 2

yes

yes

yes

yes

yes

yes

yes

yes

Remarks

Got high

Got high

Skipped often

Got high

O.D. off Naltrexone

Claims placebo

Not high

Not high

Felt sick

Not high

High; sick

Medical problems

Hint challenge

"Sick 45 min."

Admit heroin

Admit Percodan

Knows placebo
TABLE 5

Patients Who Claimed "Direct" Challenges of Naltrexone (Naltrexone III)

R.M.

DoHo

E.S.

S.P.

P.S.

W.H.

R.G.

A.M.

1 2

B.C.

S.C.

P.G.

H.S.

009

023

024

029

032

040

047

054

066

067

071

072

TOTALS

MEANS

NAS

No.

Patient

0

0

0

4

Opiate

off Nal.

0

0

4

0

0

0

0

0

Opiate

on Nal.

0

3

5

0

0

0

1

0

11

0

2

2

2 4

Prog.

Days Req Missed

8 9 2 4 9

235 144 8

154 78 5

266 165 1

216 125 2 0

9 7 21 4

3 1 12 5

227 154 2 7

184 9 2 1 8

279 119 7

295 165 4 2

350 118 2

2423 1215 148

201 107 12

URINE TEST

Quinine

on Nal.

13

4

2

2

1

2

2

4

19

0

3

3

5 5

0

0

1

0

2 0

0

1

7

1 1

1 5

1

12

Other Dir.

Chall.

+

+

+

+

+

+

+

+

+

+

+

+

1 2

Anecdotal

Report

yes

yes

yes

?

yes x2

yes x3

yes

yes x2

yes

yes

yes

yes

Term Drug Miss

Date Days Med

1 3

4

12

2

25

2

1

17

12

2

3 9

4

133

11

72

235

132

265

205

43

11

218

173

270

239

270

2113

176

11/14/74

12/5/75

3/20/75

3/29/75

6/28/75

3/7/75

3/7/75

11/19/75

1/9/76

Got high

Got high

O.D. off Naltrexone

Claims placebo

Not high

Not high

Felt sick

High; sick

Hint challenge

"Sick 45 min,

Admit Percodan

Knows placebo

Remarks

5/7/76
TABLE 6

Patients Who Were Indirect Challengers of Nalrexone (Naltrexone III)

URINE TEST

TOTALS 7 464 61 502 223 90 0 0 11 7 -

MEANS 66 8 71 31 13 - - - -

058 G.D.R. 4/25/75 4 0 7 2 1 0 0 0 0 - yes Medical problem

070 R.N. 10/25/75 121 10 134 89 52 0 0 0 6 - yes Admit heroin

073 N.H. 8/7/75 8 3 51 1 1 0 0 0 0 - yes

NAS Patient Term Drug Miss Prog Opiate Opiate Quinine Other Dir. Anecdotal Remarks No. Date Days Med Days Req Missed on Na.l off Nal. on Nal. Chall. Report

019 M.C. 1/14/75 89 14 90 51 17 0 0 1 0 - yes Got high

020 L.F. 2/21/75 123 15 130 63 16 0 0 7 1 - yes Skipped often

050 RiSp 3/24/75 37 9 59 3 0 0 0 1 0 - yes Not high

056 DaHi 5/3/75 12 10 31 14 3 0 0 2 0 - yes

The measurements of these variables were

derived from clinical data that originated

from addicted individuals who can be inconsistent informants. When raw data is generated in this fashion the researcher runs the

risk of losing some reliability and validity

in his measurements. Since this problem is

indigenous to clinical research we feel our

results were no more or less affected by this

bias than in comparable clinical research.

No doubt there were occasions when inconsistencies appeared in the data. To correct

for this bias, the variable measurements were

based upon a logical predetermined standard.

The measurement of the variable OPIATEAGE

or age of onset of opiate use serves as

a good illustration. This datum is generally

found in an intake questionnaire administered

to all patients each time they enter a component program of the Drug Dependence Unit.

In a small city like New Haven it is not

uncommon for a patient to have been a member

of several programs. This results in multiple

intake questionnaires for a particular patient.

In a number of cases we found inconsistencies in

the data that concerned this variable.

The standard employed to correct this bias

was to define the age of onset of opiate

drugs to be the earliest date that appeared

in the data. This convention failed to

distort the data since all patients were

treated symmetrically whenever there existed

discrepancies in the data.

An SPSS (statistical packages for the social

sciences) systems file was created to

statistically analyze our data. The first

analysis produced T-statistics for all continuously distributed variables by all discrete variables ie categories. The variable

combinations analyzed were (1) SAMPLES

(1,2,3,1-3, 1&2vs3)by all variables, (2) GROUP

by all variables, (3) COMPD by all variables,

(4) STABLIV by all variables, (6) CHALLENG

by all variables, and (7) DELREC by all variables, which produced over 300 pages of output containing a considerable number of individual T-statistics. A logical process or

routine was employed to break down this data.

The first step consisted of identifying those

particular T-tests that were consistently

statistically significant for the discrete

by continuous variables for all samples. By

gross inspection we were able to identify

four categories (discrete variables) that are:

(1) GROUP, (2) COMPD, (3) STABLIV, and (4)

FOLLSTAT, and four continuous variables:

(1) ETOM, (2) ETOP, (3) REQURIN, and (4)

NUMISS that were consistently associated with

statistically significant T-tests. Our next

maneuver was to assess the quality of meaningfulness of the categories by variable relationship. Two categories, COMPD and GROUP were

found to be consistently related to ETOM, ETOP,

and REQURIN, although the meaning of this

finding fails to be very important. These

variables and categories naturally overlap to

the point where they lose their power to discriminate - together they measure an equivalent went. Interestingly enough FOLLSTAT

and STABLIV were related to these variables

but to a lesser degree. At this juncture the

data appeared to suggest that: (1) no powerful relationship was extant between the continuous and discrete variables and (2) a significant relationship might be found when the

categories were related to one another. To

this end the other primary analysis in this

62
investigation was generated.

An SPSS Crosstabs procedure was employed to

to reanalyee the data. Crosstabs generate

two-way to N-way cross tabulations for

discrete variables which can be tested for

statistical significance in a number of ways

including Chi-square, Phi-coefficient, and

Kendall Tau-b when the matrix is NxN.

The discrete variables or categories in the

second analysis consisted of GROUP, COMPD,

STABLIV, FOLLSTAT, SAMPLE, and CHALLENG.

The last two variables were not found to be

significant in the first analysis; however

they were included here since the researchers

believed they were important. The variables

were analyzed by a series of 1x5, 1x4, 1x3,

and 1x2 Crosstabs procedures for samples one

and two combined, one, two, and three combined,

and one and two combined vs. thraa. This

routine produced fourteen chi-squares for

each of the three samples or a total of

forty-two. Compared to the T-analysis, this

routine produced a small quantity of data,

which was broken down in a similar fashion.

The break down process consisted of constructing a 4x5 matrix in which we plotted the

number of times a statistically significant

x

2

 or Tau-b appeared in the data from the

three working samples. This process produced

two interesting findings that involved the

variables STABLIV and FOLLSTAT (stability

of living pattern and follow-up status).

As mentioned previously, FOLLSTAT was found

to be related to four continuously distributed

variables, ETOM, ETOP, REQURIN, NUMISS. In

the second analysis this variable emerged as

being very significant. The Chi-square results

demonstrated that there was a systematic relationship between FOLLSTAT and the variables

GROUP and COMPD, which are equivalent measurements. The variable STABLIV once again emerged

as being somewhat important although the nature

of its significance differed from FOLLSTAT. In

the matrix distribution (4x5 plotting matrix)

the variable appeared diffused. It was

found to be related to GROUP, COMPD, SAMPLE,

and FOLLSTAT, but failed to cluster about one

or two variables the way FOLLSTAT did.

FOLLSTAT is a retrospective measure and therefore loses some of its power as a predictor by

definition. Nevertheless it is one of only

two variables out of thirty-five that was

consistently related to program outcome. Thus

we believe that it can be employed as a reference in the search for other variables that

may be strongly related to program success or

failure. Additional clarification is needed

to determine the function STABLIV could take

on as a predictor variable. Resnick (1971)

also has researched a similar variable; he

investigated the relationship between marital

status (as defined by an ongoing, important,

and consistent relationship with a woman,

other than a relative) and program performance. When Resnick's sample was divided

between terminators and continuing cases

a T-statistic indicated that marital status

could differentiate the two groups. This

finding lends support to our belief that with

further refinement of variable STABLIV it

could prove to be an important indicator of

program outcome.

In concluding we were able to eliminate a

significant number of variables that have

little relation to program outcome. Our data

suggest that quality performance in a low

intervention drug program is not related to a

patient’s drug history. Finally the second

analysis confirms our expectation that

FOLLSTAT is significantly related to GROUP

or COMPD. The variable STABLIV while less

significant does show some promise in the

same direction.

Ongoing Research

A further study using Naltrexone is now

underway in the Low Intervention Program.

The study began in February 1976 and is

called “Pilot Contingency Study'.'.

In essence, this protocol employs a relatively novel clinical approach to the

usage of Naltrexone in dealing with

opiate-dependent patients. It eliminates

the difficulties inherent in double blind drug

vs. placebo design. At the same time,

by maximizing the importance of patients'

behaviors it institutes a feedback mechanism which literally gives the patient a share

of control in his own medication regime.

Concretely, the patient, after a stipulated

time of taking Naltrexone, is taken off

Naltrexone until such time as his behavior

warrants a return to antagonist drug. Such

behavior includes usages of opiates and/or

frequent delinquency from program requirements (attending groups and giving urines).

If the individual does well in a programmatic sense, he is simply kept off Naltrexone

and then eventually graduated from the program.

If he is required (by his own behavior) to

return to Naltrexone he is kept on it

for one month and then returned to the

contingencv code.

In this design, patients are randomly assigned

to one of two initial treatment periods which

are two months long and six months long on

Naltrexone. These periods were chosen to be

as different from each other as possible and

also with a view to some replication of the

study periods used in earlier studies.

6 3
While it is still premature to report results

from this program, it can be said that as of

May 20, a total of 13 patients had been enrolled

and by random assignment, 8 had been put into

the long term group and five in the short term

group. One individual had already finished'

"short group" (two months) and was doing well

on the program without Naltrexone. Insufficient

time had elapsed for other results to be

produced as of the time of this writing,

Overall, the enrollment of patients, induction

onto drug, and course in program have gone

very well so far. Up to this point, there are

no program attritions and no challenges known.

Because of the early stage of development, this

information is included not for analysis but

rather to document the continuing search for a

more appropriate or effective mode of administration of Naltrexone in an outpatient setting,

It is felt that this is a more sophisticated and

ultimately more viable approach because it

recruits the motivation of the patient who is

"ready" for antagonist treatment.

Conclusions

1) Three studies using Naltrexone for treating opiate-dependent patients are described.

The three series varied in time of duration

on medication and certain other important

particulars - the first two series were

"open" series and the last was a drug vs.

placebo double-blind design. The series

are discussed together because of certain

underlying common features and because the

issue of discovering a successful modality

for administering Naltrexone is a central

concern of this research.

2) Comprehensive medical examinations support

the belief that Naltrexone is a safe substance.

3) The average patient's report leads to the

conclusion that Naltrexone is a palatable

substance but does cause some abdominal

discomfort, usually in predisposed individuals with previous functional intestinal

disorders and/or habitual use of alcohol.

4) Differential rates of retention and the

possible reasons underlying them have been

discussed in the three studies. One factor

believed related to low retention rate in

the third series, namely, challenge of

narcotic antagonist, has been discussed. It

is suspected that the high rate of challenge

in the NAS study was related to the design

of the study which employed placebo doses.

The issue has not been proved, however, since

only the "indirect" challengers (who could

have appeared in other series as well) had a

noticeably shorter duration of days on program.

It is still quite possible that there was an

overall downward effect on retention caused

by the frequency of challenge in this series

(the frequency was one-third of all patients)

and the diminished confidence of all patients

that resulted from the challenges.

5) Data analysis covering thirty-five

variables in three categories leads to

the conclusion that a number of standard

areas of information gathered on patients

in drug dependence programs are relatively

ineffectual in discriminating the more

successful from less successful patients.

At the same time, two factors have been

isolated which seem associated with

programmatic outcome and recommendation is

made for further research in this area.

These factors are stability of living pattern

and follow up status (with respect to drugs).

6) A new study now underway in the Low

Intervention Program is described in an

introductory way. The program is too young

to provide meaningful statistical data but

is, after 4 months of operation, coming

along well. The program, by using contingency

mechanisms which emphasize the patients' input

in determining medication schedules, is

designed to maximize motivational factors. It

is believed that motivational factors will,

of necessity, be more important in a narcotic

antagonist program than in the established

methods of dealing with opiate dependence.

Recruitment of a sense of self determination

may not only be timely but even essential

in formulating effective clinical programs

that offer Naltrexone.

REFERENCES

Jaffe, J.H. "Drug addiction and drug abuse."

In Goodman & Gilman. Pharmacological

Basis of Therapeutics, 1975. New York:

MacMillan Co.

Kurland, A.A.; Krantz, J.C.; Henderson, J.M.;

and Kerman, F. "Naloxone and the narcotic

abuser: A low-dose maintenance program."

The International Journal of the Addictions, 1973, 8(1), 127-141.

Martin, W.R., Jasinski, D.R., and Mansky, P.A.

"Naltrexone, an antagonist for the treatment of heroin dependence." Archives of

General Psychiatry, 1973, 28, 784-791.

Resnick, R.B., Fink, M., and Freedman, A.M.

"A cyclazocine typology in opiate dependence." American Journal of Psychiatry,

1970, 126(9), 90-94.

64
Resnick, R.B.; Volavka, J.; Freedman, A.M.;

Thomas, M. "Studies of EN-1639A (naltrexone): A new narcotic antagonist."

American Journal of Psychiatry, 1974,

131(6), 646-650.

APPENDIX A - GLOSSARY

and

Division - 1: Program Variables

(CBAD) Number of Urines Positive for Barbiturate and Amphetamines

Calculated from time of client's entry

to exit from program.

(CHALLENG) Challenges

If client used opiate drugs while

officially taking study medication.

(COILLD) Number of Urines Positive for Other

Illicit Drugs

Calculated from time of client's entry

to exit from program

(COMPD) Completion of Drug

For Naltrexone I, clients took medication

for 90 days. For Naltrexone II, clients

took medication for 180 days. For

Naltrexone III, clients took medication

for 270 days.

(COMPP) Completion of Program

Clients who were officially

graduated from the program.

(COPIATE) Number of Urines Positive for Opiate

Drugs - Calculated from time of client s

entry to exit from program.

(ETOM) Elapsed Time on Medication

Period of time in days in which the client

was officially taking study medication.

(ETOP) Elapsed Time of Program

Period of time, in days, in which the

Wikler, A. "Conditioning factors in opiate

addiction and relapse." In Wilner, D.M.,

and Kassebaum, G.G. Narcotics, 1965.

New York: McGraw-Hill Book Company.

(SAMPLE) Sample (1,2,3, 1&2, 2&3,1&2 vs.3)

(1) Subject in Naltrexone I only

(2) Subject in Naltrexone II only

(3) Subject in Naltrexone III only

(1&2) Subject in Naltrexone I and II

combined

(2&3) Subject in Naltrexone II and III

combined

(1&2 vs. 3) Subject in Naltrexone I

and II combined vs. III

Division - 2: Demographic Variables

(AGE) Age

Age at which client entered program.

(DELREC) Delinquent Record

Defined as official contact with the

criminal justice system prior to

clients' eighteenth birthday.

(MOINCAR) Months of Incarceration

Calculated by number of months

client spent in prison, jail, or

juvenile reformatory. If information was conflicting, the longest

period of confinement was used.

(NUMARRST) Number of Arrests

Determined by number of client

arrests, with or without a

conviction.

(NUMINTRT) Number of Months in Prior

client was officially logged in the program. Drug Treatment Programs

(FOLLSTAT) Follow-up Status (1,2,3) Calculated by assessing number of

This variable has three values which are months, client spent in drug

1) positive, 2) relapse to drugs, 3) unknown. treatment programs prior to start

A positive follow-up defined a person of current program. If information

who did not relapse to drugs, and demon- was conflicting, the longest length

strated acceptable social behavior. Values of stay was used.

two and three are self-explanatory. (PRDRUGTRT) Number of Prior Drug

(GROUP) Group Treatment Programs

Patients were classified as either being Calculated by assessing number of

graduated/terminated in good standing or drug treatment programs (in or

responsible drop-outs. out-patient, or in jail).

(NUMISS) Number of Missed Urines (RACE) Race

Number of urines requested but not received White or Black. No other groups

from time of client s entry to exit from were represented in the study.

program. (STABLIV) Stable Living Arrangement

(REQURIN) Required Urines Scored positively if patient had

The number of urines scheduled for a patient satisfactory living system, usually

from the day of entrance to termination with wife or girlfriend, perhaps

from the program. with family or self. Scored neg65
atively if poorly adjusted as shown

by numerous inconsistencies and/or

chaotic life style.

(YRED) Years of Education

Highest grade completed by patient

prior to admission.

Division - 3: Drug History Variables

(AMPHETAGE) Age of Onset of Amphetamine

Use.

(AMPHETYRS) Number of years patient

used Amphetamines minus any known

periods of incarceration and

other drug treatment.

(BARBAGE) Age of onset of Barbiturate

Use.

(BARBYRS) Number of years patient used

Barbiturates minus any known periods

of incarceration and other drug

treatment programs.

(COCAGE) Age of onset of cocaine use

(COCYRS) Number of years patient used

cocaine minus any known periods of

abstinence including periods of

incarceration and other drug

treatment programs.

(LIQUAGE) Age of onset of alcohol use.

(LIQYRS) Number of years patient used

alcohol minus any known periods of

abstinence including periods of

incarceration and other drug treatment

programs.

(MARJAGE) Age of onset of marijuana use

(MARJYRS) Number of years patient used

marijuana minus any known periods of

abstinence including periods of

incarceration and other drug treatment

programs.

(OPIATEAGE) Age of onset of opiate drug use.

(OPYRS) Number of years patient used opiate

drugs minus any known periods of abstinence

including periods of incarceration and

other drug treatment programs.

AUTHORS

Marc Hurzeler, M.D., David Gewirtz, M.S.,

and Herbert Kleber, M.D.

Yale University

Department of Psychiatry and

Connecticut Mental Health Center

66
PATIENT RESPONSE TO

NALTREXONE: ISSUES OF ACCEPTANCE, TREATMENT EFFECTS, AND FREQUENCY

OF ADMINISTRATION

Stephen Curran, M.A.

Charles Savage, M.D.

INTRODUCTION SUBJECT CHARACTERISTICS

The experiences concerning naltrexone to be

presented in this paper represent a subset of

the National Academy of Sciences (NAS) collaborative study. Thirty-eight subjects were

inducted to naltrexone or placebo-in a doubleblind fashion for a nine-month trial. Administration of the drugs was for the initial two

months six days a week, and thereafter on a

thrice weekly schedule. Extensive laboratory

and medical information was obtained for

assurance that naltrexone was a relatively

safe compound. Urine testing, demographic

changes and ancillary treatment measures were

continually monitored to assess the effectiveness of naltrexone in a drug rehabilitation setting.

The pertinent issues that this paper addresses concerning naltrexone are: its acceptance; treatment effects; and the frequency

for administering naltrexone.

Table 1 illustrates the characteristics of

volunteer subjects participating in the

National Academy of Sciences (NAS) Pilot

Study. These characteristics are consistent

with those obtained in various other studies

at this clinic. Subjects are generally unmarried, in their middle to late twenties,

educationally at the junior high school level,

black, and of lower economic status. Prior

experience in drug rehabilitation is minimal,

usually consisting in one previous treatment

for a duration of four months. Since subjects are legally classified as parolees or

probationers, all have criminal records with

an average of nine previous arrests.

ACCEPTANCE

The issue of the acceptability of naltrexone

67
in particular and the narcotic antagonist concept in general has always been paramount. In

view of the context in which naltrexone has

been tested, serious questioning must take

place before the scientific community accepts

definitive results on this issue. The recruitment efforts of the Narcotic Clinic indicate

that of 99 eligible candidates, 38 consented

and began antagonist treatment. This rejection rate does not necessarily imply that 62%

of the population finds naltrexone to be an

unacceptable method of treatment. On the contrary, verbal reports and follow-up behaviors

illustrate in this setting that some prospective subjects disavow any tendency to achieve

abstinence. Others find the required testing

procedures "harassing," and are quite honestly

"scared away" from the drug. While responsible investigators realize the necessity and

appropriateness for rigorous medical testing

and conforms to protocols, let no one be deluded

in thinking that within the strict adherence

to them, can the true acceptability of any

compound be judged objectively. At best, one

can only judge the acceptability of the research and secondarily the acceptance of the

drug by the active participants.

Sample Characteristics

The experience from our testing site is that

study patients report only minimal disadvantages to the medications under study. These

reports are those primarily of taste and some

mild stomach discomfort during the initiation

phase to the drug.

Using length of treatment as one indicator of

acceptance, naltrexone subjects' participation in the NAS Study was for 80.9 days and

placebo counterparts for 92.1 days. While

this duration appears to favor placebo subjects, their length of treatment is confounded by subjects using heroin for a period of

two to four weeks. This drug taking behavior

is not an option usually available to the

naltrexone subjects. Therefore, it is reasonable to say that naltrexone in this study is

comparable to placebo as an acceptable agent.

Duration of Treatment (Days) By Termination Classification (N=38)

TREATMENT EFFECTS

Table 2 illustrates the treatment outcome for

the thirty-eight subjects treated in this

study. As is indicated, four subjects completed the full nine months of study. This

category was evenly divided between the naltrexone and placebo groups.

Five subjects terminated for reasons of sideeffects and all were taking naltrexone. Three

of these subjects complained of symptoms resembling mild heroin withdrawal. While precautions were instituted to guard against

TABLE 1

initiating subject concurrently taking

heroin, urine surveillance records indicate

that each of these subjects had taken heroin

prior to naltrexone ingestion. These men

experienced the normal physiological reaction

to an antagonist drug, hence, their complaints

cannot be considered side effects. Of the

remaining two terminated subjects, one reported the symptom of nausea and the other of

constipation and stomach discomfort.

One placebo subject was discontinued as a result of an abnormality present on repeated

physical examinations. This subject experienced a significant weight loss and since he

TABLE 2

68
was not on active medication, this finding

is not attributable to the drug.

Subjects terminating under the broad category,

"all other reasons," include a myriad of reasons not related to the medications under study

although more naltrexone subjects gave this

reason. This heading consists of incarceration, transfer to another program closer to

residence, and often because the subject indicated that he could "make it on his own" without the aid of any medication. Analyses differentiating this category have not been completed since reliance on follow-up data is

indicated to document post-medication behaviors. At present cursory examination of

this category does not reveal startling trends

of significance.

The greatest proportion of subjects falls under

the "absences" category for reason of termination. While the number of subjects does not

greatly differ between the two treatment

groups (Naltrexone 5; Placebo 6), the duration

of treatment before the absences occur is noteworthy. Clearly, in reference to absconders

only, naltrexone patients remain in the research regimen three times longer than their

placebo counterparts. The occurrence of naltrexone patients remaining in treatment for

this duration is particularly interesting upon

comparison with placebo subjects who became

readdicted. Note is made of this comparison

for it exemplifies a consistent pattern in

other studies at this clinic (Kurland, Hanlon,

and McCabe, 1974) and offers a viable explanation for the absences of naltrexone patients.

The inference from this comparison is that

naltrexone subjects incur a greater susceptability to heroin use after two months of

treatment, and finding that reinforcement is

prevented, absent themselves from further

naltrexone treatment. Placebo subjects experience this same phenomenon but since

pleasure is obtained, continue to attend

the clinic and simultaneously use heroin.

The research protocol allows for a two- to

four-week pattern of heroin use before termination for reason of evidence of possible

readdiction. Hence, the placebo subjects'

duration of treatment is greater allowing for

continued heroin use.

Further examination for the cause of this

heroin use after two months of treatment was

conducted. Possibly the frequency with which

the study medication was administered contributed to this finding. The investigators note

that a sharp increase in heroin use is coincidental with a transition from six days/week

to a three days/week administration schedule.

To examine this inference, a comparison was

made between the thirty-four subjects terminating in the NAS Study (Study 1) and nineteen

subjects terminated from a more recent naltrexone/placebo study (Study 2) in which

subjects immediately receive medication three

times a week after a one-week induction schedule. The results of this gross comparison

indicate Study 1 terminated subjects' duration of treatment was 65.20 days and Study 2

terminated patients' was 31.05 days. The suggestion that subjects may remain in treatment

longer when daily clinic attendance is required may counter the utility of naltrexone

which blocks the effects of heroin for 48-72

hours. The obvious benefits to the client

and clinic when employing a thrice-weekly

schedule are many. However, these benefits

may need to be reevaluated if continued treatment participation (a general indicator of

successful progress) is maximized in a more

freauent administration schedule. This finding, as mentioned, is the result of a gross

analysis to glean possible causes for explaining drug use after two months of antagonist

treatment.

At this early phase of analyzing the data from

the NAS Study other causes may be present but

not as yet evident. The mentioned inference,

however, exhibits one facet of many questions

yet to be asked concerning the utility and

effectiveness of naltrexone.

ACKNOWLEDGMENT

This work is supported by Grant No. DA00415

from the National Institute on Drug Abuse.

REFERENCES

Kurland, A. A., Hanlon, T. E., and McCabe, 0.

Naloxone and the Narcotic Abuser: A Controlled Study of Partial Blockade.

(5),

663-672, 1974.

AUTHORS

Stephen F. Curran, M.A., Study Coordinator,

Friends Medical Science Research Center, Inc.,

22 Bloomsbury Avenue, Baltimore, Maryland

21228

Charles Savage, M.D., Principal Investigator;

Chief. Psychiatric Service: Chief. Drug Treatment Center, Veterans Administration Hospital,

3900 Loch Raven Boulevard, Baltimore, Maryland

21218

69
NALTREXONE IN METHADONE

MAINTENANCE PATIENTS

ELECTING TO BECOME “DRUG

FREE”

Neil Haas, M.D., Walter Ling, M.D., Elaine Holmes, Ph.D.

Mara Blakis, M.D., Margaret Litaker, MSW

This study examined the role of Naltrexone in

Methadone maintenance patients who wished to

become drug free. At the beginning of the

study the Methadone maintenance program had

approximately 300 patients, all male, the

majority of whom had been on the program for

over two years. The ethnic breakdown was

roughly 1/3 each for white, black and MexicanAmerican. All patients who expressed the

wish to become drug free between July 1974 and

October 1975, who were receiving a dose of

50 mg. or less and had been on the program six

months or longer were logged regardless of

their interest in Naltrexone. Patients who

were detoxifying on a disciplinary basis were

excluded. All patients were informed of the

availability of Naltrexone, its action as an

antagonist and potential usefulness and the

double-blind nature of the study; 104 patients

were logged, 15 were ineligible for the study

because of medical, alcohol or psychiatric

problems; 28 did not complete detoxification

(incomplete group); 61 patients co

detoxified from Methadone and 32 of these

letely

elected to enter the study and took at least

one dose of study medication (study group).

Those who detoxified but did not start study

medication are called refusers. In terms of

age and time on Methadone maintenance, these

groups were similar (see Fig. 1).

Many reasons were given for the decision to

detoxify. Most often they involved a wish to

be drug free and this was associated with a

wish to be free of the restrictions imposed

by Methadone maintenance, such as regular

clinic attendance, difficulty with vacations,

etc., and a wish to disassociate themselves

from the addict identity. They expressed the

belief or wish that thev could “make it on

their own.” Some had family pressures to--detoxify. Those who were most adamant that

they could make it on their own and who gave

this as their reason for detoxification tended

to be the least interested in Naltrexone.

Those who were less certain of their ability

to “make it” and who expressed some fear of

relinquishing the security and qualitative improvement in their lives (stability of work

and personal relations, difficulties with law

enforcement) that they felt Methadone maintenance had allowed them to attain, were most

70
interested in Naltrexone. The availability of

Naltrexone was a factor in tipping the decision of this group to detoxify. Some of this

group expressed interest but objected to the

double-blind because it meant giving up the

known security of Methadone maintenance for

only the possibility of an effective agent.

These patients seemed keenly aware of their

vulnerability to heroin use. Generally those

patients who expressed the fear of their own

vulnerability were most interested in Naltrexone and elected to take it after their

detoxification. The availability of Naltrexone also seemed to be a factor in their continuing their detoxification at points where

they experienced difficulty. However, these

factors did not significantly predict who did

complete their detoxification.

Detoxification from Methadone is a difficult

process involving physiologic and psychological stress. Almost all patients experienced

a high degree of anxiety during their detoxification and it was often difficult to determine clinically what symptoms were due to

anxiety and what were due to withdrawal. A

variety of detoxification programs was utilized, The main variations were: (1) patient

controlled decreases, (2) an 8-week fixed

schedule from 50 mg, that was known to the patient, and (3) a blind 8-week fixed schedule.

Generally, this was conducted on an outpatient

basis, Patients did have the option of entering the hospital for the final phase of their

detoxification, and some patients elected to

do this. In addition, supplemental medications were used symptomatically--the tricyclic/Phenothiazine combination--Triavil, Valium,

Dalmane and Darvon. Patients demonstrated

tremendous variability in the course of their

detoxification ranging from a very smooth

course with negligible difficulties to wishing

to stop after their first decrease in dosage.

The different detoxification schedules and

hospitalization did not seem to affect the

course of the detoxification as much as the

resources of the patient, the stability of

their environment and their relationships with

the staff of the program. The availiabity of

Naltrexone did encourage some patients to continue or resume their detoxification after experiencing difficulties. However, the risk

of receiving a placebo often had the opposite

effect. It is our impression that if the

study had been open, the availability of Naltrexone would have played a greater role in

motivating patients to continue their detoxification.

A number of patients who declined to start

study medication after their detoxification

feeling they “could make it on their own,”

subsequently returned after having used heroin

and requested Naltrexone instead of Methadone

maintenance. Some patients, who had only a

few doses of study medication and then dropped

out, also returned in this manner but were not

restarted because of the protocol. The return

experience is the most impressive observation

we have made. Apparently the experience of

detoxified patients in finding themselves vulnerable to using heroin seemed to give them a

more realistic view of their situation and

made Naltrexone valuable in their eyes. Their

preference at that point for Naltrexone rather

than Methadone maintenance is quite significant. The inability to use Naltrexone intermittently in such patients was an unfortunate

handicap imposed by the protocol. Had we been

able to restart patients, many who dropped out

would have dropped back in. Fran a clinical

standpoint, this is significant in that we

should expect patients to stop and start their

medication and it is no more reflective of the

medications acceptability or effectiveness

than antihypertensive agents which patients

start and stop (in part because like our patients they have no acute symptoms to motivate

strict usage of medication). A further practical observation relates to the starting

dose. We followed the induction schedule in

our protocol beginning with 10 mg. and doubling the dose daily for the next four days.

However, many of our patients tested the effect during the first two days, even though

they were told that they did not receive a

full blocking dose. Many of these patients

terminated the study at this point, feeling

that the medication was ineffective or that

they had received a placebo. We feel that

an initial dose of 30-50 mg. would provide a

moderate blockade for 24 hours and would be

useful in retaining patients--even at the risk

of inducing side effects.

This issue is exemplified by the data that almost 1/3 of our patients terminated during the

first week, and a second third bv the end of

the first month (see Fig. 2).

Safety.

adverse reactions.

We had few incidents suggestive of

One patient did experience

a psychotic depressive reaction after three

months of study medication. However, after

reviewing the course of his illness, the precipitating social and psychological stresses

and a past history of a similar episode manv

years prior, we concluded that this was probably not related to the study medication. A

number of patients did complain of gastrointestinal symptoms, particularly an “upset

stomach” during the first two weeks. This was

usually relieved by antacids and was transient. One patient did terminate himself because of a persistent upset stomach. One patient who detoxified rapidly from 80 mg. in

less than two months became highly agitated

at the end of his detoxification. He continued

to be extremely agitated after starting study

72
medication. After two weeks, study medication

was discontinued, but the agitation remained.

Subsequently, he was restarted on Methadone

with a diminution of his agitation. Although

it was believed that his agitation was due to

his rapid detoxification, other factors including legal and social problems were present.

The major reason for early termination (see

Tab. 1) was readdiction and/or a request to

return to Methadone maintenance. Eleven subjects fall into this group. Their time on

study medication ranged between one day and

eight months. Generally these patients

briefly discontinued their study medication

and became readdicted. Subsequently they

either directly requested a return to Methadone maintenance or could not be detoxified

in a resonable time in order to restart study

medication. Due to the uncertainty of the

double-blind, both staff and patients tended

to reinstate Methadone maintenance more quickly than had this been an open study. Two patients used heroin daily for two or more weeks

despite acknowledging that they could not get

an effect. They elected to return to Methadone maintenance because of the legal, financial and social problems of continued herion

use. One patient attempted to overcome the

blockade by titrating himself with sequential

injections of “half spoons;” after the seventh

half spoon he experienced a mild heroin effect

and with the next half spoon a full effect.

He then requested Methadone maintenance. As

of May 1, 1976, over half of the patients who

began study medication returned to Methadone

maintenance (see Fig. 3). This included one

patient who completed the full nine months of

study medication without a dirty urine but who

became readdicted to heroin subsequent to ending the study. More significantly, a followup questionnaire indicated that of the patients who returned to Methadone maintenance,

two out of three would return to Naltrexone

if it were available. Our continuation study

will tell us if they actually do.

Future Outlook. We are encouraged by our experience with Naltrexone and plan to continue

our investigation. Although it is not an alternative to Methadone maintenance for all patients, it does seem to be an attractive next

step for many patients who have stabilized

their life style on Methadone maintenance but

who are reluctant to jeopardize their gains

by detoxification and fear their vulnerability

to heroin use. There has also been a concomitant effect on the staff of our Methadone

maintenance program. Prior to the availability of Naltrexone, there was much discussion

of the issue of detoxification and the question of how long should patients be on Methadone maintenance. However, most staff rarely

TABLE 1

Primary Reason for Early Termination

Abnormal physical/psychiatric findings after study medications

1. (Psychotic depression)

Symptom Side Effects: 4

Speeded up )

Sleepy

Agitation

)

) One each

Upset stomach )

Illness: 1

Polycystic kidneys -- urinary tract infection.

Evidence of Readdiction and/or request for Methadone maintenance: 11

Disciplinary discharge: 1

(Stealing on grounds)

2 weeks unexcused absence: 3

Patient feels can make it on own: 5

Other -- traveling to clonic interfered with work: 1

Completed: 3

On study meds: 2

FIGURE 1

Time on Methadone Maintenance in Months at Log

6-12 13-24 >24 N Mean

S 7 9 1 6 32 25.3

R 8 11 1 0 2 9 20.75

I 7 8 1 3 2 8 23.44

Age at Time of Log

<25 25-29 30-34 35-39 >40 N Mean

S 5 8 10 9 3 2 36.32

R 5 11 5 2 6 29 30.00

I 8 9 3 8 2 8 34.25

S = Study Group

R = Refuser Group

I = Incomplete Group

72
FIGURE 2 FIGURE 3

Total Time on Study Medication at Termination (in days)

Complete

1-7 8-30 31-90 91-180 >180 9 months

9 9 5 3 1 3

Two patients still active

initiated discussions or strongly supported

their patient’s efforts to detoxify because of

their own sense of futility and feeling they

had little to offer these patients. With the

advent of Naltrexone, there was a shift in

this attitude with the staff feeling that they

now had an effective agent to offer their patients after Methadone. This helped them to

initiate exploratory discussions of detoxification with patients and to be much more supportive during detoxification rather than

subtly influencing the patient to return to

Methadone maintenance at the first signs of

any difficulty.

Conclusion. Although our experience with Naltrexone as a follow-up modality to Methadone

maintenance is still in an early stage and

difficult to evaluate, we are encouraged by

our experience with the NAS study. This is

particularly important considering the high

relapse rate following detoxification from

Methadone maintenance. It is our experience

that patients take Naltrexone not merely because of the physiologic blockade produced

but because it is our extension of the program. In the past most of our Methadone maintenance patients who detoxified quickly severed their participation in the program despite encouragement to remain active. This

allowed the patients little or no opportunity

to deal with the emotional factors of being

drug free and the prolonged abstinence syndrome often seen in Methadone maintenance with

the support of the program. Contact might be

subsequently reestablished only after readdiction to heroin occurred and treatment by

Methadone maintenance would be reinstituted.

Naltrexone gives patients a reason to continue

their active participation during this transition phase. Staff as well, view Naltrexone as

Followup Status of Patients Who Started Study

Medication as of May 1, 1976

On Study

M M NC Off Jail Medication

17 6 55 2 2

MM = Methadone Maintenance

NC = No contract >3 months

Off = No maintenance medications

adding to their own credibility with detoxified Methadone maintenance patients and motivates them to be actively involved with their

patient during detoxification and their transition to Naltrexone. Thus Naltrexone works

to enhance the overall rehabilitation program

and expand its effectiveness to both staff

and patients. Even though we had a very high

dropout rate, the retention of the study group

in the overall program was many times greater

than the patients who detoxified but refused

Naltrexone. Thus Naltrexone does seem promising as a transition treatment for Methadone

maintenance patients electing to become drug

free. In this study, the decision to take

study medication was based on self-selection.

Future work will also include attempts to define what characterizes patients who are most

likely to benefit from Naltrexone as a transition modality.

AUTHORS

Neil B. Haas, M.D., Walter Ling, M.D.,

Elaine Holmes, Ph.D., Mara Blakis, M.D.,

Margaret Litaker, MSW

Drug Dependence Treatment Center

VAH, Sepulveda, California

73
COMMENTS AND FINDINGS

FROM A NALTREXONE

DOUBLE BLIND STUDY

John Keegan, M. A.

Carol Lavenduski, A.C. S. W.

Kenneth Schooff, M.D.

PATIENT CHARACTERISTICS

AND OUTREACH

Essentially three groups of patients emerged

from the Lafayette Clinic naltrexone doubleblind study. The first group was comprised

of those who came to the program via advertisement or referral and decided it was not

what they wanted. Hence the only available

data for these individuals consists of basic

demographic information collected on an

intake face sheet. The second group was

comprised of patients who received methadone

but did not receive study medication. Since

these individuals were involved in treatment

much longer, extensive social and psychological data were also collected. The third

group was comprised of any patients

receiving study medication. The same data

collected on the second group was also

collected on these patients.

An attempt was made to determine whether

there were any characteristics which would

differentiate those receiving methadone as

opposed to those who also received study

medication. Because of the minimal data

available on those who were only seen at

intake, there were no comparisons done with

this group. The methadone and study groups

were similar in terms of analyses which compared 45 MMPI scales as well as two-point

code profile analyses. The social maladiustment scale which has items indicating

shyness and minimal social involvement was

found to be higher for the methadone group

(p<.05). However, it should be noted that

the T scores for both groups were well

within the normal range, T score <60.

The average MMPI profiles were virtually

identical characterological profiles with

elevations on the Depression and Psychopathic

deviate scales. Comparisons were also made

between the obvious and subtle scales for

74
both groups. These scales include the

depression, hysteria, psychopathic deviate,

paranoia, and mania scales. For both groups

the obvious scales were elevated above the

subtle scales, but still within the normal

range. These findings would indicate that

both groups have a tendency to exaggerate

their symptoms at the time of intake. These

findings also reflect the relative lack of

sophistication of most of the patients seen.

Demographic and social history variables were

also compared. The naltrexone patients were

significantly older (p<.05) than the methadone patients. Although no other demographic

variables were significantly different, it

was found that there were more blacks and

more single individuals in the naltrexone

group.

Three social history variables were significantly different (p<.05) between the groups.

The methadone patients had more socially

deviant fathers and siblings. More of the

naltrexone patients had both parents using

alcohol, and more mothers and fathers using

either alcohol or drugs. It was also found

that more of the methadone patients lived

with other drug abusers. These other

abusers were in many instances the wives of

the patients. Our past experience has found

drug abuse by the spouse to be a very

important prognostic indicator. The more

basic prognostic indicator may however, be

simply whether the patient currently lives

with any drug abuser. Although no other

social history variables were significantly

different between groups, it appears that

overall the naltrexone patients look better

on a variety of dimensions. They appear to

have had less criminal involvement. There

are thus fewer naltrexone patients on probation. More of the naltrexone patients

were veterans. The source of support for

the groups indicates that more of the naltrexone patients are employed and receive

their support from family or friends. They

also receive less support from public assistance , spouse, or illegal activities.

Both groups were scaled on the following

family dynamics variables: Child and Parent

Roles, Family Scapegoat, Symbiotic Relationships, Familial Communication, Family

Cooperation, Discipline of Children,

Presence of a Significant Role Model,

Sibling Rivalry, Peer Group Influence, and

Family Leadership. Although a double blind

rating on these scales was not used for the

two groups, there were nonetheless no significant differences found between the

groups. Both groups generally had poor

family interrelationships. The most

striking deficiencies were that both groups

evidence very dysfunctional discipline from

parents, and very poor communication among

family members.

CURRENT USE OF

NALTREXONE

Since the double blind study had discontinued

intake, we have taken another approach which

we believe may be more fruitful. First, we

have attempted to service the industrially

employed addict by offering multiple modalities. These modalities include either

methadone, L-Methadylacetate, naltrexone, a

Dextromethorphan hydrobromide placebo.

Patients in this design are assigned to

either methadone maintenance or an opiate

free condition based upon their MMPI, work

history, psychiatric ratings, psychological

ratings, motivational ratings, extent of

family problems, and extent of their criminal

involvement. After

either of these tracks, they are randomly

atients are assigned to

assigned within the tracks to receive either

methadone or LAAM in the maintenance track

or naltrexone or a dextro-methorphan hydrobromide placebo in the other track. In this

way, we hope to differentiate between those

who may benefit most from one form of treatment versus the other.

Patients who are on probation or parole have

been shown to do better in treatment than

those not faced with such contingencies. In

a similar manner, we believe that patients

whose source of income is contingent upon

elimination of a substance abuse problem will

also do better in treatment. We thus see

the industrially employed addict as being

more suitable for antagonist or opiate free

treatment.

SAFETY

The Detroit Naltrexone Program monitored the

physical characteristics of its patients

quite carefully. In some patients, both

systolic and diastolic blood pressure increases were noted. Some of these increases

may have been due to causes other than naltrexone. Among the possible causes were:

1) use of other substances

2) physical problems unrelated to

naltrexone

3) anxiety precipitated by detoxification

from methadone

4) anxiety precipitated by the informed

consent

The question of actual cause, however, still

7 5
remains open. Analyses of the blood pressure

records of the naltrexone and placebo

patients may be helpful. However, there may

be relatively few patients who took the naltrexone long enough to make final judgements

possible.

Many of the Detroit patients admitted abuse

of other substances including alcohol, barbiturates and amphetamines, while taking the

study medication. The mixture of other

medications with naltrexone may have been

responsible for some of the side effects

reported. Future research should clarify the

effects of such mixtures.

Since studies thus far have not analyzed the

effects on women, the treatment of husband

and wife abusers has been made more difficult

When the safety of naltrexone is assured, the

clinical utility should thus increase

dramatically.

PROBLEMS ENCOUNTERED IN

DOUBLE BLIND STUDY

The naltrexone program initially intended to

treat referrals from the criminal justice

system who were either on probation or

parole. Because of legal questions raised

about the use of a research drug with these

patients, this approach had to be abandoned.

The staff of the Substance Abuse Department

then decided to make outreach efforts among

patients who had been receiving methadone

for a prolonged period (6 months) and who

were now ready for an alternative treatment

which would eventually leave them opiate

free. Contacts were made within the Detroit

metropolitan area with directors of various

methadone treatment centers. Although these

individuals appeared receptive, their help

was minimal. One of the primary reasons for

this was because funding of methadone programs is directly related to patient census.

At the time that our program sought patients,

the methadone programs were having difficulty

keeping their patient censuses high enough to

maintain funding. Methadone programs therefore wished to keep as many patients as

possible involved in their respective

programs.

Since Lafayette Clinic is located in the

central area of Detroit, most of the referrals concerning substance abuse are made by

programs serving a primarily black population. The black community is well aware of

Lafayette Clinic’s focus on psychiatric

research. The community is therefore somewhat suspicious of treatment of community

members with a research drug such as naltrexone. It is therefore possible that this

may have hindered referrals to the naltrexone research program.

Efforts were also made to contact counselors,

social workers, and other therapists who

had day to day contact with the patients.

This succeeded in producing more referrals

but the number was still relatively small.

Furthermore, it became apparent that the

patients being referred to us were those

who were causing the greatest problems in

their former programs. The Detroit

Naltrexone Program was thus hampered by

problems in getting suitable referrals.

The initial design of the study was double

blind. This raised a variety of problems.

Among these were:

1) The patients tested their medication

and, hence, were often the only ones

to know what they received.

2) Patients who found they were not

receiving naltrexone saw no point in

continuing the program.

3) There was some attrition when patients

were informed (via informed consent)

that they might not receive naltrexone

at all.

4) The informed consent which made clear

all possible risks to be encountered,

also may have had a tendency to limit

program participation.

Thus far we have only made a beginning in

determining factors which may prognosticate

longer involvement in antagonist treatment.

It is clear that all patients are not suitable for treatment with antagonists. The

future objective must therefore be to determine more conclusively which patients are

most suitable for this treatment.

AUTHORS

John F. Keegan, M.A., Carol Lavenduski,

A.C.S.W., Kenneth Schooff, M.D., Lafayette

Clinic, Dept. Substance Abuse, Detroit,

Michigan 48207

76
FACTORS INFLUENCING

SUCCESS IN AN ANTAGONISTIC TREATMENT PROGRAM

Sadashiv Parwatikar, M.D., FRCP (C), James Crawford, M.S.,

John V.Nelkupa, Chona DeGracia, M.D.

BACKGROUND

Broad efforts have been made over the past

three years to evaluate the efficacy and

safety of antagonist drugs in the treatment

of heroin addiction. Such treatment is predicated on Wikler's hypothesis that drugseeking behavior is conditioned. Hopefully,

the use of an antagonist will prevent the

opiate "high", leave the drug-seeking behavior unreinforced and thus lead to the extinction of the habit.

Efforts with Cyclazocine demonstrated it to be

a toxicologically safe blocking agent to the

opiate "high" but producing sufficiently noxious side effects as to preclude its ready

acceptance by the treatment population. Consequently, other antagonists were explored; in

particular, early pilot studies of Naltrexone

indicated it to be a safe blocking agent -

apparently without side-effects.

Based on this and other evidence, a large

double-bind study of Naltrexone was organized.

Three complementary protocols were deployed so

as to provide a wide sprectrum of sociodemographic data.

Protocol 1, implemented in St. Louis, called

for the systematic induction of street addicts

onto study medication. Forty-two patients

volunteered for the program. They were given

an explanation, accepted on a closed ward, detoxified on Methadone and received a complete medical and psychological work-up including:

complete physical, SMA-12, hematology, urinalysis, Australian Antigen, Chest X-Ray, EKG,

mental status, psychiatric, neurological etc.

While on the ward, each met with the screening

committee, signed the informed consent and was

assigned to study medication (blind).

Of those volunteering, two were rejected for

medical reasons; one refused his random assignment; the reminder were placed on study medication in accordance with the protocol. After

complete induction and briefing, each patient

was released into the community where he was

supported by systematic counseling, vocational

evaluation, training and placement.

77
DESCRIPTION OF TREATMENT

POPULATION

During the research period, approximately 400

clients passed through the St. Louis Central

Intake Unit. Of these, 267 were logged and

received an explanation of Naltrexone. Fortytwo accepted the terms of the protocol and

were inducted. As part of the Intake procedures, a comprehensive social history was taken.

From such histories, data was extracted on age,

education, marital status, rate of employment,

rate of criminal activity and occupational

status. These data formed both the basis for a

population description and a baseline for future

compasrlson.

Upon intake, the following population statistics were gathered:

(1)

(2)

Age - the man was 24.6 with an interquartile range of 21.21 t0 27.00.

Education - the mean grade achievement was

10.975 with an interquartile range of 9.8

to 12.125.

Marital Status - twenty-one reported as

never being married; one had been married

but separated; two were divorced; sixteen

were married end/or enjoyed a commmon-law

status.

(3)

(4) Occupatlonal Status - two reported a job

status of professional; four as skilled

laborers; four as semi-skilled laborers

andtwenty-two as common laborers.

Rate of Employment - over the two-year

period immediately preceding intake. four

reported as 100% employed; three as 75%

employed; ten as 50% employed; eleven as

25 employed and twelve as totally unemployed.

(5)

(6) Rate of Criminal Activity - over the two

years preceding Intake, each study client

was classified-on the basis of his criminal involvement; one reported no criminal activity; four indicated "an occasional misdemeanor"; fourteen admitted to

occasional felonies; ten reported moderate amounts of criminal activity and

eleven indicated a long and heavy involvement in crime.

As a rule, the St. Louis clients were young

black males under legal pressure, with a history of one or more previous treatment admissions. Typlcally, each professed a desire

to really "get it together", to get a job, to

get back with their families etc. Most

appearedtobe fromabroken family of origin

with which they still maintained ties, usually

with a mother. On hearing about the antagonist drug effects, they indicated their satisfaction with the concept, made plans for

rehabilitation but seemed unable to carry

out their plans,belng constantly distracted

by the field.

PROGRAM EXPERIENCE AND

SUGGESTIONS FOR THE USE

OF NALTREXONE

As long as our patients were on the ward, they

appeared to maintain positive attitudes toward

medication but upon returning to the community,

patients appeared to experience a gradual deterioration in treatment motivation; first

missing medication upon occasion, then not

coming for some time and,finally,dropping

from treatment. In some cases our treatment

staff were able to coax them back - usually

not. Clients residing with families appeared

to maintain motivation longer than others.

It appeared particularly productive for the

treatment staff to interact with family members, asking them to encourage the client to

take the medication. Contrastingly, patients

were often placed under pressure by wives and/

or girl friends to "hurry on home - you can

make it". Such patients Invariably lost motivation more rapidly.

It would appear that the availability of a

strong compatible reference group is crucial

in the use of Naltrexone; coming daily under

the influence of such a group ensures the

taking of medication. In the absence of

some such dynamics, Naltrexone therapy simply

won't work.

Early in the program, patients tended to misbehave on the ward,notreturnlngontime from

week-end passes, not getting up on time and

failing to maintain an acceptable level of

ward orderliness and cleanliness. Concomitantly, there were numerous quarrels among the

patients and also between staff and patients.

Often bizarre and unreasonable demends were

made of the staff.

The staff met to consider the above problems.

After careful consideration, it was concluded

that these behaviors were a function of the

following:

(1) Overidentification with patients by our

ex-addict counselors.

(2) A lack of recreational activity on the

ward.

78
(3) Failure to cultivate patients' responsibility.

Staff training sessions were conducted. To

develop a feeling of professionalism, a recreational specialist was assigned to the ward;

systematic efforts were made to develop ward

government procedures in which clients were

assigned significant roles and responsibilities; whereupon, the above problems were

largely obviated.

Six to nine months after discharge, each patient was contacted. Eight were drug free.

previous research by the St. Louis team found

program retention to be related to education,

marital status, employment, occupational

status etc. Accordingly, on similar variables,

the eight drug-free clients were compared to

our other clients. As expected, the eight

successful clients were better educated, displayed higher status occupations, higher rates

of emloyment. lesser criminal activity. These

data are displayed in Tables 1, 2, 3 and 4.

Having a relatively high level of education,

a relatively high occupational status, relatively high previous rate of employment are

each good indicators of successful rehabilitation. Having a relatively high rate of previous criminal behavior or relatively low

levels on the above variables, are probably

contraindicators of success on Naltrexone.

Our experience suggests that therapy and

motivation are enhanced when:

(1)

(2)

(3)

(4)

Treatment staff maintain a posture sufficiently close as to be accepted as a role

model but sufficiently far as to cause a

mild discomfort or inadequacy feeling.

Clients are encouraged to accept responsibility and make decisions in their own

therapy.

Staff maintains rapport, not only with

clients but also with persons likely to

influence clients.

Positive reinforcement of desirable social

behavior is used rather than negative reinforcement for adverse behavior.

CLINICAL AND TOXICOLOGICAL IMPRESSIONS

During the study, especially during induction,

vital signs, blood chemistry, hematology and

EKG were carefully monitored. No apparent

medical problem was foundtobe associated

with study medication. There were, however,

some side-effects. Such side-effects were

usually mild and transitory in nature, consisting of such things as drowsiness, headaches,

sweating, stomach distress, blurring of

vision etc. It appears reasonable to conclude

that Naltrexone is a safe blocking agent to

the opiate "high" - acting up to 72 hours -

occasionally producing mild, transitory sideeffects as indicated above. (This conclusion

is consistent with the findings of an earlier

pilot study and of our present open study.)

PROSPECTS FOR FUTURE

RESEARCH

A certain amount of pessimism is generated when

one reviews our collective rehabilitative experience over the last decade. Treatment success has been very limited. Rehabilitation

requires a change in behavior. Such behavioral

changes are seemingly a function of the field

and, as such, are not sufficiently controllable

as to make such behavioral changes a planned

phenomenon.

Naltrexone, in and of itself, cannot change

behavior, but it can serve as a buffer against

the reinforcing properties of the opiate 'high!'

Taking Naltrexone,an individual can go about

his dally tasks, secure in the knowledge that

he cannot get high. As a consequence, he will

not be tempted take drugs. Being in such a

position provides respite from the drugscene pressures. Hopefully, such conditions

permit the individual to learn new attitudes,

form new associations, re-establish social

creditability and, in general, reconstitute

his identity. The greater the level of previous functioning, the better will be the

chance of rehabilitation. Obviously, some of

the indicators of success are such things as

education, marital status, occupational status,

previous rate of employment, lack of previous

criminal activity etc. By way of generalization, higher levels of socialization are indicative of more sophisticated social skills which,

in turn, are more likely to facilitate adjustment.

But having these good qualities will not of

itself assure successful rehabilitation.

Additionally, the client requires a wholesome

reference group, wholesome recreational alternatives, gainful employment, an acceptable

niche in the fabric of society. For rehabilitation, Naltrexone and personal skills provide the potentiality, but the field itself

must extend a helping hand and the opportunity.

Society must make a place for the ex-addict.

Falllng to do so foredooms rehabilitative

efforts to failure.

79
Antagonist drugs, Naltexone in particular,

have been demonstrated to be toxicologically

safe, posing no greater risks than are inherent in other chemotherapies. Unfortunately,

the question of efficacy is not nearly as

clear. Before this question can be answered,

several other ingredients are needed:

A. Clear, easily applicable criteria are

needed as indicators and/or contraindicators

for selecting or rejecting Naltrexone. We

might undertake a comprehensive regression

study, using a clearly defined measure of

treatment success as the dependent variable

and a large battery of social and psychological variables as independent variables.

Arising from this would be a set of weights.

Application of those weights would greatly

enhance the effectiveness of treatment decision.

B. Community based linkages are needed to

assure broader citizen input to treatment decision; such participation will facilitate

re-acceptance of the ex-addict. Careful plans

for bringing about change in societal attitude

is required. Skilled change agents should be

recruited to the task. Inter-institutional

cooperation on treatment decision should be

fostered; especially, between the judicial

system and the drug-treatment facilities.

C. Treatment is often thwarted by a tendency

for staff to over-identify with the drug-taking

culture. Research is needed to isolate the

contraproductive attitudes of staff. Having

accomplished such research, systematic education and attitude change can be undertaken.

D. Doubtless there are numerous potential

clients who are locked into their anti-social

attitudes because of their abject dependence

on interaction within their deviant culture.

If we are to attract them into treatment, we

must find a way of getting in touch with them.

Systems people, sociologists and anthropologists may be asked to study the primary message systems of the drug culture so as to

develop some means of direct communication.

At present, the deviant communication svstem

is relatively closed in reference to the

larger society.

E. As a condition of probation and parole,

the Criminal Justice System might ask some

of its charges to participate in further research. Such legal pressure would function

as a means of "forced compliance" holding the

client in the situation so that relearning

would take place.

PRETREATMENT RATE OF EMPLOYMENT

As a final observation - since the effectiveness of Naltrexone depends on the quality of

ancillary services, it is unreasonable to

evaluate it on the basis of urinalysis, criminality, educational Improvements, individual

support etc. If (as we have written) we wish

to test the efficacy of Naltrexone as a useful adjunct to a good treatment program,how

can we do so if one or more fundamental ingredients of rehabilitation are generally

absent from our social context? It is the

contention of this paper that we (at least

in St. Louis) are incapable of testing the

usefulness of Naltrexone unless we address

issues raised in A, B, C, D and E. Further,

in order to provide the field for such research, Naltrexone, which has been demonstrated as toxicologically safe, should be

made available to the general addict population, as a therapeutic tool for the use by

physicians in the field.

TABLE 1

LEVEL OF EDUCATIONAL ACHIEVEMENT

TABLE 2

OCCUPATIONAL STATUS

TABLE 3

80
TABLE 4 AUTHORS

PRETREATMENT RATE OF CRIMINAL

ACTIVITY

Sadashiv Parwatikar, M.D., FRCP (C), James

Crawford, M.S., Nelkupa John and Chona

DeGracia, M.D. Missouri Institute of Psychiatry, 5400 Arsenal Street, St. Louis, Missouri

81

THE NIDA CLINICAL STUDIES

8 3
A POINT OF VIEW CONCERNING TREATMENT APPROACHES

WITH NARCOTIC ANTAGONISTS

Richard B. Resnick, M.D.

Elaine Schuyten-Resnick, M.S.W.

When narcotic antagonists were first

introduced into the treatment of drug

addiction, patients were placed on

the medication without regard to

selection criteria and assessments

of "successes" or "failures" were

made only on the basis of their retention in the program. Since that

time, however, our evaluation criteria have become more refined and we

have begun to look at more complex

questions such as: Are these compounds "helpful" and if so, "for

whom" and by what treatment techniques can we augment their usefulness? A salient aspect of our naltrexone studies, for example, is

addressed to the question of "for

whom?" Hopefully when our data analysis

is completed, it will contribute to

either affirming or negating the conceptual model that we have formulated

to aid us in the differential diagnosis

and treatment of opiate dependent individuals.

For my presentation today I have chosen

to share with you some aspects of our

point of view concerning treatment

approaches based on our clinical experience. As investigators, we are

all committed to the rigors of science

with its demand for carefully controlled data. However, I am not

addressing myself to specific research

data, but rather to some issues concerning the application of this class

of compounds to clinical treatment

programs.

Although we are using psychoactive compounds sharing a specific pharmacologic

property that can and has been used

advantageously -- it would, in our

opinion, constitute a serious error for

a treatment program designated to

evaluate their clinical efficacy to

use the same model as that used to evaluate other pharmacologic therapies: compounds, for example, whose purported

function is to alter an underlying

physiologic malfunction or disease

84
process and which may relieve, eliminate

or worsen a "target symptom." It is

easy to discern drug effects when they

cause a marked change (positive or

negative) on some aspect of the psychopathology being examined -- such

as the effect that lithium has on a

manic reaction or imiprimine on depressed states. Narcotic antagonists

do not directly affect an individual's

psychopathology; their benefit is

only secondary, by protecting the

patient from the effects of selfadministered opiates.

Therefore, the model to follow is

not analogous to one in which you

can explore the degree to which the

compound, by itself, affects an

identifiable clinical syndrome that,

in most instances, is ego dystonic.

Few people, for example, derive

gratification from depressive symptoms . All addicts get gratification

from their drug use, regardless of

the consequent "secondary losses"

that may be incurred. To pursue the

analogy further -- we observe and

describe varying degrees of "secondary gain" that patients may derive

from their illness and that often

lead them to interrupt their

treatment regimen. The gain, however, for the individual addicted

to drugs is "primary" not secondary.

It is the "secondary losses" that

bring him to us for treatment. We

know with absolute certainty that

antagonists prevent relapse to

opiate addiction. It is contingent

only upon the patient's continuing

to take the medication at an adequate

dose over a sufficient period of time.

Ah, there's the rub, --- PROVIDED

HE TAKES THE MEDICATION. A major

thrust of our clinical efforts,

therefore, will need to be devoted

to bringing to bear all our ingenuity and resourcefulness to help

convert the ego functions of our

patients so that their attitude

toward continued opiate use is

changed and it becomes viewed by

them as a "primary loss" and not

as a gain. In part, it becomes

our ability to (and means wherein)

we accomplish this task that must

be evaluated. Thus the clinical

efficacy of these particular compounds becomes inseparably bound

to the efficacy of the clinics

that use them.

I will discuss some of the clinical

techniques we consider most important,

although we must emphasize the obvious:

Good clinical judgment is never fully

explainable solely on the basis of

specific techniques.

When working with narcotic antagonists,

it is essential that the staff help

patients to learn that their treatment

is not the medication alone. Obviously, to do this, the staff themselves must know it, understand it

and believe it! It takes a helluva

lot more input to treat a drug addict

than simply dispensing medication.

As Dr. Lee Schwartz, a collaborator in

our research, often reminds me: "It

takes more than a pill to cure an ill."

The medication can, however, be used

as a tool for the initial focus of

therapy -- it can be a way of enabling

the patient to begin to trust the

therapist and to establish a therapeutic alliance. Whatever diverse

therapeutic techniques are employed,

we cannot overemphasize the importance

of a good rapport and positive transference between the patient and a

therapist. This relationship can be

beneficial in many ways -- ranging

from providing support the patient

needs during the post-withdrawal

period to substituting for emotional

resources that are lacking in the

patient's life. When we first began

working with antagonists and did not

provide such therapy, our resultswere poor; they improved when each

patient was assigned to a trained and

empathic therapist and was seen

regularly, even if contacts were only

brief.

Gradually, the patient can learn to

look to the therapist -- rather than

to opiates -- for gratification of

dependency needs, relief of anxieties

and solutions to the problems and

dilemmas of his life. It is through

this therapeutic relationship that a

patient can get positive reinforcement

for making choices that will contribute to his achieving a more

stable, socially acceptable lifestyle, while deconditionins (or

at-least non-reinforcement of his

drug-seeking behavior is taking

place.

One aspect of treatment that

should be considered is the

benefit a patient may derive from

85
having conditioning theory explained to him, so that he may

begin to look for signs of conditioned responses within himself.

The value for the patients who

have this understanding has been

remarkable in some of our followup interviews. When conditioning

is explained to patients, it has

the additional benefit of alerting

them to the possibility that they

could become readdicted at some

time in the future -- even after

a long period of successful antagonist treatment.

However, stopping the antagonist

and resultinq opiate use is, by

itself, an insufficient criterion for

labeling the treatment a failure.

Would you say that digitalis is

not clinically efficacious if

a patient with congestive heart

failure stops taking it? In our

studies we have found that the

length of time patients take naltrexone increases with each

successive readmission.

The model we use should be similar

to the one we use in treating

chronic medical illnesses. A patient must

be told that whenever medication is discontinued, he can and should ask to be put back

on the antagonist whenever he feels tempted,

or has begun, to use opiate drugs

again. Imagine the positive affect

it has on patients and their

families when they can view addiction as no worse than other recurrent medical problems for which

treatment is available. The

emotional impact on the patient

is usually profound, since he has

previously experienced negative

attitudes and rejection -- if only

by being labeled a "failure" --

whenever he has become readdicted.

When the treatment staff is nonjudgmental about his opiate use,

it just "blows their minds." We've

seen this happen over and over again

-- "You mean, DOC, if I goof up, I

really can come back to the program???"

The focus of treatment needs to become for patients to change their

"lifestyles," rather than to "never

use drugs again." If this is the

correct focus, as we believe it should

be, then it follows that the treatment

staff must believe it, in order to

convey it to the patients. For certain

individuals, a meaningful commitment

to rehabilitation with an antagonist

can only be made after relapsing and

becoming readdicted one or more times.

For some it entails getting disgusted

with themselves, others need to know

their therapist long enough to trust

that the therapist cares about him

and his needs and will reach out to

help him through times of stress.

We have found that the most successfully rehabilitated patients are

those who learn to rely more and more

on the therapist for help, especially

during the early phase of treatment.

As this relationship begins to become

a trusted and consistent source of

satisfaction, these patients dwell less

and less on the instant gratification

afforded by opiates.

Here, a specific case example may best

illustrate this point:

A 28-year-old man who had been on

methadone maintenance in our program

for four years, felt "ready" to be

drug free, having made significant

changes in his life while on methadone.

His therapist concurred, but suggested

naltrexone as a transitional treatment.

He initially refused, stating that he

felt he didn't need it. For two months

following the last methadone dose,

he struggled against growing temptation to use opiates to relieve his

secondary abstinence symptoms and

severe depression, which seemed to

get worse instead of better as time

went by. He had 400 mg methadone at

home and became obsessed by the

thought of the instant relief it would

offer. During this period he saw his

therapist daily and called her frequently at night or on weekends, when

he was under stress or having severe

symptoms. Finally his symptoms became so severe he knew he could no

longer resist the temptation to use

dope again without more help. He

phoned the clinic and was told to

come right in, which he did. Riding

through East Harlem -- where he used

to take drugs -- on his way to the

clinic he experienced severe withdrawal (conditioned abstinence) and

was tempted to get out and cop some

dope. He arrived at the clinic and

said he felt it was necessary to try

the original suggestion that he take

naltrexone.

On follow-up, he stated that he knew

the naltrexone would give him "peace

86
of mind," since he would be protected

against losing control and impulsively

using drugs. He added, however, that

without the on-going relationship with

his therapist, he would have given in

to his urge to use dope and if he did

so even once, he would have become

readdicted, felt himself to have failed,

and perhaps never tried to detoxify

again. He said his experience led

him to feel that in the initial

opiate-free months, it was his therapist that helped first, then it

was the naltrexone, but without both

of these factors. he couldn't have

achieved his goal. He took naltrexone for one month only, then

stopped when he felt ready. Today,

more than two years later, this

patient continues to be opiate free.

We have had many patients express

the same theme: The antagonist

and the therapist must work together to help them.

Clinic attendance is also a

crucial issue. Methadone patients

come because they fear getting sick:

antagonist patients don't have that

worry. Their attendance must be

based on a strong desire to remain

drug-free, fear of family or other

external pressure, or a good relationship with their therapist. Few

patients can be expected to come to

the clinic because of a commitment

to their therapist initially. It

becomes a very strong message to

the patient, however, if he skips

one day of medication and is called

by his therapist to find out where

he is. Our patients often express

surprise and state that they have

never been "cared about in this way"

by other treatment programs. A few

such calls, and soon many patients

begin to respond to that caring with

a commitment to their therapist that

includes coming to pick up their

medication.

Requiring daily medication is usually

a good idea with antagonist patients,

at least in the initial months of

treatment. It not only provides

some structure to their lives and

puts them in frequent contact with

the staff, but also can serve to

alert the staff to the potential for

readdiction whenever a patient skips

a day of medication. Many patients

feel they can skip medication and

use opiates "once in a while." We

have found that antagonists become

useful in respect to this issue for

two reasons. Since the patient must

make a conscious decision to skip

medication, he cannot deny responsibility for his impulsive drug use.

Many good antagonist candidates --

those who we believe have the best

prognosis -- are also those whose

drug use is impulsive.

By helping the patient understand

these dynamics, the therapist forces

the patient to become aware of his

choices, instead of believing that

he used drugs because he was-"weakminded" and implying it was beyond

his control. We often tell patients

and their families that refusal to

take medication is analogous to

stating an intention to get "high."

A patient who is ambivalent about

taking medication on a particular day

is less likely to act on his impulse

to skip it, if he knows that doing so

is equivalent to announcing to his

family and the staff: "Today I plan

to shoot heroin." We have found that

involving the family in this way

places the patient in a situation where

he can rely on external pressures to

help him through times of ambivalence,

until he can integrate his desire to

remain drug free on a new emotional

level, under more conscious control.

In conclusion we strongly urge that

you treat your study subjects as

patients -- exercising the same degree

of concern, interest, sincerity and

dedication to relieve human suffering

and to restore health as you would do

for any other sick person.

AUTHORS

Richard B. Resnick, M.D., Elaine

Schuyten-Resnick, M.S.W.

Division of Drug Abuse

Research & Treatment

Department of Psychiatry

New York Medical College

5 East 102nd Street

New York, New York 10023

87
CLINICAL EXPERIENCES

WITH NALTREXONE IN 370

DETOXIFIED ADDICTS

Muriel Thomas, R.N., Frank Kauders, M.D.,

Marcel Harris, Judy Cooperstein, R.N.,

Gordon Hough, Ph.D., Richard Resnick M.D.

INTRODUCTION &

BACKGROUND

The Division of Drug Abuse

Research and Treatment of New York

Medical College began to use naltrexone in 1973. Since then, 370

opiate addicts have been detoxified

and inducted onto naltrexone. The

Division's clinic is located in East

Harlem, where there is a high incidence of opiate addiction. Thirtyeiaht percent of the patients treated

at the Division are black, 38% are

Puerto Rican, and 24% are white.

Heroin and/or illicit methadone are

the drugs primarily abused. Patients

being treated in the Division come

from all levels of society though

they are predominantly a low socioeconomic group. They are referred

for treatment from community agencies

such as probation and parole

officers, from nearby ambulatory

detoxification facilities, and by

patients who have told their friends

and relatives about naltrexone.

When our investigations of naltrexone first began, many patients

seeking treatment were suspicious of

a new medication. Cyclazocine was

fairly well-known in the community.

Although it was disliked at some

treatment facilities, patients at

New York Medical College had been

inducted and maintained on it without undue difficulty with side

effects. When we began using naltrexone it was necessary to do

public relations work so that both

staff and patients would be willing

to explore how satisfactory naltrexone would be as treatment.

SAFETY & SIDE EFFECTS

The first and probably most important finding from treating these

patients with naltrexone is that

88
naltrexone appears to be a safe drug

with very few side effects. The

side effects which appear most frequently (though in a very small

number of patients) are epigastric

pain, especially if the medication

is taken on an empty stomach, and

clinically insignificant elevation

of blood pressure. Epigastric pain

began to occur less frequently when

induction procedures were changed.

In the earliest patients, this was

the only symptom on the check list

that increased when naltrexone was

given following seven opiate free

days and a period on placebo. Such

pain usually made patients reluctant

to take a second dose.

Narcan injections (0.8 - 1.2 mgs

naloxone i.v.) were introduced

prior to administering naltrexone.

If the injection precipitated any

symptoms of withdrawal, the start of

naltrexone was postponed until the

Narcan test was negative. For most

patients, the Narcan test has allowed

induction on a 100 mg dose of naltrexone

with no discomfort. This finding suggests that for many patients this pain

was secondary to precipitated abstinence. A very small number of patients

still experience epigastric pain.

These patients often have a history of

gastrointestinal complaints previous to

their seeking treatment. The pain they

experience when they take naltrexone can

usually be controlled with an antacid or

by having the patient eat before ingesting the medication.

TREATMENT CONSIDERATIONS

Our second finding is that naltrexone has

been extremely valuable to many patients,

although to be most effective it requires

a positive staff attitude and a multimodality treatment program. Methadone

maintenance should be available for those

patients for whom antagonist treatment

seems unacceptable at a particular time.

Records of the flow in and out of treatment of 262 patients during the past year

and a half indicate that about 40 have

returned for readmission up to three

times. At this writing (May, 1976), 9 of

the 50 patients currently receiving naltrexone had dropped out of treatment, become readdicted, and then returned. Our

data show that patients remain in treatment longer with each successive readmission.

During the past 18 months, 20

individuals took only one dose of

naltrexone, 39 took naltrexone

more than once but for less than

one week, 132 for between one

week and three months, 50 for between 3 and 6 months, and 21 for

more than 6 months.

A search for factors that predict

response to naltrexone at intake

has found very little, beyond

patients' stated wish to become

drug free. We believe that individual counseling that begins

with a sensitive and careful intake interview and history is an

essential part of naltrexone treatment. The degree to which a counselor can involve the patient

affects retention and return to

treatment more, for example, than

apparent motivation at intake or

psychosocial status. During counseling sessions our staff helps

patients talk about and clarify

ambivalent feelings about being

drug free. Staff emphasize that

medication alone is not a cure for

patient's desire to use drugs.

Our experience has led to the view

that treatment is a process frequently involving periods of

progress followed by periods of

relapse. We communicate to the

patient that he should return to

treatment if he is tempted to use

or becomes readdicted. One of the

special virtues of naltrexone is

that patients may resume taking it

when opiate use tempts them. They

need not fear that they will later

have prohlems stopping naltrexone.

Some patients may develop transference to the institution

rather than to an individual

therapist. Most often such

patients have difficulty with

closeness and are socially isolated. One patient came to our

clinic five days a week for many

years. He refused a three day a

week schedule when he was on

methadone. When he detoxified and

was inducted onto naltrexone he

continued to come to the clinic five

days a week. Recently he has accepted

a three day a week schedule. He has

only a superficial relationship with

staff members, although several have

tried to engage him in treatment. His

transference is with the nurses and

89
the clinic in general. He must continue to come to the clinic three days

a week to continue to receive naltrexone, but our staff has the impression that in the absence of close

relationships he takes naltrexone in

order to come to the clinic, as well

as vice versa.

In general our staff accepts treatment that goes forward in these ways.

Patients enter, leave, and return to

treatment. They find rewards in the

staff and clinic, rather than simply

in the medication. In our clinic we

are not surprised that patients who

are accustomed to immediate gratification find it hard at first to stay

in treatment, but return to us later.

Very few patients can learn to manage

a disorder as complicated as opiate

addiction during their first involvement in treatment. Most often time

is needed to work out ambivalence about

treatment and about change.

SPECIAL INDICATIONS FOR

NALTREXONE

We have found that naltrexone is useful for certain other specific groups

in addition to street addicts. The

first are detoxified methadone patients.

We are studying naltrexone as a transitional treatment for these patients

following their detoxification from

methadone. In a double blind trial

comparing naltrexone and placebo, 25

patients have been treated. Patients

chosen for this trial have been on

methadone for periods between 11⁄2 and

3 years, work or go to school and have

not abused opiates for six months or

longer prior to beginning detoxification. After obtaining an informed

consent, patients were randomly

assigned to either active or placebo

naltrexone. The first 19 patients

were evaluated by staff for subjective

effects and participated in therapy

with their counselors. The most

recent six patients were assigned

to one observer blind to their

medication to control for differences in both subjective effects

ratings and counseling. All

patients were told that the medication might help relieve the discomfort that usually occurs

following methadone detoxification.

The antagonist properties of naltrexone were minimized.

All patients receiving active naltrexone showed a tendency toward

less severe symptoms compared to

those receiving placebo. The

differences between groups were

not statistically significant.

The most recent 6 patients were

also compared for response during

clinical interview. Some patients

focussed on difficulties they were

having in interpersonal relationships at home, work or school.

Less frequently somatic complaints

were discussed. For other patients

the reverse was true: during

clinical interviews they focussed

on their somatic complaints more

than on interpersonal problems.

When the double-blind code was

broken 6 months after detoxification or at termination of treatment, the patients who focussed on

interpersonal problems were found

to be on active naltrexone.

Patients primarily concerned with

somatic complaints were found to

be on placebo. In one remarkable

case, a patient who focussed on

difficulties in his relationship

with his girlfriend during the

first eight weeks of treatment

began to complain in the ninth

week about severe somatic symptoms

including joint pain, stomach

cramps, and excessive tearing and

sweating. The observer recorded

this change in the patients chart.

When the code was broken, we

learned that the patient's medication had been changed from

active to placebo for unrelated

medical reasons at the same time

as the observer had seen the

clinical change in the patient's concerns.

The differences between these groups

suggest that naltrexone may alleviate

secondary abstinence symptoms, especially lethargy, weakness, poor

appetite, and poor concentration.

Patients who felt that naltrexone was

helpful had received active medication,

while those who reported little if any

relief had received placebo. These

trials are continuing. Continued

findings of clear differences between

active and placebo naltrexone would be

an important contribution to treatment,

in light of the difficulty which many

patients report, and which is clinically observable, in detoxifying from

90
methadone maintenance. Naltrexone

maintenance for several months after

methadone detoxification can also prevent impulsive use of opiates and readdiction during this high risk period.

Proposals for future use of naltrexone

should not overlook this potential area

of investigation.

The second type of opiate dependent

individual for whom naltrexone may be

the treatment of choice is the opiateabusing medical professional. Several

physicians who were addicted to meperidine (Demerol) or pentazocine (Talwin)

have been treated in our clinic with

naltrexone. For these patients,

arrangements were made with another

physician who supervised their ingestion

of medication in lieu of their coming to

the clinic. Approval for these arrangements was granted by the FDA. We do not

know of any other more appropriate treatment for these individuals who are professionally competent but were unable to

sustain opiate abstinence. All received

concurrent private psychiatric treatment.

FUTURE DIRECTIONS

It is now possible to present clinical

impressions of the differences between

cyclazocine and naltrexone in treatment.

Induction onto naltrexone is much easier,

quicker, and freer from side effects than

induction onto cyclazocine. Cyclazocine

patients were always hospitalized during

induction, induction took longer,

and patients usually remained in

the hospital until all side effects

had subsided. During this time

a therapeutic relationship could

be established. Patients taking

naltrexone, however, usually leave

after the first dose; there is no

therapeutic reason for them to

stay. Too often, patients drop

out of naltrexone treatment before

they have established therapeutic

ties with the clinic. In addition,

naltrexone is also far easier to

discontinue than cyclazocine.

Abruptly stopping cyclazocine

causes withdrawal symptoms that

serve as a reminder to take the

medication. That reminder made it

more difficult for patients to

miss clinic visits impulsively.

These differences in ease of induction and termination suggest possibilities for the study of a combined naltrexone-cyclazocine

therapy in which patients are first

inducted on naltrexone and then

begin to receive cyclazocine concurrently. After maintenance dose

of cyclazocine is reached, naltrexone could be withdrawn and

the patient maintained on cyclazocine. We are planning a systematic assessment of this combination.

The development of long-acting

antagonist preparations would make

it more difficult for patients to

resume using opiates when they cannot or will not come to the clinic.

Evaluation of individual patient's

treatment goals would be critical

in their clinical application. An

addict who does not desire treatment for social and psychological

problems would not be appropriate

since a long-acting preparation

would enable him simply to stay

away from the clinic and avoid the

treatment he needs. Similarly a

patient who abused other drugs

whenever he was opiate free in the

streets would seem like a poor

prospect, at least until he had

been in treatment long enough for

staff to believe that his behavior had

changed. On the other hand a patient

whose life is stable but who still feels

threatened by the chance that he will

resume opiate use might receive an implant and return to the clinic every

month or six weeks for the implant to

be replenished or restored. In general

it would seem desirable to evaluate

patients on the basis of whether they

still need or desire naltrexone but

wish to stop taking it primarily because of the burden of frequent clinic

visits. For this group of patients,

the advantages of long-acting preparations would be enormous.

SUMMARY

91
AUTHORS

Muriel Thomas, R.N., Frank

Kauders, M.D., Marcel Harris,

Judy Cooperstein, R.N., Gordon

Hough, Ph.D., Richard B. Resnick

Division of Drug Abuse Research

and Treatment

Department of Psychiatry

New York Medical College

5 East 102nd St.

New York, New York 10023

92
NARCOTIC ANTAGONIST

TREATMENT OF THE CRIMINAL

JUSTICE PATIENT- INSTITUTIONAL vs OUTPATIENT- INCLUDING A

24 HOUR DETOX NALTREXONE

INDUCTION REGIMEN WITH

ORAL MEDICATION

Leonard Brahen, Ph.D., M.D., Victoria Wiechert, MPS,

Thomas Capone, Ph.D.

INTRODUCTION

A uniquely compatible affiliation exists

between the concepts of the criminal justice and correctional systems and the treatment of opiate addiction through the Department of Drug and Alcohol Addiction in Nassau

county. The concepts of diversion and rehabilitation through the prevention of crime

by the elimination of causes are merged

with medical treatment as co-existing, independent components under one comprehensive

process. The Nassau County Department of

Drug and Alcohol Addiction administers joint

antagonist programs under this process; The

Narcotic Antagonist Work-Release Program and

the Antagonist Treatment Clinic. Institutional

vs outpatient, respectively.

NARCOTIC ANTAGONIST

JAIL WORK-RELEASE

PROGRAM

In late 1972, the Nassau County Department

of Drug and Alcohol Addiction and the Nassau

County Correctional Center in a joint undertaking initiated a Narcotic Antagonist Jail

Work-Release Program. This program is now

located in the Work-Release Facility, the

minimum security area of the Correctional

Center complex. It is specifically designed to incorporate the addicted inmates

into the regular Work-Release Program by

using fully protective doses of a narcotic

antagonist, thereby immunizing addicted inmates against a narcotic high,

I. TYPES OF PATIENTS TREATED

Patients are inmates from a maximum security

correctional center who have requested privilege of work-release.

In this program the inmate candidate writes

93
a letter requesting work-release to the WorkRelease Director. The inmate’s record and

history are evaluated and he is given an interview. He then is presented to the Nassau

County Correctional Center Board for approval

for the Work-Release Program.

Most of the inmates serviced were under twentythree years of age and approximately evenly

divided between Caucasian and negro. Almost

half had never been married and over one-third

were divorced or separated. Approximately onehalf never completed high school and fully onethird had not been employed on a full time

basis in the six months preceeding admission

to the jail. One-fifth had been supported by

public assistance before admission. Most of

the inmates had a history of four or more

arrests and convictions.

A. Criteria for Admission

The Nassau County Correctional Center Board

selects suitable inmates having a prior history

of narcotic addiction. Such voluntary applicants must meet all the criteria established

by the Nassau County Work-Release Program. It

should be noted that some New York State facilities permit release to parole earlier than

usual, permitting the parolee to go on workrelease in his respective county facility,

thereby affording him an opportunity to

continue employment on release. This should

substantially increase the patient population

pool of work-release candidates.

Essentially healthy volunteer subjects are

inducted onto the naltrexone program. They

must fulfill the following criteria:

1. Age: 18 - 45 years old

2. Sex: Male

3. Selection: All adult male inmate subjects

passed by the Correctional Center Work-Release Board and accepted for this study should

beinreasonably good-physical and mental health

with a documented history of narcotic addiction

All subjects will have been detoxified and

completely free of narcotics for a minimum of

seven days prior to antagonist administration.

B. Admission Procedure

1. A complete history is obtained, physical

examination given and laboratory tests performed before the inmate enters the program

as follows:

(The starred examinations and laboratory

tests are done monthly)

*a. Physical examination

*b. Neurological examination

c. Chest X-ray

d. Slit-lamp eye examination

*e.

*f.

g .

* h

*i.

j .

k.

*l.

*m.

n.

E.K.G.

Urinalysis

Prothrombin time

CBC (with differential)

SMA -- 12/60 and 6/60

Australian Antigen

VDRL

Reticulocyte

Platelet count

Sickle Cell

2 .Psychiatric Evaluation and Psychological

Testing for baseline data and treatment planning is conducted on entering the program, and

repeated at appropriate time intervals. The

Rorschach, MMPI, Locus of Control as well as

a Psycho-Social History are administered

routinely upon admission.

3. Each subject voluntarily agrees to enter

this drug treatment program after it has been

fully explained to him, (including sufficient

information about the possible harmful effects

of the investigational antagonist so that he

can make and sign 1) an informed consent, and

2) a Rules and Regulation contract, signed

prior to his participation in the program. At

the time of the interview for work-release the

informational brochure is reviewed with the

candidate inmate.

C. Patient Care Procedures

1. Naltrexone Induction

Opiate addicted inmates are detoxified in

the maximum security facility upon entry and

are therefore “clean” for at least a month

before entering the Work-Release Program. All

of our entering patients are housed in minimum

security modules where in the first few weeks

they are not permitted out to work so that the

controlled induction studies can be accomplished.

These studies are designed to compare three different acute dose levels and different dose regimens and ultimately withdrawal studies, all

with well controlled double-blind protocol.

2. Daily Medical Administration

a. Naltrexone or placebo are administered

orally each morning before work and each evening after work, according to the plan outlined

in the present double-blind (3-D) protocol.

b. Urines are monitored by daily evening collections and analysis for commonly abused drugs.

Breathalyzer tests are done when warranted.

c. Vital signs are monitored b.i.d., morning

and evening (e.g. blood pressure, pulse, respiration and temperature) and weight is noted

every week.

d. Behavioral and somatic symtomatology is re94
corded twice daily by the nurses and by the inmates on the double-blind report forms in minicounseling sessions.

All induction medication active and placebo is

like-looking-and-tasting liquid in a cherry

syrup base administered at 6 A.M. and 7 P.M.

daily. The medication is coded by subject

number, day of treatment and whether A.M. or

P.M. dose. It is premeasured for dispensing

to the patient in 2% oz. plastic disposable

wide mouth bottles with a screw top. The

volume is brought up to 20cc with the addition

of a dark colored cherry syrup to standardize

color, taste and volume for the double-blind

studies. At the time of administration to

the patient apple juice or orange juice is

added.

3. Non-Pharmacological Support

a. Group and Individual Counseling: Patients

in the Work-Release Program are seen one

evening a week in group therapy sessions and

one evening a week in individual sessions as

needed. These sessions are conducted by appropriate licensed professional workers (e.g.

physicians, psychiatrists, psychologists,

social workers, nurses) ,

b. Vocational and Educational Services:

Vocational interest inventories, preference

schedules, and special aptitude tests are

administered. The qualified inmate may receive financial support for vocational training through the New York Office of Vocational

Rehabilitation. Such support may be continued

upon release from work-release. Continued

financial support requires a minimal level of

performance. Educational assistance and

guidance are provided for those who have terminated their education prematurely and wish

to resume their studies.

c. Community Adjustment: A Social Worker

from the Nassau County Department of Drug and

Alcohol Addiction, Social Service Department

aids the inmate’s re-entry into society including adjustments required in planning work,

family, economics, legal problems, treatment

programs, etc. Supportive community services

are provided and appropriate referrals and

contacts are made.

A Community Relations Coordinator is assigned

the responsibility for continuing contacts

and obtaining follow-up data.

ANTAGONIST TREATMENT

CLINIC

The Antagonist Treatment Clinic is an outpatient facility located on the grounds of

the Nassau County Medical Center complex.

It was initially started to continue the postincarceration patient following his release

from the Work-Release Program. It has expanded to include Parole and Probation patients

as well as other agency referrals and “street

talk” referrals,

It is a logical extension of the Narcotic

Antagonist Work-Release Program, its objective

is the interception of a law offender with a

narcotic addiction history, enroute to incarceration. The interception should avoid the

high cost recidivism cycle. This program will

provide an alternative to the drug-free treatment programs and methadone programs now

available to probation and parole.

I. Type of Patients Treated

These are out-patients who have the legal restrictions mandated by probation or parole,

other agency referrals, and “street” referrals.

Demographic information on these patients is

similar to the work-release population.

The candidates for this program are accepted

after an interview with the Director or Deputy

Directors and consulation with staff members.

Essentially healthy volunteer subjects are

permitted entry into the Antagonist Treatment

Program.

A. Criteria for acceptance are as follows:

1. History of opiate addiction, documented or

certified, no time limit.

2. Age: 18-45 years old.

3. Sex: Primarily males. Female candidates

require special consideration of risks over

benefits. Pregnancy during antagonist treatment is contra-indicated. Therefore, preventive

measures such as an IUD or the “pill” are

mandatory. Special approval from F.D.A. must

also be obtained.

4. Health Status - All subjects must, after

examination, be in reasonably good physical

and mental health.

5. Motivational Status - Should be at such a

level as to give some assurance that program

requirements will be adhered to.

6. When the court requires a probationer or

parolee be protected from addiction by chemical

means, the antagonist can serve as a methadone

alternative having a non-addictive relatively

95
safe profile with no street value.

7. Detox - The candidate must be detoxed for

at least two to four days. In some selected

candidates a transition detox antagonist induction can be done in one day (described

in Part IV).

B. Admission Procedure

The admission procedure for out-patient

treatment is followed as outlined under the

Narcotic Antagonist Jail Work-Release

Program.

C. Patient Care Procedures

1. Opiate Detoxification and Naltrexone

Induction.

In preparation for naltrexone induction the

patient is detoxified from opiates in one

of three ways:

a. Hospitalized for ten days in a Psychiatric Facility and detoxified using methadone with daily reduction of dosage and

controlled withdrawal.

b. Self-detoxification - “cold turkey”

out-patient.

c. Transitional one day detoxification -

naltrexone induction procedure whereby

detoxification and naltrexone induction

are accomplished in twelve to twentyfour hours (described in Part IV).

In general all patients on the day of induction receive naltrexone as follows: 5 mgm

initially, followed by 10 mgm, 10 mgm and

25 mgm with 20 - 30 minute intervals in

between doses.

2. Medical Administration

a. Patients are maintained on 50 mg naltrexone

daily for two weeks, then given three days a

week with 100 mgm on Mondays and Wednesdays

and 150 mgm on Fridays.

b. A urine is collected at each visit and

sent for analysis of commonly abused drugs.

c. Vital signs are monitored at each visit

and the patient weighed every week.

d. Behavioral and somatic symtomatology is

recorded at each visit in mini counseling

sessions.

3. Non-Pharmacological Support

a. Group and individual counseling: Patients

are seen one evening a week in group therapy

96

and by appointment for individual counseling.

b. Vocational and educational services:

Various vocational tests are administered

as the need arises. Educational assistance and

financial support for vocational training

through the New York State Office of Vocational

Rehabilitation are available.

c. Community adjustment: The Social Service

Department of the Nassau County Department of

Drug and Alcohol Addiction provides counseling, referrals and contacts for adjustment

toward work, family, community, etc.

A Community Relations Coordinator is assigned

the responsibility for community contacts and

follow-up data.

II. PRACTICAL EXPERIENCE WITH NALTREXONE

TREATMENT

A. Our experience suggests that the three

times a week dosage regimen is feasible and

practical for both the institutionalized workrelease and out-patient populations in a

strictly treatment oriented setting for highly motivated persons. However, with this

regimen, some therapeutic intimacy is lost so

that opportunity for effecting behavioral

change is lessened. This is one reason twice

daily contact through the controlled doubleblind study is still maintained in the WorkRelease Facility.

In an attempt towards greater motivation for

program participation, antagonist treatment

is presented as a high status program for

select, treatable persons.

Preparation of our incarcerated population

for re-entry into the community is an important

facet of our treatment package. This is evidenced by the fact that approximately 23% of

Work-Release Program patients are taken off the

program and sent to maximum security for workrelease infractions. Aggressiveness and negativistic behavior emerge as the release date

grows nearer, usually from several days to a

month before release. Patients often express

a fear of freedom in the community and going

back to family situations. Retention of

patients in the controlled incarcerated seting is approximately 70-75%.

Retention of patients in the out-patient

clinic is much less, ranging from 4 days to 590

days for the first treatment phase with a

mean of 62.3 days (N=33, S.D. 114.9). Those

who entered the second treatment phase stayed

in treatment ranging from 1 day to 91 days

with a mean of 2097 days (N=14, S.D. 25.81.

Even with the imposition of rules and regulations and the conditions of probation

or parole there is sporadic absence from
treatment. In an effort to maintain continuity of care and responsibility, patients

are permitted treatment re-entry.

The Work-Release patients as a group demonstrate a great deal of group cohesiveness.

If there is a strong, aggressive, dissatisfied

leader, the group becomes quarrelsome with

the staff and officers and demonstrates dissatisfaction and somatic concerns. In another

time span, with other patients, group members

are cooperative and have few complaints.

In contrast the clinic patients as a group

are not united. They are impatient, restless,

and have a short attention span. Detachment

and finally group disintegration often takes

place. This was a consistent pattern with

several groups that were started out-patient.

We have treated four female outpatients Due

to community minority group pressures, the

Correctional Center authorities have requested

that we treat females on work-release.

B. Uses of Naltrexone

Naltrexone supplemented by supportive services is a valuable rehabilitation tool in

a correctional setting with rules and regulations set and implemented by correctional staff.

It is also a valuable diversion technique

whereby the legal restrictions of probation

and parole operate to interrupt the cycle

of repeated incarceration.

Methadone at this time is the primary drug

treatment for narcotic addiction. The use

of methadone has produced problems owing to

the drug itself, such as: 1) creating a

“legal” addict including the adolescent heroin

user with a questionable addiction history;

2) deaths attributed to legal methadone obtained through illicit channels; 3) promotion

of criminality owing to its high “street”

value.

There is a question as to whether it is

ethically appropriate for the medical

community to provide a highly addictive

substance on a continuing basis to the

heroin addict and the alleged heroin addict

as well as to the usefulness of treatment

with high doses of narcotics which virtually

bind the patient to a lifetime in this addictive state.

Naltrexone, which is a non-addictive, relatively safe agent with no “street” value

provides an alternative treatment modality

to methadone and drug-free programs, especially where strong motivation for self

rehabilitation is present.

As a transitional modality, naltrexone may

be used as an antagonist bridge from methadone

to a drug-free state by Phase III and IV

methadone patients who have not been able to

reach the drug-free state alone or wish to

discontinue methadone maintenance.

When working with out-patients, the detoxification from opiates often presented a

problem. Our general detox procedure which

required expensive and prolonged hospitalization was difficult for many patients

who had jobs, family responsibility, etc.

For these patients a one day transition detoxantagonist induction was designed, whereby

valium and compazine are administered initially, at 4 hours, then at various awareness

levels, before the anticipated symptomatology of withdrawal begins. This regimen minimizes gastro-intestinal symptoms and the

severity of somatic and muscular spasm, and

eases the anticipated tensions of withdrawal.

Naltrexone induction is started at a very

low dose. This precipitates withdrawal, but

with a lower level of discomfort than usual.

Valium and compazine are administered periodically to maintain the initial sedation

and anti-emetic and anti-nauseant level as

naltrexone dosage is periodically increased

until full blockade is reached (50 mgm).

This process usually takes from twelve to

eighteen hours with frequent monitoring

of vital signs and accurate recording of

symptoms, complaints and procedures by the

nurse in attendance.

There are several advantages to this method

of detoxification: 1) Only one or two days at

most are lost from the patient’s regular

activities as compared to the lengthy institutional detoxification. 2) The discomfort of withdrawal is minimized compared

to the severity of self, drugless detox.

3) There is a great monetary saving. The

cost of a one day detox is minimal compared

to the expensive institutional detox of approximately $1200-$1400.

When rapid oviate detoxification is desired.

the transitional detox-naltrexone induction’

method, as described, is an alternative for

the traditional methods.

III SAFETY OF NALTPEXONE

It appears, from our studies, that naltrexone

is a relatively safe antagonist. A full

blocking dose can be administered to the

opiate-free patient without incremental induction doses, and without producing any

untoward effects. Naltrexone maintenance

doses can be abruptly withdrawn without any

withdrawal effects. (Brahen, Capone,

Wiechert, Desiderio, 1976).

97
In general our follow-up laboratory and

other examinations showed significant changes

in some areas, from pre-drug baseline examinations, but all still within normal limits.

(Brahen, Capone, Wiechert, Babinski, Desiderio,

1976).

The following tests were significantly altered

when pre-drug and post-drug data (100-200 days)

were compared.

Naltrexone induced a significant depression

in the following (but, both pre and post

drug data are within normal limits): BUN.

platelets, cholesterol, systolic and diastolic

mean blood pressure. An increase was noted

for uric acid and prothrombin time. In no

instance was either pre or post-drug data

outside normal limits. Such changes as

noted are merely suggestions and should

be followed up.

For neutrophils, lymphocytes and SGOT the

mean pre-drug values were abnormal and remained abnormal in the post-drug period, but

did not change significantly as a result of

drug administration.

No significant changes were revealed when

pre-drug EKGs were compared with repeat EKGs.

(Brahen, Capone, Wiechert , Babinski , 1975) .

IV. FUTURE STUDY AND USE OF NALTREXONE

The evidence we have collected indicates

orally administered naltrexone to be a relatively safe, low symptom producing antagonist

even at high doses.

Not all somatic and behavioral symptoms can

be attributed to drug effect. Certain individuals who can be identified with psychoological examinations show a greater tendency to experiencing ontoward placebo and

drug effects. (Brahen, Capone, Wiechert,

Desiderio, 1976). The importance of supportive services cannot be over emphasized.

Presently and in the near future, orally administered naltrexone will be used as a

transitional modality from an opiate, such

as methadone, to a drug-free state. Beyond this, with the emergence of long-acting

naltrexone for long term immunization, this

antagonist may well be the drug of choice

in the control of opiate addiction.

(Reuning, et. al.).

REFERENCES

Leonard S. Brahen, Ph.D., M.D., Thomas

Capone, Ph.D., Victoria Wiechert, MPS,

Dawn Desiderio, Antagonist: In the

Treatment of Narcotic Dependence,

Naltrexone vs Cyclazocine, Comparison

of Controlled Studies, Submitted for

Publication.

Leonard S. Brahen, Ph.D., M.D., Thomas

Capone, Ph.D., Victoria Wiechert, MPS,

Anne Babinski, B.A., R. N., Dawn Desiderio,

A Comparison of Controlled Clinical and

Laboratory Studies of the Narcotic Antagonists Cyclazocine and Naltrexone,

Paper - Third National Drug Abuse Conference, New York, New York, March 25-29,

1976.

Leonard S. Brahen, Ph.D., M.D., Thomas

Capone, Ph.D., Victoria Wiechert, MPS,

Anne Babinski, B.A., R.N., Effects of

Naltrexone on Blood Pressure and Electrocardiogram, Paper - Thirty-Seventh Annual

Scientific Meeting, National Academy of

Sciences, Washington, D.C., May 19-21, 1975.

Reuning, R., Malspeis, L., Staubus, A. E.,

Battrala, M., Luddew, T., “Application of

Naltrexone Pharmacokinetics: Importance

of Design, Metabolic Profile, Assay Specificity and Kinetic Analysis”, Proceedings

of the Third National Drug Abuse Conference,

New York, New York, March 25-29, 1976.

AUTHORS

Leonard S. Brahen, Ph.D., M.D., Victoria

Wiechert, MPS, Thomas Capone, Ph.D.

Nassau County Drug Abuse Commission

214 Glen Cove Road

Carle Place, New York 11514

98
USE OF NARCOTIC

ANTAGONISTS (NALTREXONE)

IN AN ADDICTION TREATMENT

PROGRAM

David Lewis, M.D., Ronald Hersch , Ph. D.,

Rebecca Black, Ph.D., Joseph Mayer, Ph.D.

The Washingtonian Center for Addictions in Boston, Massachusetts has

offered opioid-addicted patients the

option of receiving a long acting

narcotic antagonist, naltrexone, in

conjunction with their regular course

of treatment, since January 1, 1974.

The primary objectives of this program are: 1) to evaluate the physical

and behavioral effects of naltrexone;

2) to assess the safety of naltrexone;

and 3) to investigate the clinical

efficacy and usefulness of naltrexone

in an ongoing treatment program for

addicts.

Between January 1, 1974 and May 1,

1976, twenty patients received naltrexone for varying periods of time.

This paper will report findings on

the initial naltrexone treatment experience in this group of patients.

PATIENT SELECTION

During this study period 703 male patients between the ages of 18 and 47,

hospitalized at the Washingtonian Center

for Addictions for opioid detoxification,

were informed about naltrexone treatment

in small groups which focused on posthospitalization treatment alternatives.

Any individual patient expressing interest in exploring the usefulness of narcotic antagonists in his rehabilitation

was scheduled to discuss his interest

with the Coordinator of Outpatient Drug

Programs. During this meeting an evaluation of the personal, social-psychological and drug history was carried out,

followed by a discussion of treatment

alternatives. Naltrexone was presented

as one of several options. If patients

selected naltrexone, they were told that

99
treatment would involve daily attendance

at a clinic and appropriate counseling

no less frequently than once a week. In

addition, participation in a safety and

efficacy study was required because of

the investigational nature of the drug.

After a detailed explanation of the experimental nature of naltrexone treatment, patients were given an informed

consent to read. Patients then met with

the Principal Investigator to discuss any

questions and to sign the informed consent. This was followed by an additional

discussion with the patient and signing

of the informed consent by the hospital's

Human Subjects Officer, who verified the

subject's voluntary participation and

checked on the subject's understanding of

the risks involved in taking an investigational drug.

Of the 703 male patients undergoing opioid detoxification who were informed

about the option of narcotic antagonist

treatment, 131 expressed serious interest

in the program. Forty-five (45) eventually signed informed consents, but only

twenty subjects actually completed the

baseline evaluation phase and received

naltrexone.

PATIENT ATTITUDES TOWARD

NALTREXONE TREATMENT

During the early phase of the study 'an

evaluation was made of the attitudes and

reactions toward naltrexone of male patients undergoing opioid detoxification.

Twenty (20) such patients eligible for

the naltrexone study were interviewed

with a structured questionnaire about

their perceptions and expectations regarding naltrexone as a possible treatment for their addiction. Four of

these patients later participated in

the naltrexone study. All four felt,

prior to receipt of naltrexone, that

naltrexone would give them the time

necessary to stabilize their lives.

Of the twenty patients interviewed

half stated that they would not choose

to receive naltrexone, for one of

three reasons: 1) aversion to use of

any chemical support; 2) dislike of

program structure (daily clinic visits and many laboratory tests); and

3) general aversion to participating

and "being used" in a new and unknown

treatment method.

Ambivalence about the use of "another

drug" was the most commonly reported

reason for nonparticipation in a naltrexone program. There was almost a

unanimous feeling on the part of these

patients that they would not participate in methadone maintenance treatment

and, even though they distinguish between the use of naltrexone in comparison to methadone, there was a generalized attitude that dependence on

taking any drug was bad.

It was our expectation that patients

would be concerned with the possible

toxic and side effects of naltrexone

and that this would be one reason for

avoidance of the study. However, contrary to expectations, while patients

were aware of the potential risk of

toxicity and of side effects, only two

of the 20 patients stated that such a

risk would be a deterrant to participation in the study.

Later, patients undergoing opioid detoxification expressed another concern

which emerged as a major reason for

nonparticipation in the study--the

fear of being unable to get high.

This fear was often manifested by an

intense concern about the details of

naltrexone action. Specifically,

patients would ask how long the effects

of the drug last, what medications

could be used for the relief of pain

in case of an accident, and whether

taking naltrexone for a period of time

would alter their previously experienced

reactions to opioids; that is, reduce

their future ability to get high. In

spite of reassurance that the project

was entirely voluntary, that they could

withdraw from the project at any time,

and that they could still experience the

opioid high after 24-48 hours after stopping naltrexone, several patients with

this concern decided not to participate

in the study.

DEMOGRAPHIC CHARACTERISTICS OF NALTREXONE

PATIENT

Table 1 shows the demographic characteristics of the twenty subjects.

The mean age at the start of treatment

was 27.8 years. The duration of addictive opioid use was 7.1 years with 20.8

100
TABLE 1

Table 1. Demographic Data - Naltrexone

Study (n = 20)

Mean

Age 27.8 years

Length of Addiction 7.1 years

Age of Initial Addiction 20.8 years

Previous Number of Treatments 4.1

Education 11.8 years

I.Q. 103.8

Race Percent

White 85%

Black 15%

Religion

Catholic 65%

Protestant 20%

Other 15%

Marital Status

Single 40%

Married 35%

Separated/Divorced 25%

years being the average age at onset of

addiction. The average oatient completed

high school and was in the normal range

of intelligence. The mean number of

previous treatment attempts was 4.1

and included psychotherapy, detoxification, methadone maintenance, and

therapeutic communities. Fifteen

(15) percent of the patients were

employed at the time of naltrexone

induction.

The patients who volunteered for

naltrexone were demographically more

like the patients on our methadone

maintenance treatment program than

the patients on our detoxification

program, even though those who volunteered for naltrexone actually were

on the detoxification program at the

time they volunteered. Naltrexone

patients are older than patients on

the detoxification program, more are

white, and more are working at the

onset of treatment.

STUDY PROCEDURES:

NALTREXONE INDUCTION,

PHYSICAL AND BEHAVIORAL MEASURES

Most of the patients were hospitalized throughout the detoxification

period. During this phase, they had

neither visitors nor passes. They

participated in daily group psychotherapy along with other (non-naltrexone) drug patients who were being detoxified. After detoxification was completed, baseline measures of physical status, including

Sympton Check List, chest x-ray,

ECG, and blood tests, were performed.

Several baseline psychological tests

were also obtained: Current and Past

Psychopathology Scale (CAPPS); Wechsler Adult Intelligence Scale (WAIS);

the Minnesota Multiphasic Personality

Inventory (MMPI); and Profile of Mood

States (POMS). Subjects also received naltrexone placebo daily during

this baseline period. During the

baseline period, seven to ten days

after the last detoxification dose of

methadone, naloxone challenges were

performed. During the challenge the

physicians, nurse, and counselor were

present and pupillometry, pulse,

blood pressure, and observations for

signs of withdrawal were recorded.

Following the naloxone challenge,

naltrexone was substituted for placebo in increasing 10 mg doses until

a level of 50 mg was reached. At

this point, most patients were attending our outpatient clinic and

received the 50 mg maintenance naltrexone dose daily. Some patients chose to

enter half-way houses or stay at the

Extended Inpatient Service of the Washingtonian Center for Addictions, an

eight-week rehabilitation program focusing on prevocational adjustment skills.

All patients were required to participate in individual or group psychotherapy and to participate in repeated

measures to assess the safety of the

drug. In addition to these measures,

the Symptom Check List and Profile of

Mood States (POMS) were administered

bi-weekly. The Symptom Check List is a

list of 37 physical and psychological

states or experiences. All patients

were asked to rate themselves on the

basis of absence or presence of the symptoms within the preceeding 24 hour period. A score of "0" indicates "not at

101
all”; 1 indicates "mild"; and 2 indicates

"severe". The POMS is a self-rated

questionnaire with six factors; Depression-Dejection; Anger-Hostility; Tension-Anixety; Vigor-Activity; FatigueInertia; and Confusion-Bewilderment.

In addition to individual factor scores,

a Total Mood Disturbance Score is derived by combining the scores across all

six factors.

TREATMENT RESULTS

As indicated in Table 2, the average

duration of receipt of naltrexone was

6.0 weeks, with a range of less than one

week to 21 weeks.

TABLE 2

Table 2. Duration of Receipt of

Naltrexone May 1, 1976)

Number of

Subjects

4

6

4

6

Interval

(Days)

0-7

8 -21

22 - 56

57 - 147

Total 20

Mean: 42 days

(6.0 weeks)

Median: 24.5 days

(3.5 weeks)

This duration contrasts with treatment

duration of two other opioid-addicted

populations (methadone maintenance and

drug abstinent patients) who were treated

in the Outpatient Service of the

Washingtonian Center for Addictions

at the same time as the naltrexone

patients. Methadone maintenance

patients remained in treatment an

average of 22.4 weeks, while drug

abstinent patients remained in

treatment an average of 2.0 weeks.

Analysis of patient data from the

Profile of Mood States, the Symptom Check List, and the Minnesota

Multiphasic Personality Inventory

was limited by the small number of

patients (n=20) and the sequential

termination of patients from the

102

program (n=10 after three weeks of

naltrexone treatment). Breakdown

of patient scores on these measures

according to length of stay on the

program, however, indicates that the

patients who continue on naltrexone

the longest show less baseline psychopathology, less baseline mood

disturbance, and fewer baseline

symptoms than patients dropping out

within the first two weeks. Later

follow-up of both groups indicates

that the patients who continued in

naltrexone treatment longest were

more likely to be employed and less

likely to be addicted as of May 1,

1976.

These findings are consistent with

data on other methods of treatment,

which indicate that psychologically

healthier patients continue longer

and have more positive outcomes in

treatment than less psychologically

healthy patients.

Project staff currently have direct

contact or reliable, although incomplete, information on 75% (15) of the

20 patients who have participated in

the study. Table 3 indicates the

current addiction status of all subjects, as of May 1, 1976. Three patients are currently receiving naltrexone and are drug-free: and seven

who are not currently receiving naltrexone are known to be drug-free,

so that ten (50%) are currently drugfree; three (15%) are known to be

readdicted; one 5%) is deceased* and

the status of 6 (30%) is unknown.

Of the seventeen subjects no longer receiving naltrexone, twelve (70%) remained in abstinence treatment after they

stopped taking naltrexone. These 12 patients remained in treatment after cessation of naltrexone an average of 5.3

weeks, an average of 0.7 weeks less than

they had been in naltrexone treatment.

In addition, 12 of 19 (63%) remaining

patients were known to be employed on

May 1, 1976, compared with three of 20

(15%) patients employed at the onset of

treatment.

Repeated physical and neurological examinations, electrocardiograms, blood

hematology and chemistries, as well as

*Death occurred 80 days after last naltrexone

dose. The medical examiner's opinion was

related to complications of rheumatic heart

disease, probably an arrhythmia.
TABLE 3

Table 3. Current Addiction Status of

Naltrexone Subjects

(May 1, 1976)

Current Addiction Number of

Status Subjects

Abstinent (receiving 3

naltrexone)

Abstinent (not 7

receiving naltrexone)

Deceased (80 days after 1

cessation of naltrexone

Readdicted 3

Unknown 6

Total 20

analysis of patient histories and symptom check list, do not reveal any toxic

effects which can be attributed to naltrexone.

CLINICAL ISSUES:

NALTREXONE AND ADDICTION

TREATMENT

Many addicts become overwhelmed in the

absence of external supports and controls. The naltrexone is an external

control against the impulse and possibly

the desire to use heroin, a control which

our patients value, but about which all

are ambivalent.

Initially almost all issues of control are focused on the power of the

drug, naltrexone, to counteract the

effects of heroin. Some patients

want to explore the "power" of this

external control against the powerful heroin. They report that they

experiment early in their treatment

to test the effectiveness of the

antagonist. Typically, this is done

in a systematic fashion, almost as

if they need to quantify the drug's

effect. For example, one patient

103

purchased a large quantity of heroin

and offered to share it with two of

his friends, 24, 36, and 48 hours

after his last dosage of naltrexone.

After witnessing his friends inject

the heroin at each of these points in

time and verifying with them that they

were high, he then tried to shoot up

himself. He reported to us that he

did not experience any opioid effects

until the 48th hour and that at that

point he experienced what he felt was

a minimal effect.

The majority of our patients have

self-tested the effectiveness of the

drug, although not always in the methodical manner described above.

only one such test, all of them are

convinced that the drug is effective

and most discontinue all opioid testing. Whether or not the effectiveness of the naltrexone blockade is

tested by the patients, the belief is

established early in treatment that

the antagonist completely protects

against the heroin high.

Once they are convinced of the drug's

effectiveness many patients experience an initial reduction in the desire for heroin and a marked decrease

in obsessional thinking about heroin acquisition and the heroin high.

For some patients this initial reaction is short-lived and there is a

resurgence of obsessive thinking about heroin or, similarly, of phobic

thinking about the abstinence state,

often accompanied by extreme fears

of never again being able to get

high. Some patients, disillusioned

that the naltrexone did not eliminate

their thoughts about heroin, terminate naltrexone treatment at this time.

For the patients who remain on naltrexone the balance between the wish

to get high and the fear of abstinence

can be a continuing issue, although the

conflict may diminish in intensity.

Another phenomenon observed is that,

usually within the first 3-4 weeks on

naltrexone, many patients begin to test

out the necessity of using naltrexone as

an external control against the desire

to use heroin. In an attempt to achieve

a balance between the external control

afforded by the drug and their own internal controls, some wait until the

moment before the clinic closes before

running in to get their daily naltrexone.

Others miss clinic appointments to see

if they can abstain from heroin, for a

brief period of time, without naltrexone.
One patient, for example, for the first

two months on the program, attended

clinic nearly every day. Later, he began

to reject this external control by developing a pattern of skipping naltrexcne

doses on weekends. He connected this

behavior with his fear of becoming too

dependent on the naltrexone and on the

clinic structure, and with his wish to

test out whether or not he would use

heroin if he did not take the naltrexone.

He was gravitating toward wanting to

exercise complete control internally, at

least part of the time. On these weekends, however, he managed to remain abstinent by believing, as he reported,

that the naltrexone effect really lasted

more than 24 hours.

Some patients attempt to use external

control other than naltrexone; controls

over which they feel they have more power than over naltrexone. Some are controls they used to attempt to remain

abstinent from heroin in the past when

they were not taking naltrexone. For

example, they may leave the city for a

day or lock themselves in their house to

avoid temptation. It is as if they attempt to show that they, alone, without

the help of the naltrexone, can exercise

adequate control over the urge to use

heroin.

As treatment and length of naltrexone use

progresses, some patients realize that

they can exercise partial control themselves, rather than depending entirely

upon the external control, naltrexone.

Many are conscious of their participation in establishing the balance between

external and internal controls. One

patient stated, for example, that he

now found it unnecessary to "change

everything at once". Energy was available for uses other than either

total control or lack thereof, and

the impact of "external circumstances" was reduced, allowing him to

introspect and make decisions about

his behavior, thoughts, and feelings.

The use of naltrexone reduces the

fear that external environmental

factors will cause a loss of control. After "testing" themselves in

a non-drug environment on weekends,

patients further become aware that

they can also be on the street, in

the places where they normally would

take heroin, without taking heroin.

This enlargement of the non-threatening, formerly self-destructive life

space allows patients to feel freer.

The patients who stayed in treatment

104

for the longer periods of time progressed from missing naltrexone on

weekends to missing doses occasionally

during the week.

Further evidence of this greater sense

of freedom and internal control is

evidenced by patients' statements

that they have more opportunities to

develop self control with naltrexone

treatment than they had with a therapeutic community or with methadone

maintenance treatment. One patient,

for example, a graduate of both methadone and therapeutic community alternatives, reported that the narcotic antagonist treatment approach

was the first treatment approach in

which he did not feel that he had to

belittle himself and to keep his

thoughts and feelings about the staff

and other patients under control. He

felt that in this treatment alternative the staff did not have anything

"to hold over his head". Additionally, he felt he could do as he

wished with regard to the continuance

or noncontinuance of his treatment

without experiencing the ill effects

of either methadone detoxification or

expulsion from the extended family

atmosphere of a therapeutic community.

This same patient reported also that

in the past he was never able to express any anger to program staff

until it had built up to the point. of

explosion. While on naltrexone, he was

more aware, open, and in control of his

feelings of annoyance and anger. In

contrast to over-control of his feelings

or exploding in an uncontrolled manner,

he confronted the staff and told them

what he found annoying. When the staff

reacted by changing their own behaviors

toward him, he reported that this was

the first time that he had expressed anger and achieved a positive effect on

others.

Staff, of course, must be constantly

alert, as in the last example, to the

patient's need for balance between external and internal controls. They must

help the patient learn that thev will not

be punished for continuing attempts at

self-control such as missing clinic appointments. Rather, they must be allowed

the latitude to acquire a balance between

external and internal controls, without

painful or damaging consequences. In

fact, it is our impression that patients

who remain abstinent following cessation

of naltrexone treatment are those who

are best able to achieve internalization
of control. AUTHORS

In summary, naltrexone treatment attracts a small subpopulation of the ad- David C. Lewis, M.D., Ronald G.

dict population who remain in treatment

with the drug for a shorter duration

Hersch, Ph.D., Rebecca Black, Ph.D.,

than our methadone maintenance patients

Joseph Mayer, Ph.D.

but longer than our drug abstinent outWashingtonian Center for Addictions

patients.

41 Morton St.

Boston, Massachusetts 02130

No demonstrable toxicity from the drug

has been demonstrated. Seventy percent

of our naltrexone project patients remained in abstinent outpatient therapy

after they stopped taking naltrexone;

50% are known to be currently drug-free:

and 63% are currently employed. Clinical evaluation of the patients receiving

naltrexone suggests that the experience

of control over the urge to take heroin

and over themselves is a major concomitant of the use of naltrexone. Ingestion of naltrexone provides a degree of

external control, reducing the preoccupation with heroin and releasing energy

for the pursuit of other goals.

105
AN ANALYSIS OF NALTREXONE

USE-ITS EFFICACY SAFETY

AND POTENTIAL

Ralph Landsberg, D.O., Zebulon Taintor, M.D., Marjorie Plumb, Ph.D.,

Leonard Amico, B. A., Nancy Wicks, B. S.

CLINICAL SETTING

The Buffalo Naltrexone Project is located in the

500 bed county hospitai, which is one of the

affiliated hospitals of the State Universitv

of New York’s Medical School in Buffalo. This

program operates within the Department of Psychiatry where the Emergency Drug Abuse Service and

other drug related research programs are also

located.

PATIENT SELECTION

Patients treated within the hospital for problems

of substance abuse, excluding alcohol, are representative of the patients who were interviewed

for or inducted onto naltrexone. The data presented covers the period from June 1974 through

May 1976, a total of 24 months. Table I shows

the usual race, age and sex distribution. Of

a total of 42 patients who received naltrexone,

four came from methadone maintenance, two were

inducted prior to release from jail, three came

from the V.A. Hospital drug program in a drugfree state and 33 came directly from street

heroin use.

RECRUITMENT

The problem of recruitment in our community is

ever present. In spite of more than adequate

media coverage, including ‘radio, television and

newspapers, there was initially a reluctance to

participate because of the experimental nature

106
TABLE 1 TABLE 2

of the medication. In a small addict community

such as ours (the best estimate is somewhere in

the neighborhood of 2,000) this type of adverse

comment spreads rapidly. Although this criticism

has receded with time, the present disenchantment

with methadone and the tendency to equate methadone and naltrexone present recruitment problems.

It appears that constant and repetitive media

exposure should be a greater priority in recruitment than attempting to enlist patient referrals

from methadone oriented programs, since a reluctance of methadone maintenance programs to refer

patients for narcotic antagonist treatment has

been apparent. Ultimately, however, there should

be no problem in attracting large numbers to naltrexone once the drug is proven safe and released

for general use.

CLINICAL EXPERIENCE

Of the 91 patients who were interviewed and

screened for eligibility to participate in the

naltrexone study, 42 were eventually given naltrexone. Table II delineates the various reasons

the other 49 did not enter the study. It is no

surprise that 32% of these patients had elevated

liver iso enzyme values, and 22% opted for methadone maintenance treatment. As anticipated, the

largest group of non-participants, 38.7% was

comprised of those people who were lost to

follow-up after initial screening. Generally,

drug dependent patients are not well motivated

to become drug free and are very skeptical of

new treatment modalities.

In an attempt to determine the feasibility of

outpatient induction and thereby the applicability of naltrexone administration to large

groups of patients, 25 of the total 42 patients in the study were indeed inducted on

an outpatient basis. Only 17 of these 25 patients were using heroin; the other 8 patients

had already been detoxified from heroin while

in jail or in other drug programs, and all 8

had remained drug free while on the street.

Therefore, while a total of 25 patients were

inducted on an outpatient basis, only 17 had

to be treated in an outpatient ambulatory

methadone detoxification program, remain drug

free at least seven days, and then take naltrexone on a daily basis during the induction

phase. Fifteen patients succeeded in completing that process and progressed to the three

times per week dose stage while two patients

dropped out of the study. Since the other

eight patients had already been detoxified

and had no problem in taking naltrexone, 23

of the 25 patients were successful in completing outpatient naltrexone induction.

Refer to Table III.

TABLE 3

Characteristic N 

Outpatient induction 25

Inpatient induction 17

Dose Range

t.i.w. 150 - 150 - 150

100 - 100 - 100

200 - 200 - 200

100 - 100 - 150

50 - 50 - 75

Duration of naltrexone in days

4

2

1

26

1

1- 7

8- 30

31 - 90

91 - 180

over 181

11

9

13

10

107
A successful outpatient heroin detoxification

and induction onto naltrexone of 92% of patients who chose that mode rather than hospitalization would auger well for the application of this mode to large numbers. However,

it must be noted that an inordinate amount

of staff support, beyond that which is normally available in most treatment programs,

was expended in order to accomplish this high

rate of success.

During the early months of the study some

patients were placed on 200 mg. dose three

times per week and a few were placed on a

100 mg. dose t.i.w. However, later on most

patients were placed on 100, 100 and 150 mg.

(Monday, Wednesday and Friday) and more

recently, several patients have had a two

times per week schedule (Tuesday and Friday)

of 150 mg. each dose. Two patients have received a 50, 50, 75 mg. dose. Refer to

Table III. Regardless of the dosage schedule,

it has not, in any detectable manner, affected

the patients’ ability to remain drug free.

Only one patient has expressed a feeling that

he was not receiving enough naltrexone, an

observation made relative to a vague feeling

of uneasiness on Sundays following two weeks

of 50 mg. t.i.w. This feeling disappeared

when his Friday dose was increased 75 mg.

Table III also reveals the number of days of

treatment.

It would appear that naltrexone is a drug that

lends itself to wide flexibility in the manner

and method of administration and is well suited

to use in and by differing treatment philosophies. Dosage schedules and time intervals of

administration are also fairly flexible.

Significant in our induction procedure was the

administration to as many patients as possible

of a battery of questionnaires and psychological

test instruments. From these we hoped to obtain

a profile of individuals who elect naltrexone

and to determine whether or not they may significantly differ in personality, sociodemographic,

or drug history characteristics from patients in

other treatment modalities. This may be important

for future selection of patients.

The data presented here are from 23 naltrexone

patients who completed the Minnesota Multiphasic

Personality Inventory (Hathaway and McKinley,

1951). 29 who completed the Beck Depression Inventory (Beck, Ward, Mendelson, Mock and Erbaugh,

1961), and from between 25 and 30 who completed

various items on the Buffalo Inventory, a

locally developed multi-purpose questionnaire

which provides demographic and drug history information (Emergency Drug Abuse Service, revised,

1973). Our results are compared with those

obtained in other studies. Because extensive

information was available for a group of 163

male patients in methadone treatment (132 in a

methadone maintenance program and 31 in methadone

detoxification) who had completed the same instruments and because both groups came from the same

community, particular attention was paid to the

similarities and differences between these groups.

In taking this data into consideration, it must

be noted that this is an exploratory study of a

Small sample of naltrexone patients. The results

are suggestive at best and must not be construed

as definitive.

DEMOGRAPHIC AND DRUG

HISTORY INFORMATION

The Buffalo Inventory is aimed at obtaining

precise information concerning the patient’s

basic history, such as age and level of education,

as well as measures of the severity of his drug

addiction. Tables IV and V present the results

for eight demographic variables and eight drug

history variables thought to be of particular

interest. It will be noted that differences

between naltrexone and methadone patients are

minimal except that, on the average, naltrexone

patients appear to be a somewhat older group

(34 years vs. 26 years) and the mean length of

habit of naltrexone patients is 14.3 years in

contrast to 5.8 years for methadone patients.

While we have no certain explanation for this

difference, our clinical impression is that older

heroin users are more exhausted by the drug world

“hustle” and are more amenable to becoming drugfree. Frequency of use of other drugs with heroin

is very similar despite the difference in

length of habit, but is somewhat less than we

might have expected. Apart from age and

length of habit, our drug history and demographic data do not appear to discriminate

between patients choosing treatment with

naltrexone and those choosing methadone

treatment.

MINNESOTA MULTIPHASIC

PERSONALITY INVENTORY

Probably the best known of all “objective”

psychological test instruments and the one

most widely used in the study of drug abusers,

the MMPI consists of 550 true-false questions

which yield ten clinical scales and four

validity scales. Typically, addicts have

been found to have elevations on the psychopathic deviate and hypomania scales. According to Hill, Haertzen and Glaser (1960),

this 4-9 profile is indicative of “antisocial,

amoral, impulsive, irritable, hostile and

108
TABLE 4

DEMOGRAPHIC CHARACTERISTICS OF NALTREXONE AND METHADONE MAINTENANCE PATIENTS

VARIABLE NALTREXONE N METHADONE N

mean age

race Black

Caucasian

Puerto Rican

mean level of education (years)

longest stretch of employment (years)

youthful offenders

ever arrested for breaking law

currently have charges

presently on parole

34.47

80.00%

10.00%,

10.00%

10.93

4.65

35.71%

79.31%

10.71%

10.00%;

30

30

30

28

28

29

28

30

26.63

56.44%

43.562

00.00%

11.57

3.14

47.17%

88.7%

31.01%

5.00%

163

163

159

146

159

160

161

160

psychopathic" traits. Although it should be

pointed out that some recent studies find a

characteristic 2-4-8 pattern for the addict

population (Berzins, Ross and English, 1974),

the 4-9 pattern is regarded as "the profile

of the social delinquent, alienated from

society and likely to act out his resentment"

(Burke and Eichberg, 1972).

Table VI presents the mean profile derived

from 23 naltrexone patients who completed the

MMPI and compares it with the profile for the

methadone group and the composite adult addict

profile in the classic Hill et al. study.

Mean scores for the several MMPI scales for

naltrexone and methadone patients are also

separately shown on Table VII.

The naltrexone patient profile is very similar

to that of Hill et al. except that the naltrexone profile is somewhat more elevated, and

the naltrexone D (depression) score is markedly

higher. When the naltrexone profile is further compared to profiles for subgroups which

Hill et al. have labeled "psychopathic",

"neurotic" and "schizoid" it is clear that

naltrexone patients most closely resemble the

psychopathic subgroup.

The 4-7-8 profile for the methadone patients

is less characteristic of addict groups.

This suggests that this particular methadone

group may have more schizophrenic-like psychopathology than the naltrexone group. Overall, the naltrexone group appears more nearly

"normal" than the methadone group, and indeed

its scores on four scales (Hs, Pd, Pt and SC)

are significantly lower (p< .001).

BECK DEPRESSION

INVENTORY

Used here as a self-report, this instrument

consists of 21 items which reflect differing

symptoms or characteristic features of depression.

Each item involves a series of statements graduated in severity on a scale of 0 to 3. The

respondent's total score thus depends both on the

number of separate symptoms or features of depression he endorses and on the degree of severity

indicated for each. Table VIII presents means

and standard deviations for naltrexone and methadone patients and for three comparison samples.

It will be seen that on the average the naltrexone

group appears to be mildly depressed while the

methadone maintenance group are characterized as

not depressed according to Beck's norms. However,

the difference between the naltrexone and methadone maintenance group was not statistically

significant.

Furthermore, there was considerable variation in

Beck scores among both groups, with scores of the

naltrexone patients ranging from 0 to 27 at the

time of induction. We were unable to demonstrate

109
TABLE 5

DRUG HISTORIES OF NALTREXONE AND METHADONE MAINTENANCE PATIENTS

VARIABLE NALTREXONE N METHADONE N

length of habit (mean years) 14.30

use of heroin daily 84.02%

2-3 times/week 11.54%

weekends 3.85%

no. of sacks in cooker one 19.23%

two 19.23%

three 19.23%

four 19.23%

more than four 23.08%

use other drugs with heroin daily

2-3 times/week

rarely

nover

14,81%

7.41%

48.155

29.63%

times tried to kick never 3.85%

once 15,384

more than once 80,77%

times sought treatment never 20.83%

one 16.67%

two 12.50%

three 0.00%

four 16.67%

more than four 33.33%

times in methadone detox. never

one

two

three

four

more than four

20.00%

36.00%

20.00%

4.00%

8.00%

12.00%

times in methadone maint. never

one

two

three

four

more than four

36.00%

28.00%

12.00%

16.00%

8.00%

0.00%

30

26

26

27

26

24

25

25

5.82

94.30%

5.70%

0.00%

9.38%

39.38%

24.38%

14.38%

12.50%

14.74%

15.38%

42.31%

28.21%

4,434

17.28%

78.40%

17.07%

28.46%

23.58%

18.70%

2.44%

9.76%

30.02%

29.27%

19.51%

8.13%

.81%

3.25%

59.35%

32.52%

6.50%

1.63%

0.00%

0.00%

163

158

160

156

162

123

123

123

ANALYSIS OF DRUG SAFETY

any relationship between level of depression at To determine adverse effects of naltrexone on

induction and length of stay in naltrexone treatment, but the possibility cannot be ruled out

patients, the laboratory data performed on all

that such a relationship might emerge if our

subjects was reviewed. An analysis of blood

sample size were larger.

pressure readings by the “t” test for related

measures was performed to determine whether there

110
TABLE 6 TABLE 7

MMPI profiles: Naltrexone (N=23; males)

Maintenance (N=106; males)

former narcotic addicts

from Lexington, Ky.

was a significant difference between the induction

and later treatment blood pressures. Because of

insufficient data or initial hypertension, only

13 patients were used in the analysis. There

was no significant increase in systolic or diastolic values during treatment by this analysis

in the 13 patients.

A continuing problem was the occurrence of elevated liver iso enzyme values involving SGOT,

SGPT or alkaline phosphatase. Nine patients had

elevated values at various times. In each case,

patients admitted to excess alcohol intake, and

with cessation of drinking, iso enzyme values

began decreasing toward normal values. Two

patients who had values five times normal were

given placebo naltrexone for 30 days with no

change in values, until they seriously undertook

to stop all alcohol intake. Following that, once

again all levels began to decline toward normal

values. It is very difficult in this type of

patient population to determine the effect of

naltrexone on the liver (antecedent effects of

drugs and concomitant excess alcohol intake).

Fourteen percent of the patients showed a relative increase in lymphocyte counts during treatMEAN MMPI SCORES (WITH K CORRECTION) FOR NALTREXONE

.AND METHADONE MAINTENANCE PATIENTS

SCALES NALTREXONE METHADONE

L

F

K

Hs

D

HY

Pd

Mf

Pa

Pt

Sc

Ma

Si

3.96 3.58

9.65 10.84

11.61 11.36

14.85 21.49

24.04 23.07

21.70 21.44

28.47 32.26

26.13 27.25

10.57 11.78

29.83 40.75

30.26 42.89

24.80 26.53

26.70 29.25

ment. This unexpected result indicates a

possible area of investigation to determine

whether naltrexone does influence lymphocyte

counts.

In all other parameters studied including

serial EKG, urinalysis, SMA 14 and monthly

physical exam, no evidence of adverse effects

attributable to naltrexone were noted.

Why did patients who were taking naltrexone

on a regular basis stop? Table IX lists the

various reasons, and of interest is the only

real and continuing complaint involving the

taking of naltrexone that has surfaced throughout the 24 months of the study. Fourteen

patients complained of abdominal distress

following the taking of naltrexone. The complaint of gastric upset, pain, cramping and

belching persisted in spite of antacids,

food intake prior to medication and a decrease

in the mg. dose of naltrexone. This was

either the primary or secondary reason given

by eight patients for finally deciding to

terminate themselves from the study.

111
NALTREXONE POTENTIAL

What place do we envision for naltrexone in

the future? At present, the chemotherapeutic

treatment for opiate drug dependence has

relied solely upon methadone, either in

maintenance or detoxification. Naltrexone,

a narcotic antagonist, with proven safety,

flexibility and a high degree of efficacy,

provides a much needed addition to the chemotherapeutic treatment approach.

Our clinical experience strongly suggests

that patient selection is of paramount importance in predicting successful treatment with

naltrexone. We have shown that demographic

and prior drug history variables hold little

promise for differential selection, nor do

those psychological test scores we have

examined to date appear to be useful for

prediction. Nevertheless, it is our distinct

impression that motivation is a major factor

not only initially but throughout treatment.

This is particularly true since the taking

of naltrexone, in contrast to methadone, offers

no gratification in itself nor does it have

a negative recruitment effect. Truly, therefore, naltrexone presents a treatment modality

for those opiate drug dependent persons highly

motivated to become drug free.

Despite our findings of safety and efficacy

of naltrexone, the method of naltrexone induction presents a problem which is an important

consideration. Because of its antagonistic

action producing the abstinence syndrome, inpatient detoxification and induction is the

preferred treatment. However, the extrapolation of this method to large numbers of

patients is precluded by consideration of

economic factors and stress on other resources.

TABLE 8

PRIMARY REASON FOR DISCONTNUING

NALTREXONE N =33

SECONDARY

REASON

1. Hepatitis - not related to naltrexone 2

2. treatment success - patient and staff

decision 7

3. patient felt he no longer needed

naltrexone 3

4. could not tolerate inpatient hospital

stay on psychiatric ward 1

5. peer group pressure to return to drug

use, wanted to return to drug use,

abusing other drugs, alcoholic 3 1 #10

6. gave no reason 7 2 #10

7. left town 4 2 #10

8. jail 1

9. wanted methadone maintenance 1

10. complained of stomach distress 3 1 #5

11. thought naltrexone made him sick 1

REFERENCES

N MEAN S D

2 9 13.00

163 9.79

BECK DEPRESSION INVENTORY: MEANS AND STANDARD DEVIATIONS

8.80

6.24

M

M

SAMPLE SEX

naltrexone

methadone maintenance

(Plumb, D'Amanda, Taintor, 1975)

Phoenix House inductees

(DeLeon, Skodol, Rosenthal, 1973

hospital inpatient

(Beck, 1961)

Beck norms:

no depression

mild depression

moderate depression

severe depression

M-F 38 23.24 9.36

M-F 153 6.51 9.65

M-F 115 10.9 8.1

M-F 127 18.7 10.2

M-F 134 25.4 9.6

M-F 133 30.0 10.6

TABLE 9

Our experience has demonstrated a high degree

of success in outpatient induction. The limiting

factors we see are the small number of inductions

that can be handled at one time and the inordinate

amount of staff support required for successful

treatment from beginning to end.

While there is no question of the potential of

naltrexone for treatment of opiate drug dependency, it must, like other treatment modalities,

be deployed selectively.

Beck, A. T., Ward, C. H., Mendelson, M., Berzins, J. I., Ross, W. F., and English, G. E.:

Mock, T. E., and Ergaugh, J: An inventory

for measuring depression.

Subgroups among opiate addicts: A typological

Investigation.

561-571. 1961. 65-73. 1974.

112
Burke, E. L. and Eichberg, M.A.: Personality

characteristics of adolescent users of dangerous drugs as indicated by the Minnesota Multiphasic Personality Inventory.

291-298.

Delon, G., Skodol, A., and Rosenthal, M.S.:

Phoenix House: changes in psychopathological

signs of resident drug addicts.

131-135. 1973.

Emergency Drug Abuse Service: Buffalo

Inventory. Unpublished intake instrument.

Revised, 1973.

Hathaway, S. R., McKinley, J. C.: 

New York. Psychological Corporation. 1951.

Hill, H. E., Haertzen, C. A., and Glaser, R.:

Personality characteristics of narcotic

addicts as indicated by the MMPI.

127-139. 1960.

Plumb, M., D'Amanda, C., and Taintor, Z.

Unpublished research grant, 1975.

AUTHORS

Ralph Landsberg, D.O.

Assistant Clinical Professor of Psychiatry

School of Medical Service

State University of New York at Buffalo 14215

Principal Investigator

Naltrexone Project *

Zebulon Taintor, M.D.

Associate Professor of Psychiatry

New York Medical College

Marjorie Plumb, Ph.D.

Assistant Professor

Department of Psychiatry

State University of New York at Buffalo

Leonard Amico, B.A.

Research Assistant

Department of Psychiatry

State University of New York at Buffalo

Nancy Wicks, B.S.

Project Coordinator

Department of Psychiatry

State University of New York at Buffalo

ACKNOWLEDGMENT

*NIMH Contract HSM4273259ND

113
CLINICAL EFFICACY OF

NALTREXONE:

A ONE YEAR FOLLOW UP

Richard Resnick, M.D., Michael Aronoff, M.D.,

Greta Lonborg, M.A., Richard Kestenbaum, Ph.D.,

Frank Kauders, M.D., Arnold Washton, Ph.D.,

Gordon Hough, Ph.D.

Our research on naltrexone, beginning

in 1973, focused initially on the pharmacology of the drug as a prelude to

investigating its clinical efficacy in

treating narcotic addition. We explored naltrexone's safety, toxicity,

side-effects, antagonism to heroin, and

pharmacokinetics (Resnick et al., 1974;

Volavka et al., 1975; Verebely et al.,

1976; Volavka et al., 1976). Our

studies of naltrexone's clinical

efficacy have focused mainly on

isolating from a wealth of demographic, psychosocial, and drug

history data, factors which may

serve as reliable predictors of

treatment outcome. From this study

we hoped to determine a description

of those individuals most likely to

benefit from treatment with naltrexone.

The data was obtained at intake and

correlated with treatment outcome at

12 months. Based on earlier retrospective studies using cyclazocine,

(Resnick et al., 1970; Resnick et

al., 1971) and on our clinical impressions, we formulated the hypothesis that heroin addicts treated

with naltrexone who were opiate-free

at 12 months after entering treatment would more likely 1) have more

years of addiction: 2) have a higher

capacity for object relations; 3)

show higher levels of psychosocial

functioning; and 4) have histories

of longer opiate-free periods during

the course of their addiction than

those who become re-addicted.

METHOD

An extensive battery of information

was obtained at intake and subsequently was reviewed for accuracy

for patients who remained in treatment. If a patient met medical and

other criteria for receiving naltrexone he was detoxified from opiates

114
and remained opiate-free for a 5-10 day

period before naltrexone was started.

Naltrexone was dispensed in the clinic,

usually 3 times/week, with no take home

doses. Each patient was assigned a primary therapist who provided ancillary

services and who monitored his clinical

course. Twelve months after receiving

the first naltrexone dose, patients

were categorized as beinq opiate-free

or opiate-dependent. This judgment

was made by staff consensus on the

basis of their continued contact with

patients and/or their friends and relatives, urinalysis and Narcan tests.

TABLE 1

COMPARISON OF PATIENTS OPIATE-FREE

AND OPIATE-DEPENDENT AT TWELVE MONTHS

Table 1 shows how we arrived at the

study sample. There were 191 successive applicants over 10 months on whom

intake information was obtained Of

this total population, 110 were excluded from the study sample as shown

in the Table: two were excluded for

medical and/or psychiatric ineligibility; four were transfers from

cyclazocine without having an interim

period of readdiction; sixty-six were

unable to complete detoxification and

never started naltrexone; and thirtyeight took naltrexone less than

one week, i.e. only one or two doses.

This latter group either 1) stopped

medication because of initial sideeffects that they found unacceptable

(these were usually due to symptoms

of precipitated abstinence); or 2)

they did not wish to receive this

treatment, and requested naltrexone

for an ulterior purpose, usually to

gain admission to the hospital, since

methadone maintenance or detoxification alone was not provided in our

facility. The study group was

comprised of 81 individuals who received naltrexone for one week or

longer.

RESULTS

Of the 81 patients, 27 were opiatefree (33%) and 54 were opiate-dependent (67%) one year after starting

naltrexone. Thirteen of the 54

opiate-dependent patients were

enrolled in a methadone maintenance

treatment program. A comparison

of selected intake parameters for

the opiate-free and the opiatedependent patients at one year

after starting treatment is shown

in Table 2.

TABLE 2

* N=19 for opiate-free: N=32 for opiate-dependent

** N=8 for opiate-free, N=22 for opiate-dependent

Consistent with our hypothesis, the

opiate-free as compared to the

opiate-dependent group at 12 months

had been addicted for a greater

number of years, had shown at intake a lower level of opiate dependence according to money spent

for opiates during preceding

months, had a history of longer

opiate-free periods interspersed

during the course of addiction,

and were better able to maintain a

marital relationship. These

differences, however, were not

statistically significant.

115
The number of weeks that patients

took naltrexone did significantly

differentiate opiate-free from

opiate-dependent patients at 12

months. Other findings were that

1) relapsing patients tended to

come back to treatment and stay

for longer periods of time -- the

mean number of days on naltrexone

during the first episode of treatment for patients who relapsed to

opiate use and then came back to

treatment was 30 days, while

during the second treatment episode it was 85 days; and 2) the

proportion of patients in either

the opiate-free or opiate-dependent groups at any one time was

essentially stabilized after 6

months, although individual

patients shifted between the two

groups during the study period.

In other words, outcome (in terms

of opiate-free or opiate-dependent

status) assessed at 9, 12 and 15

months, in each case using the

same patient population, showed a

constant ratio of number of opiatefree to opiate-dependent patients

TABLE 3

COMPARISON OF PATIENTS ON NALTREXONE AT LEAST ONE

WEEK AND PATIENTS UNABLE TO COMPLETE DETOXIFICATION

although the individuals comprising

the two groups shifted back and

forth from opiate-free to opiatedependent status during the course

of the study.

We looked also for possible differences between patients who received

naltrexone for at least one week

(N=81) and those who never completed

detoxification (N=38). Table 3 compares psychosocial factors for these

two patient groups. One outstanding

difference between the groups is that

the mean amount of opiates used during

the 6 months prior to treatment was

significantly larger for patients who

did not complete detoxification (i.e.

never received naltrexone). Another

is that nearly twice as many subjects

who took naltrexone for at least one

week were employed at the time of

intake as compared to subjects who did

not successfully detoxify.

DISCUSSION

The present study explored whether

patient characteristics identifiable

at intake correlate with treatment outcome and can be used to delineate candidates most likely to benefit from

treatment with naltrexone. In prior

studies, we addressed the question of

who would most likely benefit from

cyclazocine. Descriptive criteria that

could identify such patients were found

(Resnick et al., 1970), but a subsequent

study showed that the patients selfselection of treatment modality correlated equally well with retention

and outcome (Resnick et al., 1971).

In our current study we were not able

to determine for whom naltrexone treatment is most helpful among patients who

self-select this treatment.

The present study did find that time on

naltrexone significantly differentiated

opiate-free from opiate-dependent patients at 12 months. This finding

suggests that naltrexone contributes

to a favorable outcome as the time in

treatment increases. A critical

efficacy issue, therefore, is to

assess factors that aid in preventing patients from dropping treatment

prematurely. In the absence of

identifiable predisposing variables

associated with remaining in treatment, we considered whether nonpharmacologic treatment factors may

have affected patient retention and

outcome. We believe that the

efficacy of naltrexone in this study

was related to staff ability to

involve patients in counseling and

to patients' capacity to respond.

We did not, however, isolate or

control for these treatment variables. They could not be assessed

adequately in retrospect.

116
Therefore, we are planning a study

of naltrexone efficacy in which

individual psychotherapy is the

dependent variable and is compared

to intervention that includes

medical care and concrete services

only. This study will ask 1)

whether outcome differs between

groups receiving naltrexone alone

or naltrexone plus individual

psychotherapy: and 2) what factors

contribute to the length of time

that a patient takes naltrexone

once he has started when the variable of individual psychotherapy is

controlled for. Our hypothesis is

that psychotherapeutic intervention

will have a positive effect on

patients remaining in treatment and

progressing toward rehabilitation.

The literature has no reports of

systematic assessments of this

hypothesis. Information derived

from the projected study will help

provide indications for the most

appropriate clinical setting for

using naltrexone.

Finally, our finding that relapsing

patients tended to remain in treatment longer with each successive

readmission suggests that evaluations of efficacy will require a

follow-up period of longer than one

year.

REFERENCES

Resnick, R., Fink, M., Freedman, A.M. A

Cyclazocine Typology In Opiate Dependence.

American Journal of Psychiatry 126:1256-1260,

1970.

Resnick, R., Fink, M., Freedman, A.M. Cyclazocine Treatment of Opiate Dependence: A Progress Report. Comprehensive Psychiatry

12:491-502, 1971.

Resnick, R., Volavka, J., Freedman, A.M., and

Thomas, M. Studies Of EN-1639A (Naltrexone):

A New Narcotic Antagonist. American Journal

of Psychiatry 131:646-650, 1974.

Verebely, K., Volavka, S.J., Mule, S., and

Resnick, R.B. Naltrexone Biological Disposition and Opiate Antagonism In Man. Clinical

Pharmacology and Therapeutics, in press, 1976.

Volavka, J., Gaztanaga, P., Resnick, R.B. and

Freedman, A.M. EEG and Behavioral Effects of

Naltrexone in Man. Electroencepkalography and

Clinical Neurophysiology 38:107, 1975.

Volavka, J., Resnick, R.B., Kestenbaum, R.S.,

and Freedman, A.M. Short-Term Effects of

Naltrexone in 155 Heroin Ex-Addicts. Biological Psychiatry, in press, 1976.

AUTHORS

Richard B. Resnick, M.D., Michael

Aronoff, M.D., Greta Lonborg,

M.A., Richard Kestenbaum,

Ph.D., Frank Kauders, M.D.,

Arnold Washton, Ph.D., and

Gordon Hough, Ph.D.

Division of Drug Abuse Research and Treatment

New York Medical College

5 East 102nd Street

New York, New York 10023

117
THE NIDA BEHAVIORAL STUDIES

118
THE THEORETICAL BASIS OF

NARCOTIC ADDICTION

TREATMENT WITH

NARCOTIC ANTAGONISTS

Abraham Wikler, M.D.

The theoretical basis of narcotic addiction

treatment with narcotic antagonists was well

stated by Martin et al. (1966). Briefly, outpatient maintenance of a previously detoxified opioid addict on a daily oral opioidblocking dose of a narcotic antagonist is

expected to accomplish two objectives: (a)

to remove the incentive for seeking and

using opioid drugs; and (b), to extinguish

conditioned abstinence (including “craving”)

should this phenomenon occur as a response

to environmental stimuli to which unconditioned abstinence had previously become

conditioned (Wikler, 1948; 1965). Needless to add, such a period of out-patient

maintenance on a narcotic antagonist should

be used to “rehabilitate” the patient - i.e.,

to train him in the skills necessary for

holding a socially useful iob. to form new,

mutually supportive relationships with nondrug using persons, and to persuade him to

give up the illegal “hustling” activities

which had become self-reinforcing during previous periods of opioid addiction. Such a

period of out-patient maintenance on a narcotic antagonist would have advantages over detoxification followed by enforced abstention from opioids (by prison sentences

with or without a subsequent probationary

period) in that it would permit the patient to expose himself to conditional

environmental stimuli which evoke “craving”

and possibly other conditioned abstinence

phenomena, without the danger of their reinforcement by the pharmacological actions

of opioid drugs. Eventually, if the patient so exposes himself frequently enough,

such conditioned abstinence phenomena

should become extinguished through repeated

non-reinforcement.

extinction,” to be carried out initially

while the patient is still an in-patient at

the hospital (where he was detoxified) and

subsequently as an out-patient on narcotic

antagonist maintenance. Along the lines of

Emphasizing the importance of extinction of

conditioned abstinence and of drug-seeking

behavior for minimizing the probability of

relapse after out-patient maintenance on the

narcotic antagonist has been discontinued,

Wikler (1974) proposed a program of " active

119
the models used to extinguish conditioned

responses and behavior in animal experimentation, it was suggested that as inpatients, previously detoxified patients

blocked by a narcotic antagonist be exposed

to conditioned stimuli that evoke “craving”

and perhaps other conditioned abstinence

phenomena and be permitted to self-inject

themselves with heroin repeatedly ad

libitum: hopefully, under narcotic-antagonist blockade, self-injection of heroinwould ultimately cease. Appropriate conditioned stimuli might consist of heroinrelated pictures (Teasdale, 1973) or the

presence of previously detoxified patients

self-injecting themselves with heroin in

the unblocked condition. After completion

of such active extinction under narcotic

antagonist blockade as an in-patient, the

patient may go on out-patient status, still

receiving his daily oral blocking dose of

the narcotic antagonist. It was assumed

that under the different conditions of outpatient status, the patient would again

display opioid-seeking behavior, which

should not be discouraged, as further extinction of this behavior under “natural”

conditions is to be desired. The progress

of such patient-regulated “hustling” for

and extinction of opioid-seeking behavior

could be monitored by frequent, though unscheduled urine-testing for morphine. It

was suggested that maintenance on a narcotic antagonist should be continued for

about 10 months to one year (beyond the

duration of protracted abstinence, which

lasts about 30 weeks, Martin and Jasinski, 1969) and if urine screen remains

negative for morphine, the narcotic

antagonist could then be discontinued.

Conditioned abstinence and opioidseeking behavior having been extinguished,

and the patient having been “rehabilitated,” the probability of relapse would

be greatly reduced.

That in the rat well-established intravenous morphine self-injection can be

extinguished by pre-treatment with

naloxone and presentation of a conditioned

reinforcer in the operant chamber has been

demonstrated by Davis and Smith (1974).

There is some question of whether in this

study the decline in lever-pressing for

morphine was not due to aversive conditioning, rather than to extinction, inasmuch as after pre-treatment with naloxone,

no transient increase in lever pressing rate

was observed prior to the rapid fall in

lever-pressing rate. Naloxone may have

precipitated a grossly undetectable abstinence syndrome, inasmuch as the rats had

been self-injecting morphine, albeit in a

very small unit dose, 60 mcg/kg, for 3 days

prior to naloxone pre- treatment. However!

in other intravenous morphine self-injecting

rats, apparent extinction was accomplished

by substituting saline for morphine solution

in the operant chamber and presentation of

the conditioned reinforcer; no transient

increase in lever-pressing rate was observed

under these conditions either.

As might have been anticipated, however,

carrying out active extinction in man presents special problems because of his cognitive ability to perceive the experimental

arrangements and alternative courses of action open to him which even the experimenter

could not foresee. From as yet unpublished

reports, it appears that these are two major

problems connected with attempts at inpatient extinction with the aid of narcotic

antagonists: (a) the patient simply refuses

to self-inject himself with heroin or another

opioid while he is blockaded by a narcotic

antagonist, on the grounds that he “knows

that he will not get high;” and (b) the

patient reports that the narcotic antagonist “took all my craving” away - i.e. ,

the narcotic antagonist seems to have a

“satiating” effect.

The question of whether or not the opioid

antagonists exert a hitherto unknown agonistic, “satiating” effect on opioiddeprived receptors is very important from

both the theoretical and practical standpoints. If a placebo can be found which

produces an unpleasant after- taste similar

to that produced by naltrexone, then a

double-blind experiment on initiation of

self-injection with heroin or hydromorphone

may answer this question. If affirmed, a

“satiation” effect of an opioid antagonist

would render extinction trials both impractical and useless. Then reliance will have

to be made on prolonged, though limited

maintenance on an opioid-antagonist with,

of course, efforts at re-education and

social rehabilitation (which would be

necessary in any case). However, should

the results of such an experiment be negative - i.e., naltrexone does not have a

“satiating” effect, then perhaps it may be

possible to modify the extinction procedure

in such a way as to make experimental extinction possible, despite the addict’s

learned discrimination (his prior knowledge

that naltrexone will block heroin effects,

including “euphoria”) . For example, an

addict may be admitted to the hospital and

“detoxified.” Then he may be allowed to

work for and self-inject “earned” heroin

(amounts subject to specified limits) on

one day. Three or four days later, a

“naloxone test” is made to determine if

there is any residual physical dependence,

120
and if the results are positive, “naloxone

tests” are repeated every three days until

the results are negative. Then naltrexone

placebo (with the metallic after-taste) is

administered by mouth and again the addict

is permitted or persuaded (by monetary reinforcement, if necessary) to work for and

self-inject “earned” heroin. Following

this, “naloxone tests” are made as before

until the results are negative (or, the

data from the previous “naloxone tests”

may be accepted as an estimate of the time

required for physical dependence to dissipate). Then a full 24-hour blocking dose

of naltrexone is administered by month and

the subject is again permitted or persuaded

(by monetary reinforcement, if necessary)

to work for and self-inject “earned” heroin.

Thereafter. the full 24-hour blocking dose of

naltrexone is administered by mouth every day

and the extinction procedure is repeated until the addict no longer works for and selfinjects heroin. For other addicts, the

naltrexone placebo day should be omitted,

attempted extinction (by monetary reinforcement , if necessary) being carried out under

full 24-hour blocking doses of naltrexone.

This is necessary to insure that addicts

will not be able to anticipate whether or

not the oral medication on the first day

will block the effects of self-injected

heroin. Or, another method may be tried.

On the first day, the “detoxified” addict

is given a partial blocking dose of naltrexone p.o., and he is permitted to work

for and receive heroin on that day. At

intervals determined by negative “naloxone

tests” for physical dependence that may

have been acquired by self-injection of

heroin, the procedure is repeated with

progressively increasing doses of naltrexone p.o., up to and including the

day (or days) on which a full 24-hour

blocking dose of naltrexone is administered and the addict finally ceases

to self-inject himself with heroin

[despite monetary reinforcement). It

may be expected that the proposed program

will have to be modified to nullify unforeseen, ingenious methods which the addicts may employ to “decode” the oral

medication conditions. At any rate, by

going “Beyond Skinner” (anticipating what

the addict may do to discriminate naltrexone placebo from naltrexone) it should

be possible to achieve experimental extinction of heroin-seeking behavior under

hospital conditions.

Flexibility and ingenuity is also necessary

in the maintenance of a patient on a narcotic antagonist in out-patient status. A

close personal relationship between the

patient and therapist is essential. The

elements of conditioning theory, conditioned

abstinence and “craving” as well as conditioned “hustling” should be explained to the

patient, so that he could recognize these

phenomena for what they are, rather than

ascribe them to the “flu.” After out-patient

extinction has proceeded, the relationship

between the therapist and the patient should

be such that the therapist can furnish positive reinforcement for socially acceptable

behaviors. Quitting naltrexone or other

narcotic antagonist should be expected, but

the relationship between therapist and patient should be maintained nevertheless-and

every effort should be made to brine the

patient back into the narcotic antagonistextinction treatment program without prejudice. In short, it should be remembered

that a clinic is very different from an

animal operant chamber and that in man,

unlike the rat and monkey, the experimenter has met his match. Nevertheless, the

principles of conditioning and extinction

still hold - it is up to the experimenter

to modify the animal paradigm of active

extinction in a manner that will resolve

the difficulties created by the patient’s

powers of discrimination of the stimulus

and reinforcement conditions set up by

the experimenter.

heroin. Do not administer any opioid

antagonist. Allow some of the subjects

to self-inject heroin without narcotic

antagonist-blockade, while the others are

Addendum: If it is proven that narcotic

antagonists do have a “satiating” effect,

then extinction of conditioned abstinence

may be carried out as follows. Admit a

group of detoxified addicts to the hospital and have them sign a contract (with

monetary rewards) to stay in the hospital

at least one month regardless of whether

or not they are permitted to self- inject

not permitted to self-inject anything.

Watching fellow-subjects self-inject heroin

without being able to do likewise is likely to evoke strong “craving” and other

signs and/or symptoms of conditioned abstinence which, on daily repetition should

gradually wane and eventually extinguish.

Then these subjects should be placed on

full blocking doses of naltrexone and discharged to out-patient status where extinction of heroin-seeking behavior may

take place if daily naltrexone medication

is maintained and the subject “hustles”

for heroin or other opioids. New detoxified addicts should now be admitted to reform the hospital in-patient group and

permitted to self-inject heroin without

narcotic antagonist blockade, while those

who had been allowed previously to selfinject heroin without blockade are now detoxified and then carried through the con121
ditioned abstinence extinction procedure,

signing another contract if necessary. After these subjects are discharged to outpatient status on naltrexone, the in-patient

group can be re-formed again by admission of

new detoxified addicts, and the extinction

and discharge sequence can be repeated inACKNOWLEDGMENT

Preparation of this article was supported,

in part, by Research Grant No. DA 01131

from the National Institute on Drug Abuse.

REFERENCES

Davis, W.M., S.G. Smith: Naloxone use to

eliminate opiate-seeking behavior: need for

extinction of conditioned reinforcement.

Biol. Psychiat., 9: 181-189, 1974.

Martin, W. R. , C.W. Gorodetzky, T.K. McClane:

An experimental study in the treatment of

narcotic addicts with cyclazocine. Clin.

Pharmacol. Ther., 7: 455-465, 1966.

Martin, W. R. , D.R. Jasinski: Physiological

parameters of morphine dependence in man -

tolerance, early abstinence, protracted

abstinence.

1969.

J. Psychiat. Res., 7: 9-17,

narcotic- addicts. Int. J. Addict., 8: 273-

292, 1973.

Teasdale, J.D.: Conditioned abstinence in

AUTHOR

definitely. For controls, some of the subjects who had been permitted to self-inject

heroin without blockade may be detoxified

and discharged to out-patient status on

naltrexone without going through the conditioned abstinence extinction procedure.

Wikler , A.: Recent progress in research on

the neurophisiologic basis of morphine addiction. Amer. J. Psychiat., 105: 329-

338, 1948.

Wikler , A.: Conditioning factors in opiate

addiction and relapse. In: Narcotics (D.I.

Wilner, G.G. Kassebaum, eds.). McGraw,

Hill, New York, 1965 (pp. 85-100).

Wikler, A.: Requirements for extinction

of relapse-facilitating variables and for

rehabilitation in a narcotic-antagonist

treatment program. In: Narcotic Antagonists (M.C. Braude, L.S. Harris, E.L. May,

J.P. Smith, J.E. Villareal, eds.). Advances in Biochemical Psychopharmacology,

Vol. 8. Raven Press, New York, 1974 (pp.

399-414).

Abraham Wikler, M.D.

Department of Psychiatry

University of Kentucky

Medical Center

Lexington, Kentucky

122
LIMITATATIONS OF AN

EXTINCTION APPROACH TO

NARCOTIC ANTAGONIST

TREATMENT

Roger Meyer, M.D., Mary Randall, M.S., Cecily Barrington, B.A.,

Steven Mirin, M.D., Isaac Greenberg, Ph.D.

In a 1966 study, Martin proposed the use of

cyclazocine in the long-term treatment of

heroin addicts.(l) Wikler has proposed a

behavioral program that would involve the

active extinction of both classically conditioned abstinence and operantly conditioned

self-administration of heroin by the patient

who is using a narcotic antagonist.(2)

While narcotic antagonists have been used in

ambulatory settings for a number of years,

Wikler's formulation remains the sole

approach to narcotic antagonist treatment

that is based solidly in theory and data

from laboratory experiments on the one hand,

while utilizing the special properties of

narcotic antagonists on the other. Wikler's

formulation is based upon the notion that

stimuli previously paired with unconditioned

abstinence symptoms will elicit the abstinence syndrome in opioid-free, former narcotics users. Under these circumstances, the

ex-addict will readily relapse to heroin use

in the presence of familiar environmental

stimuli.(3) Wikler has proposed that in the

presence of former associates and other relevant stimuli, the addict treated with narcotic antagonists will repeatedly challenge

with opiates. In the process of his repeated

blocked opioid administrations, extinction

would be expected.(2) Because of the

centrality of the extinction hypothesis to

narcotic antagonist treatment of the narcotics user, it is important to review more

recent data which may alter this formulation

of narcotic antagonist treatment.

In defining "extinction," experimental

psychologists have (it seems to me) been more

vague than they have been in some other

areas.(4) In its simplest form, extinction

of food reinforced behavior in a hungry animal involves the following elements:

1) the stimulus properties of the environment

(including the hungry animal) are similar to

circumstances when the behavior was reinforced by food and 2) the conditions are such

that the behavior can occur but reinforcement will not occur. The usual consequence

of this condition is that the previously

reinforced behavior will increase in frequency and amount prior to its elimination,

and the threshold of aggressive behavior will

123
be lowered making aggressive behavior more

likely.

In the opioid-dependent animal in the morphine

self-administration paradigm, extinction of

drug-seeking behavior will occur if saline is

substituted for morphine as a reinforcer. (5)

If low doses of naloxone are administered to

an opioid-dependent animal, drug-seeking

behavior will increase, presumably in response

to precipitated abstinence.(6) Such behavior

will be suppressed in the presence of high

blocking doses of naloxone, since abstinence

relief is impossible.(6) Extinction of the

operant response in the opioid-dependent

animal appears to occur. It is also clear

that the behavior will readily be reestablished under conditions where reinforcement

again consequates the behavior.

Extinction of classically conditioned autonomic responses occurs when a conditioned

stimulus is repeatedly presented in the

absence of the unconditioned stimulus. Under

these circumstances, the autonomic response

will no longer occur in response to the conditioned stimulus. Thus, Goldberg and

Schuster observed rapid extinction of conditioned abstinence responses (associated

with a red light).(7) In contrast, stimuli

associated with morphine reinforcement (e.g.,

a red light present with each self-injection

of morphine) acquired secondary reinforcing

properties that persisted up to 19 days after

complete withdrawal of morphine.(8) Like

the red light in the experiment of Goldberg

and Schuster, specific stimuli can be paired

(in a classical conditioning paradigm) with

previous episodes of drug withdrawal or

narcotic antagonist administration in a

dependent animal (conditioned abstinence).

Specific stimuli may also be associated with

the primary reinforcing properties of the

drug, as described by Goldberg, Schuster,

and Woods (8) and others. In the experiments

of Smith and Davis (9), rats will work for

the sound of the pump previously paired with

repeated morphine administrations. In

summary, in the operant paradigm, animals

will “work” for opioids (or saline) in the

presence of stimuli previously associated

with drug availability, and will also “work”

for conditioned reinforcers (i.e., stimuli)

previously paired with morphine administration (e.g., the sound of the pump).

In the presence of stimuli associated with

the previous unavailability of opioids, former addicts should operate under S, conditions and not work for drug reinforcement

(e.g., the Vietnam heroin user returned to

the United States). By contrast, under

stimulus conditions previously associated

with drug availability, relapse is expected

(

SD). As Wikler has pointed out, extinction

will not take place in prisons and other

drug-free institutions not previously associated with drug use (i.e., under conditions

of drug unavailability).(3) The essential

question that we have been attempting to

define over three years in human and animal

experiments with narcotic antagonists is

whether behavior observed under narcotic

antagonist administration is consistent

with notions of extinction of operant and/or

classical conditioning, or whether it is

more consistent with other explanations

(e.g., satiation, aversive conditioning, or

discrimination leaming.(10, 11, 12, 13)

The question has important implications not

only in terms of the approach that treatment

programs may take with individual patients,

but it is also of importance in terms of

the optimal length of treatment with narcotic

antagonists and the manner of their use. It

also might have implications for the potential efficacy of depot preparations.

METHODS

The methods employed in our work have been

extensively described at previous meetings of

this organization and will again be described in a paper to be presented later in

the session. In essence, heroin administration under blocked conditions was observed on

a research ward for ten days. The narcotic

blocking drug was administered (1) under

nonblind conditions when all subjects experienced narcotic blockade after a period of

ten days of unblocked heroin administration ,

on the same ward, (2) under nonblind conditions where subjects did not experience

unblocked heroin prior to naltrexone blockade,

and (3) under double-blind conditions of

administration where subjects received either

naltrexone or naltrexone placebo. In the

latter condition, blocked subjects were

present on the research ward at the same

time as unblocked subjects receiving heroin.

In the latter design, the combination of

patients on the ward at any time could

include a heterogeneous sample (one, two, or

three patients on naltrexone, with three, two,

or one patient on placebo) or a homogeneous

sample (all patients on naltrexone).

Data will be reported on 31 subjects who

experienced narcotic blockade on the unit and

and were offered naltrexone at follow-up.*

These vatients had a mean of 7.6 years of

heroin use (range 4-20) for which treatment

was attempted a mean of 5.5 times in the

*Aftercare data will be reported on all

patients who have been admitted to the unit.

(see below)

124
past (range 2-25).

Informed consent procedures have been described extensively elsewhere and are appended

at the end of this report.

Narcotic Blockade: For all but two patients,

narcotic blockade was produced by the daily

oral administration of 50 or 75 mg naltrexone.

During double-blind studies, an equivalent

volume of placebo syrup was administered. In

the initial study, involving two patients

under blocked conditions, blockade was

achieved by administering naloxone 500 mg

four times per day.

Naltrexone was given at follow-up at the patients' local pharmacies. In the past 14

months, naltrexone consumption at the pharmacy

was consequated by the payment of $1 to the

patient after he took his daily dose. For each

consecutive seven days of naltrexone consumption, $5 was banked at the hospital to be collected by the patient when he came for his

monthly physical.

All patients were supervised by nursing staff

thirty minutes after ingesting the narcotic

blocking drug in order to assure that the

medication was consumed and not regurgitated.

Outpatient naltrexone consumption was super

vised by the pharmacist.

Heroin Administration: Heroin was administered intravenously under medical supervision, and subjects always had the option

of not taking heroin during the period of

availability. The heroin administration

schedule permitted patients to consume up

to 6 me on Day 1 and 60 mg on Day 10 with an

increase of 6 mg per day between Days 1 and

10. The permissible two-hour dose increased

from 0.5 mg on Day 1 to 5 mg on Day 10;

by waiting four hours between doses the

subject could double his two-hour dose; by

waiting six hours the subject could triple

his dose. After six hours no further accumulation was permitted. Patients “worked”

for heroin on an operant device: they

accumulated points for which they were given

a receipt every two hours. The points could

be exchanged for heroin of specified potency.

Mood and Craving Assessments: In addition

to utilizing heroin administration as an

operant, subjects reported their desire for

heroin on a craving scale which was a 100 mm

line on which the subjects were asked to

record their “craving for heroin” (from most

to least). Subjects recorded their craving

scores daily throughout the study and before

and after each heroin administration. As

reported elsewhere, craving scores correlated very strongly with actual heroin selfadministration behavior under blocked and

nonblocked conditions. Pulse, blood

pressure, respiratory rate, and temperature

were recorded daily (at 8 a.m.) and before

and after heroin administration. Pupil

diameter was recorded before and after the

first administration of the day. An Osgood

Semantic Differential Mood Self-Report was

administered to the patients daily (at

8 a.m.) and before and after each heroin

injection.

The Relationship Between Blocked Heroin

Consumption and Demographic and Experimental

Variables: Actual heroin consumption under

blocked conditions was studied as a function

of demographic and experimental factors.

The total number and frequency of administrations and the total amount of heroin actuallyconsumed under blocked conditions served as

the operant and the principal dependent

variable in this analysis. The ages, years

of heroin use, age at which use began,

number of treatment episodes, and number of

months in jail since beginning heroin were

the demographic variables which were utilized

to determine the effect of age, duration of

addiction, and duration of presumably drugfree periods upon heroin self-administration

behavior observed on the research ward. The

ward conditions which were systematically

studied included: blind or nonblind administration of naltrexone, experience of

narcotic blockade with or without prior

experience of unblocked heroin administration

on the research ward, number of subjects per

study, and homogeneous versus heterogeneous

sample.

Followup Data: Because of the postulated

relationship between “extinction of the

operant response” and long-term outcome in

the community utilizing a narcotic antagonist,

data were also assessed relative to the

outcome of patients who had experienced narcotic blockade on the research ward in terms

of their outcome in the community (in particular, attempting to relate outcome in the

community to frequency of heroin administration under blocked conditions). We have

also compared the outcome of patients who

only experienced unblocked heroin administration on the unit with those who experienced

blockade in terms of community follow-up on

naltrexone. We have also compared initial

and longer-term outcome in the community for

patients in nonblind and double-blind

studies in which consumption of naltrexone

in the community after discharge was and was

not consequated with a monetary reward of

$1 per day.

Finally, data will be discussed in relationship to data gathered in animal selfadministration studies carried out in conjunction with Dr. Joseph Cochin and

125
TABLE 1

HEROIN SELF-ADMINISTRATION UNDER DIFFERENT STUDY CONDITIONS

NONBLIND CONDITIONS DOUBLE-BLIND CONDITIONS

(Designs 1 & 2) (Design 3)

Homogeneous Sample Homogeneous Sample Heterogeneous Sample

S's experience Total n = 6

Unblocked Design #1 only

BLOCKED Heroin on Ward

HEROIN Before Antag- Mean # of Doses: 4.20

ADMINISTRATION onist Blockade Mean Total Dose: 33.20 mg

S's Did not Total n = 3

Experience Design #1 n = 1

Unblocked Design #2 n = 2

Heroin on

Ward Before Mean # of Doses: 21.22

Antagonist Mean Total Dose: 327.00 mg

Blockade

Total n = 5

Mean # of Doses: 5.40

Mean Total Dose: 27.40

Total n = 17

Mean # of Doses: 11.47

Mean Total Dose: 131.24
Mr. Gilbert Carnathan at Boston University,

Department of Pharmacology.

RESULTS

Table I describes the experimental conditions

that emerged from the nonblind and doubleblind study designs. The total amount of

heroin and number of self-administrations

under each of these conditions are compared.

The frequency of heroin administration under

blocked conditions was positively correlated

with the reported years of heroin use

(Spearman r = 0.45, p = < .01) and negatively

correlated with age of onset of heroin use

(r = -0.33, p < .05) (i.e., those who started

heroin at an earlier age challenged with

greater frequency). Other demographic variables (number of months in prison and number

of previous treatment episodes) did not show

any relationship to frequency of administration under blocked conditions on the ward.

Multiple Mann-Whitney U tests were employed

initially to examine the effects of group

size, homogeneity of sample, and nonblind

versus double-blind conditions upon frequency

of heroin self-administration in the presence

of a narcotic antagonist. None of these

factors served to differentiate rates of

heroin self-administration under blocked

conditions. Indeed, subjects with longer

addiction histories (7-20 years) used more

heroin under blocked conditions when compared with individuals with shorter addiction

histories (4-6 years) in the same designs.

Figures 1, 2, and 3 describe the heroin

self-administration patterns of three subjects with shorter histories of addiction,

while Figures 4, 5, and 6 describe these

patterns in three more experienced users.

Within the double-blind design, some patients

experienced narcotic blockade in a group

with no unblocked subjects on the unit, while

other subjects experienced blockade in the

presence of subjects who were “getting high.”

Thus far, three subjects have separately

experienced narcotic blockade in the presence of more numerous peers who were “getting

high” self-administering heroin while on

placebo naltrexone. Table II describes the

outcome data. The differences between

groups were not statistically significant

because of the samll size of the sample.

In addition, two out of three blocked subjects in the majority placebo condition

(i.e., isolated antagonist administration)

had used heroin for more than seven years.

However, after adjusting for the effect of

years of heroin use, the data still indicated

a trend suggesting that heroin administration

under blocked conditions (in an individual

subject) may be more frequent where the

demand conditions of the environment are

consistent with an overwhelming stimulus

of heroin availability (e.g., three subjects

getting high while one subject is blocked).

Relationship Between Blockade on the Ward and

Naltrexone Consumption in the Community:

Finally, we examined the relationship between

heroin administration under blocked conditions on the research ward and motivation to

consume naltrexone in the community at least

one day after discharge. There was no

relationship between antagonist consumption

in the community and frequency of administration under blocked conditions on the research

ward. There was also no statistical difference in outcome between those who consumed

placebo on the ward (and got “high” on heroin)

compared with those who experienced narcotic

blockade in the research setting. Thus, the

participation of the patients in a program

of narcotic challenges in the presence of

other individuals who were getting high on

heroin appeared to have no effect upon later

naltrexone consumption in the community.

Over a three-year period of time, 83 patients

have been admitted to the four-bed research

ward for these studies,* of whom 49 completed the research ward experience and

were eligible for treatment with naltrexone

in the community. Of the 49 who were

eligible for outpatient treatment, 40

actually consumed naltrexone in the community.

In the nondouble-blind studies (Group 1), 21

subjects were admitted and ten were eligible

for naltrexone consumption in the community;** in the double blind studies prior to

monetary consequation of naltrexone consumption in the community (Group 2)) 30 patients

were admitted and 15 were eligible for

naltrexone consumption; while in the doubleblind studies after we initiated monetary

consequation of naltrexone consumption in

the community (Group 3), 32 patients were

admitted and 23 were eligible for naltrexone

consumption in the community. (Table III)

All ten subjects in Group 1 actually con-

*Eight additional subjects have been admitted

for acute studies and two patients were put

on naltrexone as outpatients because they

were not deemed eligible for the inpatient

studies.

**Only six patients in this group completed

the 60 days during a single admission; two

patients were readmitted after discharge for

misbehavior and were allowed to complete the

study on the second admission; one patient

was admitted for blockade only and one

patient signed out AMA after receiving naltrexone and refusing to stay on the ward

during the 10 days of experimental blockade.

127
TABLE 2

BLOCKED HEROIN ADMINISTRATION IN DOUBLE-BLIND STUDIES

HOMOGENEOUS SAMPLE HETEROGENEOUS SAMPLES

Majority Equal Majority

All Antagonist Antagonist Number Placebo

N=5 N=9 N= 5 N=3

Mean # of administrations 5.400 10.33 9.4 18.33

Mean Total Dose 27.400mg 120.89mg 96.60mg 220.00mg

# Doses F = 1.663, p < .211

Total Dose Consumed F = 1.245, p < .323

sumed naltrexone in the community while five

out of 15 and 19 out of 23 in the remaining

groups actually consumed naltrexone in the

community. Chi-square determination indicated a statistically significant difference

in actual naltrexone consumption between

subjects in Groups 1 and 3 compared with

Group 2. Multiple T-tests were performed to

compare longer-term naltrexone consumption

in patients from the three groups who

actually began naltrexone consumption in the

community. Median naltrexone consumption at

one month, three months, and six months in

the three groups was compared. There was a

trend for patients in Group 1 (p = <0.1) to

consume naltrexone longer in the community

than patients in Groups 2 and 3. There were

no differences in the three groups relative

to six months consumption of naltrexone. Of

the ten patients who have remained on naltrexone for more than 90 days, seven relapsed

to opioid use after stopping naltrexone, two

have remained drug free, and one is continuing on naltrexone and in individual counseling. Both patients who have continued drug

free after stopping naltrexone had changed

the location of their residence and had

found stable employment. All but one of the

seven patients who relapsed after stopping

naltrexone were unemployed at the time of

relapse. Six patients consumed naltrexone

in the community from 60 to 90 days; all but

one relapsed to opioid use. The single

exception was steadily employed at the time

that he discontinued naltrexone. One of

those who relapsed was working at the time

of this relapse and another patient who

relapsed ultimately moved out of state as a

fugitive from justice. We have no follow-up

data on him subsequent to his departure. Six

patients consumed naltrexone from 30 to 60

days and four of the six relapsed subsequent

to stopping naltrexone. Two of the patients

are currently in treatment. Eighteen

patients consumed naltrexone from 0 to 30 days

(as of April 30); three of the patients are

continuing naltrexone consumption as part of

their overall treatment program. The remainder relapsed to opioid use. Relapse for many

of our patients was not marked by an inevitably bad outcome since a number of patients

followed their relapse with reentry into

treatment with methadone maintenance, selfhelp groups, and, in some cases, naltrexone.

Relation Between Background Data, Experimental

Conditions, and Outcome: Demographic variables from the TCU (Texas Christian University, Institute of Behavioral Research,

Narcotic Addict Reporting Program Admission

Record) forms filled out on all patients on

admission were coded and factor analyzed.

Using the Varimax solution of orthogonal

rotation, factor scales were obtained by

taking the average of those items which had

loadings of 0.40 or higher on a given factor

after all items had been converted to standardized T-scores. Seven factor scales were

obtained. Three distinct outcomes were compared: patients who were eligible but failed

to consume naltrexone; patients who took

naltrexone for 1-30 days; and patients who

consumed naltrexone for more than 30 days.

A two-way analysis of variance compared

patients in the three groups relative to the

seven factors. Two of the factors had relevance to outcome on naltrexone. Patients who

were arrested at a younger age, started heroin

128
FIGURE 1

FIGURE 2

FIGURE 3

at a younger age, participated in more treatment programs, and were not raised by two

parents through age 12, tended to do poorly

(F = 4.59, p <.015). In addition, patients

whose mothers (F = 1.631, p <.210) and

fathers (F = 1.776, p <.184) had the least

education tended to do best in terms of actual

naltrexone consumption. Multiple chi-square

analyses with each of the demographic variables treated individually confirmed these

relationships. In aadition, those patients

living with spouse, parents or relative on

admission did better than those patients

living with friends, living alone, or with no

stable arrangement. (Chi-square = 13.583,

p <.194) Patients participating in the

double-blind studies where naltrexone consumption in the community was not consequated

(by $1/day) did significantly more poorly

than patients who participated in the nonblind

studies or patients who participated in

double-blind studies where naltrexone consumption in the community was consequated (chisquare = 21.592, p <.002).

Anecdotally, we can report that opioid

challenges to narcotic blockade in the community were rare. When patients did choose

to challenge, they generally did so when

they thought that the narcotic blocking drug

had cleared. Alternatively, patients have

reported that they have encountered former

associates and pushers in their neighborhood

and used the presence of naltrexone to

reinforce their determination to remain

opioid free.

DISCUSSION

Heroin self-administration (under blocked or

unblocked conditions) in an experienced

addict is a complex operant which we have

defined in terms of the frequency and total

dose of heroin self-administration over a

ten-day period. Naltrexone self-administration in the community is also a complex

operant which, based upon our data, appears

to be more likely to occur in our program

among patients with certain demographic

characteristics and in patients who may have

differed in “motivation” to consume naltrexone at the start of the outpatient period.

Those individuals who participated in

nonblind naltrexone administration on the

ward (Group 1 patients) were motivated to

remain on the inpatient unit for nonblind

naltrexone administration. Patients who

participated in the double-blind studies

were prepared to remain on the ward for a

shorter period of time and took naltrexone

under conditions when they expected that

they may or may not receive naltrexone during

the period of heroin availability. Thus,

129
it was our impression that the research

design in the first group of patients may

have screened out the “less motivated”

individuals prior to discharge. This

impression seems to have been borne out

since all ten patients who received naltrexone on the ward actually consumed the drug

in the community at follow-up. In contrast,

only five of 15 patients in the second group

actually consumed naltrexone in the community. When we contingently reinforced

naltrexone consumption in the community, 19

of 23 graduates of the double-blind study

actually consumed naltrexone in thecommunity. Thus, to some extent, contingent

reinforcement of naltrexone consumption in

the community may have overcome the diminished screening function of the inpatient

double-blind studies. Nevertheless, “more

motivated” patients from the first study

designs did tend to consume naltrexone for

a greater number of visits over the course

of the first three months in the community.

The best predictors of outcome were related

to demographic variables and some experimental conditions, but not to the experience

of blocked heroin on the ward. Long-term

outcome was related best to stable employment, but the sample has been too small at

this time to draw definitive conclusions.

Heroin consumption under blocked conditions

on the ward did appear to anticipate outcome

in the community in the following respect:

naltrexone consumption serves as a discriminative stimulus (S ) for heroin being unavailable to the patiet. The power of a cognitive label relative to the power of a conditioned stimulus has been described by

Wikler in a study of five “post addicts” who

received subcutaneous injections of nalorphine or normal saline in lieu of regularly

scheduled doses of morphine or methadone at

irregular intervals and on different days.

Saline injections rapidly ceased to invoke

a conditioned response once it was clear that

the subjects “had been watching each other

and if the first one to receive an injection

did not get ‘sick’ within two to three

minutes they all concluded that the ‘shot was

a blank’ and reacted accordingly.“(2)

Cognitive function served to alter the stimulus properties of the experiment such that

saline injections ceased to elicit the withdrawal syndrome.

In previous reports, we have pointed out the

relationship between self-reported assessments of craving and the presence of heroin

on the research ward.(10) These data are

remarkably consistent with data reported by

Ludwig (14) relative to subjective reports

of craving in alcoholics in response to the

“alcohol stimulus.” In our studies, craving

scores remain elevated under blockade so

FIGURE 4

FIGURE 5

FIGURE 6

130
TABLE 3

AMBULATORY NALTREXONE CONSUMPTION IN ALL PATIENTS ADMITTED TO THE RESEARCH UNIT

Group 1

Nonblind studies

Admitted 21

Eligible for

Naltrexone 10

Consumed Naltrexone

in the Community 10

Group 2 Group 3

Double-blind studies prior Double-blind studies after

to consequation of ambula- consequation of ambulatory

tory naltrexone consumption naltrexone consumption

30

15

5

32

23

19

long as heroin self-administration continues.

Once the patient concludes that he is not

going to get high, he ceases to self-administer heroin. In reports of his work,

O’Brien (15) has observed that patients

begin to find Dilaudid self-administration

to be an aversive experience over time,

ostensibly because the stimulus conditions

have changed and the environment no longer

signals opioid availability. Under these

conditions, opioid self-injection apparently

becomes aversive. The data are also consistent with the outpatient data gathered

by Kleber and colleagues in New Haven (16)

which indicate that patients on cyclazocine

only rarely challenged blockade.

The inpatient data gathered by us suggest

that patients continue to self-administer

heroin under blocked conditions so long as

they anticipate that heroin may be

“available.” When they learn that heroin is

unavailable (i.e., that they are on naltrexone), their craving for heroin falls

dramatically and they stop heroin challenges.

It is possible that when unemployed outpatients in familiar drug-using environments

stop using naltrexone (even after six months),

the stimulus properties of their environment

(interoceptive and exteroceptive) again

suggest the availability of heroin.

Some have argued that active extinction procedures are not necessary to effect extinction (17) since patients will extinguish

classically conditioned responses in the

presence of the conditioned stimuli

previously associated with abstinence

phenomena. At a previous meeting of this

group O’Brien and his co-workers presented

data that suggested that patients who had

been through his forced extinction paradigm

did not manifest autonomic changes in

response to slides of heroin self-administration behavior. (15) In contrast, patients

who had merely been detoxified or who were

being maintained on methadone maintenance

did evince such autonomic responses in

response to such slides. Our human data do

not permit an assessment of whether classically conditioned abstinence was extinguished in the presence of naltrexone. They

merely suggest that active extinction does

not appear to take place in the presence of

naltrexone. As Wikler has stated,

Mere withdrawal of opioids and

prolonged retention of the patient

in a drug-free environment does

not extinguish the conditioned

responses any more than satiating

a rat with food and keeping it

away from a Skinner box for a

period of time will ‘cure’ it of

its lever-pressing ‘habit,’ previously reinforced by food

rewards under conditions of food

deprivation. By analogy with

extinction procedures known to

be effective in the laboratory,

131
post-detoxification treatment

programs should include procedures for active extinction of

both ‘conditioned abstinence’

and pharmacologically reinforced opioid-seeking behavior,

namely: repeated elicitation

of conditioned abstinence

without the possibility of

reinforcing this conditioned

response by reestablishment of

unconditioned physical dependence;

and frequent repetition of the

addict self-injection ritual

under conditions that preclude

suppression of opioid abstinence phenomena conditioned or

unconditioned.(2)

The mere presence of other addicts getting

high over a ten-day period on our research

ward did not result in persistent heroin

self-administration under blocked conditions,

although persons experiencing blockade as

individuals in the presence of three subjects getting high tended to maintain heroin

self-administration behavior for a longer

oeriod of time. Frequency of self-administration under blocked conditions appeared

to correlate best with number of years of

prior heroin use, data remarkably consistent

with laboratory rodent self-administration

studies we will be reporting at these

meetings.(18) The persistence of this

behavior during naloxone blockade is consistent with the findings of Goldberg, Woods,

and Schuster that stimuli repeatedly paired

with intravenous self-injections of morphine

during self-maintained dependence will persist for prolonged periods of time.(8) In

contrast, classically conditioned responses

were extinguished rapidly in other studies.

(7) The questions that we have raised about

the extinction paradigm in antagonist treatment should not lead to conclusions about

the eventual efficacy of these drugs. They

may suggest ways of incorporating specific

psychotherapeutic, behavioral, and social

interventions in a total treatment program.

In an excellent review article by Ludwig (14),

the author suggests that “a wide range of...

interoceptive cues (e.g., produced by apprehension, loneliness, viral infections, etc.)

. . . could be capable of evoking the experience

of craving and thus be capable of increasing

the predisposition to drink” in alcoholic

patients. In the conditions of our research

ward, the discovery by our patients that

they were on naltrexone in the double-blind

study (or the period of naltrexone administration in the nonblind studies) was associated

with a diminution in anxiety, tension, and

depression. It is our impression that the

cognitive labeling process is of great

importance in the successful treatment of

the narcotics user with naltrexone. During

conditions when the stimulus properties of

the environment (interoceptive and exteroceptive) suggest the availability of heroin,

patients experience a dysphoric response

that may not only be marked by classically

conditioned abstinence, but also by anxiety

and tension associated with an approachavoidance conflict associated with the

euphoric high generated by previous opioid

administrations, as well as previous

encounters with the aversive consequences

of drug use. In this circumstance, tension

escalates and relief can be obtained by the

administration of an opioid. The dysphoria

is labelled “craving” and is associated with

a feeling of inevitability. Conditioned

abstinence phenomena may only be one part

of the symptom picture, but we suspect that

the ambivalence in the conflict may be more

central to the relapsing phenomenon as it

manifests in human beings. Naltrexone

consumption is a conscious act by the

patient to enter a drug-free setting for a

period of 24-48 hours. It is marked by

tension reduction because in the circumstances the stimuli associated with heroin

availability (including classically conditioned abstinence) are not present. It is

probably not surprising that our success

rates with naltrexone are analogous to the

success rates of Antabuse in the treatment

of alcoholism. While alcohol consumption

on Antabuse does have aversive consequences, both Antabuse in the alcoholic and

naltrexone in the narcotics user involve a

conscious decision by the patient to avoid

interoceptive and exteroceptive stimuli

that are associated with the availability of

the drug of abuse. It is possible that we

would have seen more insistent heroin

challenges under conditions of precipitated

narcotic withdrawal or under conditions

where naltrexone and placebo administration

were carried out in a random, double-blind,

cross-over design (i.e., the prolongation of

uncertainty re: heroin availability). Since

the drug is not normally used therapeutically

in either of these situations, the design

that we have actually employed may have

greater significance so far as treatment

applications are concerned. Our data

suggest that contingent reinforcement of

naltrexone consumption may offer some shortterm advantages relative to the initiation

of naltrexone consumption by the patient

in the community. Motivation to continue

naltrexone consumption, however, appears to

be a function of the availability of alternative reinforcers (e.g., job; meaningful,

affectional relationships, etc.). We would

urge that programs utilizing naltrexone

consider these needs in developing their

treatment programs. It is our impression

132
that depot preparations will be seen by

patients as a “sentence” to a drug-free

setting and that extinction will no more

take place under conditions of depot

administration than under conditions which

we have observed. Moreover, our data on

patients who have been on naltrexone for

six months suggest that, even the patient

on long-term antagonist treatment must

eventually confront the time when he is

naltrexone free and opioids are again

“available.”

INFORMED CONSENT

PROCEDURES

The informed consent of heroin addicts for a

research program that at some time involves

the administration of heroin is an issue to

be carefully considered and reviewed. In

addition to the usual human studies committee

reviews, this project was also scrutinized

by a group of citizens from the Governor’s

Drug Abuse Prevention Planning Council in

Massachusetts and staff persons from the

Departments of mental health and public

health in this state. At the federal level,

separate committees of the Food and Drug

Administration and the National Institute of

Mental Health reviewed the procedures in

terms of the ethical and humane considerations and the likely benefits and risks to

the subject.

ACKNOWLEDGMENTS

This research was supported by NIMH Grant

#5 P01 DA 00257: Harvard-Boston University

Center for Biobehavioral Studies in the

Addictions: NIMH Contract #HSM 42-72-208:

A Research Paradigm for the Study of Opiate

Antagonists, McLean Hospital, Belmont,

Massachusetts (Expired December 31. 1974)

and SAODAP Grant #DA 4 RG 010: Clinical’

Research Center, McLean Hospital, Belmont,

Massachusetts, 02178.

From the Department of Psychiatry and Center

for Biobehavioral Studies in the Addictions.

Harvard Medical School, and Drug Abuse

Research Center, McLean Hospital, Belmont,

Massachusetts, 02178.

All persons were recruited by referral from

drug rehabilitation facilities in Massachusetts or by former patients. Prior to

acceptance in our program, each individual

was evaluated medically and psychiatrically.

Admission to another facility for inpatient

or outpatient detoxification prior to

admission to the research facility was

recommended to all patients. Verbal descriptions of the project were supplemented by

an eight- to ten-page patient handbook, which

was given to the patient prior to admission.

He was also taken on a tour of the research

ward and McLean Hospital, and was given the

opportunity to talk with former patients.

On the day of admission, he was interviewed

by an attorney (a member of the hospital

Human Studies Committee), who, after being

satisfied that the patient was well informed

and understood fully the nature of the

proiect. obtained the individual’s signature

on the informed consent form. No patient

was accepted by referral from the criminal

justice system, and all patients were volunteers who were free to leave the project

at any time. Each could receive up to $700

for participation in the program. If a

patient did drop out, he was permitted to

keep money already earned during his stay.

REFERENCES

1. Martin, W. R. , Gorodetzky, C.W., and

McClane, T. K.: An experimental study in

the treatment of narcotic addicts with cyclazocine. Clin. Pharmacol. Ther. 7:455-465,

1966.

2. Wikler, A.: Requirements for extinction

of relapse-facilitating variables and for

rehabilitation in a narcotic-antagonist

treatment program. In: Narcotic Antagonists,

Braude, M.C., Harris, L. S., May, E. L.,

Smith J. P. and Vilarreal, J. E. (Editors),

8:399-414, Raven Press, 1973.

133
3. Wikler, A.: Conditioning factors in

opiate addiction and relapse. In:

Narcotics, Wilner, D. I. and Kassebaum, G. G.

(Editors), pp. 85-100, McGraw Hill, New York,

4. Holland, J. G. and Skinner, B. F.:

The Analysis of Behavior, McGraw Hill,

New York, 1961.

5. Schuster, C. R. and Johanson, C. E.:

Behavioral analysis of opiate dependence.

In: Opiate Addiction: Origins and Treatment,

Fisher, S. and Freedman A.M. (Editors),

p. 77, V. H. Winston and Sons; Washington,

D. C. and Halstead Press, New York, 1974.

6. Woods, J. H. and Villareal, J. E.:

Effects of naloxone and the self-administration of codeine, pentazocine and cocaine in

the monkey. In: Problems of Drug

Toronto, Canada, 1, pp. 833-846, 1971.

Dependence, Proceedings of NAS/NRC Meeting,

7. Goldberg, S. R. and Schuster, C. R.:

Conditioned nalorphine-induced abstinence

changes: Persistence in post-dependent

monkeys. J. Exp. Anal. Behav. 10:235-242,

1967.

8. Goldberg, S. R., Woods, J. H., and

Schuster, C. R.: Morphine: Conditioned

increases in self-administration in rhesus

monkeys. Science 166:1306-1307, 1969.

9. Davis, W.M. and Smith S.G.: Naloxone

use to eliminate opiate-seeking behavior:

Need for extinction of conditioned reinforcement. Biol. Psychiat. 2:181-189, 1974.

10. Meyer, R.E.: On the nature of opiate

reinforcement. In: Addiction, A Comprehensive Treatise, P. G. Boume (Editor),

Academic Press, Inc., pp. 21-35, New York,

1974.

AUTHORS

Roger E. Meyer, M.D.

Mary Randall, M.S.

Cecily Barrington, B.A.

Steven M. Mirin, M.D.

Isaac Greenberg, Ph.D.

11. Meyer, R. E., Mirin, S. M., and Altman,

J. L.: The clinical usefulness of narcotic

antaeonists: Implications of behavioral

research. Amer. J. Drug and Alcohol Abuse

2(3), 1976.

12. Meyer, R.E., Mirin, S.M., Altman,

J. L., and McNamee, H. B.: A behavioral

paradigm for the evaluation of narcotic

antagonists. Arch.. Gen. Psych. 33(3):

371-377, 1976.

13.

The

and

the

Meyer, R. E., Randall, M., Mirin, S. M.,

and Davies, M.: Heroin self-administration:

effects of prior experience, environment,

blockade. Submitted for publication to

J. of Psychiatric Research.

In: Proceedings of the 4th Annual Alcoholism

Conference of the National Institute on

Alcohol Abuse and Alcoholism: Research

Treatment and Prevention, Chafetz, M. E.

(Editor). DHEW 76-284, pp. 3-22, 1975.

14. Ludwig, A. M.: The irresistible urge

and the unquenchable thirst for alcohol.

15. O’Brien, C. P., et al.: Systematic

extinction of narcotic drug use using

narcotic antagonists. In: Problems of

Dependence, Proceedings of NAS/NRC meeting,

Mexico City, pp. 216-222, 1974.

16. Kleber, H., Kinsella, J. K., Riordan,

C., Greaves, S., and Sweeney, D.: The

use of cyclazocine in treating narcotic

addicts in a low-intervention setting.

Arch. Gen. Psych. 30 37, 1974.

17. Resnick, R.: Personal Communication.

18. Carnathan, G., Meyer, R. E., and

Cochin, J.: Narcotic blockade, length of

addiction, and persistence of intravenous

morphine self-administration in rats.

In: Problems of Drug Dependence, Proceedings

of NAS/NRC Meeting, Richmond, Virginia, 1976.

Dr. Meyer is Associate Professor of

Psychiatry, Harvard Medical School, Director

of Harvard-Boston University Center for

Biobehavioral Studies in the Addictions, and

Associate Director of Alcohol and Drug Abuse

Research Center, McLean Hospital, Belmont,

Massachusetts.

134
Ms. Randall is a Statistician, Alcohol and

Drug Abuse Research Center, McLean Hospital,

Belmont, Massachusetts.

Ms. Barrington is a Research Assistant,

Alcohol and Drug Abuse Research Center,

McLean Hospital, Belmont, Massachusetts.

Dr. Mirin is Assistant Professor of Psychiatry, Harvard Medical School, and Clinical

Director of the Narcotic Antagonist Research

Project, Alcohol and Drug Abuse Research

Center, McLean Hospital, Belmont,

Massachusetts.

Dr. Greenberg is Assistant Psychologist,

Alcohol and Drug Abuse Research Center:

Psychology Laboratories, McLean Hospital,

Belmont, Massachusetts.

135
NALTREXONE IN A

BEHAVIORAL TREATMENT

PROGRAM

Charles O’Brien, M.D., Ph.D.

Robert Greenstein, M.D.

Arguments favoring narcotic antagonist treatment usually emphasize the conditioning factors

in addiction. Wikler's pioneering clinical

observations (Wikler, 1948) and experimental work

stimulated much thought and effort in this area.

Now that a drug is available which seems to satisfy many of the criteria for a clinically useful narcotic antagonist, how are we progressing

in the application of these theoretical principles? In order to address this question, we

must first examine some of the conditioning factors in human narcotic addiction. Animal studies

have been invaluable in the development of this

area (for an excellent review, see Wikler, 1973),

but cognitive factors make direct extrapolation

to the clinical situation very difficult.

CONDITIONED ABSTINENCE

When a detoxified addict reports the onset of

withdrawal symptoms on return to his drugusing environment, we my wonder whether he is

attempting to rationalize his relapse or perhaps

he is reporting protracted abstinence (Martin,

136

1972). Patients may report these symptoms after

return from months or years in a prison or therapeutic community. There is now clinical evidence that these symptoms occur naturally in

patients receiving methadone maintenance (Whitehead, 1974; O'Brien, 1975b) and experimental

evidence that they can be produced in a laboratorv (O'Brien, 1975a). After a classical

conditioning procedure, a previously neutral

stimulus was able to elicit yawning, tearing,

lacrimation, and changes in heart rate, respiration, blood pressure, and skin temperature.

These changes showed evidence of extinction

after repeated unreinforced trials.

The changes may, of course, be more subtle.

Teasdale (1973) reported evidence of tension when addicts were shown slides of drugrelated materials. Meyer (1976) reported

increased craving scores when addicts on a

research ward were in a "drug available"

situation. Our group has noted increased

craving and decreased skin temperature (a

sign of withdrawal) in detoxified addicts

going through "cooking-up" rituals in preparation for self-injection.
Since the data now support the clinical

reports, we can assume that at least some

detoxified addicts develop conditioned abstinence symptoms, although we have little

information as to which situations are the

most provocative. Naltrexone may be helpful

by allowing the patient to be exposed to

these stimuli while in the cognitive set of

the "no drug available situation." Of

course, the strength of the conditioned

responses may be reduced by this cognitive

set just as Meyer's (1976) patients reported reduced craving when they knew heroin

was not available. This factor would prolong the time required for extinction of

these responses, and would raise the possibility that they would reappear when the

patient stops naltrexone, i.e., the cognitive set is different.

NEEDLE RITUAL

CONDITIONING

A second type of conditioning is related to

the "needle freak" phenomenon (Levine,

1974). This has been observed occasionally

by clinicians and refers to the effects produced by the ritual of injection itself

rather than to the pharmacological effects

of the drug injected. The potency of street

heroin is notoriously variable and some

bags contain little or no measurable heroin.

Among applicants for methadone treatment,

10-20s have multiple fresh needle marks but

negative naloxone tests for physical dependence (Blachly, 1973; O'Brien, 1975b).

Stimuli which have reliably preceded drug

effects may exert effects themselves when

they occur in the absence of the drug.

These stimuli may include the environment

of the shooting gallery, the smell of the

"cooker," the act of "tying off" and flushing the syringe with blood, and the internal

effects of the adulterants (e.g. quinine).

The conditioned effects theoretically might

be opposite to the narcotic agonist effects.

This would be counteradaptive effects

of Wikler (1973) or the opponent process

as proposed by Solomon (1974). Siegel

(1975) has experimental evidence in rats

supporting the counteradaptive effects and

perhaps explaining part of the phenomenon

of tolerance. Our own work with humans has

thus far not detected counteradaptive effects in

addicts after saline injection or blocked narcotic

injections. Patients show withdrawal phenomena

(craving, decreased skin temperature) during preinjection rituals, but after injection they report

mildly pleasant effects (taste, some rush, occasionally some high) when saline or narcotic in

the presence of naltrexone is injected (O'Brien,

1975b).

Our group has been trying to determine whether

patients on naltrexone are benefited by techniques which extinguish the effects of these

rituals. We have permitted addicts to selfinject narcotics or saline in the laboratory

under naturalistic conditions. In our pilot

work (O'Brien, 1974) we showed that the first

few injections of either hydromorphone (1 to

4 mg) or saline are interpreted as pleasurable,

although pupillary changes are minimal. These

pleasurable effects in the presence of an antagonist (either cyclazocine or naltrexone) are

rapidly extinguished, however, and subsequent

injections become neutral or annoying. We

are currently conducting a study of the effects

of this procedure as compared to naltrexone and

only traditional counseling. Patients are

assigned to either extinction trials or a control group. Our initial follow-up (6 months

post treatment) shows a slight (not significant)

increase in proportion remaining opiate-free

for those who participated in the trials. A

major difficulty with the study is that patients

become so annoyed by the procedure that they

usually refuse to participate in more than a few

trials (5 to 10). Those who take more trials

(up to 45) tended to do better, but the numbers

are too few to be conclusive. One consistent

finding was that those who remained on naltrexone

longer tended to do better whether or not they

participated in self-injection.

ACTIVE VS. “PASSIVE”

EXTINCTION

The finding that duration on naltrexone seems to

predict outcome at follow-up suggests the possibility that efforts at self-injection may be

unnecessary. The patients in our control group,

however, cannot be considered to be undergoing

"passive" extinction. Passive extinction implies

lack of active control by the subject. This

would apply to an animal kept in a cage apart

from the previously-conditioned situation or

to a human addict kept in prison away from the

drug environment. Extinction in these cases

does not occur, although there may be considerable decay in strength of responses

depending on the duration of conditioning

and duration of separation from the test

stimuli.

137

The influence of cognitive set is an important

consideration when dealing with humans. In order

to study what might occur in the natural situation, the test situation must be as realistic as

ethically possible. When the subject expects to

feel no effect from an injection, he usually

reports no effect. We have some data on individual patients which indicates that even objectively recorded autonomic changes may be

influenced by cognitive expectations.
Our control group underwent active extinction because they maintained control over

their access to drug-related stimuli. Some

of them tested the naltrexone with a

"street fix" and some did not. We do not

yet know whether spontaneous voluntary

testing has any effect on outcome, but we

intend to investigate this variable. The

control group did not go through self-injection rituals in the laboratory, but they

did expose themselves to many of the other

stimuli which had formerly preceded drug

effects. It may either be unnecessary or

provide only minimal advantages to expose

the patient to all drug-related stimuli

up to and including the act of injection.

The question is not whether extinction

should be active or passive, but how far

down the chain of drug-related stimuli need

we systematically extinguish? Also, need

we apply principles of systematic extinction? Perhaps as Meyer (1976) suggests, we

should focus on the contingencies which

increase the probability of long-term naltrexone ingestion among out-patients and

let extinction take care of itself. These

questions have not yet been answered.

HOW COMPLETE IS THE

NALTREXONE BLOCK?

Our work with self-injection has given us

the opportunity to assess the completeness

of antagonist blockade under double-blind

conditions. The results show that while

naltrexone at 120 mg markedly reduces

narcotic effects up to 48 hours, some effects remain. Table I summarizes some of

our previously published data (O'Brien,

1975c) on 82 trials, 48 hours after 120

to 200 mg naltrexone. We have similar data

for 24 hours and 72 hours and for higher

naltrexone doses. The hydromorphone trials even at 1 or 2 mg showed on the average

greater effects as measured by patient,

observer, and pupillometry than saline

trials. Only 17% of the 3-4 mg hydromorphone trials were rated as no effect whereas 97% of the saline trials were rated this

way. Ratings of rush, high, and pupil constriction all followed this dose-response

trend. These effects, of course, were

slight and might well be missed in a singleblind or nurse injection study. There is

also the possibility that hydromorphone has

a greater affinity than morphine for opiate

receptors and thus would show effects in

the presence of naltrexone while heroin

would not. More importantly, the effects

were not sufficiently rewarding to induce

the subjects to continue self-injection.

We have not found a significant decrease in these

effects over time on naltrexone, but it is possible that they may be reduced as active naltrexone

metabolites accumulate with repeated doses.

IS NALTREXONE CLINICALLY

EFFECTIVE?

There seems to be no doubt that naltrexone is

effective as an antagonist of narcotic effects

and so far it seems to be reasonably safe. But

are patients helped by our present methods of

administering the drug? 'Those of us who have

used the drug in fairly large numbers of patients

can all cite examples of patients who did well

on naltrexone and even some patients who remained

drug free for extended periods after stopping

naltrexone. Our own six month follow-up data

is presented elsewhere in this symposium. So

far, however, no one has shown that the remission

rate for patients on naltrexone exceeds spontaneous remissions in similar untreated patients.

Further there have been no controlled comparisons with other treatments for narcotic addiction. Of course, no other addiction treatment

meets these criteria either. Such studies are

difficult, but not impossible to perform. Perhaps the comparison should be with another drugfree approach such as therapeutic community,

rather than a maintenance approach. Here, just

as with naltrexone, there is a high attrition

rate and a high relapse rate after treatment

is stopped. In fact, it is our impression that

therapeutic community graduates can benefit from

a period on naltrexone after returning to the

community, but we have been unable to get sufficient numbers for an adequate trial. Most of our

efforts at follow-up are contaminated because

our patients have received multiple kinds of

treatments and it is misleading to attribute

outcome to the one you happen to be studying.

The life table approach seems to hold promise

in sorting this out. As far as the conditioning

aspects are concerned, a wide variety of autonomic conditioned responses have been found

which are available for extinction. This is

only part of the illness, however. We have

not solved the problem of cognitive set and

we certainly cannot work in isolation from the

complex social factors such as education, employment and poverty which may be much more potent

than treatment variables.

From the Department of Psychiatry, University

of Pennsylvania and the Philadelphia Veterans

Administration Hospital, supported by NIDA

Grants DA 00586 and DA 01218.

Reprint requests to Dr. Charles O'Brien, (152)

VA Hospital, University and Woodland Aves.,

Philadelphia, Pa. 19104

138
TABLE 1

Effects of double-blind challenge injections 48 hours

after taking 120-200 mg of naltrexone

placebo hydromorphone dose

0 1 or 2 mg 3 or 4 mg

Number of trials run 30 28 24

I. “High” and “Rush” 0 (0%) 1 (4%) 3 (12%)

Mean pupil constriction (mm)* - .25 .25

“Rush” (patient rating; 0-3) - 1.0 2.0

“Effect” (observer rating; 0-5) - 2.0 2.7

II. “Rush” only 1 (3%) 9 (32%) 17 (71%)

Mean pupil constriction (mm)* .00 .30 .38

”Rush” 1.0 1.0 1.1

“Effect” 1.0 1.0 1.5

III. No effect** 29 (97%) 18 (64%) 4 (17%)

Mean pupil constriction (mm) .04 .16 .31

* This is actual change (un-magnified) under low light, non-flash conditions.

** On five of these (four at 1-2 mg Dilaudid; one at 3-4 mg) the observer rated

a “slight” or “questionable” effect. No effect was reported by the patients.

REFERENCES

Blachly, P.H.: Naloxone for diagnosis in methadone programs. JAMA, 224:334-335, 1973.

Levine, D.G.: "Needle Freaks": Compulsive selfinjection by drug abusers. Am. J. Psychiatry,

131:297-300, 1974.

Martin, W.R.: Pathophysiology of narcotic addiction: Possible roles of protracted abstinence in

relapse, in Drug Abuse - Proceedings of the

International. Conference, edited by C.J.D. Zarafonetis, Philadelphia: Lea and Febiger p 153-

159, 1972.

139

Meyer, R.E., Mirin, S.M., Altman, J., McNamee,

H.B.: A behavioral paradigm for the evaluation

of narcotic antagonists. Arch. Gen. Psych., 33:

371-377, 1976.

O'Brien, C.P., O'Brien, T.J., Mintz, J. and Brady,

J.P.: Conditioning of narcotic abstinence symptoms in human subjects. Drug and Alcohol Dependence, 1:115-123, 1975a.

O'Brien, C.P.: Experimental analysis of conditioning factors in human narcotic addiction.

Pharmacological Reviews, 27:533-543, 1975b.
O'Brien, C.P., Greenstein, R.G., Mintz, J., and

Woody, G.E.: Clinical experience with naltrexone. Amer. J. of Drug and Alcohol Abuse, 2:365-

377, 1975c.

Siegel, S.: Evidence from rats that morphine

tolerance is a learned response. J. of Comp.

and Physical Psychology, 89: 498-506, 1975.

Solomon, R.L. and Corbitt, J.D.: An opponentprocess theory of motivation: Temporal dynamics

of affect. Psychological Review, 81:119-146,

1974.

Teasdale, J.: Conditioned abstinence in narcotic addicts. Int. J. Addict., 8:273-292,

1973.

Whitehead, C.C.: Methadone pseudowithdrawal

syndrome: Paradigm for a psychopharmacological

model of opiate addiction. Psychosomatic

Medicine, 36:189-198, 1974.

Wikler, A: Recent progress in research on the

neurophysiologic basis of morphine addiction.

Am. J. Psychiatry, 105:329-338, 1948.

Wikler, A.: Requirements for extinction of

relapse-facilitating variables and for rehabilitation in a narcotic antagonist treatment program, in Narcotic Antagonists, edited by M.C.

Braude, New York, Raven Press. p 399-414, 1973.

AUTHORS

Charles P. O'Brien, M.D., Ph.D. and

Robert Greenstein, M.D., University of

Pennsylvania and Philadelphia VA Hospital

University and Woodland Avenues

Philadelphia, Pennsylvania 19104

140
CLINICAL EXPERIENCE WITH

NALTREXONE IN A BEHAVIORAL

RESEARCH STUDY:

AN INTERIM REPORT

Robert Greenstein, M.D., Charles O’Brien, M.D., Ph.D.,

Jim Mink, Ph.D., George Woody, M.D., Nancy Hanna, B.A.

INTRODUCTION

Early studies of naltrexone showed that it was

a potent antagonist of narcotics with minimal

agonistic properties (Martin 1973). There

were indications that naltrexone was potentially an ideal antagonist for clinical use. It

was apparently safe, nonaddicting and relatively-long-acting. A single 50-mg oral dose

blocked the effect of 25 mg of heroin for up

to 24 hours, and large doses provided "protection" for 48 to 72 hours (Resnick 1974).

Wikler (1974) proposed that human subjects

taking narcotic antagonists be encouraged to

undergo a series of blocked, or unrewarded,

opiate self-injections to produce extinction

of drug using behavior. In practice, most

patients stabilized on antagonists test the

blockade once or twice and then stop because

they feel they are wasting their money.

O'Brien (1974, 1975) reported a pilot study

in which patients treated with cyclazocine

participated in a series of self-injections

of hydromorphone or saline in a double-blind

procedure. Subsequently we have tested similar procedures using naltrexone. Our initial

experience with 54 naltrexone patients has

been reported (O'Brien, 1975). The following

is an update of the Naltrexone-Behavioral Research Project and includes the methodology of

naltrexone stabilization and medical observations.

METHOD

1. Clinic setting and patient population:

The Drug Dependence Treatment Service (DDTS)

of the Veterans Administration Hospital,

Philadelphia treats drug dependent veterans

in the southeastern Pennsylvania-New JerseyDelaware region. 761 patients were seen at

the clinic in 1975, with over 300 active each

month. Subjects for the naltrexone project

were recruited from the clinic and from three

detoxification units in Philadelphia. Contact

was maintained with methadone maintenance programs and therapeutic communities in the area,

but a negligible number of people were referred by them. From October, 1973 through March,

1976, a total of thirty months, 264 patients

expressing an interest in Naltrexone were

141
screened and evaluated. Of these, 142 successfully completed detoxification and took at

least one dose of naltrexone. Thirty-one were

treated two or more times for a total of 179

treatment episodes. The average age of patients treated was 26.9, with a range of 20 to

47 years. Fifty-nine percent were black, and

40% were white. One subject was Puerto Rican.

Two women with hysterectomies were included in

the treatment population. The average length

of dependence on opiates was five and a half

years, with a range of one to 24 years.

Sixty-three patients (44%) were working or in

school when they applied for treatment and 47

(33%) were married. Twenty-three percent were

non-veterans. Fifty percent were addicted to

street heroin when screened, 33.7% were in

methadone maintenance treatment, and 16.5%

were drug free because they recently completed

detoxification or were released from prison.

A large portion of the heroin addicted patients

had been treated previously with methadone at

the clinic and asked for naltrexone when they

returned.

2. Intake and Screening:

During screening patients were evaluated by

a staff psychiatrist, drug counselor, research

nurse, and psychology technician. Physical

examination, laboratory studies, including a

CBC, SMA-12, serology, Australian antigen and

urinalysis, EKG, and chest X-Ray were done

routinely. A Brief Psychiatric Rating Scale,

Wonderlic Personnel Test, Gordon Personal

Profile, Beck Depression Inventory, and anxiety and symptom check lists were completed.

Patients with active medical disorders such

as gastric ulcer, hepatitis, or heart disease, and women with child bearing potential

were not eligible for treatment.

3. Induction:

A Naltrexone-Behavior Research Fact Sheet

was given to interested patients and questions

concerning the program were answered by the

staff. The consent form, including a description of the behavioral aspects of the program,

was reviewed and signed after completion of

detoxification. The naloxone test, a safe,

reliable method for determining the presence of significant physical dependence on

opiates (Blachly, 1973) was done prior to

starting naltrexone. Thus, patients who still

had significant physical dependence experienced precipitated withdrawal for 30 to 60 minutes

following injection of naloxone, rather than

the prolonged withdrawal of four to twelve

hours which might follow an initial oral dose

of naltrexone. A relatively large dose of naltrexone (0.4 - 0.8 mg) was administered intravenously in order to produce definitive

results. In addition to subjective and observer ratings of the symptoms precipitated by

naloxone, pupillometry using a polaroid reduced-flash technique was done on 50 subjects.

Changes in the size of the pupil were an objective measure of naloxone effect. Pictures

were taken at baseline and again ten minutes

after naloxone injection.

Naltrexone Placebo was given for one to three

days and the naloxone test was administered

48 to 120 hours after the last dose of opiate.

If the test was negative (no response) or

mildly positive (+1: a warm feeling in the

stomach, a mild chill, slight irritability,

and minimal or no pupillary dilation) 10 mg

of naltrexone was given one to two hours after

the test. If no withdrawal symptoms were observed within 2 hours, a second dose (25 to

50 mg) was given. If the naloxone test was

moderately or strongly positive, patients

were asked to wait another 24 to 48 hours before the test was repeated and naltrexone was

given. Strongly positive (+2 to +4) responses

consisted of pupillary dilatation, chills,

anxiety, abdominal cramps, and diarrhea; these

disappeared 40 - 60 minutes after the naloxone

injection.

Most patients were inducted onto naltrexone in

the hospital. Of the 179 treatment episodes

45 were started on an outpatient basis. Fifteen of these were done at the start of a

second or third treatment episode. In outpatient Induction, a history of being opiatefree a minimum of 48 hours was required. Urine for drug screening was collected and a

naloxone test was done. If the test was negative, patients were given a dose of naltrexone

placebo. followed one hour later by 10 to 25

mg of naltrexone. If there were no withdrawal symptoms during the next hour, they

were told they had a low level of protection

against narcotics and were sent home. The

next day they were given 25 or 50 mg of naltrexone, and the dose was then increased daily

until the maintenance level was reached. All

naltrexone in the study was dispensed in juice

and no take-home doses were allowed.

4. Outpatient maintenance:

Patients were stabilized on 100 mg of naltrexone on Monday and Wednesday and 150 mg on

Friday. During outpatient treatment, counselling sessions with a research nurse or drug

counselor were scheduled one to three times

per week. In addition, group therapy for

naltrexone patients was conducted during one

13 month period.

5. Medical evaluation:

Physical examination, laboratory studies, and

EKG’s were repeated at two and four weeks,

then monthly and at termination. Chest X-rays

were done at three and six months of treatment,

142
and at termination. Vital signs were taken

at each medication visit and symptom check

lists were filled out by the research nurse

once weekly. Patients with medical problems

were evaluated by a staff physician and were

referred to the appropriate specialists when

indicated.

RESULTS

1. Induction:

Naloxone, used as described, usually produced

minimal or no changes in recently detoxified

addicts. Of 134 tests done 48 to 120 hours

after the last dose of heroin or methadone,

only 19 were strongly positive. Fourteen of

these nineteen patients insisted on starting

naltrexone within 24 hours of the naloxone

responses because of their "need" to leave

the hospital. All developed precipitated

withdrawal again when a low dose of naltrexone

was ingested. As a result of this experience,

we no longer permit this option. All of the

patients with minimal or no response to naltrexone were safely started on naltrexone

with no symptoms or only mild precipitated

withdrawal.

2. Early Dropouts:

Graph 1 shows the length of time in treatment

for those patients who were given naltrexone.

Of the 142 who began induction, 28 stopped

naltrexone after one or two doses and another

30 stopped treatment during the first week.

Half of the early dropouts complained of

anxiety or abdominal cramps. The rest were

asymptomatic but changed their mind about

taking naltrexone. When they returned to the

clinic after several days or weeks, they reported being unable to feel up to 25 bags of

heroin when used up to 24 hours after taking

naltrexone. Although all patients expressed

firm motivation about giving up drugs when

they asked to start on naltrexone, marked

ambivalence was evident later. Several said

they tried naltrexone because it was a new

drug and they wanted to see whether it would

make them high. Others wanted to see if it

"really worked," and once they found that it

did, they stopped it. Two patients worried

that their ability to get high had been taken

away permanently. Some with chronic anxiety or

depression felt these symptoms were relieved

by opiates and exacerbated by naltrexone. Almost all of the early dropouts requested methadone maintenance treatment.

3. Short and long term treatment:

Patients were arbitrarily divided into a short

term group of 43 who attended for one to eight

GRAPH 1

weeks and a long term group of 41 who took naltrexone for more than eight weeks. Tables I

and II compare urine results for the two groups

with methadone maintenance patients matched

for time in treatment. Urines were analyzed by

thin layer chromatography and were confirmed

by radioimmuno assay and gas chromatography.

Morphine could be detected for up to three days,

quinine and amphetamines for a week, and barbiturates for four or five days after use. Several patterns of drug use were apparent from

interviews and urine analysis. Some patients

never tested naltrexone's blockade, and their

urines were clean throughout treatment. Many

used opiates early to determine if they were

protected. Thereafter they did not use because

they "didn't want to waste the money." Nine

used amphetamines and four used barbiturates

intermittently. Eleven patients with histories

of regular alcoholic intake drank while taking

naltrexone (Four of them also abused amphetamines). One was terminated because he came

to the clinic drunk on three occasions and a

second stopped because of epigastric distress.

Another had elevated bilirubin during treatment

(see medical findings). Graphs 2 and 3 give a

more detailed analysis of the patterns of drug

use in 52 patients. For each of the three

treatment duration groups an index was calculated by dividing the number of weeks during

143
TABLE 1 TABLE 2

COMPARISON OF URINE RESULTS FOR LONG-TERM (>8 WEEKS)

NALTREXONE PATIENTS WITH A MATCHED GROUP OF METHADONE

PATIENTS (NAL=30; METH=19)

COMPARISON OF URINE RESULTS FOR SHORT-TERM (1-8 WEEKS)

NALTREXONE PATIENTS WITH A MATCHED GROUP OF METHADONE

PATIENTS (NAL=40; METH=30)

which the patient had one or more positive

urine tests by the total number of weeks in

which at least one urine was obtained. An index of 100 indicates a positive urine for every

week tested, 50 indicates a positive in half

the weeks tested, and zero indicates no documented use. The short-term patients showed

more evidence of street opiate use, but even

the long term patients continued to use opiates

at a fairly steady rate despite the presence of

naltrexone. Interestingly, the use of nonopiates seemed to decrease over time (graph 3).

Perhaps the non-opiates (barbiturates, amphetamines) were being used early in treatment as

an attempt at self-medication while patients

were getting adjusted to naltrexone.

Ancillary prescription medication was discouraged after the first week, but 10% of the patients were treated for varying intervals with

minor tranquillizers and two were treated with

amitriptyline.

Long term patients had better working relationships with their counselors and participated in individual and group therapy more

regularly. Most of them were considered

"good" patients by the staff. They were cooperative and "well motivated," in contrast

to the early dropouts, many of whom were felt

to be uncooperative, challenging, and unreliable. Four patients initially thought to be

"bad" remained in treatment more than four

months and showed marked improvement in their

behavior. Those with drug-free friends and

those who moved away from neighborhoods associated with drugs stayed in treatment longer and had better outcomes.

4. Multiple treatment episodes and irregular

attendance:

Thirty-one of the 142 patients underwent two

or more distinct treatment episodes, in which

at least one month elapsed between doses of

naltrexone. One patient was treated on three

occasions for a total of four distinct episodes for a total of 13% months. Those with

more than one treatment episode were using

opiates several times a week or were physically dependent when they returned. When a

patient was conflicted about restarting naltrexone, or when he was missing doses frequently, staff asked him to "make a decision"

to take naltrexone regularly or choose another

type of treatment. Three patients with poor

attendance signed contracts agreeing to attend regularly, but this had little effect.

One who took naltrexone for three and a half

months missed medication almost once a week,

and another treated for seven months missed

one or two days a week on several occasions.

The first patient used opiates when he missed,

but the second did not.

Reasons for missing medication varied. Some

patients wanted to "feel" heroin and returned

to treatment to prevent readdiction. Others,

especially later in treatment, wanted to test

themselves to see whether they could resist

narcotics when not protected by naltrexone.

In general, those who stayed in treatment

longest had the best attendance records and

planned termination more carefully.

5. Medical findings

Only three significant medical conditions

developed in the course of 179 treatment

episodes. One patient with chronic recurrent

hepatitis and episodic alcoholic intake had

an elevated bilirubin which peaked at 3.4 mg%

in the third month of treatment and returned

to 1.2 mg% at termination, five and a half

months after starting naltrexone. A medical

consultant diagnosed subclinical hepatitis.

144
GRAPH 2

MEAN INDEX OF OPIATE USE OVER

TIME FOR THREE GROUPS OF

PATIENTS DIFFERING IN DURATION

OF TREATMENT

One patient took naltrexone 13% months and

developed Idiopathic Thrombocytopenic Purpura (ITP) and another developed an allergic

skin rash after six weeks of treatment (see

case histories).

Laboratory values, EKG's and chest X-rays remained within normal limits for most patients.

There were fluctuations in liver function studies and in the percentage of lymphocytes but

no patterns were evident, and values were similar to those found in methadone patients.

Eleven patients had transient non-specific STT wave changes in EKG tracings. Two patients

with Wolff-Parkinson-White syndrome were treated for two and four months respectively and

had no EKG changes or cardiovascular symptoms.

Eleven had blood pressure increases of five to

10 mm diastolic and/or systolic over baseline

recordings taken at rest in the hospital. Two

hypertensive patients were evaluated medically

and treated for hypertension during the study.

The first took methyldopa as prescribed and

had well controlled blood-pressures. The second was treated on three occasions for a toGRAPH 3

MEAN INDEX OF NON-OPIATE USE

OVER TIME FOR THREE GROUPS

OF PATIENTS DIFFERING IN

DURATION OF TREATMENT

tal of three and a half months. He took antihypertensive medication irregularly and did

not adhere to his diet. His pressures were

poorly controlled before, during, and after

treatment with naltrexone and ranged from 130/

85 to 160/110.

Five patients were terminated because of concurrent medical problems. Naltrexone was

discontinued twice in the patient with poorly

controlled hypertension. One woman dropped

out during a recurrence of a renal infection.

A patient with a history of drinking and gastric ulcer, in remission, began drinking after

induction and developed gastritis. He was

readmitted to the hospital, naltrexone was

stopped, anti-acids and a special diet were

ordered, and epigastric distress subsided in

two days. The last two cases are presented

below:

Case History #1

GS is a 24 year old single white male who took

naltrexone in four distinct treatment episodes

145
for a total of 131⁄2 months. He had an exacerpation of acne during his first induction onto

naltrexone in April, 1974, and suffered a head

injury playing ice hockey prior to his third

induction in April, 1975, but otherwise did

well in treatment and had no medical complications. He was drug free for several weeks

after each treatment episode, but reverted to

opiate use each time. He began naltrexone for

the fourth time on February 19, 1976. He complained of weakness and lethargy during the

first ten days of treatment, but then felt

well. The patient was hit in the jaw playing

hockey on March 5 and his mouth swelled. The

next day he drained the swelling with a syringe. Gne day later "spots" appeared on his

tongue and shoulders. He took two doses of

penicillin and one dose of tetracycline that

evening because he thought he had infected himself. On March 8 he came to the clinic and

hemorrhagic bullae were seen on his tongue and

oral mucosa, there was a right mandibular dental cyst, and petechiae were present over his

arms and legs.

GS was admitted to the hematology service of

the VA Hospital and bloodwork revealed a

platelet count of 2000/cu mm. Hemoglobin

had dropped from a baseline of 14.6 gm% to

13.5.Reticulocyte count was 2%. White count

was 7,300 with 68% neutrophiles, 22% lymphocytes, 3% eosinophiles and 7% monocytes. No

atypical lymphocytes were seen and a mono

spot test was negative. Serum electrophoresis

was within normal limits. Mouth X-ray showed

a dentigious cyst behind a partially impacted

right lower third molar. Bone marrow was normal. Idiopathic Thrombocytopenic Purpura was

diagnosed and Prednisone 60 mg daily was started. By March 17 the platelet count returned

to 22O,000/cu mm and petechiae subsided. The

last naltrexone had been 150 mg. on March 5.

The patient denied drug use during this treatment epidose and all urines were negative for

drugs.

GS was discharged from the hospital on March

17. Prednisone was gradually lowered and it

was discontinued at the end of April. The

patient is currently being followed in drug-free

counselling and his platelet count has remained within normal limits.

Standard antigen-antibody assays conducted at

the University of Pennsylvania did not show a

causal relationship between naltrexone and

lowered platelet count. Experimental assays

of radiolabled serotonin release, the amount

of immunoglobulin (IgG) on platelets, and

antiplatelet activity in the patient's serum

were inconclusive. The Hematology service

felt the clinical course was compatable with

either ITP or drug induced immune platelet

destruction.

Since ITP may follow viral infections, serum

for viral studies was collected while GS was

in the hospital and after discharge. None of

the titers indicated an acute viral infection,

although the lethargy during the first ten

days of the last treatment episode may have

been related to an undetected infection. ITP

may also occur after bacterial infections.

The patient's manipulation of the mandibular

cyst on the day prior to developing hemorrhagic bullae may have caused an infection, but

blood and throat cultures were negative.

Case History #2

RH is a 25 year old single veteran who has

used opiates for seven years. He started naltrexone on February 17, 1976 and did well with

no street drug use (urine verified). On

March 27 he developed a sore throat and fever

to 102° F. Two days later a skin rash with

intense itching appeared on his lower extremities, forearms, and anteriorly over both shoulders. His last dose of naltrexone had been

150 mg on March 26.

MR. H. was admitted to the hospital where

throat cultures grew out alpha streptococcus

and neisseria. Blood count showed 14,200

white blood cells with 75% neutrophiles, 15%

lymphocytes, 5% eosinophiles, and 5% monocytes.

No atypical lymphocytes were seen. Liver enzymes were normal and bilirubin was 1.5 mg%.

Medical and dermatologic consultants felt the

clinical picture was strongly suggestive of a

morbilliform drug eruption with features of

serum sickness. Skin biopsy showed a nonspecific dermal infiltrate of lymphocytes and

polymorphonuclear cells.

The patient was treated with Periactin for

pruritis and by March 31 was afebrile, his

sore throat subsided, and the rash resolved.

He was discharged asymptomatic on April 1 and

was treated in drug free counselling. He did

well until April 7 through 10 when he used six

bags of heroin each day. He returned to the

clinic on April 12 and requested naltrexone.

RH was readmitted to the hospital and was

given 1 cc of naltrexone placebo in juice on

April 12 and 13. A low dose naloxone test on

April 13 was negative (0. 1 cc intradermally

followed by 1.0 cc IM). At 4:00 pm on April

13 he was given 5 mg of naltrexone and was

observed overnight. On April 14 ten mg of

naltrexone was given at 8:00 am and 20 mg was

given at noon. Erythema and pruritus of both

palms appeared at 8:00 pm on April 14 but subsided by the following morning. No further

naltrexone was given. On April 20, six days

after the last naltrexone exfoliative dermatitis of the palms and fingers of both hands began and lasted for a total of six days. Medical and dermatology services considered the

146
erythema, itching, and exfoliative dermatitis

of the hands to be confirmation of an allergic

skin reaction and serum sickness. The patient

began using opiates heavily two weeks after

stopping naltrexone and is presently in treatment with methadone maintenance.

Termination and follow-up:

Patients were encouraged to consider treatment

for a minimum of two months. They were told

that the longer they took naltrexone, the

better their chances of preventing relapse to

narcotics. Planned terminations and supplementary drug-free therapy were discussed in

counselling sessions. Nevertheless my patients, particularly early dropouts, left

treatment prematurely and failed to tell staff

in advance. No patients reported difficulties

when stopping naltrexone and none described

withdrawal symptoms. Some who were stabilized on naltrexone reported opiate blockade for

up to six days after stopping naltrexone, but

this was not verified in the clinic.

A follow-up study was begun in November, 1975.

Patients were seen by a follow-up counselor

during screening, and addresses and telephone

numbers were verified. Interviews were scheduled one and six months after stopping naltrexone. Twenty-six of 30 scheduled patients

(87%) were contacted at the one month mark

and 19 of 25 (76%) were seen at six months.

Forty-four urines were collected in 45 interviews (98%). The results of the follow-up

urines are shown in Table III. The percentage of patients opiate free was the same at

both 1 month and 6 month Follow-ups.

Discussion:

Naltrexone may have a place in the step-wise

treatment of opiate users as described by

Goldstein (1976). Many patients did well in

treatment and some seen for a relatively short

time apparently benefited from it. But naltrexone appeals to a small percentage of patients. Careful screening for "well motivated"

subjects would increase the retention rate,

but would eliminate the possibility of evaluating antagonists across the broad spectrum of

patients seen in a drug treatment clinic. In

fact several poor risk patients did extremely

well. The decision to begin induction of naltrexone two to four days after methadone was

based on earlier experience with cyclazocine

in which patients complained about the length

of time they had to stay in the hospital to

be stabilized on cyclazocine. Naloxone is

predictive of the degree of withdrawal to be

expected following 10 mg of naltrexone orally.

It is, therefore, useful in avoiding severe

prolonged symptoms which might otherwise occur

in vulnerable patients.

Even when minimal or no withdrawal symptoms are

observed when starting naltrexone, the dropout

rate is high. Since naltrexone is nonaddicting and has no reinforcing qualities in itself,

patients can stop easily by missing several

doses. Longer acting forms of naltrexone are

being developed, but patients wishing to return to opiates would only have to wait longer

for the antagonist effect to disappear. Our

impression is that the quality of counseling

affects time in treatment and outcome. Counseling, therefore, should be incorporated into

studies of longer-acting antagonists.

From a medical point of view, naltrexone appears safe and nontoxic. In the patient with

Idiopathic Thrombocytopenic Purpura, a causal

relationship was not clearly shown. Why sensitivity to naltrexone should develop after

13% months and four treatment episodes is not

understood. ITP may follow viral infections

and it is possible that a viral illness was

present during the first ten days of this

treatment episode. ITP may also follow bacteral infections and it is conceivable that this

patient may have infected himself when he drained the mandibular abscess. In the patient

with an allergic skin rash and serum sickness,

a causal relationship between naltrexone and

the condition seems to be supported. Restarting naltrexone was followed by palmar erythema

and itching and exfoliative dermatitis of the

Fingers and palms. No other allergic or toxic

manifestations with naltrexone have been reported.

The degree of street opiate use seen in patients taking naltrexone was somewhat surprising. It was still significantly less than

that seen in methadone patients matched For

time in treatment, but the degree of street

opiate use was greater than that noted in some

prior antagonist studies (Kleber, 1974;

O'Brien, 1375). The urine tests used here

(RIA) were quite sensitive and the false positive rate has been low. The lack of extinction of this behavior (Graph 2) seen over 9

weeks suggests that longer term treatment

should be conducted.

The follow-up study though based on a small

sample is encouraging, and indicates that

longer term treatment is associated with better out-come. A high proportion of follow-up

evaluations after termination is feasible and

we intend to continue this procedure until an

adequate sample is obtained. All antagonist

programs should have follow-up and tracking

of terminated patients built into the project.

Comparisons with other modalities such as

therapeutic community and methadone could

provide clinically useful information.

147
TABLE 3

POSITIVE URINES FOR OPIATES AFTER TERMINATON OF

NALTREXONE TREATMENT AS A FUNCTION OF TIME IN NALTREXONE

TREATMENT (N=44)

Time in Treatment

<1 week (N=16)

1-8 weeks (N=19)

>8 weeks (N=9)

X

2 = 8.39; df = 2; p< .025

Positive Opiate-free

81% 19%

74% 26%

22% 78%

1. Follow-ups were done at one month (N=25) and six months (N=19). Twelve

patients were in treatment at the time of follow-up; thirty-two were

not. Differences in urine test results did not approach significance

and were negligible. Accordingly, results as a funtion of these factors

have been pooled in the table.

2. Positive urine tests for abusable non-narcotic drugs (amphetamines,

barbiturates, or quinine only) have been included in the opiate-free

column. Three such results were obtained, one in each length-of-treatment

group.

3. Three patients are included in the table twice. Two of these had two

distinct treatment episodes and two follow-up interviews. One was followed up at both one and six months after a single treatment episode. Seven

patients were in methadone maintenance treatment. Six of them had positive tests for morphine. All seven are included in the positive column.

4. One patient in the 1-8 week group was in prison at the time of follow-up

and is included in the Opiate-free column.

From the Department of Psychiatry, University Reprint request to Dr. Greenstein, 152 VA

of Pennsylvania and the Philadelphia Veterans Hospital, Philadelphia Pa. 19104.

Hospital. Supported by NIDA Grant IROI DA01218

148
REFERENCES

Blachly, P.H.: Naloxone for Diagnosis in Methadone Programs. J.A.M.A., 224:334-334, April,

1973.

Goldstein, A.: Heroin Addiction: Sequential

Treatment Employing Pharmacologic Supports.

Arch Gen Psychiatry, 33:353-358, March, 1976

Kleber, H., Kinsella, J.K., Riordan, C., Greaves

S., and Sweeny, D.: The use of cyclazocine in

treading narcotic addicts in a low intervention

setting. Arch Gen Psychiatry, 30:37-42, 1974.

Martin, W.R.: Naltrexone, an Antagonist for

the Treatment of Heroin Dependence: Effects in

Man. Arch Gen Psychiatry, 28:784-791, June,

1973.

O'Brien, C.P., Chaddock, B., Woody, G., and

Greenstein, R.: Systematic Extinction of Narcotic Drug Use Using Narcotic Antagonists.

Committee on Problems of Drug Dependence,

National Academy of Sciences, Washington D.C.,

pp 216-222, 1974.

O'Brien, C.P.: Experimental analysis of conditioning factors in human narcotic addiction.

Pharmacological Reviews 27:553-543, 1975.

O'Brien, C.P., Greenstein, R., Mintz, J., and

Woody, G.: Clinical Experience with Naltrexone, Am J of Alcohol and Drug Abuse 2 (3)

pp 365-377, 1975.

O'Brien, C.P.: Use of Naltrexone in a Behavior

Program. 38th Annual Meeting of NRC Committee

on Problems of Drug Dependence Naltrexone

Satellite Session, 1976.

Resnick, R.B., Volavka, J., Freedman, A.M., and

Thomas, M.: Studies of EN-1639A (Naltrexone):

A New Narcotic Antagonist. Am J Psychiatry

131:6, June, 1974.

Wikler, A.: Opoid Antagonists and Deconditioning in Addiction Treatment. presented at

symposium on Drug Dependence - Treatment and

Treatment Evaluation, Scandia International

Symposia, Stockholm, Sweden, 15-17, October,

1974.

AUTHORS

Robert Greenstein, M.D.,

Charles P. O'Brien, M.D., Ph.D.

Jim Mintz, Ph.D., George E. Woody, M.D.,

Nancy Hanna, B.A.

Veterans Administration Hospital

University and Woodland Avenues

Philadelphia, Pennsylvania 19104

149
COMPARISON OF TWO

NALTREXONE TREATMENT

PROGRAMS: NALTREXONE ALONE

VERSUS NALTREXONE PLUS

BEHAVIOR THERAPY

Edward Callahan, Ph.D., Richard Rawson, Ph.D.,

Michael Glazer, M.A., Beverly MCCleave, B.A.,

Richard Arias, B.A.

The H.A.L.T. Project is a heroin addiction research and treatment program funded by NIDA

through UCLA. H.A.L.T. is an acronym for

Heroin Antagonist and Learning Therapy. The

primary goal of this three-year project is to

compare the effectiveness of naltrexone, behavior therapy and a combination of the two as

outpatient treatments for heroin addiction.

While some data from the behavior therapy

group will be presented, the primary focus of

this paper is an evaluation of naltrexone

alone as a singular treatment intervention as

compared to naltrexone in conjunction with a

comprehensive behavioral treatment program.

DEMOGRAPHIC ANALYSIS

The H.A.L.T. Project is located in Oxnard,

California. Oxnard is located on the Pacific

Coast, approximately fifty miles north of Los

Angeles. Oxnard is the largest city in

Ventura County, an agriculturally based area

of 450,000 people. Approximately 60,000

Mexican-American/Chicanos live in Ventura

County with 30,000 or roughly one-half living

in Oxnard. There are 8,000 Blacks who live

in the county, and about 80% of them live in

Oxnard.

From December 1, 1974 until May 1, 1976, 167

potential subjects Filled out a brief onepage first contact intake sheet. Completion

of this sheet resulted in the random assignment of the potential subject to one of the

three treatment groups. Subjects had to be

male, at least eighteen years of age, and using

heroin for at least one year. Table 1 illustrates the distribution of the 167 subjects

according to ethnic group and treatment group

assigned. Table 2 presents the mean age, edu150
cational level, age at first use of heroin,

and numbers of years addicted to heroin, according to ethnic group. These data were collected on 57 people or 34% of the subjects

assigned, since many of the subjects never

returned to complete the background information questionaire. Currently this information

is being collected at the initial contact in

order to make data collection more complete.

Number of Clients Assigned to Each Treatment Group

A comparison of the three ethnic groups on

the four measures listed in Table 2 indicated that there were no significant difFerences on these background measures (F<1,

in all cases). Therefore, a summary description of the subjects who have participated at

H.A.L.T. is as follows: ethnically, the population is 52% Chicano, 40% White and 8% Black;

the mean age is twenty-six; the mean educational level is eleventh grade; the mean age

of First heroin use is eighteen; and the mean

length of heroin addiction is eight years.

Demographic Characteristics

PROGRAM DESCRIPTION

In order for a subject to earn the services

and benefits offered by the program, it is neccessary to complete a two week entry probation

period, as outlined by a contingency contract.

The purpose of the first week of this probation is to detoxify the subject, using either

an inpatient detoxification hospital unit or

by using outpatient medication. During the

second week, the first seven doses of naltrexone are taken and the therapy program

is initiated. IF a subject completes a

required amount of the contracted responsibilities and takes all seven doses of naltrexone, he earns active client status.

Percentage of the 167 Subjects Achieving Active Client Status

Following completion of the entry probation

requirements, subjects begin a six-week stabilization phase. During this treatment phase

the naltrexone schedule consists of 50 mg.

doses Monday through Friday, a 100 mg. dose

on Saturday and no dose on Sunday.

There are three treatment goals for subjects

in the naltrexone/behavior therapy group during this period. The first is establishing

a consistent naltrexone taking schedule.

Second, a coordinated behavior therapy program is started. This program contains

three main parts. First, contingency contracting is used to structure the treatment

program. Each subject is always on contract, and the contracts are used to structure program responsibilities, acceptable

levels of performance, and steps to achieve

life goals. Secondly, subjects make multiple daily data phone calls to the project. This aids in identifying subject

problem areas and in keeping in close

TABLE 1

TABLE 2

TABLE 3

contact with the subjects. Last are the

actual behavioral technologies, which

tend to be divided into two parts. First,

thought stopping, covert sensitization and

assertion training are used to aid the subject in staying away from heroin use, lifestyle behaviors and contacts. Second, deep

muscle relaxation, assertion training and

life management training, which involves

getting the client to engage in new social

and recreational activities, are used to

guide the subjects into a new drug-free

lifestyle. Finally, it is expected that at

the end of the six-week stabilization period

all subjects will be employed or in school.

Subjects in the naltrexone alone group are expected to demonstrate regular naltrexone taking behavior and to obtain employment or an

educational placement, but are not exposed to

151
any of the behavior therapies. In all phases

at least three supervised urine specimens are

taken per week.

Following the stabilization phase subjects begin

a four to six month maintenance phase. During

this treatment phase, the naltrexone schedule is

100 mg. on Monday and Wednesday and 150 mg. on

Friday. Subjects in the naltrexone/behavior

therapy group are seen in therapy for approximately one hour each time they receive their naltrexone dose. Subjects in the naltrexone alone

treatment group merely receive their naltrexone

and give urine specimens. The naltrexone alone

subjects usually remain at the project for short

periods of time for staff social contact, which

appears to be very important for many of them.

If they request personal counseling, they are

referred to local mental health agencies.

As of May 1, 1976, only one subject had progressed past the maintenance phase into the pre-graduation phase. During the pre-graduation phase,

most naltrexone subjects will begin a thirteenweek fading schedule. They will alternate weeks

on an off of naltrexone, gradually increasing

the time off of naltrexone. This will give

them the opportunity to experience drug urges

and life stresses without being opiate-blocked

although still in contact with the program. If,

at the end of this thirteen-week period there

have been no opiate positive urines, the program will have successfully been completed.

While this may be varied for individual subjects,

it is the tentative program which subjects

expect.

CLIENT PERFORMANCE

Probationary Period

Out of the 167 subjects assigned to a treatment

group, 45 or 27% have earned active client

status. The percentage of subjects earning

active status computed in terms of treatment

group by ethnic group is shown in Table 3. It

should be noted that two White, one Chicano and

one Black subject were reassigned from the naltrexone group to the behavior therapy group

for medical reasons.

As shown in Table 3, 21% of the behavior therapy

group subjects, 30% of the naltrexone/behavior

therapy subjects and 33% of the naltrexone alone

group subjects were successful in earning active

client status. An X2 analysis of these data indicated that the success rates were not significantly different, based on treatment group assignment (X2 = 2, 2.25, df = 2, P>.1).

The success of subjects in earning active

status significantly differs according to

ethnic group. As shown in Table 3, 41% of the

Whites, 28% of the Blacks and 17% of the

152

Chicanos were successful in earning active

client status. An X

2 comparison indicated

that the difference is highly significant

(X2 = 11.27, df = 2, P<.01). While the

number of Black subjects (n=14) is too small

to be conclusive, the number of Whites (n=63)

and Chicanos (n=90) suggests that it is more

difficult for Chicano subjects to earn their

way into the H.A.L.T. Project than for White

subjects. This difference is particularly

striking in the naltrexone/behavior therapy

group, where 69% (9 of 13) of the White subjects earned entry, while only 12% (4 of 34)

of the Chicanos were successful.

One possible reason for the difference in

entry success rates between Whites and Chicanos is the ethnic makeup of the H.A.L.T. staff.

There are one White, one Black and two Chicano

counselors on the staff. However, the director, research coordinator, clinical coordinator and administrative assistant are all White.

Also, the area's Chicano heroin subculture

appears to be much larger, more complex and

more reinforcing than the local white heroin

subculture. It is also possible that there

are background variables other than race which

differentiate the two populations. Although

there were no differences in the background

variables listed in Table 2, a more detailed

analysis of background including drug history, family makeup, legal history and experience with other drugs, may provide some additional information concerning the White/

Chicano entry success differences.

NALTREXONE TAKING

BEHAVIOR

Ninety-six people have been scheduled to start

naltrexone between January 1975 and May 1, 1976.

As shown in Figure 1, fifty subjects were assigned to naltrexone and forty-six to naltrexone/behavior therapy. Of these ninety-six

subjects, 14 of 50, or 28% of the naltrexone

subjects took a first dose, and 15 of 46, or

33% of the naltrexone/behavior therapy subjects took a first dose. This suggests that

approximately 30% of all subjects scheduled

to take naltrexone actually took a first dose.

Before discussing the successful 30%, the 70%

who were not successful will be discussed.

Of the 50 assigned naltrexone subjects, 20 had

no contact with the program following the

initial contact. Gut of these 30 subjects in

the naltrexone group who attempted to enter

the program: 7 were medically ineligible.

Therefore, in the naltrexone alone group, 14

of 23 or 61% of the subjects who attempted to

start the drug did take a first dose. In the

naltrexone/behavior therapy group 32 of the 46
assigned subjects returned for a second contact.

Of these 32, 2 were medically ineligible.

Therefore, of the 30 subjects who attempted to

start naltrexone in the naltrexone/behavior

therapy group 15 of 30, or 50% were successful.

Overall, 53 eligible subjects made an active

attempt to begin naltrexone and 29 or 55% did

take a first dose.

As of May 1, 1976, the average length of time

on naltrexone for the 29 subjects who took a

first dose was 65.2 days. However, as shown

in Figure 1, there was a substantial difference between the naltrexone alone and naltrexone/behavior therapy group. The mean number

of days on naltrexone for the naltrexone alone

group is 44 days, while for naltrexone/behavior

therapy the mean duration is 85 days. Figure 2

presents the total number of days on naltrexone

for each of the 29 subjects. The dotted line

which extends across the entire panel for each

treatment group indicates the mean number of

days on naltrexone for each group. The dotted

lines within each of the bars indicates stops

and restarts on naltrexone for that subject.

The bars with horizontal lines represent subjects who as of May 1 were still receiving

naltrexone.

A t-test comparison on the difference between

the two groups mean durations on naltrexone

could not be computed due to extreme heterogeneity of variance. However, the Wilcoxin

Rank Sum Test indicates that the duration of

days on naltrexone is significantly higher for

subjects in the naltrexone/behavior therapy

group than for subjects in the naltrexone group

(P<.025). It is clear, therefore, that the

duration of time on naltrexone can be increased

significantly by the concurrent involvement of

the subject with a comprehensive behavior

therapy treatment program.

URINALYSIS

Figure 3 illustrates urine results from December 1, 1975 to May 1, 1976 for active clients

in each of the three treatment groups. During

this five month period, 14 of 102 urine samples

or 13.8% were opiate positive for subjects in

the behavior therapy group. In the naltrexone

group, 6 of 131 or 4.6% of the urines were positive for opiates and 8 of 259 or 3.1% of the

urines were opiate positive for subjects in the

naltrexone/behavior therapy group. A comparison of these urine results indicated that there

was a significant difference between the groups

in ratio of opiate negative to total urines

given (X2 = 15.79, df, P<.01). The source of

this difference results from a significantly

greater number of opiate-positive urines occurring in the behavior therapy group than in the

naltrexone groups.

EMPLOYMENT/SCHOOL DATA

Figure 4 presents the percentage of subjects

either employed or in school upon entering

H.A.L.T. (Pre), and at last contact (Post).

This data is only for those subjects who earned

active client status. The number of subjects

per treatment group is: behavior therapy - 22,

naltrexone - 14, naltrexone/behavior therapy15. As shown by Figure 4, there is a substantial increase in employment or school for subjects in all three treatment groups during

their involvement at H.A.L.T.

NALTREXONE-MEDICAL &

SAFETY CONSIDERATIONS

There are three areas of medical and safety

considerations which are important to review:

factors affecting medical/psychological eligibility; problems insuring subjects are opiatefree prior to administration of the first dose;

reported symptoms and physiological functioning of subjects while taking naltrexone.

FACTORS AFFECTING

ELIGIBILITY

As reported above, 9 out of 96 subjects

examined were medically or psychologically

ineligible to begin naltrexone. The disorders

which produced these ineligibilities were: two

cases of diabetes; two abnormal EKG's; one

case each of active hepititis; a nephrectomy;

Myasthenia Gravis; Valley Fever (Coccidiodomycosis); and a psychiatric diagnosis of borderline schizophrenia. Since these cases represent less than 10% of all persons scheduled

to begin naltrexone, it seems reasonable to

conclude that medical ineligibility does not

appear to hamper the usefulness of naltrexone

as a treatment for heroin addiction. It

should be noted that all of these subjects were

allowed to earn their way into H.A.L.T. and

receive therapy as non-research behavior

therapy subjects. Four of these nine subjects achieved active status.

PROBLEMS INVOLVING

FIRST DOSE

The major problem in preparing subjects for

their first dose of naltrexone has been to

keep subjects opiate-free for five days prior

to the first dose. Two methods have been

153
FIGURE 1 FIGURE 2

Figure 1. Left panel, number of clients assigned to take dose of naltrexone and number

of clients receiving the first dose. Right

panel, mean number of days on naltrexone for

each of the groups receiving naltrexone.

FIGURE 3

Figure 3. Five months of urinalyses for each

of the three treatment groups.

Figure 2. Number of days on naltrexone for

each naltrexone and naltrexone/behavior therapy client.

FIGURE 4

Figure 4. Percentage of subjects employed or

in school before contact with H.A.L.T. (Pre)

and at last contact with H.A.L.T. (Post).

154
used to accomplish this., The first, and most

certain method has been to have subjects com--

plete a seven-day detoxification - program

at an inpatient detoxification center

in Palmdale, California. The detoxification

program at Palmdale typically uses six days of

methadone to detoxify heroin addicts. However,

H.A.L.T. subjects are given arm bands to wear

and have special notation on their records to

insure that they receive methadone for the

first two days only. They are then administered Darvon-N, Valium and Chloral Hydrate to

complete the last five days of detoxification.

This insures that on the day they leave the

detoxification center they have been opiate-free

for five days. The Palmdale detoxification

staff understands the purpose of naltrexone and

the need for five opiate-free days. Transportation to and from the detoxification unit is

provided by the H.A.L.T. Project to reduce the

number of subjects who fail to return directly

from Palmdale to the H.A.L.T. Project.

Even with these precautions, there have been

difficulties with this method. The most common

problem is that a substantial number of subjects

do not complete the detoxification program,

even though they have contracted with H.A.L.T.

to do so. Also, there has been one case of a

sympathetic nurse giving a subject a dose of

methadone on the sixth day of detoxification.

Had the subject not reported this methadone

use prior to his scheduled first dose of

naltrexone, it could have resulted in a naltrexone-induced withdrawal reaction.

Although there have been difficulties in using

an inpatient detoxification program, the

problems involved with outpatient detoxification

have been far worse. This approach is

sometimes used for clients who are not able to

go to Palmdale due to work, family or other

reasons. In a majority of these cases, Dalmane and Valium have been used as prescribed

by the local substance abuse program to produce a five day "clean" period in order to

start naltrexone. Three consecutive opiatefree urines are required as evidence that the

subject has been opiate-free for five days

prior to his first dose. This has been

extremely difficult to achieve. This difficulty is particularly evident in subjects with a

long history of heroin use.

Due to the problems with outpatient detoxification, subjects scheduled to begin naltrexone are strongly urged to go to an inpatient

detoxification center, though this approach is

far from a guarantee that the client will

eventually start on naltrexone.

Of the 53 medically eligible subjects who

attempted to start naltrexone, 29 or 45% of

these subjects did not successfully remain

opiate-free for five days in order to start

naltrexone. In singling out the major factor

which has hindered the implementation of naltrexone use at H.A.L.T., it is this problem

of detoxification in order to begin naltrexone.

REPORTED SYMPTOMS AND

PHYSIOLOGICAL FUNCTIONING

H.A.L.T. naltrexone subjects have reported a

variety of physical symptoms. The most common have been stomach cramps, decreased sexual potency, irritability, anxiety, low energy,

and difficulty sleeping. Six subjects reported discontinuing naltrexone due to physical

side-effects. Of these six subjects four reported discontinuing due to severe stomach

cramps, one due to decreased sexual potency,

and one due to frequent nosebleeds. This last

subject later reported that the nosebleeds had

occurred prior to starting naltrexone, and

continued after its discontinuation. He later

restarted naltrexone and has reported no

recurrence of the nosebleeds.

By far the most common symptom has been

stomach cramps. Although only four subjects

have discontinued naltrexone due to stomach

cramps, many subjects have reported them. One

suggestion given to subjects has been to eat

before taking their dose. Some alleviation

of stomach cramps has occurred when subjects

ate prior to taking a dose of naltrexone.

Subjects who begin naltrexone after heavy

heroin use tended to report more frequent and

more intense stomach cramps.

The only other symptom which has been reported

with any frequency is decreased sexual potency. One subject discontinued naltrexone for

this reason. Shortly thereafter, a number of

reports of decreased sexual potency occurred.

These reports were predominantly from acquaintances of the subject who discontinued due to

problems in sexual potency. The subjects were

reassured that there had been'no prior research to show that naltrexone affected sexual functioning. Within two weeks these subjects all reported normal sexual functioning.

Three subjects were taken off naltrexone when

naltrexone could not be ruled out as a factor

in their three different medical problems.

One case of high blood pressure, one case of

severe weight loss and one case of a developing

Cataract resulted in the discontinuation of

naltrexone on the order of the staff physician.

Although in the cases involving high blood

pressure and weight loss there had been a

prior history of these problems, it was felt

by the staff physician that discontinuation

was necessary. In the case of the subject who

developed a cataract, there had been an eye

155
injury immediately prior to the development of

this condition. While the staff physician was

reasonably certain that naltrexone was not

involved in this condition, the subject was

discontinued as a precaution against the

possibility that naltrexone might worsen the

cataract.

A review of the physical examination data

shows no systematic changes in physiological

functioning. There have been no changes in

hematology reports, medical urinalysis,

electrocardiogram reports, or chest x-ray

reports. Daily blood pressure readings have

shown no systematic changes for any clients.

In short, except for the cases reported above,

there have been no adverse physiological

effects detected from naltrexone use.

One last incident which bears on the medical/

physiological aspects of naltrexone concerns

the possibility of flushing naltrexone out of

the body with large quantities of fluids. One

subject reported that he could take a 150 mg.

(3 day) dose on Friday night, drink a quart

bottle of vinegar, then drink a large amount

of beer, shoot and feel the effects of heroin

by the middle of the third day. He would

follow this with more vinegar and beer in order to take his dose of naltrexone and not experience naltrexone-induced withdrawal. He

reported having accomplished this on three

occasions. The question raised by this report

is, can naltrexone be flushed out of the

system with large quantities of fluid? If

there is evidence of this occurring, w-ill an

increased dosage make this technique less

effective?

DISCUSSION

One year's experience with naltrexone at the

H.A.L.T. Project has confirmed that naltrexone

is a viable outpatient treatment for heroin

addiction. Although there are a variety of

ways to measure the effectiveness of naltrexone as a treatment, the most critical

data, the follow-up data are still to be

collected.

Therefore, while no final statement can yet be

made on the long-term effectiveness of naltrexone there are a number of conclusions which

can be reached based on the data collected at

H.A.L.T.

The difference in the number of days on naltrexone between the naltrexone group and naltrexone/behavior therapy group is an important

finding. This comparison clearly indicates

that naltrexone taking behavior can be maintained for a longer period with the concurrent involvement in a behaviorally oriented treatment program.

A survey of subjects' attitudes toward naltrexone suggests that participation in the naltrexone/behavior therapy group promotes a

different attitude toward naltrexone than the

attitude held by subjects who are in the naltrexone alone group. Subjects in the naltrexone/behavior therapy group view naltrexone

as an aid in staying opiate-free while they

attempt a change in lifestyle, habits and

friends. This is an attitude which is presented

and reinforced by the staff and the nature

of the behavior therapies used.

Subjects in the naltrexone group view naltrexone more as a "medication" for heroin addiction, which if taken for a period of time

will produce a "cure" for heroin addiction.

Even though subjects in the naltrexone group

are encouraged to make changes in their

lives while taking naltrexone, the lack

of a structured therapeutic program results

in a more passive acceptance of naltrexone

as a "cure". Currently data are being collected to document these attitudinal differences and to document whether these attitudinal differences are accompanied by actual

changes in relevent behavior.

Another important consideration which has

seriously affected the usefulness of naltrexone is the problem of detoxification and preparation for the administration of the first

dose of naltrexone. Approximately 45% of all

subjects attempting to begin naltrexone fail.

It is proposed that a one to two week inpatient program in which to detoxify subjects

and initiate naltrexone would be more successful. In this facility, detoxification could

occur. followed by the initial doses of naltrexone with an intensive orientation to

the behavior therapy program. Using this

facility. a realistic attitudinal set toward

naltrexone and behavioral techniques could

be fostered, and then transferred into the

outpatient setting.

Finally, H.A.L.T. analysis of subjects earning

entry into H.A.L.T. shows a significant difference in success rates between Whites and

Chicanos. At this point it is impossible to

document the reasons for this difference.

Although the ethnic composition of the H.A.L.T.

staff may be a factor in this difference, it is

likely that there are profound socio-cultural

differences in attitudes toward drug use.

Currently, more extensive data are being

collected from subjects upon initial contact

with the program. These data may help to

identify factors which affect the different

entry and attrition rates.

In summary, during a period of one year naltrexone was given to twenty-nine subjects.

156
Fifteen of these subjects concurrently participated in a comprehensive behavior therapy

program.

The subjects in this naltrexone/behavior

therapy group were maintained on naltrexone

for nearly twice as long as naltrexone group

clients who received no therapy.

If the chances for readdiction are reduced

by increased time on naltrexone, then the

data states that naltrexone should be dispensed as part of a broader therapeutic

strategy. Follow-up data, which will be

collected during the next year will test the

validity of this hypothesis.

ACKNOWLEDGMENTS

This work was supported by NIDA Grant DA01059-02. The authors would like to thank

Robert P. Liberman, M.D. for assistance and

constructive criticism of this work. Thanks

also go to Nancy Thornton for her expert

technical assistance. In addition, thanks go

to Daniel Dominguez, Daniel McNally and Marcie

Chavez for their efforts.

AUTHORS

Edward J. Callahan, Ph.D., Richard A. Rawson,

Ph.D., Michael A. Giazer, M.A., Beverly A.

McCleave, B.A., Richard D. Arias, B.A.

Camarillo-Neuropsychiatric Institute

H.A.L.T. Program

746-E. Main St.

Ventura, California 93003

157
NALTREXONE IN THE

MANAGEMENT OF HEROIN

ADDICTION: CRITIQUE OF

THE RATIONALE

Avram Goldstein, M.D.

INTRODUCTION

We are conducting an experimental trial of

a new approach to the use of naltrexone in

the management of heroin addiction. Street

addicts are first stabilized on a long-acting

surrogate opiate, levo acetylmethadol (LAAM)

for a period of 1 year. The purpose of this

first phase is to buy time, during which the

addict can give up heroin use and make the

life style changes that are essential to

achieving abstinence. After detoxification

from LAAM, naltrexone maintenance is offered.

A major aim of our program is to teach the

patients what naltrexone can do, and to

develop their motivation to use naltrexone.

The basic rationale of our stepwise approach

has been described fully elsewhere (Goldstein

1976), and a preliminary report on the operation of our program has been presented

(Wilson and Goldstein 1976). The first

patients to detoxify from LAAM are only now

beginning the naltrexone phase, so a further

progress report is not justified at this time.

Instead, I shall use this opportunity to discuss some controversial aspects of the use

of naltrexone.

NALTREXONE AND

IMPULSIVE USE

The pharmacologic basis of naltrexone therapy

is not in question. This antagonist, given in

adequate oral dosage (e.g. 120 mg) three times

weekly, maintains a sufficient degree of blockade of the opiate receptors to prevent the

psychotropic effects of opiate agonists like

heroin. Naltrexone itself appears to be without pharmacologic action other than to block

opiate effects; thus, it is a drug with virtually no significant toxicity. If naltrexone

were taken regularly, the subject would very

likely not use heroin (or not continue to use

heroin) because heroin would no longer have a

positively reinforcing effect. The competitive

nature of the blockade, permitting high doses of

heroin to override the protection afforded by

naltrexone, might be thought to be disadvantageous, because the subject can "cheat" by using

more heroin than usual. But this would make

little sense, for a simpler and cheaper alternative is available: to omit a dose of naltrexone

in order to experience the desired effect of

heroin. Naltrexone, therefore, can only work

158
well if it is taken regularly; in short, it can

only work if there is a high degree of motivation

to use it (Resnick et al. 1974).

One may well ask, if a subject is sufficiently

motivated to use naltrexone, and therefore is

presumably strongly desirous of not relapsing to

heroin use, why the same motivation would not

protect him without the use of an antagonist.

The answer is that naltrexone can protect against

impulsive use and can prevent the consequences of

impulsive use. In this respect, although their

pharmacologic actions are very different, naltrexone and disulfiram (Antabuse) share a common

rationale. The protective medication is taken at

a time when motivation is high, then later, if

circumstances arise that would typically lead to

use of the agonist drug, there is strong reason

to avoid that behavior.

Case histories of recidivist addicts demonstrate

the importance of impulsive behavior in initiating relapse. Relapse to heroin use in abstinent

ex-addicts is rarely cogitated and planned in

advance. Conditioned abstinence (“craving”) can

be elicited by accidental encounters with active

addicts, and can also be produced experimentally

(O’Brien 1976). On the street, the victim may

experience a helpless feeling of inability to

control his own behavior in the events that culminate with a needle in his vein. I recall vividly a staff member in a methadone clinic, who

was well maintained on methadone and had been

abstinent from heroin for more than a year. This

man confessed to me, in a state of agitation,

that he had just a few minutes before, in the

clinic parking lot, been shown a syringe and

needle and offered some heroin, and -- as though

in a fugue state -- had "shot up". A former

addict had been abstinent for eight years, had

moved to another city, had an excellent job, was

supporting a family, and was in good financial

and social circumstances. One day, quite unexpectedly, he met a former "shooting partner" on

the street. Within an hour, he had accepted an

invitation to share some “good stuff” -- the

start of a downward spiral that ended with a

fullblown addiction and the loss of job, family,

and possessions. Impulsive heroin use is also

often precipitated by a domestic quarrel or

other major stress.

Because motivation is the key requirerement for

possible success with naltrexone, I believe

it is futile to expect street addicts to

accept and use this drug; yet the major collaborative studies to date on the efficacy

of naltrexone have been conducted with just

such subjects. No wonder the results have

been disappointing. But poor results in a

trial doomed lo failure from the start should

not preclude attempts to find the right

approach. How can we motivate addicts to use

naltrexone? Only, I believe, by first helping them achieve life situations as nonaddicts that by their own assessments, are

worth defending and maintaining. This can

not be accomplished miraculously, overnight.

Small steps may succeed, where big ones fail.

Stepwise progress in rehabilitation is facilitated by short-term support with a surrogate

opiate, permitting heroin use to be stopped

abruptly without physical or emotional disturbances, while the clinic staff assists with

the practical changes that are required in

various spheres of life -- health care, employment, education, legal aid, individual

and family counselling, housing, breaking

away from old “friends”, establishing better

interpersonal relationships, building a sense

of self-worth. We do not know if a l-year

period of surrogate opiate support is adequate;

perhaps a longer time is needed, as suggested

by data on abstinence at follow-up in relation

to duration of methadone maintenance (Stimmel

and Rabin 1974).

EXTINGUISHING HEROIN-USE

BEHAVIOR

It has been proposed (Wikler 1974)) based upon

operant conditioning experiments with animals,

that heroin-using behavior has to be extinguished actively if an antagonist is to work.

If an animal has learned to self-administer an

opiate by bar-pressing, and an antagonist is

then given, there is a transient increase in

bar-pressing followed by gradual extinction,

since the reinforcer no longer acts. It is

argued, therefore, that addicts should be encouraged to inject heroin while maintained on

naltrexone, in order to extinguish that behavior. I believe the analogy is false, in that

it discounts the role of cognition in the control of human behavior. We are able to anticipate consequences and to modify our behavior

accordingly. Consider one of those seductive

Las Vegas gambling machines, the "one-armed

bandit". We know from previous experience

that by feeding coins into the machine we can

sometimes get a payoff, and even occasionally

hit a jackpot. Now one day we find an officiallooking sign on the machine: “Out of Order".

Do we keep feeding coins in nonetheless, as the

rat or monkey would do, until eventually, getting no payoff, we extinguish our gambling behavior? Certainly not. If we have good reason

to believe the sign (e.g., through a discussion

with a maintenance engineer, or through previous

conviction that similar signs have been correct),

we don't waste even a single coin. Thus, it is

not surprising that many subjects taking naltrexone may not use heroin to test and verify the

protection (Meyer et al. 1976). The knowledge

that naltrexone is in one's system is the sign

that says "Heroin Won't Work". In this connection, the observation that naltrexone can diminish

159
"craving" (Meyer et al. 1976) is entirely understandable, since "craving" is generally elicited

by the possibility of obtaining a drug rather

than by its unavailability. It follows from this

analysis that naltrexone can only work if the

patient understands how it works and believes

that it will work.

The analysis presented above suggests the possibility that placebo might be just as effective

as naltrexone. But this is false logic. On

ethical and legal grounds, the use of a placebo

cannot be kept secret. And any attempt to compare naltrexone with placebo in an ethical and

legal manner (subjects being informed of the

possibility of receiving a placebo in a blind

design) invites the subject to test by using

heroin, thereby not only destroying the supposedly blind design, but also jeopardizing the subject's welfare. I believe that the technique of

placebo control is inappropriate in this context,

and that data from naltrexone trials that included placebos should be viewed with serious reservations.

ANTAGONISTS AND THE ENDOGENOUS OPIOID PEPTIDES

(ENDORPHINS)

Finally, I should like to mention the newly discovered endogenous opioid peptides (endorphins)

in pituitary (Teschemacher et al. 1975 ; Cox

et al. 1975) and brain (Hughes et al. 1975).

Could their existence have some bearing upon the

use of antagonists? We know now that the opiate

receptors, which are blocked by naltrexone and

other antagonists, are really endorphin receptors. It must be assumed that they play some

physiologic role in the nervous or endocrine

systems. How can we block these receptors without interfering with their normal function? The

answer to this question is not yet clear. There

seems to be a paradox, in that brain levels of

naltrexone (or naloxone) sufficient to block the

effects of heroin or morphine do not cause any

significant disturbances in lower animals or

humans.

There are at least two interpretations.

First, it is possible, though unlikely,

that an antagonist could block an exogenous

agonist more effectively than an endogenous

one -- particularly one released very close

to the receptors. Second, and more probable,

the endorphin system could ordinarily be on a

"standby" basis, to be called into play by

special conditions like stress or pain. If

that were true, one would expect no effects

of antagonist unless the endorphin system

were first properly activated; we have yet

to discover how to do this experimentally.

If we can generalize from the actions of heroin and morphine, we can surmise that endorphins are involved in obtunding pain by the

same curious mechanism responsible for opiate

analgesia. This "analgesia" is characterized

by a profound and generalized alteration of

affect, in which indifference to all aversive stimuli (not only pain) occurs. Thus,

it is possible that the primary effect of

endorphin is to modulate changes of mood and

responses to stress. These speculations suggest that we must study the effects of naltrexone in humans more carefully than we have

done thus far -- and not only in ex-addicts

but in normal subjects as well.

The possibility should be entertained that

heroin addiction may cause persistent damage

to the endorphin system (through a classical

hormonal negative-feedback loop), or even

that a preexisting endorphin deficiency could

play a role in predisposing some people to

opiate addiction, as I suggested several years

ago (Goldstein 1975). If and when it becomes

possible, by means of immunoassays, to measure

endorphin levels in body fluids, we may be able

to learn the relationships between the addicted

state and endorphin function. We should be prepared to alter our thinking about the appropriate

indications for surrogate opiate maintenance and

for antagonist maintenance if such studies uncover the existence of an endorphin deficiency

syndrome.

ACKNOWLEDGMENTS

The thoughts expressed in this paper reflect

the influence of many investigators, but none

more than Dr. Richard B. Resnick, whose innovative contributions over the years have so obviously molded my attitudes toward the treatment of addiction. The support of grants DA-923

and DA-1199 from the National Institute on Drug

Abuse is also acknowledged.

REFERENCES

Cox, B.M., K.E. Opheim, H. Teschemacher, A.

Goldstein: A peptide-like substance from

pituitary that acts like morphine. 2. Purification and properties. Life Sci. 16:1777-

1782. 1975

Goldstein, A.: Are opiate tolerance and dependence reversible: Implications for the

treatment of heroin addiction, in H. Cappell

and A.E. LeBlanc (eds.): Biological and Behavioral Approaches to Drug Dependence. Proc. International Symposia on Alcohol and Drug Research.

Toronto, October 23-25, 1973, Addiction Research

160
Foundation, Toronto, 1975.

Goldstein, A.: Heroin addiction. Sequential

treatment employing pharmacologic supports.

Arch. Gen. Psychiat. 33:353-358. 1976.

Hughes, J., T.W. Smith, H.W. Kosterlitz, L.A.

Fothergill, B.A. Morgan, H.R. Morris: Identification of two related pentapeptides from the

brain with potent opiate agonist activity.

Nature 258:577-579. 1975

Meyer, R.E., S.M. Mirin, J.L. Altman, H.B.

McNamee: A behavioral paradigm for the evaluation of narcotic antagonists. Arch. Gen.

Psychiat. 33:371-377. 1976

O'Brien, C.P.: Experimental analysis of conditioning factors in human narcotic addiction.

Pharmacol. Rev. 27:533-534. 1976

Resnick, R.B., E. Schuyten, E. Cooper, L.

Schwartz: Narcotic antagonists: A point

of view concerning treatment approaches.

Presented at the National Institute on Drug

Abuse, Narcotic Antagonist Clinical Research

Review Conference, Seattle, Washington,

September 30-October 1, 1974.

Stimmel, B., J. Rabin: The ability to remain

abstinent upon leaving methadone maintenance:

A prospective study. Amer. J. Drug Alc. Abuse

1:379-391. 1974

Teschemacher, H., K.E. Opheim, B.M. Cox, A.

Goldstein: A peptide-like substance from

pituitary that acts like morphine. 1. Isolation. Life Sci. 16:1771-1776. 1975

Wikler, A.: Requirements for extinction of

relapse facilitating variables and for rehabilitation in a narcotic antagonist treatment

program, in L.S. Braude, L.S. Harris, E.L. May,

et al (eds.): Narcotic Antagonists: Advances in

Biochemical Pharmacology. New York, Raven Press,

1974, vol. 8, pp. 399-414.

Wilson, T.G.G., A. Goldstein: From heroin addiction to abstinence, by stages, using LAAM and

naltrexone. Proc. 3rd National Drug Abuse Conference, New York, N. Y., March 25-29, 1976.

AUTHOR

Avram Goldstein, M.D.

Addiction Research Foundation

Palo-Alto, California 94304

161
CURRENT STATUS OF NALTREXONE SAFETY DATA

162
INTERIM REPORT ON CLINIC

INTAKE AND SAFETY DATA

COLLECTED FROM 17 NIDAFUNDED NALTREXONE

STUDIES

Alex Bradford, M.S., Frank Hurley, Ph.D.

Oksana Golondzowski, Catharine Dorrier

INTRODUCTION AND

BACKGROUND

This article will provide an interim summary of

the results of review and analysis of patient

intake and safety data collected through February 29, 1976 from 17 NIM-sponsored studies of

the narcotic antagonist, naltrexone.

Seven of these studies -- of which most were

started in early 1974 under SAODAP grants --

had as one goal the accumulation of data to

provide information on the agent's safety.

These studies were generally of an open design,

although in some, for certain periods or for

specific subpopulations, blinding or control

group measures were employed.

NIDA additionally contracted the National Academy of Sciences to administer (under the NAS

Committee on Clinical Evaluation of Narcotic

Antagonists) five other studies of naltrexone

in a pilot program to determine the feasibility

of double-blind trials of narcotic antagonists

in the context of narcotic addiction therapy;

these double-blind, placebo-controlled studies,

begun in August 1974, were designed to collect

data pertinent to the preliminary evaluation

of efficacy of naltrexone as well as its safety

in treatment of three populations of narcotic

addicts.

Although it was not possible to implement the

original plan of expanding this program, the

five clinics participating were allowed to

start new studies using separate protocols and

study designs; for purposes of this article

these five continuation studies, which "began"

in about December 1975, are regarded as separate studies, hence a total of 17 studies reported. The decision to continue these studies

163
was made in order that the test agent might be

allowed to remain available as a treatment option at the participating clinics, and in order

to provide sufficient data for the purposes of

Phase II safety review by the Food and Drug

Administration.

The patient population tested in all 17 studies

can be broken down into three major groups --

“street addicts,” “methadone maintenance”

patients, and “post-addicts,” the latter so

called because they are known to have been

opiate-free for a relatively long period (usually at least six months, often a period of

incarceration by the criminal justice system)

before entering the present study. The protocols for the five NAS-administered. controlled

studies -- which are otherwise substantially

identical -- differ to accord with the divergent requirements of these three target populations.

Since the five NAS “continuation” studies began

no earlier than December of 1975, the numbers

of subjects of these studies for whom safety

data are currently available are too small for

meaningful inclusion here. Safety data collected for the seven NIDA studies are currently

being reviewed and have not been included.

This article will therefore present findings

with respect to subject intake and retention

for all 17 studies, but will present safety

data for only five (except for medical terminations in the seven NIDA studies).

PATIENT INTAKE AND

RETENTION

Table 1 indicates patient intake data and retention status for the 17 naltrexone studies

as of February 29, 1976, the cutoff date for

this report. Due to basic differences among

the three sets of studies it is inappropriate

to make inter-set comparisons on the basis of

this table. Figures given for the 10 NAS studies represent subjects assigned to either the

active or inactive test medication groups; figures given for the seven safety studies administered directly by NIDA are only for subjects

receiving naltrexone.

At the cutoff date, 1,536 patients had been

logged in as potential subjects of the 17 studies. Of these, 649 dropped out or were discontinued as study subjects before receiving

study medication. A total of 883 had begun

receiving study medication, which consisted of

placebo in 107 cases among the NAS study subjects. Thus as of that date a total of 776

subjects had had experience of receiving experimental naltrexone treatment.

Of the 883 subjects beginning any study medication, the study participation of 353 subjects

had been terminated on or before the 29th day

of medication; 275 subjects had been discontinued between one and three months; 154 between three and six months; and the remaining

101 subjects had continued on study medication

for over six months.

Retention on study medication

Figure 1 is a graphic representation of subject

retention during the course of the study medication periods of the seven NIDA safety studies (naltrexone subjects only) and the five

original NAS studies (naltrexone and placebo

subjects). (Example: Figure 1 shows that, at

the beginning of the fifth month after beginning study medication, approximately 20% of

those NIDA study subjects who began naltrexone

medication remained in the study.)

In viewing Figure 1, it should be noted that

planned medication periods in the NIDA studies

ranged from three to 12 months. Thus the reasons for discontinuation of medication of NIDA

study subjects between the third and sixth

months included program termination in approximately 10 percent of the cases that the curve

reflects.

As the figure indicates, retention rates among

naltrexone subjects in the five original NAS

studies were somewhat higher than those among

placebo subjects from the beginning of the

sixth week through the end of the 33rd week.

In summary, comparison of these slopes indicates a common relatively rapid attrition over

the first two months of study medication; this

attrition rate tends to flatten out at about

the fourth month. Comparison of the slopes

also indicates that -- given the basic differences between the two sets of studies, and

especially the differences in scheduled durations of study medication periods -- retention

on naltrexone in the NIDA and NAS studies was

roughly equivalent.

SAFETY

Terminations for medical reasons

As Table 1 indicates, a total of 883 subjects

in all 17 studies had begun study medication

as of the February 29 cutoff date. Of the 735

of these subjects whose participation was subsequently terminated before completion of the

scheduled medication period, 47 (6.4%) were

discontinued for medical reasons, including

34 exhibiting symptoms and/or side effects

listed on data form NAS-7 and 13 for whom ab164
TABLE 1

Summary of Clinic Intake and Patient Status

On 17 NIDA-Sponsored Studies Evaluating the Narcotic Antagonist Naltrexone

Data as of February 29, 1976

NAS NAS

CENA Continuation NIDA

Studies Studies Studies Total

Number of subjects logged.

Number of subjects whose active

study participation was terminated before receipt of initial

study medication.

Number of subjects who have not

yet received any study medication and whose participation has

not been terminated.

Number of subjects starting

study medication.

Number of subjects who received

study medication and whose

participation was subsequently

terminated.

a. Refusal to continue taking

study medication

b. Symptom side effects (NAS-7)

c. Abnormal findings on NAS-5A or

NAS-5B

d. Evidence of readdiction

e. Prolonged period(s) of absence

f. All other reasons

Number of subjects who are currently

receiving study medication and

whose participation has not been

terminated.

735

543

192

183

19

13

4

20

52

75

9

37 764

1

0 4

36 655

16

1

3

536 735

70

18

90

34

1 8 13

1 33 54

6 228 286

4 179 258

20

105

119

1536

649

4

883

148

Duration of Study Medication*

1 - 29

30 - 89

90 - 179

> 180 0 70 101

655 883

75 18 260 353

55 13 207 275

31 5 118 154

31

192 36

*Study medication - 98 and 9 subjects in the NAS CENA and NAS Continuation Studies

respectively received placebo as their study medication. All other subiects

received naltrexone.

165
normal findings were recorded on either the

laboratory form, NAS-5A, or the physical/psychiatric form, NAS-5B.

Table 2 indicates the distribution of 45 of

these subjects, whether receiving naltrexone

or placebo medication, by the clinic’s recorded

reason for termination and by recorded categorization of the medical abnormality as “possibly drug-related” (PDR), "probably not drugrelated” (PNDR), or “unable to determine”

(UTD). Complete data on the remaining two of

these 47 subjects were not available at the

time of this writing.

It will be seen (Table 2) that 39 (5.0%) of

the 776 subjects on naltrexone and six (5.6%)

of the 107 subjects on placebo medication were

discontinued from study participation for medical reasons. The most common reasons for medical terminations were abdominal pains, cramps,

or upset stomach (ten naltrexone, no placebo

subjects; reported as possibly drug-related in

two cases, probably not drug-related in four,

unable to determine in four); and withdrawal

symptoms (ten naltrexone, two placebo subjects;

reported as possibly drug-related in three

naltrexone and one placebo case, probably not

drug-related in four naltrexone and one placebo case, and unable to determine in the

three remaining naltrexone cases). Five naltrexone and one placebo subject were discontinued reportedly due to nervousness or anxiety; this was recorded as probably not drugrelated in four naltrexone subjects, and unable to determine in the remaining naltrexone

case. Hepatitis was the reported reason for

discontinuation of three other naltrexone

subjects.

The one remaining naltrexone subject whose

symptoms as indicated were “possibly drug-related” developed idiopathic thrombocytopenic purpura . After naltrexone medication was stopped,

the symptomatology cleared and platelet count

stabilized.

* * * * *

Note: The following sections pertaining to the

safety of test medication will present findings

only from the original set of five NAS-administered studies, where results for naltrexone

can be contrasted directly with those for the

placebo controls in those studies. It is anticipated that safety data being collected on

subjects receiving naltrexone in the other 12

naltrexone studies will ultimately be contrasted

with comparable data on the naltrexone group in

this set of NAS studies, to determine the overall consistency of safety findings among all

subjects tested with naltrexone.

Abnormal physical/psychiatric findings

Results of regularly scheduled physical and

psychiatric examinations were recorded on data

form NAS-5B. Findings were reported as “normal”

or “abnormal” for each of five items on all

subjects: physical examination; EKG; X-ray

(chest); psychiatric examination; and neurological examination. A sixth, optional item --

slit lamp examination -- was additionally recorded for 20 subjects.

Table 3 summarizes the findings for each of

these items for all study subjects who were

“normal” at baseline with respect to the item

(or had no recorded baseline evaluation for

the item) and who were evaluated for the item

at least once during the Study Medication

Period. It will be seen that “abnormal” findings resulted from physical, psychiatric, and

neurological examinations slightly more frequently among naltrexone subjects than in the

placebo group. While statistical analysis of

these data is inappropriate, these minor frequency differences do not in themselves appear

meaningful; medical review of the individual

cases in which abnormal findings were made revealed no problems which placed the safety of

naltrexone in question.

Analysis of laboratory and symptom/side effects

data

Three basic approaches were taken in the review

and analysis of data pertaining to laboratory

findings (form NAS-5A) and to symptoms and side

effects (form NAS-7). Since the results of

these three approaches constitute the subject

of the following sections on safety, this section will describe the three approaches.

The first approach consisted in reviewing in

detail data on those subjects who experienced

prolonged or pronounced laboratory abnormalities or signs or symptoms. An effort was then

made to determine whether these subjects exhibited common problems and to contrast these

problems as they occurred among naltrexoneversus inactive-medication subjects within the

NAS studies (as noted above, results for the

naltrexone group are being compared to results

from the other 12 naltrexone studies).

The second approach began with the derivation

of frequency counts for the number of times

any subjects exhibited abnormal lab values or

any signs or symptoms. Two uses were made of

these figures. First, they were used to obtain ratios reflecting number of abnormal readings per total number of readings made in the

course of study medication per subject. Second, a review was made of all abnormal findings recorded within certain time periods during the period of study medication, to determine whether any abnormalities appeared to be

166
FIGURE 1

Cumulative Proportion of Subjects Participating in the Study at the End of Each Time Period

NAS CENA and NIDA Studies

time-specific with regard to onset, duration,

or remission.

The third approach employed regression analysis for the detection of any consistent change

over time (slope analysis) and of more subtle

medication-group differences (analysis of covariance). These are relatively sensitive

analyses, which control for recorded baseline

status and permit the detection of relatively

slight differences between study medication

groups and of relatively subtle changes over

time within each medication group; the slopes

of change for the two groups are then compared

to distinguish changes common to both groups

from changes specific to one group. The results of analysis using this approach are

meaningful only in the context of medical review to determine the clinical significance

of the differences and changes detected.

Laboratory data

Twenty-eight required and five optional tests

covering hematology, blood chemistry (SMA-12),

and urinalysis were run at baseline, at two

and four weeks after initiation of study medication, and monthly thereafter during the

Study Medication Period. For purposes of indicating “abnormal” values, specific limits

(somewhat broader than conventional “normal

ranges”) were established in advance.

Gross findings: In order to monitor lab safety parameters and to select appropriate subjects for review, twelve specific lab variables were designated as a key set; a review

was made of cases in which findings for two

or more of these 12 variables were “abnormal.”

The 12 variables and their predetermined

"normal” limits were as follows: total RBC

167
(4.6-6.2 x 106); total WBC (4.5-10.8 x 103);

hematocrit (40-54 gm%); hemoglobin (13-18 gm%);

FBS (60-120 mgm%); BUN (6-23 gm%); alkaline

phosphatase (25-85 mU/ml); SGOT (7-50 mU/ml);

LDH (90-225 mU/ml); urine albumin (0).

Of the 192 subjects (94 on naltrexone, 98 on

placebo) beginning study medication, lab findings for these variables were "abnormal" in at

least two instances for 23 naltrexone subjects

and 26 placebo subjects. Review of all lab

data on these subjects revealed no apparent

overall differences between study medication

groups. Table 4 indicates the frequency with

which these subjects presented three or more

"abnormal" readings on any of the lab variables

recorded. Frequencies of "abnormal" lab baseline values were generally equivalent for the

two medication groups. It is noted that SGOT

values during the Study Medication Period exceeded the predetermined upper "normal" limit

in nearly half of all cases; statistical analysis of SGOT data -- summarized in Table 5 --

indicated no significant medication-group differences with respect to this variable.

Review was also made of the ratio of all "abnormal" readings to the total number of lab

readings recorded during the Study Medication

Period; and, for each month during the Study

Medication Period, of the ratios of numbers of

subjects with "abnormal" readings to total numbers of subjects for whom lab evaluations were

made during the month. This review resulted in

the following observations:

(1) A slightly higher proportion of naltrexone

subjects than of placebo subjects presented abnormal lymphocyte values (generally exceeding

the predetermined upper limit);

(2) A slightly higher proportion of naltrexone

subjects presented hematocrit values below the

predetermined lower limit; and

(3) A slightly higher proportion of placebo

TABLE 2

Summary of 45 Subjects Terminated

from Study Medication for Medically Related Reasons

(Sample Sizes: Naltrexone = 676; Placebo = 107)

Primary Reason Given

General Withdrawal Symptoms

Abdominal Pain/Upset Stomach

Drowsiness, Disorientation/

Insomnia

Loss of Appetite, Depression

Anxiety, Nervousness

Reduced Sex Drive

Back Pains

General Illness

Cataract

Hepatitis

Idiopathic Thrombocytopenic

Purpura

Recurrence of Kidney Infection

Labile Hypertension

Psychotic Episode

Weight Loss (Withdrawal Symptoms)

Totals

PDR indicates "Possibly Drug-Related"

UTD indicates "Unable to Determine"

PNDR indicates "Probably Not Drug-Related"

168

0

0

0

0

2

1

1

0

0

1

0

0

0

0

1

P

6

N

10

10

3

1

5

1

1

0

1

3

1

1

1

1

0

39

Clinic Impression Total

1

1

1

1

1

1

Placebo Subject Group

PNDR PDR UTD PNDR

Clinic Impression

Naltrexone Subject Group

PDR

3

4

2

1

1

1

1

1

1

15

UTD

3

2

1

4

4

1

4

1

3

1

6 18 1 0 5
TABLE 3

Summary of All Subjects Whose Baseline Evaluation

Was Not "Abnormal" and Had at Least One

Study Medication Period Evaluation

With Respect o the Physical/Psyhiatric Finding Data

subjects presented fasting blood sugar levels

exceeding the predetermined upper limit.

None of these differences was of a degree suggesting significance. With respect to all

other lab variables, the numbers and proportions of subjects with “abnormal” readings were

approximately equivalent for the two medication groups.

Statistical analysis: Four analyses of covariance adjusting for baseline lab values were run

on all subjects for whom lab data were recorded

during each of the first three months of study

medication; and on all lab data collected during the study on the 23 variables with distributions appropriate for this type of analysis.

Of the 92 analyses run, only one -- on albumin

(limits: 3.5-5.5 gm%) -- indicated a statistically significant difference between study

medication groups, and this occurred only at

the third month. Table 5 summarizes the results of all analyses of data pertaining both

to albumin and SGOT.

Analysis of Covariance

Summary of Results for Lab Values Having

Any Study Medication-Goup Differences

Or in Which the Group Means Were "Abnormal"

TABLE 4

Gross Finding

Lab Values for Which Any Medication-Group Differences

Was Observed of for Which Both Medication Groups

Exhibited a High Incidence of "Abnormal Values"

(Sample size: naltrexone=23; placebo=26)

169

To test for more gradual changes over time, and

for differences between study medication-group

slopes, linear regression models were generated

for 20 appropriate lab values. Included in

these analyses were data on all subjects for

whom laboratory reports were made both at baseline and again during the first and second 45-

day periods after starting study medication (32

naltrexone subjects and 35 placebo subjects).

Slope estimates which were statistically significantly different from zero resulted in four

out of these 40 tests. All four instances

occurred in the naltrexone study subject group;

these were the slope estimates for hematocrit

(slope estimate = 0.22802, p < 0.0162), uric acid

(slope estimate = 0.26293, p<.0051), and pH

(slope estimate = 0.13796, p < .0402). However,

in only two instances were the study medicationgroup slope estimates significantly different.

These are summiarized in Table 6. It is reiterated that the differences resulting from this

analysis -- while statistically significant --

are meaningful only in the context of medical

review to establish clinical relevance.

TABLE 5

Symptom data

Forms NAS-7, listing 24 possible symptoms (including an “other” category), were completed

at baseline and at weekly intervals throughout

the Study Medication Period. Specific symptoms

were not named by the recorder (i.e., the subject was asked "How were you feeling during the

past week?” and, if the subject indicated a

particular symptom, he was asked “How bad was

that?” and the severity of his response was

recorded on a four-point scale.)

Gross findings: A review was made of those

cases in which the most frequent and/or severe

symptoms were recorded; these cases included

12 naltrexone subjects and five placebo subjects. Additionally, a review was made of all
cases with symptoms marked other than “none”

both for overall incidence and for over time

changes based on biweekly review points. Those

symptoms most nearly suggestive of a difference

between medication groups -- occurring with

greater frequency in the naltrexone group --

tended to refer to the gastrointestinal system,

e.g. “abdominal pain or cramps” and “nausea or

vomiting.”

Statistical analysis: At least four weekly

symptom forms (NAS-7) were collected for 58

naltrexone subjects and 49-51 (depending on

symptom) placebo subjects. Data on these subjects were analyzed using simple 2x2 tests

in order to detect statistical differences

between medication groups with respect to simple incidence of “other than ‘none”’ recordings

both in the first 60 days of study medication

and over the course of the Study Medication

Period.

TABLE 6

Summary of the Two Lab Values in Which

Statistically Significant Findings Resulted

The incidence of subjects for whom any symptom

recordings of other than “none” were made was

less than 10% on ten of the 24 items recorded,

including “Increased Thirst,” “‘High’ Feeling,”

“Increased Energy,” “Speeding,” “Numb Feeling,”

“Difficulty Concentrating,” “Delayed Ejaculation,” “Decreased Potency,” “Dizziness," and

“Skin Rash.” With respect to ten additional

items -- “Diarrhea,” “Feeling Down,” “Low Energy/Fatigue,” “Difficulty Sleeping,” “Anxiety/

Nervousness," “Irritability,” “Headache,”

“Chills,” “Joint/Muscle or Back Pains” and

“Other” -- the medication groups were not statistically differentiable in either the 60-day

or overall test.

The naltrexone group experienced a greater incidence of the remaining four items; the study

medication-group difference was statistically

significant, or approached significance, in

each instance. Table 7 summarizes the results

of analysis of data pertaining to these four

symptoms.

Summary

In 17 studies of naltrexone, a total of 1,536

patients had been logged in as potential study

subjects as of February 29, 1976. Of these,

883 had been started on study medication, including 107 on placebo as controls. A relatively high rate of attrition was seen in all

studies over the first two months of study

medication; this attrition rate tended to

flatten out at about the fourth month.

Of the 883 subjects beginning study medication,

47 (5.3%) were subsequently terminated for medical reasons. The data available on 4.5 of these

subjects indicate equivalent percentages, both

with respect to the total number of dropouts

in the two study medication groups (naltrexone:

39 of 676, or 5.0%; placebo: 6 of 107, or 5.6%)

and to the number of dropouts which the clinic

reported as “possibly drug-related” (naltrexone: 6 out of 676, or 0.9%; placebo: 1 of 107,

or 0.9%). However, one of the “possibly drugrelated” dropouts developed idiopathic thrombocytopenic purpura after the administration

of naltrexone for approximately 13 months during four separate treatment admissions.

Statistical review of the data and subsequent

analyses of the five double-blind, placebocontrolled studies administered by the National

Academy of Sciences revealed no significant

medication-group differences with respect to

the physical/psychiatric or laboratory data.

A review of the symptom data and analyses indicates that the frequency of occurrences of certain of the gastrointestinal tract symptoms

recorded was somewhat higher in those subjects

treated with naltrexone. Specific symptoms

involved included “Loss of Appetite,” “Abdominal Pain or Cramps,” “Nausea or Vomiting,”

and “Constipation.” However, the relative

severity of these symptoms for all subjects

experiencing any symptomatology was not statistically differentiable with respect to

study medication group.

170
TABLE 7

Subject Distribution of Average Symptom Severity Score During First 60 Days

of Study Medication and Overall with Summary of 2 x 2 X2

Analysis of Symptom Incidence

Includes All Subjects Having At Least Four Readings

Symptom Severity Interval

Alex Bradford, M.S. Oksana Golondzowski

Frank L. Hurley, Ph.D. Catharine Dorrier

AUTHORS

Biometric Research Institute, Inc.

Washington, D.C.

171
Time Topic or Title

SUNDAY

JUNE 6

(8:30-10:30 a.m.)

SESSION I: Naltrexone -

Current Status of Federal

Research and FDA Regulations

8:30-9:00 NIDA's Naltrexone Research Program

9:00-9:20

9:20-9:40

9:40-10:00

10:00-10:20

10:20-10:30

10:30-10:50

- Agenda -

Satellite Conference on Naltrexone

In Conjunction with the

38th Annual Scientific Meeting

Committee on Problems of Drug

Dependence

Richmond Hyatt House

Richmond, Virginia

June 6 7, 1976

Requirements for Drug Development

Preclinical Toxicity Studies of

Naltrexone

The Effects of Naltrexone in the

Chronic Spinal Dog and Acute

Spinal Cat; Possible Interaction

with Naturally-occurring Morphinelike Agonists

The Development of Sustained Action

Preparations of Narcotic Antagonists

Open Discussion

BREAK (Coffee)

(10:50-12:30 p.m.) SESSION II: The NAS CENA Studies

10:50-11:10 Evolution of the National

Academy of Sciences Study of

Naltrexone

11:10-11:30 Philosophy and Status of the

NAS CENA Studies

11:30-11:50 Varying Clinical Contexts for

Administering Naltrexone

11:50-12:10 Patient Response to Naltrexone:

Issues of Acceptance, Treatment

Effects, and Frequency of Administration

Speaker

CHAIRMAN:

Demetrios A. Julius, M.D.

Demetrios A. Julius, M.D.

Edward C. Tocus, Ph.D.

Monique Braude, Ph.D.

William Martin, M.D.

Robert E. Willette, Ph.D.

CO-CHAIRMEN:

Alex Bradford, M.S.

Walter Ling, M.D.

Samuel Kaim, M.D.

Leo Hollister, M.D.

Marc Hurzeler, M.D.

Stephen Curran, M.A.

172
Time

12:10-12:30

12:30-2:05

(2:05-3:35 p.m.)

2:05-2:25

2:25-2:45

2:45-3:05

3:05-3:15

3:15-3:35

(3:35-5:15 p.m.)

3:35-3:55

3:55-4:15

4:15-4:35

4:35-4:55

4:55-5:15

(7:30-10:00 p.m.)

7:30-9:00

9:00-10:00

Topic or Title Speaker

Open Discussion

BREAK

SESSION III: The NAS CENA Studies

(Continued)

Naltrexone in Methadone Maintenance Patients Electing to Become

'Drug Free'

CHAIRMAN:

Walter Ling, M.D.

Neil Haas, M.D.

Comments and Findings from a

Naltrexone Double Blind Study

John Keegan, M.A.

Factors Influencing Success

in an Antagonist Treatment Program James Crawford, M.A.

Open Discussion

BREAK (Coffee)

SESSION IV: The NIDA Clinical

Studies

Clinical Experience with

Naltrexone in 370 Detoxified

Addicts

Narcotic Antagonist Treatment

of the Criminal Justice PatientInstitutional vs. Outpatient -

Including a 24-Hour Detox Naltrexone

Induction Regimen with Oral Medication

Use of Narcotic Antagonists

(Naltrexone) in an Addiction

Treatment Program

An Analysis of Naltrexone Use--Its

Efficacy, Safety and Potential

Open Discussion

BREAK

SESSION V: Current Assessment of

Naltrexone's Safety

Interim Report on Clinic Intake and

Safety Data Collected from 17 NIDAFunded Naltrexone Studies

Open Discussion: Is Naltrexone Safe

for Use in Heroin Addicts

CO-CHAIRMEN

Demetrios A. Julius, M.D.

Alex Bradford, M.S.

Muriel Thomas, R.N.

Leonard Brahen, M.D.

David Lewis, M.D.

Ralph Landsberg, D.O.

CO-CHAIRMEN:

Walter Ling, M.D.

Alex Bradford, M.S.

Alex Bradford, M.S.

173
Time

MONDAY

JUNE 7

(7:00-10:30 p.m.)

7:00-7:20

7:20-7:40

7:40-8:00

8:00-8:20

8:20-8:30

8:30-10:30 p.m.)

8:30-8:50

8:50-9:10

9:10-9:30

9:30-10:30

Topic or Title Speaker

SESSION VI: The NIDA Behavioral CHAIRMAN:

Studies Abraham Wikler, M.D.

The Theoretical Basis of Narcotic Abraham Wikler, M.D.

Addiction Treatment with Narcotic

Antagonists

Limitations of an Extinction

Approach to Narcotic Antagonist

Treatment

Roger E. Meyer, M.D.

Naltrexone in a Behavioral Treatment Program

Charles O'Brien, M.D.

Comparison of Two Naltrexone Treat- Edward J. Callahan, Ph.D.

ment Programs: Naltrexone Alone Versus

Naltrexone plus Behavior Therapy

BREAK (Coffee)

SESSION VII: The Use of Naltrexone

in Treatment of Heroin Addiction

Naltrexone in the Management of

Heroin Addiction: Critique of the

Rationale

Clinical Experience with Naltrexone

in a Behavioral Research Study

Clinical Efficacy of Naltrexone:

A One Year Follow-Up

Open Discussion: Use of Naltrexone

in Treatment of Heroin Addiction

CO-CHAIRMEN:

Walter Ling, M.D.

Alex Bradford, M.S.

Avram Goldstein, M.D.

Robert Greenstein, M.D.

Richard Resnick, M.D.

174
The current naltrexone research program has been supported by the National Institute on

Drug Abuse under the following contracts and grants.

Samuel C. Kaim, M.D. SAODAP Contract DA 3AC694

NIDA Contract 271-76-3301

Marc Hurzeler, M.D. NIDA Contract HSM-42-72-3301

Neil Haas, M.D. SAODAP Grant DA 4PG 023

Walter Ling, M.D.

Kenneth Schoof, M.D. NIDA Contract HSM 42-73-255

John Keegan, M.A.

Sadashiv Parwatikar, M.D. NIDA Contract HSM 42-72-116

Richard B. Resnick, M.D. NIDA Contract HSM 42-73-258

Leonard Brahen, Ph.D., M.D. NIDA Contract HSM 42-72-210

NIDA Grant DA 01259

David Lewis, M.D. NIDA Contract HSM 42-73-264

Ralph Landsberg, D.O. NIDA Contract HSM 42-73-259

Charles Savage, M.D. NIDA Grant DA 00415

Stephen Curran, M.A.

Roger E. Meyer, M.D. NIDA Grant DA 00257

Charles P. O'Brien, M.D., Ph.D. NIDA Contract HSM 42-73-225

Robert Greenstein, M.D. NIDA Grant DA 01218

Alex Bradford, M.S. NIDA Contract 271-75-3050

175
NALTREXONE

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naltrexone reduction products and quantitative assay of urine and bile following administration of naltrexone, alpha-naltrexol, or

beta-naltrexol. Res. Corn. Ckem. Pathol.

Pharmacol., 12:43-65, 1975.

Martin, W.R.; Jasinski, D.R.; Mansky, P.A.:

Characteristics of the blocking effects of

EN-1639A (N-cyclopropylmethyl-7, 8-dihydro14-hydroxynomorphinone HCl). Presented to

Committee on Problems of Drug Dependence,

National Research Council, Toronto, 1971.

Martin, W.R.; Jasinski, D.R.: Characterization of EN-1639A. Clin. Pharm. Therap.,

14:142, 1973.

Martin, W.R.; Jasinski, D.R.; Mansky, P.A.:

Naltrexone, an antagonist for the treatment

of heroin dependence effects in man. Arch.

Gen. Psychiat., 28:784-791, 1973.

Martin, W.R.: Realistic Goals for antagonist

therapy. Amer. J. Drug & Ale. Abuse, 2:353-

356, 1975.

Meyer, R.E.; Mirin, S.M.; Altman, J.;

McNamee, H.B.: A behavioral paradigm for the

evaluation of narcotic antagonists. Arch.

Gen. Psychiat 33:371-377, 1976.

O'Brien, C.P.; Greenstein, R.A.; Mintz, J.;

Woody, G.E.: Clinical experience with naltrexone. Amer. J. Drug & Alc. Abuse, 2:365-

377, 1975.

Pollock, S.H.; Fujimoto, J.M.: A partial

characterization of naloxone and naltrexone6-ketone reductase in rabbit and chicken.

Pharmacologist, 16:225, 1974.

Resnick, R.; Schuyten, E.; Kestenbaum, R.;

Volavka, J.; Freedman, A.M.: Narcotic antagonists and methadone maintenance: comparative aspects of two treatment modalities.

Presented to National Conference on Drug

Abuse, Chicago, March, 1974.

Resnick, R.; Volavka, J.; Freedman, A.M.;

Thomas, M.: Studies of EN-1639A (naltrexone):

a new narcotic antagonist. Amer. J. Psychiat.,

131:646-650, 1974.

Resnick, R.; Volavka, J.; Freedman, A.M.:

Short-term effects of naltrexone: a progress

report. Proceedings of the Committee on Problems of Drug Dependence of the National

Academy of Sciences, pp. 250-263, 1974.

Resnick, R.; Volavka, J.; Gaztanaga, P.;

Freedman, A.M.: Clinical pharmacology of

naltrexone. Presented to 9th Congress of the

Collegium Internationale Neuropsychopharmacologicum, Paris, July, 1974.

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Reuning, R.; Malspeis, L.; Staubus, A.E.;

Bathala, M.; Luddew, T.: Application of naltrexone pharmacokinetics: importance of

design, metabolic profile, assay specificity

and kinetic analysis. Presented to Third

National Drug Abuse Conference, New York,

March, 1976.

Schecter, A.J.; Grossman, B.A.: Experience

with naltrexone: a suggested role in drug

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in the Field of Drug Abuse, (Senay, E.;

Shorty V.; Alslene. H., eds.). Schenkman

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1974, p. 754.

Schecter, A.: Clinical use of naltrexone

(EN-1639A). Part II: Experience with the

first 50 patients in a New York City treatment clinic. Amer. J. Drug & Alc. Abuse,

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Schecter, A.; Kanders, F.: Patient deaths in

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Abuse, 2:443-449, 1975.

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M.; D'Amanda, C.; Greenwood, J.: Experiences

with naltrexone in Buffalo. Amer. J. Drug &

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gas-liquid chromatography. Pharmacologist,

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Rosenthal, D.: Isolation and identification

of a new metabolite of naltrexone in human

blood and urine. Res. Corn. Chem. Pathol.

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S.J.: Quantitative determination of naltrexone and beta-naltrexol in human plasma using

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R.B.: Naltrexone in man: disposition and

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Freedman, A.M.: EEG and behavioral effects

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178

monograph series

Following is a list of the current monographs

available in the Research Monograph series:

1 5

Young Men and Drugs: A Nationwide Survey

Author: John A. O'Donnell. Ph.D. et al.

Report of a national survey of drug use by men

20-30 years in 1974-5. pp. 144

Findings of Drug Abuse Research

An annotated bibliography of NIMH and NIDAsupported extramural grant research 1967-74

Volume 1 - pp. 384; Volume 2 - pp. 377

2

Operational Definitions in Socio-behavioral

Drug Use Research 1975

Editors: Jack Elinson, Ph.D. and David Nurco, Ph.D.

Task Force articles proposing consensual definitions of concepts and terms used in psychosocial research to achieve operational comparability. pp. 167

3

Aminergic Hypotheses of Behavior:

Reality or Cliche?

Editor: Bruce J. Bernard, Ph.D.

Articles examining the relation of the brain

monoamines to a range of animal and human

behaviors. pp. 149

4

Narcotic Antagonists: The Search for LongActing Preparations

Editor: Robert Willette, Ph.D.

Articles reporting current alternative inserted

sustained-release or long-acting drug devices.

pp. 45

6

Effects of Labeling the "Drug-Abuser"- An Inquiry

Author: Jay R. Williams, Ph.D.

Analysis and review of the literature examining

effects of drug use apprehension or arrest on

the adolescent. pp. 39

7

Cannabinoid Assays in Humans

Editor: Robert Willette, Ph.D.

Articles describing current developments in

methods for measuring cannabinoid levels in

the human body by imnunoassay, liquid and

dual column chromatography and mass spectroscopy techniques. pp. 120

8

Rx 3 times/wk LAAM - Methadone Alternative

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

Comprehensive summary of development of LAAM

(levo-alpha-acetyl methodol), a new drug for

treatment of narcotic addiction. pp. 127

180
Monograph

1

2

3

4

5

6

7

8

All monographs can be ordered from either

the U.S. Government Printing Office (GPO)

or from the National Technical Information

Service (NTIS).

Following is the ordering information for

both sources:

GPO NTIS

Superintendent of Documents National Technical Information Service

U.S. Government Printing Office U.S. Department of Commerce

Washington, D.C. 20402 Springfield, Virginia 22161

Vol. 1: Stock #017-024-0467 @ $7.00

Vol. 2: Stock #017-024-0466-9 @ $5.05

not available

Stock #017-024-0048-4-7 PB #246 338

@ $2.50 papercopy: $6.75; microfiche: $2.25

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181