National Institute on Drug Abuse

RESEARCH

MONOGRAPH SERIES

Buprenorphine:

An Alternative

Treatment for

Opioid

Dependence

U.S. Department of Health and Human Services • Public Health Service • National Institutes of Health

121
Buprenorphine: An

Alternative Treatment

for Opioid Dependence

Editor:

Jack D. Blaine, Ph.D.

Research Monograph 121

1992

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES

Public Health Service

Alcohol, Drug Abuse, and Mental Health Administration

National Institute on Drug Abuse

5600 Fishers Lane

Rockville, MD 20857
ACKNOWLEDGMENT

This monograph is based on the papers and discussions from a technical

review on "Buprenorphine: An Alternative Treatment for Opioid Dependence”

held on March 16-17, 1989, in Rockville, MD. The technical review was

sponsored by the National Institute on Drug Abuse (NIDA).

COPYRIGHT STATUS

The National Institute on Drug Abuse has obtained permission from the

copyright holders to reproduce certain previously published material as noted in

the text. Further reproduction of this copyrighted material is permitted only as

part of a reprinting of the entire publication or chapter. For any other use, the

copyright holder’s permission is required. All other material in this volume

except quoted passages from copyrighted sources is in the public domain and

may be used or reproduced without permission from the Institute or the authors.

Citation of the source is appreciated.

Opinions expressed in this volume are those of the authors and do not

necessarily reflect the opinions or official policy of the National Institute on Drug

Abuse or any other part of the U.S. Department of Health and Human Services.

The U.S. Government does not endorse or favor any specific commercial

product or company. Trade, proprietary, or company names appearing in this

publication are used only because they are considered essential in the context

of the studies reported herein.

NIDA Research Monographs are indexed in the "Index Medicus.” They are

selectively included in the coverage of “American Statistics Index,” "BioSciences

Information Service,” “Chemical Abstracts,” “Current Contents,” “Psychological

Abstracts,” and “Psychopharmacology Abstracts.”

DHHS publication number (ADM)92-1912

Printed 1992

ii
Contents

Page

Introduction

Jack O. Blaine

1

Buprenorphine-Background to Its Development

as a Treatment for Opiate Dependence 5

John W. Lewis and Donald Walter

Behavioral Pharmacology of Buprenorphine: Issues Relevant

to Its Potential in Treating Drug Abuse 12

James H. Woods, Charles P. France, and Gail D. Winger

Assessment of Buprenorphine in a Drug Discrimination

Procedure in Humans 28

George E. Bigelow and Kenzie L. Preston

Human Laboratory Studies of Buprenorphine 38

Jack H. Menedelson and Nancy K. Mello

Primate Studies of the Behavioral Pharmacology

of Buprenorphine 61

Nancy K. Mello and Jack H. Mendelson

Phase II Clinical Trials of Buprenorphine: Detoxification and

Induction Onto Naltrexone 101

Thomas R. Kosten, Charles Morgan, and Herbert D. Kleber

iii
Development of Buprenophine for the Treatment of Opioid

Dependence 120

Rolley E. Johnson and Paul J. Fudala

List of NIDA Research Monographs 142

iv
Introduction

Jack D. Blaine

Buprenorphine is a partial μ-opioid agonist and -antagonist marketed in the

United States as an injectable analgesic by Reckitt & Colman Pharmaceutical

Division. Recent studies performed in large part by the National Institute on

Drug Abuse (NIDA) Addiction Research Center and by NIDA grantees indicate

that buprenorphine possesses an interesting and unique mixed partial μagonist-antagonist profile, which should make it useful therapeutically for

detoxification and maintenance treatment of heroin- and methadone-dependent

persons. Thus, buprenorphine combines the characteristics of methadone and

naltrexone, having both agonist and antagonist actions depending on the

circumstances of its use. Buprenorphine potentially has important clinical

significance because it offers the possibility of being acceptable to opiateabusing patients seeking treatment; it decreases their heroin use, has a better

safety profile than pure agonists (e.g., methadone), and does not produce a

clinically significant level of physical dependence; thus, discontinuation from

buprenorphine is easier than detoxification from methadone.

Buprenorphine from the scientific viewpoint illustrates the potential promise

offered by various novel opioid compounds that were developed following

recent advances in understanding the neuropharmacology of opioids. In

humans, buprenorphine has less intrinsic agonist activity than morphine and

should have a low abuse potential compared with other opioid agonists. In

the initial and limited clinical studies, buprenorphine treatment by the sublingual

route appears to be acceptable to narcotic addicts. These clinical studies

demonstrate that buprenorphine can be substituted for reasonable doses of

heroin or methadone in dependent persons and can be subsequently withdrawn

without undue discomfort and with excellent safety. Therefore, buprenorphine

appears to be a promising alternative to the currently available treatments for

opioid dependence. More recently, scientists have also been exploring its

potential for the treatment of cocaine addiction.

NIDA is the Federal agency with primary responsibility for research on the

health effects of abused drugs, the nature of the addictive process, and the

effects of drugs on our society. NIDA’s research enhances the effectiveness

1
of drug abuse treatment and prevention efforts by expanding the knowledge

resources on which these efforts are based. After careful review and priority

setting, NIDA concentrates its research resources on areas of drug abuse that

most seriously challenge the Nation’s public health. In line with this research

direction, a NIDA technical review meeting was held March 16-17, 1989, in

Rockville, MD, sponsored by the Treatment Research Branch of the Division of

Clinical Research, NIDA.

The NIDA research monograph series, including this one published by the

Institute’s Community and Professional Education Branch, is an established

vehicle for dissemination of scientific information in the drug abuse field.

Geared to researchers, the series is designed to cover the full range of basic,

applied, and developmental research supported by NIDA. The monographs

constitute an essential step in the process of developing and carrying forward

NIDA’s research objectives.

This publication seeks to gather together most of what is known about

buprenorphine-its metabolism and kinetics, clinical efficacy and safety,

behavioral pharmacology, and effects in animals and humans. There are

considerable data from clinical and animal studies to demonstrate the acute

safety of the drug when used as an analgesic. Clinical studies reviewed in

this monograph as well as others conducted since the technical review indicate

that buprenorphine shows promise as a treatment for heroin addiction.

One of the major advantages of using buprenorphine as a treatment drug is

that addicts are willing to take it. Buprenorphine is somewhat reinforcing but

does not produce the “rush” effect so familiar to opiate addicts. A daily

sublingual dose of 8 mg has been shown to be effective in suppressing

heroin self-administration and does not produce clinically significant physical

dependence based on the mild nature of abstinence symptoms noted after

abrupt discontinuation of the medication. Buprenorphine appears to be a

safe drug; the potential for lethal overdose is remote even at 10 times the

therapeutic dose. That it may be administered sublingually removes

association with injection apparatus, which in itself may be reinforcing to

some intravenous drug users. Finally, buprenorphine may even have an

effect on cocaine as well as heroin self-administration. This is especially

important since many serious heroin addicts use both heroin and cocaine

when available.

However, there are problems yet to be solved. One of these is the formulation

of the drug for a practical treatment regimen. Buprenorphine has low

bioavailability when administered orally. The preferred route of administration

is sublingual, but this presents problems for take-home medication programs

2
because the sublingual formulation would be vulnerable to diversion and

abuse by injection. However, if the product is not available for home dosing,

its usefulness for long-term maintenance is limited. Some creative solutions

have been proposed for the problem in Lewis and Walter’s chapter, such as

incorporating naloxone or naltrexone, both of which have low bioavailability

sublingually but would antagonize the effect of the agonist if the capsule were

dissolved and injected. Combination formulations would not discourage use

by nondependent opiate users or subjects maintained on buprenorphine but

would contain sufficient antagonist to precipitate the abstinence syndrome in

an opiate-dependent individual if the buprenorphine-antagonist combination

product were injected. Lewis and Walter also believe that combination products

could be made less attractive to nondependent users if sufficient naltrexone

were present to attenuate the agonist effects of buprenorphine.

The abuse potential of any treatment drug must be balanced against its

safety and efficacy relative to other pharmacotherapies currently available.

Considering all the data currently available, it would appear that buprenorphine

is a promising treatment drug for opiate addiction and may even be useful

when that addiction is combined with occasional-to-frequent cocaine use.

Buprenorphine appears to be as effective as methadone for detoxification of

heroin addicts but does not induce significant physical dependence in humans

and can be discontinued without severe withdrawal symptoms.

Although some preliminary studies seem to indicate that buprenorphine has a

modulating, therapeutic effect on cocaine usage, contradictory data have also

been reported recently. NIDA must evaluate, in larger, well-controlled clinical

trials, how buprenorphine affects the practice of speedballing (intravenous use

of heroin combined with cocaine), methadone plus cocaine usage, and solo

cocaine usage in various forms and with varying frequencies.

Since this technical review, several buprenorphine-methadone comparison

trials have been completed by Dr. Thomas Kosten and Dr. Rolley E. Johnson,

and Dr. Walter Ling is conducting another. Drs. George Bigelow and Jack

Mendelson have also continued their studies of buprenorphine. NIDA is, at the

time of this writing, almost ready to undertake a large, multicenter clinical trial of

sublingual buprenorphine at 12 sites, assessing four doses of the drug (1,4,8,

and 16 mg) in 480 to 720 street heroin addicts. This will be a 16-week safety

and efficacy study. NIDA hopes to use the results as a final pivotal study

toward a buprenorphine new drug application.

NIDA views buprenotphine as a safer, more acceptable maintenance or

detoxification option for many opiate-dependent addicts. It also envisions

3
buprenorphine as an intermediary drug (i.e., between methadone and being

drug-free) for those patients who wish detoxification from methadone.

The Institute is preparing a buprenorphine combination product, incorporating

the antagonist naloxone. NIDA expects that this preparation will be ready by

fall 1992 and will be tested in clinical trials with a view toward take-home

dosing.

Although buprenorphine appears to be a bright new tool in the treatment of

heroin addiction, it is important to refrain from viewing it as a chemical panacea.

Drug addiction has multiple causes and is a complicated disorder. NIDA

anticipates that buprenorphine and its successor pharmacotherapies will

attenuate drug addiction, but it is unlikely that any single drug will eliminate it.

AUTHOR

Jack D. Blaine, M.D.

Chief

Treatment Research Branch

Division of Clinical Research

National Institute on Drug Abuse

Parklawn Building, Room 10A5600 Fishers Lane

Rockville, MD 20857

4
Buprenorphine—Background to Its

Development as a Treatment for Opiate

Dependence

John W. Lewis and Donald Walter

INTRODUCTION

Buprenorphine was developed by Reckitt & Colman Products as an analgesic

following the interest generated in the mixed agonist-antagonist class of

opioids. These were seen as offering clinically useful analgesia with greater

safety and lower liability to abuse than the opiate agonists (Lewis 1982).

Buprenorphine is now known to be a partial agonist at p-receptors and

an antagonist at -receptors (Leander 1988). At these receptor subtypes,

it has high and almost equal affinity. The kinetics of buprenorphine’s

opiate-receptor interactions are slow, giving it a very long duration of action.

This can be related to the results of direct dependence studies in animals and

humans, when naloxone failed to precipitate abstinence and abrupt withdrawal

produced only mild and often delayed effects (Lewis et al. 1988).

These characteristics, though not fully established at the time, suggested

to D.R. Jasinski that buprenorphine could be a useful treatment for opiate

dependence because it had some of the characteristics of methadone and

other characteristics more akin to the pure opiate antagonist naltrexone. In

their definitive study, Jasinski and colleagues (1978) confirmed the above

characteristics and in addition showed that buprenorphine produced a limited

level of morphine-like subjective effects that made it acceptable to addicts

and on repeated administration blocked the effects of large single doses of

morphine for at least 24 hours.

Thus, the potential utility of buprenorphine in the treatment of opiate

dependence has been recognized for more than 10 years, and clinical studies

to evaluate this potential have been undertaken during this period. Most of the

significant studies are reviewed in this volume. This chapter discusses (1) the

potential contribution of the package of data assembled for the registration of

buprenorphine as an analgesic to the obtaining of a new drug application for

5
the drug as a treatment for opiate dependence; (2) human pharmacokinetic

studies with the analgesic product; and (3) the formulation of buprenorphine

for detoxification and maintenance indications.

REGULATORY STATUS

In many countries, buprenorphine is approved as an analgesic for injection (0.3

mg) and sublingual (0.2-mg tablet) use. Buprenorphine was first marketed in

the United Kingdom in 1978 for injection and was marketed in 1981 and 1982

as a sublingual tablet. In the United States, only the injection is available; the

ampule was launched in 1986. Buprenorphine is controlled internationally in

Schedule Ill of the Psychotropic Convention of 1989. In the United States, it

is listed in Schedule V of the Controlled Substances Act, with a narcotic drug

designation.

PACKAGE OF SAFETY DATA

Preclinical Safety

Buprenorphine has a full preclinical safety package that comprises data on

chronic toxicity in four species and from acute toxicity and mutagenicity studies,

carcinogenicity studies in two species, and a full range of reproduction studies

in two species. Absorption, distribution, metabolism, and excretion studies have

been carried out in five animal species.

Clinical Safety

A comprehensive number of clinical studies have been carried out to determine

the safety and analgesic efficacy of buprenorphine by the sublingual route, with

data available from more than 10,000 patients. The majority of these patients

received doses of up to 1.2 mg per day; however, approximately 1,200 patients

have received doses greater than 1.2 mg per day, with more than 200 of these

receiving sublingual buprenorphine for periods greater than 1 month.

HUMAN PHARMACOKINETICS

Buprenorphine is a very potent drug, and only low doses are needed in the

treatment of pain. A consequence of this is that blood levels of the drug are

also low and difficult to assay. Most of the human pharmacokinetic studies

have been carried out using a sensitive radioimmunoassay (RIA) (Bartlett et al.

1980); however, the antibody used in the assay cross-reacts to the N-dealkyl

metabolite. A method in which buprenorphine is extracted prior to RIA (Hand

et al. 1986) has proved difficult to validate. Soon after dosing, most of the

6
immunoreactivity in plasma is buprenorphine, whereas later, a mixture of

buprenorphine and metabolites is present. These observations should be

taken into account when pharmacokinetic data are interpreted.

Oral

Early clinical studies showed that, as in animal studies, orally administered

buprenorphine was extensively metabolized by the intestine and liver during

its absorption. The low oral bioavailability makes this route of administration

impractical and costly. Three other routes of administration have been studied

in detail: intravenous (IV), intramuscular (IM), and sublingual.

Intravenous

Buprenorphine is readily distributed into tissues, giving a large volume of

distribution of the order of 10 L/kg. The elimination profile is multiexponential

(Bullingham et al. 1980, 1982) but can be simplified as a rapid distribution

phase (T1/2 2 minutes) and a slower elimination phase with a plasma half-life

of 3 to 5 hours. A further very slow phase of elimination of immunoreactivity

(t1/2>24 hours) is apparent from studies using longer observation periods.

Buprenorphine is cleared from plasma predominantly by biliary excretion

following conjugation with glucuronic acid or Ndealkylation and conjugation.

A small amount of drug and metabolites is cleared slowly by the kidney (Cone

et al. 1984). Some enterohepatic circulation of drug and metabolite occurs,

and this, coupled with the slow urinary excretion, probably accounts for the

protracted terminal elimination phase.

Intramuscular

Buprenorphine is rapidly absorbed by the IM route (Tmax=5-15 minutes), and

the bioavailability is good, ranging between 40 and 90 percent relative to an IV

dose (Bullingham et al. 1980). The elimination profile is similar to that following

IV administration, comprising two elimination phases.

Sublingual

The rate of absorption of buprenorphine is slower by the sublingual route, giving

a mean Tmax at approximately 200 minutes. Sublingual bioavailability is of the

order of 55 percent (range 16 to 94 percent) (Bullingham et al. 1982). Other

studies indicate good dose proportionality over the analgesic dose range, but

no data are available for the higher sublingual doses used in the treatment of

opioid dependence. The elimination profile is similar to that observed for the

other routes, comprising two phases of elimination of immunoreactivity, with

plasma half-lives of 3 to 5 hours and >24 hours.

7
Following three-timesdaily chronic sublingual dosing of 0.4 mg, steady-state

levels of buprenorphine were achieved at about 4 days. The elimination profile

following chronic dosing was similar to that following a single dose.

A study of the excretion of buprenorphine and its metabolites following 1

and 2 mg of sublingual buprenorphine showed that buprenorphine was

excreted predominantly via the feces, whereas a small amount of conjugated

buprenorphine and N-dealkyl buprenorphine and its conjugate were slowly

excreted via the urine (Cone et al. 1984).

FORMULATION

For a product to be used in the treatment of addiction, an oral dosage form

is preferred over parenteral unless the “injection” is in depot form requiring

infrequent administration. Buprenorphine has good sublingual bioavailability

but poor availability by the oral route. In the analgesic dose range, 10 mg of

IM morphine is equivalent to 0.4 to 0.6 mg buprenorphine sublingually and to

2 to 3 mg orally. From the studies of Jasinski and colleagues (1978), Johnson

and Fudala (this volume), and Bigelow and Preston (this volume), it can now

be estimated that for treatment of opiate dependence, approximately 4 mg

of sublingual buprenorphine is the equivalent of a daily dose of 40 mg of

oral methadone. The equivalent oral dose of buprenorphine (about 20 mg)

would have an adverse effect on the daily cost of treatment. Moreover, the

considerable amount of clinical safety data available from sublingual analgesic

studies makes sublingual the route of choice for the addiction-treatment

product. Most of the reported clinical studies of opioiddependent subjects

have used this route.

The problem with use of the sublingual route for a treatment product is that the

drug, for it to be absorbed, must be readily soluble in water. This means that

an insoluble, sublingual formulation designed to be noninjectable also would

not be absorbed. Thus, a sublingual buprenorphine product given as takehome medication in maintenance programs would be vulnerable to diversion

and abuse by injection. Such diversion would negate a major objective of the

proposed development of buprenorphine: the reduction of IV drug abuse and

the spread of acquired immunodeficiency syndrome.

Of course there will be no problem if the product is not available for take-home

use. A product used for detoxification and maintenance for up to 3 months

can be administered daily at the drug treatment clinic. To ensure that such a

product is rapidly absorbed by the intended route (not swallowed) and cannot

be sequestered in the mouth, a solution of buprenorphine is the preferred

presentation.

8
The limitation imposed by disallowing a take-home product would not be

practicable for maintenance because nearly all methadone programs allow

take-home after 3 months of satisfactory participation. A buprenorphine

maintenance product would have to be either protected against diversion in

the take-home situation or presented at a dose level and in a formulation that

would allow three-times-a-week dosing similar to that used for naltrexone. This

would require a product with a 48- to 72-hour duration. Data obtained at the

Addiction Research Center on every-other-day dosing do not encourage the

belief that sublingual buprenorphine at reasonable doses possesses sufficient

duration of opiate-blocking effect for such a regime to be viable.

At present the only available method of protecting against diversion of takehome sublingual buprenorphine is the incorporation of a pure antagonist, either

naloxone or naltrexone. Several products incorporating naloxone (but not

naltrexone) into oral formulations of opiates have been developed, including a

methadone-maintenance product (Gordon et al. 1974). The rationale for these

products is that naloxone has very low oral bioavailability, considerably lower

than that of the oral opiates. Thus, an amount of naloxone can be introduced

into the opiate preparations that will have no effect when taken orally but will

antagonize the effect of the opiate if the oral product is dissolved in water and

injected.

Combinations of buprenorphine with naloxone for analgesic use by injection

and as a sublingual tablet have been developed (Reckitt & Colman Products).

The principle behind the injection product is that in nontolerant/nondependent

patients the combination behaves like buprenorphine, with very little attenuation

of the agonist effect due to the very different pharmacokinetics and kinetics of

the drug-receptor interaction of the two drugs. In tolerant/dependent subjects,

the combination behaves like naloxone, and abstinence is precipitated.

Thus, diversion in a population of dependent opiate users would be strongly

discouraged. The sublingual combination of buprenorphine and naloxone also

benefits from the superior sublingual bioavailability of buprenorphine over

naloxone in a manner similar to that of the oral naloxone combinations.

The analgesic combinations are:

Injection: buprenorphine 0.3 mg+naloxone 0.2 mg

Sublingual: buprenorphine 0.2 mg+naloxone 0.2 mg

Combinations with these ratios would not discourage injection by nontolerant/

nondependent opiate users or by subjects maintained on buprenorphine and, in

this regard, would be unsatisfactory as maintenance products. To be injectionproof, a combination product would need to contain sufficient antagonist to

9
attenuate substantially the agonist effect of buprenorphine when injected. The

agonist effect by sublingual administration would be largely dependent on the

superior sublingual bioavailability of buprenorphine over the antagonist.

Naltrexone, which is approved for maintenance as an oral product, is preferred

to naloxone for incorporation into a sublingual buprenorphine product for takehome use. Its duration of action is significantly longer than that of natoxone,

more evenly matching that of buprenorphine. Naloxone’s short duration of

action means that, even if present in substantial dose in the combination, it

would only delay the onset of buprenorphine’s agonist effects.

Because naltrexone is more potent than naloxone, it is estimated that the

ratio of sublingual naltrexone to buprenorphine to prevent injection by opiatedependent abusers is between 1:6 and 1:4. To be injection-proof, the

proportion of naltrexone would need to be increased to between 1:2 and

1:1. Assuming a unit dose of buprenorphine between 4 and 8 mg, the

naltrexone present (minimum of 1 mg, for example) is likely also to precipitate

abstinence in opiate-dependent subjects by the sublingual route. As a result,

such a product could not be used for detoxification, since transfer to it from

a state of dependence on street opiates or methadone would be extremely

uncomfortable. The procedure would therefore be to stabilize subjects on the

buprenorphine-alone detoxification product before transfer to the combination.

The buprenorphine/naltrexone combination product, which for convenience

could be a sublingual tablet, should permit greater flexibility in the use of

naltrexone as an opiate-blocking drug because transfer between the

combination and the antagonist in both directions should be readily achieved.

CONCLUSION

Development of buprenorphine for the treatment of opiate addiction should be

directed to a sublingual buprenorphine-alone product for detoxification/shortterm maintenance, for which a considerable amount of supporting clinical safety

data from analgesic studies is available. To prevent diversion and injection of

a sublingual buprenorphine maintenance product, incorporation of naltrexone

should be explored.

REFERENCES

Bartlett, A.J.; Lloyd-Jones, J.G.; Rance, M.J.; Flockhart, I.R.; Dockray, G.J.;

Bennett, M.R.D.; and Moore, R.A. The radioimmunoassay of buprenorphine.

Eur J Clin Pharmacol 18:339-345,1980.

1 0
Bullingham, R.E.S.; McQuay, H.J.; Moore, A.; and Bennett, M.R.D.

Buprenorphine kinetics. Clin Pharmacol Ther 28:667-672, 1980.

Bullingham, R.E.S.; McQuay, H.J.; Porter, E.J.B.; Allen, M.C.; and Moore,

R.A. Sublingual buprenorphine used postoperatively: Ten hour plasma

drug concentration analysis. Br J Clin Pharmacol 13:665-673, 1982.

Cone, E.J.; Gorodetzky, C.W.; Yousefrejad, D.; Buchwald, W.F.; and Johnson,

R.E. The metabolism and excretion of buprenorphine in humans. Drug

Metab Dispos 12:557-581,1984.

Gordon, M.; Pircio, A.W.; Caruso, F.S.; and Pachter, I.J. Approaches to the

problem of opiate abuse. In: Report of 36th Annual Scientific Meeting,

Committee on Problems of Drug Dependence, 1974. National Academy of

Sciences, National Academy of Engineering, and National Research Council.

ISBN No. 0-309-02244-4. Washington, DC: National Academy of Sciences,

1974. pp. 498-513.

Hand, C.W.; Baldwin, D.; Moore, R.A.; Allen, M.C.; and McQuay, H.J.

Radioimmunoassay of buprenorphine with iodine label: Analysis of

buprenorphine and metabolites in human plasma. Ann Clin Biochem

23:47-53,1986.

Jasinski, D.R.; Pevnick, J.S.; and Griffith, J.D. Human pharmacology and

abuse potential of the analgesic buprenorphine. Arch Gen Psychiatry

35:501-516,1978.

Leander, J.D. Buprenorphine is a potent K-opioid receptor antagonist in

pigeons and mice. Eur J Phamracol 151:457-461,1988.

Lewis, J. The antagonist analgesic concept. In: Glatt, M.M., and Marks, J.,

eds. The Dependence Phenomenon. Lancaster, England: MTP Press,

1982. pp. 81-102.

Lewis, J.W.; Rance, M.J.; and Sanger, D.J. The pharmacology and abuse

potential of buprenorphine: A new antagonist analgesic. Adv Subst Abuse

3:103-154,1983.

AUTHORS

John W. Lewis, D.Phil.

Research Director

Donald Walter, Ph.D.

Program Manager—Buprenorphine

Reckitt & Colman Products

Dansom Lane

Kingston-upon-Hull HU8 7DS

UNITED KINGDOM

11
Behavioral Pharmacology of

Buprenorphine: Issues Relevant to

Its Potential in Treating Drug Abuse

James H. Woods, Charles P. France, and Gail D. Winger

INTRODUCTION

Buprenorphine is a partial opioid agonist that, because of its long duration

of antagonist action and unusual profile of agonist action, has considerable

promise for the treatment of narcotic drug abuse. This chapter reviews the

effects of buprenorphine in animal preparations that have been useful in

elucidating the mechanisms of action of opioid drugs and advances the

concept that buprenorphine activates p-type central receptors as a partial

agonist with noncompetitive actions. Evidence for this is drawn from in vitro

and in vivo preparations sensitive to a variety of opiate actions. This view of

buprenorphine’s central actions provides a conceptual framework for the

interpretation of its behavioral and physiological actions.

The effects of chronically administered buprenorphine, although critical when

the drug is considered in a treatment setting, unfortunately have not received

much experimental attention. It is hoped that the framework developed in this

chapter will anticipate some of the issues associated with buprenorphine’s

action during chronic administration. The actions of buprenorphine in a variety

of preparations are described, beginning with a consideration of its binding

characteristics and its actions in smooth-muscle preparations, progressing to a

consideration of its behavioral actions, including its ability to produce analgesia,

respiratory depression, discriminative stimulus (i.e., subjective) effects, and

reinforcing stimulus effects, and ending with its capacity to produce and alter

dependence.

BINDING CHARACTERISTICS

Opioids bind in the central nervous system to recognition sites that can be

differentiated into three major types: the so-called μ-receptors, -receptors,

and &receptors. Buprenorphine has been shown by a variety of investigators

12
to displace tritiated ligands that have selective affinities for each of the

three receptor types (Sadee et al. 1982). Many investigators, using in vitro

rhesus monkey brain techniques, have found that buprenorphine has no

marked selectivity for any of the three types of opiate receptor sites. The

authors’ work, carried out in vitro (F. Medzihradsky, unpublished observations),

suggests that buprenorphine has a slightly higher affinity at the μ-receptor

binding site as compared with that at the -binding site. Using in vivo receptor

binding techniques to examine opioid receptor types, Sadee and coworkers

(1982) found that at small doses buprenorphine has selective affinity in rat brain

for μ-receptor sites and at larger doses has affinity for other opioid receptor

sites. Richards and Sadee (1985) using in vivo receptor binding procedures in

rats, report that buprenorphine has similar affinity for μ- and -sites and less

affinity for sites.

Buprenorphine dissociates from opioid receptor binding sites very slowly

(Hambrook and Rance 1976). As will be seen later when buprenorphine’s in

vivo actions are considered, this facet of the drug’s action is extremely helpful

in interpreting some of the actions of buprenorphine that are quite novel in

comparison with other opioid p-partial agonists. Evidence for slow dissociation

is reported by Rance and Dickens (1978), who have found that the opioid

antagonist diprenorphine, if given prior to or at the same time as buprenorphine,

is far more effective in preventing buprenorphine’s attachment to opioid

receptors than if the antagonist is given after buprenorphine has had an

opportunity to attach to opioid receptor sites.

SMOOTH-MUSCLE PREPARATIONS

As do other opioid agonists, buprenorphine exerts an inhibitory action on

electrically stimulated smooth-muscle preparations that have opioid receptors.

Buprenorphine’s concentration-related inhibitory actions reach their maxima

relatively slowly and are not as complete as are those of prototypic opioid

agonists. This partial inhibitory effect is consistent with a partial agonist

action at opioid receptors, and it can be prevented by prior administration of

narcotic antagonists. There is evidence that buprenorphine exerts inhibitory

effects through actions on both μ- and -opioid receptors in various smoothmuscle preparations (Kajiwara et al. 1986). Once an inhibitory effect has been

obtained with buprenorphine, in contrast to that produced by most other opioid

agonists, it is resistant to reversal by narcotic antagonists or by washing; this

resistance is indicative of an irreversible phase of action on opioid receptors

(Schulz and Herz 1976).

13
ANALGESIA

Buprenorphine has complex analgesic actions that differ across analgesic

assays and species. Rance (1979) has reported that buprenorphine has

analgesic activity in the mouse writhing assay and the rat tail-pressure assay

but not in the rat tail-flick assay; buprenorphine acts as an antagonist of the

analgesic effect of morphine in the rat and mouse tail-flick assays. This pattern

of activity is not unlike other partial agonist opioid analgesics. Generally, in

assays that are sensitive to the effects of analgesics, that is, assays that

demonstrate analgesia following administration of relatively small doses of full

agonists, buprenorphine exerts maximum levels of analgesia. In less sensitive

assays, those requiring relatively large doses of full agonists to produce

analgesia, buprenorphine is less likely to have an analgesic action.

In some analgesic assays, buprenorphine produces peak analgesic action at

relatively small doses; at larger doses, the analgesic effect is attenuated (Rance

1979). This unusual inverted-U-shaped dose/effect curve of buprenorphine has

provoked much discussion and is most frequently thought to reflect some form

of autoinhibition. Rance and associates (1980) found that naloxone produced a

symmetrical rightward shift of both limbs of the buprenorphine dose/response

curve.

At small doses, lower than those at which it produces analgesia, buprenorphine

acts as antagonist of the analgesic actions of full opioid agonists. The authors

and other researchers have observed that it antagonizes the analgesia

produced by μ- and -agonists in a variety of species (Negus and Dykstra

1988; the authors, unpublished observations). The larger the dose, the longer

is the duration of antagonist action. Cowan and colleagues (1977) were the

first to point out that buprenorphine has a long duration of antagonist action

in comparison with other standard opioid antagonists. Under appropriate

conditions, buprenorphine can be used to produce a noncompetitive

antagonism of the analgesic actions of morphine. Tallarida and Cowan

(1992) capitalized on this noncompetitive antagonism of morphine to make

the first calculation of an association constant for morphine’s analgesic effect

in the rat.

In the rhesus monkey warm-water tail-withdrawal assay, a modification of

Dykstra and Woods (1986), it was found that buprenorphine produces a

temperature-dependent analgesia of modest magnitude compared with

that produced by full opioid analgesics of either the μ- or -type (Dykstra et

al. 1987). A comparison of alfentanil and buprenorphine analgesic effects is

shown in figure 1; it can be seen that, whereas alfentanil can produce a full

analgesic action at both 50 and 55 °C, buprenorphine produces an incomplete

14
FIGURE 1. Comparison of alfentanil (left) and buprenorphine (right) analgesic effects
analgesia at 50 °C and has no analgesic action at 55 °C. At 50 °C, one can

also see the inverted-U-shaped dose/response curve that was noted above

in rodents. Similar to what was shown by Rance and coworkers (1960) in

rodents, both the ascending and descending limbs of this curve are shifted to

a comparable extent to the right by prior administration of the opioid antagonist

quadazocine (figure 2).

Figure 3 demonstrates the antagonist effects of buprenotphine in analgesia

assays: Buprenorphine at a dose of 0.1 mg/kg produces a rightward shift in

the analgesia dose/effect curves for the μ-receptor agonist alfentanil and the

-receptor agonist U-50,466. Thus, buprenorphine’s antagonist actions are

clearly observed at μ- and -receptors.

In summary, the analgesic actions of buprenorphine are apparently quite

complex, depending as they do on the particular assay system, animal

species, and dose conditions used. It is necessary to use the concept of

μ-partial agonist with irreversible actions to account for this pattern of activity.

FIGURE 2. Buprenorphine analgesic effects after administration of

quadazocine

16
FIGURE 3. Antagonist effects of buprenorphine in analgesia assays
RESPIRATORY EFFECTS

Doxey and coworkers (1977) compared the effects of intra-arterial

buprenorphine and morphine on arterial pCO2, in conscious rats. Whereas

morphine produces a dose-related increase in pCO2, buprenorphine again

produces an inverted-U-shaped dose/effect curve with a maximum increment

of pCO2 much less than that produced by morphine. In rhesus monkeys,

the authors have compared buprenorphine to other partial agonists, such

as nalbuphine, with respect to the respiratory stimulation produced by

increasing concentrations of CO2. Compared with full agonists, such as

alfentanil, buprenorphine and nalbuphine have shallow dose/response curves

and produce limited suppression of respiration. Doses of nalbuphine and

buprenorphine that cause a modest decrement in CO2-stimulated respiration

act as antagonists of respiratory depression produced by alfentanil. Thus,

buprenorphine has a partial agonist action in respiratory systems similar to

that shown in other opioid-sensitive biological systems.

DISCRIMINATIVE STIMULUS EFFECTS

In animals trained to discriminate between the stimulus effects of μ-receptor

agonists, such as codeine or etorphine and saline, buprenorphine produces

a full μ-agonist-like action. This effect is attained with small doses of

buprenorphine in rats, pigeons, and primates. For example, in rhesus

monkeys trained to discriminate etorphine from saline, buprenorphine will

produce etorphine-appropriate responding in doses of 0.03 to 0.1 mg/kg

(Young et al. 1984). In pigeons trained to discriminate morphine from saline,

doses of naltrexone that prevent morphine from producing a discriminative

stimulus effect also prevent buprenorphine from producing morphineappropriate responding (figure 4). On the other hand, if buprenorphine is

allowed to produce its discriminative stimulus effect, naltrexone, even in

doses far above those necessary to reverse the discriminative stimulus

effects of morphine, fails to reverse this effect of buprenorphine. Thus, in

drug-discrimination assays, buprenorphine produces an irreversible p-agonist

action, just as it does in other behavioral assays such as analgesia (figure 5).

In pigeons, buprenorphine produces a discriminative stimulus effect that is

of strikingly long duration. A dose of 5.6 mg/kg evokes a morphine-like

discriminative effect for as long as 5 days (France et al. 1984).

REINFORCING STIMULUS EFFECTS

Rhesus monkeys, given the opportunity to self-administer buprenorphine,

readily do so. In fact, many partial p-agonist analgesics will maintain

responding in rhesus monkeys (Young et al. 1964). On the other hand,

18
FIGURE 4. Dose/effect curves showing naltrexone antagonism of the discriminative stimulus effects of morphine

(left panel), oxymorphazone (middle panel), and buprenorphine (right panel) in pigeons trained to

discriminate 5.6 mg/kg of morphine from saline (n=5)

KEY: , no pretreatment; , 0.01 mg/kg of naltrexone; , 0.1 mg/kg of naltrexone; , 1.0 mg/kg of naltrexone

NOTE: Naltrexone was administered 10 minutes before the first dose of each test drug.

SOURCE: France, C.P.; Jacobson, A.E.; and Woods, J.H. Discriminative stimulus effects of reversible and

irreversible opiate agonists: Morphine, oxymorphazone and buprenorphine. J Pharmacol Exp Ther

230:652-657, 1964. Copyright 1964 by American Society for Pharmacology and Experimental

Therapeutics.
FIGURE 5. Dose/effect curves showing the relative reversibility of the

discriminative stimulus effects of morphine (left panel),

oxymorphazone (middle panel), and buprenorphine (right panel)

in pigeons trained to discriminate 5.6 mg/kg of morphine from

saline (n=5)

Key: , single injection of each agonist followed by saline injections; , tests

in which each agonist (doses given on abscissae) was followed by

increasing doses of naltrexone

SOURCE: France, C.P.; Jacobson, A.E.; and Woods, J.H. Discriminative

stimulus effects of reversible and irreversible opiate agonists:

Morphine, oxymorphazone and buprenorphine. J Pharmacol Exp

Ther 230:652-657, 1994. Copyright 1984 by American Society for

Pharmacology and Experimental Therapeutics.

20
buprenorphine maintains low rates of responding in the baboon, compared

with other narcotics such as butorphanol, pentazocine, and nalbuphine (Lukas

et al. 1983). In progressive ratio assessments, buprenorphine and nalbuphine

both maintain lower breakpoints than do full agonists such as codeine or

alfentanil (G.D. Winger, unpublished observations). These data may reflect

a reduced reinforcing stimulus efficacy of some partial μ-agonists.

TOLERANCE AND DEPENDENCE

From the first descriptions of the effects of buprenorphine in rodents (Cowan

et al. 1977), it has been clear that, when buprenorphine is given chronically

to mice, tolerance to its analgesic actions is observed.

Subsequently, other investigators have noted tolerance development to

analgesic effects of buprenorphine in rats (Berthold and Moerschbaecher

1988). Tolerance to other behavioral effects of buprenorphine also is observed,

including effects on food-maintained, schedule-controlled behavior in rodents

and primates (Berthold and Moerschbaecher 1988; Dykstra 1989). Tolerance

that develops to buprenorphine has not been characterized pharmacologically

to any great extent; this is an area of research in need of extensive

investigation.

In morphine-dependent rodents (Cowan et al. 1977) and in morphinedependent monkeys (Gmerek 1984), buprenorphine precipitates a withdrawal

syndrome comparable with that produced by competitive antagonists such as

naltrexone or quadazocine. The potential irreversibility of the antagonist actions

of buprenorphine (figure 6) is indicated by the fact that much larger amounts of

morphine are required to reverse the withdrawal precipitated by buprenorphine

than to reverse the withdrawal syndrome precipitated by naltrexone or

quadazocine (Gmerek 1984; Gmerek and Woods 1985).

Attempts to produce physiological dependence on buprenorphine in animals

generally have been negative; both deprivation-induced withdrawal and

antagonist-induced withdrawal are difficult to demonstrate following chronic

administration of buprenorphine (Woods and Gmerek 1985). A smaller number

of studies have shown a modest withdrawal syndrome that develops quite a

while after chronic administration of buprenorphine has been terminated. In

a particularly intriguing experiment by Dum and associates (1981) a chronic

regimen of buprenorphine, which does not produce dependence, was shown

to enhance the capacity of morphine to produce dependence. It is only with

this indirect procedure that buprenorphine can clearly be shown to augment

dependence. The absence of a withdrawal syndrome on termination

of buprenorphine chronic administration has been attributed to the slow

dissociation of buprenorphine from the μ-opioid receptor (Rance 1979).

21
FIGURE 6. Morphine suppression of 14-hour deprivation-induced abstinence

and withdrawal precipitated by naloxone , naltrexone ,

MR 2266 , cycazocine , Win 44,441 , and

buprenorphine (H) in morphine-dependent rhesus monkeys

(mean of 6)

NOTE: P.I.=preinjection; Ant.=antagonist administration

SOURCE: Gmerek 1984. Copyright 1984 by Churchill Livingstone (Edinburgh).

CONCLUSIONS

To develop a reasonable descriptive framework for understanding the

physiological and behavioral effects of buprenorphine, it is helpful to refer to

principles of receptor theory (Kenakin 1987) that cannot be elaborated here in

any great detail. First, it is important to appreciate that all the agonist actions of

buprenorphine at behavioral levels of description can be reasonably attributed

to p-receptor activation. In support of this notion, increasing doses of the full

μ-agonist alfentanil first produce discriminative and reinforcing stimulus effects,

followed by analgesia and eventually respiratory depressant effects. These

effects occur through a common receptor, as demonstrated by pA2, analysis

22
using quadazocine (Dykstra et al. 1987; the authors, unpublished observations),

and they may be assumed to require increasing amounts of receptor

occupancy, as indicated by the increase in dose required to evoke them.

This is schematically indicated in figure 7. It might be supposed that k-agonists

with low efficacy would be able to mimic the effects produced by low doses of a

full agonist, that is, those effects that occur with the occupation and activation of

a few receptors. Such a low-efficacy agonist would be unable, however, to

mimic the effects produced by a high dose of the full agonist, effects requiring

occupation and activation of many receptors. In fact, a compound of low

efficacy would be expected to antagonize the effects of large doses of a highefficacy compound because the former drug would occupy the receptors but

would produce no effect. Buprenorphine fits this conceptual scheme by readily

producing discriminative effects in a variety of preparations and producing a full

analgesic effect in assay systems that require little receptor occupation and

activation. In analgesia assay systems in which more receptor occupation and

activation is required, or in measures of respiratory depression, buprenorphine

produces limited effects and, indeed, acts as an antagonist of a full agonist (the

authors, unpublished observations).

It should be possible, based on various behavioral assays, to order μ-opioid

agonists based on their apparent efficacy. One potential ordering of these

compounds is shown in the middle portion of figure 7. Nalbuphine appears

to exert its discriminative stimulus, reinforcing stimulus, and analgesic actions

through a common μ-receptor (the authors, unpublished observations). Along

with buprenorphine, it produces a limited respiratory depressant action in

the rhesus monkey but produces a greater degree of analgesia than does

buprenorphine. These data are consistent with the ordering of nalbuphine,

in efficacy, between buprenorphine and alfentanil.

Finally, after demonstrating how buprenorphine’s agonist effects can be related

to those of other μ-agonists, it is important to point out how buprenorphine

is distinct from other partial μ-agonists Buprenorphine’s uniquely slow

receptor dissociation kinetics are probably responsible for the noncompetitive

antagonist effects of buprenorphine that are not observed with other p-partial

agonists described to date. These kinetics account for the rightward and

downward shifts of the effects of full agonists produced by buprenorphine,

initially described by Tallarida and Cowan (1982). The authors have made

similar observations in rhesus monkeys. The unusual receptor kinetics of

buprenorphine also might account for the prolonged nature of the antagonist

effects of buprenorphine when administered in moderate and high doses.

Since the agonist actions of buprenorphine are not observed at this time,

it is probably also necessary to invoke the notion that acute tolerance to the

agonist actions of buprenorphine occurs with a single administration of the

drug.

23
FIGURE 7. Top: hypothetical ordering of receptor-occupation requirements

of various behavioral tests. Discriminative stimulus effects

develop with the fewest number of receptors occupied, and

respiratory depression requires the most. Middle: relative

apparent efficacy in rhesus monkeys of several drugs that bind to

the μ-receptor. Quadazocine and naltrexone have no apparent

efficacy, whereas alfentanil has greater apparent efficacy than

buprenorphine or nalbuphine. Bottom: order of dissociation of

three opioids from the μ-receptor. Buprenorphine dissociates

most slowly and alfentanil most rapidly with quadazocine being

intermediate.

24
The studies that will be extremely important for the development of

buprenorphine as a drug for the treatment of narcotic drug abuse are those

that involve a careful description of agonist and antagonist actions on behavior

during chronic administration. It is important to characterize these agonist/

antagonist actions of buprenorphine in comparison with the actions of

competitive antagonists and short-acting reversible agonists such as

alfentanil. When these data are in hand for animals, it will be far easier

to develop a rational clinical pharmacology of buprenorphine that will be

appropriate to drug abuse treatment situations.

REFERENCES

Berthold, C.W., and Moerschbaecher, J.M. Tolerance to the effects of

buprenorphine on schedule-controlled behavior and analgesia in rats.

Pharmacol Biochem Behav 29:393-396,1988.

Cowan, A.; Lewis, J.W.; and MacFarlane, I.R. Agonist and antagonist

properties of buprenorphine, a new antinociceptive agent. Br J Pharmacol

60:537-545, 1977.

Doxey, J.C.; Everitt, J.E.; Frank, L.W.; and MacKenzie, J.E. A comparison of

the effects of buprenorphine and morphine on the blood gases of conscious

rats. Br J Pharmacol 60:118P, 1977.

Dum, J.; Blasig, J.; and Herz, A. Buprenorphine: Demonstration of physical

dependence liability. Eur J Pharmacol 70:293-300, 1981.

Dykstra, L.A. Behavioral effects of buprenorphine and diprenorphine under a

multiple schedule of food presentation in squirrel monkeys. J Pharmacol Exp

Ther 226:317-323, 1983.

Dykstra, L.A.; Gmerek, D.E.; Winger, G.; and Woods, J.H. Kappa opioids in

rhesus monkeys. II. Analysis of the antagonistic actions of quadazocine

and beta-funaltrexamine. J Pharmacol Exp Ther 242:421-427, 1987.

Dykstra, L.A., and Woods, J.H. A tail withdrawal procedure for assessing

analgesic activity in rhesus monkeys. J Pharmacol Methods 15:263-269,

1986.

France, C.P.; Jacobson, A.E.; and Woods, J.H. Discriminative stimulus effects

of reversible and irreversible opiate agonists: Morphine, oxymorphazone and

buprenorphine. J Pharmacol Exp Ther 230:652-657,1984.

Gmerek, D.E. The suppression of deprivation and antagonist-induced

withdrawal in morphine-dependent rhesus monkeys. Neuropeptides 5:19-22,

1984.

Gmerek, D.E., and Woods, J.H. Effects of beta-funaltrexamine in normal and

morphine-dependent rhesus monkeys: Observational studies. J Pharmacol

Exp Ther 235:296-301, 1985.

Hambrook, J.M., and Rance, M.J. The interaction of buprenorphine with the

opiate receptor: Lipophilicity as a determining factor in drug-receptor

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kinetics. In: Kosterlitz, H., ed. Opiates and Endogenous Opioid Peptides.

Amsterdam: Elsevier/North-Holland, 1976. pp. 295-301.

Kajiwara, M.; Aoki, K.; Ishii, K.; Numata, H.; Matsumiya, T.; and Oka, T.

Agonist and antagonist actions of buprenorphine on three types of opioid

receptor in isolated preparations. Jpn J Pharmacol 40:95-191, 1986.

Kenakin, T.P. Pharmacologic Analysis of Drug-Receptor Interaction. New

York: Raven Press, 1987.

Lukas, S.E.; Griffiths, R.R.; and Brady, J.V. Buprenorphine self-administration

by the baboon: Comparison with other opioids. In: Harris, L.S., ed.

Problems of Drug Dependence 1982: Proceedings of the 44th Annual

Scientific Meeting, The Committee on Problems of Drug Dependence, Inc.

National Institute on Drug Abuse Research Monograph 43. DHHS Pub. No.

(ADM)83-1264. Washington, DC: Supt. of Docs., U.S. Govt. Print. Off.,

1983. pp. 178-183.

Negus, S.S., and Dykstra, L.A. Kappa agonist properties of buprenorphine in

the shock titration procedure. Eur J Pharmacol 156:77-86, 1988.

Rance, M.J. Animal and molecular pharmacology of mixed agonist-antagonist

analgesic drugs. Br J Pharmacol 7:281S-286S, 1979.

Rance, M.J., and Dickens, J.M. The influence of drug-receptor kinetics on the

pharmacological and pharmacokinetic profiles of buprenorphine. In: Van

Ree, J.M., and Terenius, L., eds. Characteristics and Function of Opioids.

Amsterdam: Elsevier/North-Holland, 1978. pp. 65-68.

Rance, M.J.; Lord, J.A.H.; and Robinson, T. Biphasic dose response to

buprenorphine in the rat tail flick assay: Effect of naloxone pretreatment.

In: Way, E.L., ed. Endogenous and Exogenous Opiate Agonists and

Antagonists. New York: Pergamon Press, 1980. pp. 387-394.

Richards, M.L., and Sadee, W. In vivo opiate receptor binding of oripavines to

mu, delta and kappa sites in rat brain as determined by an ex vivo labeling

method. Eur J Pharmacol 114:343-353,1985.

Sadee, W.; Rosenbaum, J.S.; and Herz, A. Buprenorphine: Differential

interaction with opiate receptor subtypes in vivo. J Pharmacol Exp Ther

223:157-162,1982.

Schulz, R., and Herz, A. The guinea-pig ileum as an in vitro model to analyse

dependence liability of narcotic drugs. In: Kosterlitz, H., ed. Opiates and

Endogenous Peptides. Amsterdam: Elsevier/North-Holland, 1976. pp. 319-

326.

Tallarida, R.J., and Cowan, A. The affinity of morphine for its pharmacologic

receptor in vivo. J Pharmacol Exp Ther 222:198-201,1982.

Woods, J.H., and Gmerek, D.E. Substitution and primary dependence studies

in animals. Drug Alcohol Depend 14(3-4):233-247, 1985.

Young, A.M.: Stephens, K.R.; Hein, D.W.; and Woods, J.H. Reinforcing and

discriminative stimulus properties of mixed agonist-antagonist opioids.

J Pharmacol Exp Ther 229:118-126, 1984.

26
ACKNOWLEDGEMENT

Research and preparation of the manuscript were supported by U.S. Public

Health Service grant DA-00254.

AUTHORS

James H. Woods, Ph.D.

Professor

Charles P. France, Ph.D.

Assistant Research Scientist and Assistant Professor

Departments of Pharmacology and Psychology

University of Michigan

Ann Arbor, MI 48109-0826

Gail D. Winger, Ph.D.

Associate Research Scientist

Department of Pharmacology

University of Michigan

Ann Arbor, MI 48109-0626

27
Assessment of Buprenorphine in a

Drug Discrimination Procedure in

Humans

George E. Bigelow and Kenzie L. Preston

INTRODUCTION

Drug discrimination testing is a behavioral procedure that is widely used to

characterize and classify the pharmacological effects of psychoactive drugs.

In this procedure subjects are given explicit behavioral training in identifying

specific training drugs and are then tested with novel drugs or doses to

determine if they are identified as being similar to the training drugs. Drug

discrimination training proceeds by providing controlled experimental exposures

to the training drugs and by providing contingent reinforcement (reward) for

correct identification responses. When subjects successfully learn the drug

discrimination, the stimulus effects of the training drugs serve as cues for

which identification response will be reinforced on that trial. When a novel drug

or dose is identified as being similar to a training drug, this presumably indicates

a similarity in the stimulus effects produced by those two drug/dose conditions.

The drug discrimination paradigm is illustrated schematically in figure 1, which

represents a three-choice drug discrimination procedure. In this illustration,

each of three training drugs is associated with a different identification

response; each of these three responses leads to reinforcement only in the

presence of its own associated drug stimulus condition.

The drug discrimination methodology was developed in the animal laboratory,

where it has received extensive application as a tool for characterizing and

classifying the nature of psychopharmacological drug effects. Procedurally,

the drug discrimination procedure is designed to assess the stimulus effects

of drugs (i.e., the extent to which test drugs’ stimulus effects are similar to

those of training drugs). For drugs in the opioid class, it appears that the drug

discrimination procedure also can provide information about the underlying

neuropharmacological mechanisms of drug action. In particular, it appears

that opioids acting as agonists at μ- vs. -opioid receptor sites have different

28
FIGURE 1. Schematic representation of a three-choice drug discrimination

procedure, showing the association of contingent reinforcement

with different specific responses under each of several different

drug stimulus conditions

stimulus effects and that drug discrimination behavior may be used to infer

probable opioid receptor activity (Holtzman 1993).

Drugs’ stimulus effects may be related to their subjective effects. There is

substantial face validity to the notion that drugs that produce similar subjective

29
effects might be behaviorally discriminated as similar also. There is less face

validity to the reverse relationship (that drugs with similar stimulus effects might

produce similar subjective effects), perhaps because of our uncertainty about

the nature or locus of the stimulus effects upon which discriminations might

be based. Nevertheless, it is commonly speculated that drug discrimination

behavior may provide an index of drugs’ subjective effects. Such speculation

has been inherently untestable in the animal laboratory. Human subjects,

however, uniquely provide the opportunity to assess both stimulus effects and

subjective effects simultaneously.

This chapter provides a summary of several studies from the authors’ laboratory

in which buprenorphine has been tested using the drug discrimination

procedure in human volunteers to assess concurrently the similarity of its

stimulus effects to those of other opioids and its effects on self-reported

subjective experience (Bigelow and Preston 1989).

OPIOID DRUG DISCRIMINATION IN HUMANS: GENERAL METHODS

Participants

Participants in these studies were healthy adult male volunteers with

substantial histories of illicit opioid drug abuse who continued to abuse

opioids intermittently but who were currently not physically dependent.

Volunteers received medical examination, including urinalysis for drugs

of abuse, provided a medical and drug use history, and were monitored in

the residential unit for several days to ensure they were drug-free and

nondependent prior to study initiation. Volunteers provided written informed

consent and were paid for their research participation.

Setting

The studies were conducted in a residential laboratory, where participants

resided throughout the study duration. Study durations were approximately 7

weeks. A variety of recreational activities was available within the laboratory.

Urinalysis monitoring of volunteers was conducted intermittently throughout

each study to ensure subjects’ abstinence from drugs other than those

administered as part of the study.

Experimental Sessions

Experimental sessions were conducted daily, 7 days per week. The sequence

of events was: predrug data were collected; drug was administered; 20 minutes

were allowed for drug absorption; and then the assessment session began.

30
The assessment session was of approximately 100 minutes in duration and

included assessment both of drug discrimination behavior and of self-reports of

subjective drug effects.

Drug Administration

Drugs were administered by intramuscular (IM) injection to the deltoid muscle

of the arm by research nursing staff. All procedures were double blind and

randomized. The training drugs were designated only by randomly determined

arbitrary letter codes (e.g., A, B, C or J, K, L). Drug doses were adjusted for

body weight and expressed on a per 70 kg basis. Hydromorphone has served

as a standard morphine-like pure p-receptor agonist. The other drugs studied

have been the opioid mixed agonist-antagonists currently marketed in the

United States—pentazocine, butorphanol, nalbuphine, and buprenorphine.

Discrimination Procedures

Training and testing of the drug discrimination proceeded in three phases. In

the first phase, designated the "training” phase, each subject received two

exposures to each of the training drugs; they were told the arbitrary letter code

of the drug at the time of injection and were told to attend carefully to the drug’s

effects and to try to learn to recognize the effects of each training drug and

to discriminate among them. In the second phase, designated the “test of

acquisition” phase, each subject again received two exposures to each of the

training drugs, but they were not told the letter code until after the assessment

session. In each of these two phases the amount of money the subject earned

in the session was determined by his accuracy during the assessment session

in identifying the correct letter code of the drug administered. In the third phase,

designated the “test” phase, each subject received exposures to a range of

doses of the drugs being tested. Since these drugs/doses were usually

different from the training drug conditions, there was no “correct” response to be

rewarded; the subject was informed at the end of the assessment session that

this had been a test session, that the identity of the drug given in that session

could not be revealed, and that his earnings for that session were determined

by the accuracy of discrimination performance in prior test of acquisition

sessions. To provide continued training and incentive for correct discrimination

performance, test of acquisition sessions were randomly distributed throughout

the test phase.

During each assessment session the subject could indicate his drug

discrimination response by pressing keys labeled with each of the arbitrary

drug letter codes associated with the training drugs. There were two such

discrimination performance opportunities, each of 8.5minute duration. During

31
each of these the subject could earn points later exchangeable for money by

pressing the correct key. Points could be earned at a maximum rate of one per

second (i.e., a fixed-interval 1-second schedule of reinforcement).

Subjective Effect Measures

During each assessment session the subject also completed a standard battery

of subjective effect self-report questions. These included adjective rating scales

of items describing effects associated with opioids, visual analog scales (VAS)

of global aspects of drug effects, and a short form of the Addiction Research

Center Inventory (ARCI). The VAS provided ratings on a 100-point scale of the

extent to which the subject experienced “Any Drug Effect,” “Liking” for the drug

effect, “Good Effects,” “Bad Effects,” “High,” and “Sick.” The ARCI included the

Morphine-Benzedrine Group (MBG) scale, which is empirically derived as

sensitive to opioid agonist effects and is commonly characterized as providing

an index of drug-induced “euphoria.”

EVALUATION OF BUPRENORPHINE IN A THREE-CHOICE

HYDROMORPHONE-PENTAZOCINE-PLACEBO DISCRIMINATION

Four nondependent postaddict volunteers were tested with a range of doses of

buprenorphine (0.11-0.9 mg/70 kg) after having been first trained on a threechoice discrimination between IM saline, 3 mg/70 kg hydromorphone, and 45

mg/70 kg pentazocine (Preston et al. 1989). Also tested was a range of doses

of hydromorphone and of the opioid mixed agonist-antagonists-pentazocine,

butorphanol, and nalbuphine.

Drug discrimination results for buprenorphine and the two training drugs

are shown in figure 2. Saline was discriminated as being saline-like.

Hydromorphone showed a dose-related increase in being discriminated as

like the hydromorphone training dose. Similarly, pentazocine showed a doserelated increase in being discriminated as like the pentazocine training dose.

Buprenorphine, however, was not reliably discriminated as being like either of

the training drugs. Subjects’ discrimination responses were divided evenly

between hydromorphone-appropriate and pentazocine-appropriate.

Not shown are the data for butorphanol and nalbuphine, which indicated that

butorphanol at high doses (6 mg/70 kg) generalized completely to the

pentazocine training condition, whereas nalbuphine (in doses up to 24 mg/70

kg) generalized partially to pentazocine and partially to hydromorphone.

Selected subjective effect results for buprenorphine and the two training drugs

are shown in figure 3. Only hydromorphone and buprenorphine produced

32
FIGURE 2. Drug discrimination results are shown for a range of doses of

hydromorphone, pentazocine, and buprenorphine for subjects

trained to discriminate among saline, hydromotphone, and

pentazocine. The buprenotphine data are based on four subjects,

the hydromorphone and pentazocine data on six subjects.

significant elevations on the MBG scale score of the ARCI. On the “Good

Effects” VAS, both hydromorphone and buprenorphine produced similar doserelated elevations.

33
FlGURE 3. Selected subjected effects data are shown for a range of doses of

hydromotphone, pentazocine, and buprenorphine. The data were

collected concurrently with the behavioral drug discrimination data

shown in figure 2 and are based on the same sample sizes.

Brackets are standard errors of the mean.

Subsequent Drug Discrimination Studies

Subsequent to the study described above, the authors have evaluated

buprenorphine in two other drug discrimination procedures, the reports of which

have not yet been published. These are described here only rather generally,

for the purpose of characterizing the additional information they provide

concerning the overall profile of pharmacological activity of buprenorphine.

Hydromorphone vs. Saline Discrimination

Four nondependent postaddict volunteers were tested with a range of doses of

buprenorphine after having been first trained on a two-choice discrimination

between IM saline and 3 mg/70 kg hydromorphone (described briefly in Bigelow

3 4
and Preston 1969). Also tested were a range of doses of hydromorphone

and of the other opioid mixed agonist-antagonists-pentazocine, butorphanol,

and nalbuphine. In this two-choice procedure all the active opioids were

discriminated as being more similar to hydromotphone than to saline.

Subjective effect data showed buprenorphine to be the only one of the mixed

agonist-antagonists to produce significant score elevations on the MBG scale

of the ARCI, as did hydromorphone.

Hydromorphone-Butorphanol-Saline Discrimination

Six nondependent postaddict volunteers were tested with a range of doses of

buprenorphine after first having been trained on a three-choice discrimination

between IM saline, 3 mg/70 kg hydromorphone, and 6 mg/70 kg butorphanol.

Also tested were a range of doses of hydromorphone, pentazocine,

butorphanol, and nalbuphine. Only hydromorphone and buprenorphine

were discriminated as having stimulus effects similar to the hydromorphone

training dose. Nalbuphine and butorphanol were discriminated as being

butotphanoi-like. Pentazocine generalized partially to both hydromorphone

and butorphanol, but completely to neither. Subjective effect data again

showed similarities in the effects of hydromorphone and buprenorphine in

contrast to those of butorphanol.

SUMMARY AND CONCLUSIONS

These studies indicate that buprenorphine shares stimulus effects with other

opioid drugs and that in overall profile of effects buprenorphine is more similar

to hydromorphone than are the other opioid mixed agonist-antagonists testedpentazocine, butorphanol, and nalbuphine. This characterization is supported

by the behavioral drug discrimination results and by the subjective effect selfreport results.

In the drug discrimination assessments buprenorphine showed a pattern of

generalization that was different from that of the other opioid-mixed agonistantagonists. It did not generalize completely to either pentazocine or

butorphanol, but it did generalize to hydromorphone in two studies and

partially in a third. Both nalbuphine and pentazocine showed at least partial

generalization to butorphanol, but buprenorphine did not. Butorphanol showed

little generalization to hydromorphone except in the two-choice hydromorphone

vs. saline discrimination in which all the tested mixed agonist-antagonists

generalized to hydromorphone.

The subjective effect self-report data also revealed a pattern of response

to buprenorphine that was different from that to the other mixed agonist35
antagonists. In particular, buprenorphine’s profile of acute subjective effects

was similar to that of hydromorphone. There were dose-related increases on

various scales reflecting positive subjective effects, with little evidence of the

dysphoric effects that are characteristic of high doses of the other mixed

agonist-antagonists.

These data are compatible with the view that buprenorphine is a partial agonist

at the μ-receptor Although they do not demonstrate the ceiling on magnitude

of pharmacological effects that would be characteristic of a partial agonist, they

do demonstrate that buprenorphine’s profile of activity—both stimulus effects

and subjective effects-is similar to that of the pure μ-agonist hydromorphone.

REFERENCES

Bigelow, G.E., and Preston, K.L. Drug discrimination: Methods for drug

characterization and classification. In: Fischman, M.W., and Mello, N.K.,

eds. Testing for Abuse Liability of Drugs in Humans. National Institute on

Drug Abuse Research Monograph 92. DHHS Pub. No. (ADM)89-1613.

Washington, DC: Supt. of Docs. U.S. Govt. Print. Off., 1989. pp. 101-122.

Holtzman, S.G. Discriminative stimulus properties of opioid agonists and

antagonists. In: Cooper, S.J., ed. Theory in Psychopharmacology. Vol. 2.

London: Academic Press, 1983. pp. 1-45.

Preston, K.L.; Bigelow, G.E.; Bickel, W.K.; and Liebson, I.A. Drug

discrimination in human postaddicts: Agonist-antagonist opioids.

J Pharmacol Exp Ther 250:184-196, 1989.

ACKNOWLEDGEMENT

The work described in this chapter was supported by National Institute on Drug

Abuse grants DA-00050, DA-04089, and DA-06120.

AUTHORS

George E. Bigelow, Ph.D.

Professor of Behavioral Biology

Kenzie L. Preston, Ph.D.

Assistant Professor of Behavioral Biology

Department of Psychiatry and Behavioral Sciences

Behavioral Pharmacology Research Unit

The Johns Hopkins University School of Medicine

36
Francis Scott Key Medical Center

4940 Eastern Avenue

Baltimore, MD 21224

37
Human Laboratory Studies of

Buprenorphine

Jack H. Mendelson and Nancy K. Mello

INTRODUCTlON

During 1978, Jasinski and associates (1978) reported their initial studies of the

human pharmacology and abuse potential of buprenorphine. They found that

buprenorphine (8 mg/day) blocked the subjective and miotic effects of high

doses of morphine (60/120 mg/day) for up to 29.5 hours. They also concluded

that buprenorphine maintenance, unlike other opiate agonists, does not induce

significant physical dependence in humans. These studies stimulated the

authors’ evaluation of the effectiveness of buprenorphine for suppressing

heroin self-administration by heroin-dependent men (Mello and Mendelson

1980; Mello et al. 1982). In this chapter, data obtained in those studies are

reexamined, with special emphasis on both safety and effectiveness of the

drug for treatment of opioid and perhaps cocaine abuse. Findings obtained

in studies of buprenorphine and cocaine effects on anterior pituitary function

(Mendelson et al. 1982, 1988) also are presented. These data are relevant

for use of buprenorphine as a pharmacotherapeutic adjunct for reducing risk

for infectious disease, induding acquired immunodefiiiency syndrome (AIDS),

by persons who abuse both opiates and cocaine. Finally, new data concerning

a buprenorphine preparation that includes the opioid antagonist naloxone

(Mendelson et al. 1989) are presented. These studies highlight findings that

may be relevant to reducing illicit diversion of buprenorphine in clinical

treatment settings as well as to increasing the safety of new programs

invoking buprenorphine maintenance for intravenous (IV) heroin abuse.

BUPRENORPHINE EFFECTS ON HEROIN SELF-ADMINISTRATION BY

HEROIN-DEPENDENT MEN

During 1980 and 1982, the authors described a series of studies designed to

determine the effectiveness of buprenorphine for suppressing heroin selfadministration by heroin-dependent men (Mello and Mendelson 1980; Mello et

al. 1982).

38
Methods

Ten adult male volunteers with a history of heroin abuse gave informed consent

for participation in studies to evaluate the effects of buprenorphine on heroin

self-administration in an inpatient clinical research study. No subject was under

any legal constraint. Subjects were selected from volunteers who had failed in

conventional treatment programs.

Subjects were in good health, as determined by clinical and laboratory

examination. Each subject was given a complete physical examination,

mental status assessment, chest x-ray, electrocardiogram, and the following

laboratory assessments: albumin, alkaline phosphatase, bilirubin, total blood

urea nitrogen, calcium, chloride, cholesterol, creatinine, glucose, iron, lactic

acid dehydrogenase. phosphorus, potassium, serum glutamic oxaloacetic

transaminase, sodium, total protein, triglycerides, uric acid, routine urinalysis,

hematocrit, hemoglobin, white blood count differential, and Australian antigen

and serology. Urine screens for opiate and other drug use by the subjects were

performed upon their admission to the research ward.

These subjects had abused heroin for an average of 10.4 years (range 1 to 19

years). The average age was 28.6 years (range 24 to 32 years). Most subjects

had grown up in communities near Boston and had an average of 12.4 years of

formal education (range 11 to 16 years). At the time of selection for the study,

seven subjects were unemployed, and three had recently worked at semiskilled

jobs.

Six subjects participated in a single study in which three subjects were

assigned to buprenorphine and three to its placebo. Four subjects participated

in two separate studies and received both buprenorphine and placebo in a

counterbalanced order (i.e., two received buprenorphine first and two received

placebo first), Consequently, final data are reported for seven subjects

assigned to buprenorphine and seven subjects to placebo under double-blind

conditions. Two other volunteers left the study on days 6 and 10, respectively.

One subject assigned to buprenorphine was discharged for illicit drug use

(diazepam), and one subject assigned to placebo left for personal reasons.

Subjects were recruited in groups of four and lived on the clinical research ward

throughout the 40-day study. The research ward contained two semiprivate

bedrooms, a nursing station, a kitchen and lavatories, examining and testing

rooms, an operant equipment room, and a spacious day room comfortably

furnished with television, high fidelity equipment, and other recreational

materials. The clinical nursing staff was present 24 hours each day.

39
Subjects were fully informed about the duration and sequence of the

experimental conditions, and each procedure was carefully explained.

Buprenorphine was described as an experimental drug that may “block the

heroin high” and eventually may be used like methadone for long-term

maintenance treatment. Subjects were told they would receive either

buprenorphine or its placebo but neither they nor the nursing staff would be

told which. Subjects were asked to report any discomfort or unusual effects

experienced during buprenorphine (or placebo) administration. Subjects were

told that minimal side effects, such as fatigue or nausea, and some pleasurable

subjective effects were reported during previous buprenorphine evaluations.

Upon discharge, subjects were offered an opportunity for outpatient

maintenance on the long-acting antagonist naltrexone. Naltrexone was

available for 1 year after discharge. Staff attempted to maintain contact with

subjects after discharge. An aftercare program was developed for each

subject at an outpatient-treatment program near his home. Subjects who left

the program early also were given referrals to a drug-treatment program.

Sequence of Drug Conditions. The successive drug conditions for the

buprenorphine and placebo groups are shown in table 1. The buprenorphine

induction, maintenance, and withdrawal schedules were identical to those used

by Jasinski and coworkers (1978). After a 5-day, drug-free baseline, subjects

were given ascending doses of buprenorphine (or its placebo) for 14 days. An

ascending dose schedule was used to assess the physiological and behavioral

effects of various doses of buprenorphine and to ensure patient safety. An

initial buprenorphine dose of 0.5 mg/day subcutaneous (SC) was gradually

increased in 0.5-mg increments for 12 days and 1-mg increments for 2 days

to a final dose of 8 mg/day SC. The volumes of buprenorphine and placebo

injections were equivalent at each dose level.

Subjects were maintained on 8 mg/day of buprenorphine (or placebo) for 10

days, during which they could work at a simple operant task for IV heroin. Six

subjects were maintained on 8 mg/day of buprenorphine for 10 days. One

subject developed hypotension, a side effect typical of opioid agonists, and

was maintained on 4 mg/day of buprenorphine.

Subsequently, subjects were gradually withdrawn from buprenorphine over

5 days. The dose-reduction sequence was as follows: 7, 6, 5, 3, and 1 mg/day.

Subjects who were assigned to placebo buprenorphine and used heroin were

detoxified with methadone in progressively decreasing doses (25 to 5 mg/day)

over 5 days.

40
TABLE 1. Sequence of drug conditions

Buprenorphine Group

(n=7)

Buprenorphine

Placebo Group

(n=7)

Condition Duration*

(days)

Drug-free baseline Drug-free baseline

Buprenorphine Buprenorphine

(0.5-8 mg/day SC) placebo (=volume x.c.)

Heroin Heroin

(21 or 40.5 mg/day IV)+ (21 or 40.5 mg/day IV)+

buprenorphone buprenorphine

(8 mg/day SC) placebo

Buprenorphine Methadone

detoxification detoxification

(7-1 mg/day) (25-5 mg/day)

Drug-free baseline Drug-free baseline

Naltrexone Naltrexone

(10-50 mg/day) (10-50 mg/day)

5

14

10

5

3

3

*Total days=40

SOURCE: Adapted from Mello et al. 1982. Copyright 1982 by the American

Society for Pharmacology and Experimental Therapeutics.

A 3-day, drug-free period preceded exposure to naltrexone to reduce the

possibility that naltrexone might precipitate withdrawal from the opiate agonist

effects of buprenorphine. Buprenorphine is highly lipophilic and has been

shown to dissociate very slowly from tissue (Rance and Dickens 1978;

Hambrook and Rance 1976). Although the protocol specified a gradual

increase in naltrexone dosage from 10 to 50 mg/day over 3 days before

discharge, only one subject elected to be discharged on naltrexone. Two other

subjects left before the naltrexone condition, on days 30 and 34, respectively.

Heroin Self-Administration Procedures. Medical and ethical considerations

preclude study of spontaneous patterns of unrestricted heroin selfadministration as has been possible for marijuana (Mendelson et al. 1974,

1976) alcohol (Mello and Mendelson 1965, 1972) sedatives (Griffiths et al.

1976; Pickens et al. 1977), and some forms of polydrug use (Mello et al. 1978).

Subjects were limited to a total of three heroin injections each day, once every 8

hours (at 9 a.m., 5 p.m., and 1 a.m.). The effects of buprenorphine on selfadministration of both low and high doses of heroin were examined. A total of

21 mg/day of heroin was available for the first 5 days and 40.5 mg/day for the

second 5 days. Subjects could refuse to take any heroin dose earned, but they

41
were not allowed to take fractional doses (e.g., 3 mg instead of 7 mg). Subjects

were not told that the heroin dose would be increased on day 6.

Drugs. Heroin (98 to 99 percent pure) was obtained from the National Institute

on Drug Abuse (NIDA), Rockville, MD, in 8-mg sterile vials. Heroin was diluted

with saline immediately before injection. Subjects injected heroin intravenously

under the supervision of a physician. During the 10 days of heroin availability,

24-hour physician coverage was provided, and the nursing staff was trained in

the use of emergency medical equipment. Heroin in a total daily dose range of

40 to 60 mg has proven to be safe, and the IV self-administration procedure has

not been associated with any medical complications (Meyer and Mirin 1979;

Mello et al. 1981).

Buprenorphine hydrochloride was provided by Reckitt & Colman, Ltd., Hull,

England, through NIDA. Buprenorphine was diluted with sterile water adjusted

to pH 4 with HCI. The buprenorphine solution (4 mg/mL) was passed through a

Millipore filter to remove pyrogens before SC administration. Equal volumes of

sterile water adjusted to pH 4 were used as a vehicle control.

Heroin and Money-Acquisition Procedures. Operant procedures were used

to evaluate the effects of buprenorphine on heroin self-administration. Operant

performances for heroin and money were compared, and the effects of heroin

use on operant work patterns were examined.

Subjects could work for money at a simple operant task throughout the study.

This provided a measure of buprenorphine (or placebo) and heroin effects

on performance. The opportunity to work for money also was intended to

encourage subjects to remain in the study, inasmuch as heroin was available

for only 10 of the 40 study days. This procedure previously has been proven

effective in minimizing patient attrition (Mello et al. 1981).

Subjects could work for points for heroin on the last day (day 14) of the

buprenorphine induction period and each day of heroin availability. Heroin

points could be accumulated and spent throughout the 10-day heroin

availability period. Operant points earned for money and for heroin were not

interchangeable. Subjects chose whether to work for money or for heroin

each time they turned on their operant instruments by pressing the appropriate

button on a panel in the day room (Mello et al. 1981). Subjects could work at

the operant task at any time for as long as they wished. A 5-minute pause in

responding required reactivation of the operant instrument.

To earn points for money or heroin, subjects were required to press the button

on a portable operant manipulandum on a second-order fixed ratio (FR) 300,

42
fixed interval (FI) 1-second schedule of reinforcement (FR 300 [FI 1 second: S]).

Only the first response after 1 second had elapsed was recorded as an effective

response by the programing circuitry. Responses emitted at a rate faster than

once per second had no programed consequence. Each effective response

was followed by a brief stimulus light flash on the operant panel. Three hundred

effective responses on the FI 1-second schedule of reinforcement earned one

purchase point in about 5 minutes. Each heroin injection cost 18 purchase

points. Approximately 90 minutes of sustained performance were required to

earn enough purchase points to buy one heroin injection (7 to 13.5 mg) or to

acquire $1.50 in cash paid upon completion of the study. Subjects had to work

about 4.5 hours each day to earn the 54 purchase points necessary to buy all

three heroin injections available daily.

A record of points earned for heroin and for money was available continuously

on counters located on the operant panel on the day room wall. Whenever a

subject accumulated 18 purchase points, he could press a drug request button

to inform staff that he wished to take the next available heroin dose. The

requisite number of purchase points then was subtracted from his total points.

Additional details of the operant manipulandum and apparatus have been

described previously (Mello et al. 1981).

Points earned for heroin that were not spent during the period of heroin

availability could not be exchanged for money. To avoid penalizing subjects

who were assigned to buprenorphine maintenance and elected not to use

heroin, however, points earned for heroin on the last day of the baseline

period could be exchanged for money at the end of the study.

In addition to money earned by working at the operant task, subjects also could

earn money for cooperation with various procedures. For example, subjects

could earn about $144 by cooperating with routine medical assessments and

completing the various self-report forms. An additional $80 was paid for

participation in blood collection procedures. Consequently, subjects could earn

about $224 for cooperation. If a subject damaged the operant equipment or

other laboratory equipment, he was fined accordingly. This simple schedule

of compensation has been effective in maintaining cooperation and retaining

subjects in the study (Mello et al. 1981).

Data Recording and Analysis. The pattern, rate, and duration of operant

responding for heroin and money were automatically recorded by the

programing circuitry. Cumulative recorders provided an analog record of

operant response patterns. The number of purchase points earned and the

number of heroin purchases also were automatically recorded. Time (minutes)

spent working at the operant task for money or for heroin was recorded on

43
running time meters. Individual patterns of operant performance and heroin use

are presented graphically. Group data and within-subject comparisons of

operant performance across drug conditions were evaluated with t tests.

Medical Status and Related Measures. A physician examined each subject

daily to assess possible drug side effects. Clinical interviews and mental-status

exams were combined with physical and neurological examinations. Vital signs

were taken three times each day, and clinical laboratory assessments were

completed once each week.

A series of multidisciplinary studies of the behavioral and biological effects of

buprenorphine and heroin was conducted concurrently with the behavioral

studies described in this report. The effects of buprenorphine on prolactin and

luteinizing hormone levels also were studied (Mendelson et al. 1982). Samples

for measurement of buprenorphine levels in plasma were collected periodically

for analysis at the NIDA Intramural Research Program. A Profile of Mood

States was completed daily and before and after each heroin injection. The

duration and latency of the heroin ‘rush” were assessed after each heroin

injection. The effects of buprenorphine and heroin on cigarette smoking also

were studied (Mello et al. 1985).

Results

Subjective and Physiological Effects of Buprenorphine. The mixed agonistantagonist buprenorphine produced somatic and sedative effects similar to

those previously reported for opiate agonists (Mansky 1978). Constipation

was the most frequent and persistent opioid-like effect of buprenorphine.

Half the subjects developed tolerance to this side effect by the 21st day of

buprenorphine exposure. Only three subjects reported feeling drowsy during

buprenorphine induction, and tolerance developed rapidly to this sedative

effect. Decreased libido was reported by most subjects at high doses of

buprenorphine (7 to 8 mg/day). Although decreased libido was reported at low

doses of buprenorphine during induction, similar changes in libido were not

reported during detoxification, when buprenorphine doses were reduced to

3.0 mg/day. Other somatic effects (e.g., itching, headache, dizziness, tinnitus,

dry mouth, and urinary hesitancy) were reported only occasionally during the

early phase of buprenorphine induction. Reports of changes in appetite and

sleep patterns were infrequent and transient. Other transient side effects

included development of a mild erythematous blotchy rash on the arms and

trunk within 2 hours of buprenorphine injection (0.5 mg/kg) in one subject. The

rash did not persist or recur. At buprenorphine doses of 6.5 to 8.0 mg/day, one

subject developed muscle twitching at the injection site, which disappeared after

4 days at 8.0 mg/day.

44
Five of the seven subjects tolerated buprenorphine well and had no persistent

debilitating side effects. Two subjects developed sufficiently severe

idiosyncratic reactions to buprenorphine to require modification of the protocol.

One subject developed hypotension after 2.0 mg/day of buprenotphine. Blood

pressure fell to 100 systolic/60 diastolic and remained low as buprenorphine

doses were increased to 4.0 mg/day. The hypotension was associated with

feelings of panic, and the subject reported being “scared, terrified, paranoid,

and lonely.” Similar panic reactions were not reported by other subjects.

Buprenorphine doses for this subject were not increased above 4.0 mg/day

because his blood pressure remained in the range of 90 to 100 systolic and 50

to 70 diastolic throughout the study.

A second subject developed severe nausea and vomiting after 0.5 mg/kg of

buprenorphine. This subject reported frequent severe nausea and vomiting

after using opiates. The severity of his reaction, however, dictated a slower

progression of buprenorphine dose increases over the first 7 days of

buprenorphine induction. This subject developed tolerance to the

buprenorphine-induced nausea and vomiting within 8 days and was able to

tolerate high doses of buprenorphine comfortably without recurrence of the

nausea. No other clinically significant side effects were reported.

All subjects reported that buprenorphine had opiate-like effects on mood,

characterized by a generalized feeling of contentment. No sensation of a

“rush” or “high” was reported after SC buprenorphine injection. Although

this study was conducted under double-blind conditions, it is likely that the

buprenorphine group correctly surmised that they were receiving an active

drug. On the first day that subjects could work for points for heroin (day 14 of

the induction period), the buprenorphine group earned significantly fewer heroin

points than did the placebo group (p <.01). Several placebo subjects said they

thought they were receiving buprenorphine, but this expectancy did not appear

to influence heroin self-administration. The placebo-maintained subjects did not

report side effects during the induction or maintenance phase.

BUPRENORPHINE EFFECTS ON HEROIN SELF-ADMINISTRATION AND

OPERANT PERFORMANCE

Effects of buprenorphine and placebo maintenance on heroin selfadministration are shown in figure 1. Three subjects, maintained on placebo

only, administered 100 percent of all available heroin each day. In contrast,

three subjects who received only buprenorphine self-administered only 2 to 4

percent of all heroin available. Three other subjects who were maintained on

placebo and buprenorphine in a crossover study self-administered 93 to 100

percent of all heroin available during the placebo condition; however, on

45
FIGURE 1. Available heroin self-administration during buprenorphine and

placebo conditions

SOURCE: Mello, N.K., and Mendelson, J.H. Buprenorphine suppresses heroin

use by heroin addicts. Science 207:657-659,1960. Copyright 1980

by American Association for the Advancement of Science.

buprenorphine maintenance, heroin self-administration was significantly

suppressed to 69 to 96 percent of levels administered during placebo

maintenance. One subject (number 5) maintained on 4 mg of buprenorphine

per day, reduced heroin self-administration to 55 percent of the dosage

administered during the placebo condition.

Buprenorphine maintenance did not have significant effects on operant

performance. Comparisons of the total number of operant points earned by the

placebo maintenance group and the buprenorphine maintenance group during

each condition (baseline, induction, maintenance, and detoxification) showed

no statistically significant differences.

4 6
OPlATE AND COCAINE EFFECTS ON PROLACTIN SECRETION:

POSSIBLE COMORBIDITY FOR INFECTIOUS DISEASE, INCLUDING AlDS

The effects of opiate agonists on prolactin secretion appear to be similar in all

species. As has been demonstrated by many investigators, plasma prolactin

levels are increased by opiates in rats (Clemens and Sawyer 1974; Dobrin and

Mares 1974; Ojeda et al. 1974; Zimmerman et al. 1974; Bruni et al. 1977;

Cocchi et al. 1977) and in humans (Tolis et al. 1975, 1978; Ellingboe et al.

1980).

Cocaine abuse also affects prolactin secretion. Gawin and Kleber (1985) found

decreased prolactin levels in men and women who were studied in outpatient

clinic settings for the treatment of cocaine abuse. Dackis and Gold (1985)

found that plasma prolactin levels increased in men treated in inpatient facilities

for cocaine abuse and that these increased levels were significantly higher than

those in age-matched normal men. Cocores and colleagues (1986) reported

occurrence of hyperprolactinemia as well as self-reports of sexual dysfunction in

7 of 10 cocaine abusers.

The authors recently have determined plasma luteinizing hormone, prolactin,

testosterone, and cortisol levels in 16 patients after hospital admission for

cocaine abuse during the course of 4 weeks of hospitalization and before

discharge (Mendelson et al. 1988). Significant hyperprolactinemia was

detected when the patients were admitted to the hospital, and elevated prolactin

levels persisted until the time of discharge. The authors have concluded that

persistent elevation of plasma prolactin levels following cocaine withdrawal

may reflect a chronic cocaine-induced derangement in neural dopaminergic

regulatory systems.

The authors have studied the effects of buprenorphine on plasma prolactin

levels during maintenance and withdrawal (Mendelson et al. 1982). The

sequence of drug conditions for these studies is shown in table 1. Although a

significant increase in plasma prolactin levels during buprenorphine induction

was observed, plasma prolactin values were not in the hyperprolactinemic

range. The increments in prolactin levels during buprenorphine induction and

maintenance were relatively small (when contrasted with the drug-free period)

and were within the normal range of adult male values.

Figure 2 shows plasma prolactin levels in patients who were cocaine abusers.

Hyperprolactinemia observed on admission persisted until the patient’s

discharge from the hospital. In contrast, plasma prolactin levels obtained from

patients during induction and maintenance on buprenorphine were within the

range for normal adult males.

47
FIGURE 2. Plasma prolactin levels for cocaine abusers on admission and

discharge from hospital treatment and in heroin-dependent

subjects during buprenorphine induction and maintenance

There is increasing evidence that prolactin may be an important neuroendocrine

modulator of immune function. A recent report in Science noted that “several

lines of evidence indicate that prolactin may be an important immunoregulatory

hormone” as a function of “the critical influence of pituitary prolactin release on

maintenance of lymphocyte function and on lymphokind-dependent

macrophage activation” (Bernton et al. 1999). The authors of this chapter

postulate that cocaine-induced hyperprolactinemia may be an important factor

in the comorbidity of cocaine abuse for AIDS risk. Therefore, if buprenorphine

pharmacotherapy will be effective in suppressing cocaine self-administration by

cocaine abusers, as suggested by the findings of Mello and Mendelson (this

volume), buprenorphine maintenance may help reduce risk for infectious

disease, including AIDS.

A NALOXONE-BUPRENORPHINE PREPARATION FOR ENHANCING

SAFETY OF BUPRENORPHINE MAINTENANCE THERAPY

Although the abuse potential of buprenorphine appears to be low, and lethal

overdose of the drug is precluded by the antagonist component of the drug

48
(Lewis et al. 1983; Banks 1979) there is a potential for illicit buprenorphine

use. One pharmacologic strategy for reducing abuse liability of opioid agonist

drugs prepared for oral administration is the addition of a short-acting opioid

antagonist such as naloxone to the pharmaceutical preparation. For example,

0.5 mg of naloxone hydrochloride has been added to capsules containing 50

mg of pentazocine hydrochloride (Talwin Nx) (Legros et al. 1984). Naloxone

has no pharmacologic activity in dosages of 0.5 mg when administered orally

because of its low oral bioavailability (1 percent) (Gordon et al. 1974). If

pentazocine is administered parenterally, however, naloxone inhibits the effects

of pentazocine, and this has resulted in a decrease in reports of pentazocine

abuse (Poklis 1984).

The efficacy of naloxone for reducing parenteral abuse of buprenorphine is

difficult to predict, because buprenorphine alone is equivalent to naltrexone,

a potent opiate antagonist, in blocking subjective and miotic effects of high

doses of morphine (Jasinski et al. 1978; Martin et al. 1973). Mendelson and

colleagues (1989) recently have reported findings from a study to determine if

the opioid agonist effects of buprenorphine on prolactin stimulation could be

inhibited by concomitant parenteral administration of naloxone. Since plasma

prolactin levels increase following administration of most morphine-like opioid

agonist drugs, the effect of naloxone on the prolactin response may be of help

in predicting efficacy of opioid antagonists for inhibiting the potential abuse of

buprenorphine.

Methods

Six healthy adult males between the ages of 18 and 39 (mean age 26.71±7.5

years) provided informed consent for participation in this study. All subjects had

normal physical examinations, including an electrocardiogram; they also had

normal blood chemistry and blood hemogram studies. Subjects did not have

any past or current history of alcohol or drug abuse. No subject was receiving

any medication, and none had consumed alcohol for at least 48 hours prior to

each study.

Each subject was studied on six occasions ranging from 7 to 27 days (x=10,

SD=±8) apart. On each study day an IV catheter was inserted into the subjects

arm vein. At zero time the subject received a simultaneous intramuscular (IM)

injection within 30 seconds of either buprenorphine (0.3 mg) and saline or

buprenorphine (0.3 mg) and naloxone (0.15-0.6 mg). Each subject also

received two simultaneous injections of saline.

Blood samples for determination of plasma prolactin, plasma naloxone, and

plasma buprenorphine levels were obtained immediately before and at 10, 30,

49
and 55 minutes following simultaneous injections. Plasma prolactin levels were

measured in duplicate, using a double antibody radioimmunoassay similar to

that described for human gonadotropins (Midgley 1966). Radioiodinated

prolactin was purchased from Cambridge Medical Diagnostics, Billerica, MA.

Antiprolactin serum (NIAMDD-anti-hPRL-2, also known as AFP-C11580) and

human prolactin reference preparation (NIAMDD-hPRL-RP-1, also designated

AFP-231C), prepared by Dr. A.F. Parlow, were obtained from the National

Hormone and Pituitary Program at the National Institutes of Health. Results are

expressed as nanograms of hPRL-RP-1 standard per milliliter of plasma. Intraassay and interassay coefficients of variance (CV) were 4.6 percent and 10.2

percent, respectively. Assay sensitivity was 2.3 ng/mL.

Plasma naloxone levels were measured by radioimmunoassay using a specific

antisera provided by Dr. C.E. lnturrisi following a procedure described by Hahn

and colleagues (1983). Tritiated naloxone at a specific activity of 50 Ci/mmol

was purchased from Amersham International Plc., United Kingdom. The mean

interassay CV over a sample concentration range of 0.1 to 5.0 ng/mL was 6.5

percent. Assay sensitivity was 0.1 ng/mL.

Plasma buprenorphine levels were measured by a previously described

radioimmunoassay procedure (Bartlett et al. 1980). Tritiated buprenorphine

was provided at a specific activity of 2.6 Ci/mmol by Reckitt & Colman. The

mean interassay CV over a sample concentration range of 0.1 to 1.0 ng/mL

was 4.6 percent. Assay sensitivity was 0.1 ng/mL.

Data analysis for determining significant differences was carried out with a

two-way analysis of variance for repeated measures.

Results

The mean baseline prolactin levels for the six subjects prior to injection of

saline, buprenorphine, or naloxone were within the range of normal values for

adult males (x=13.2 ng/mL, SE=0.7). Figure 3 shows plasma prolactin levels

following concurrent administration of two doses of saline or concurrent

administration of saline and 0.3 mg buprenorphine intramuscularly (top panel).

Following saline injections, there was a small decrease in plasma prolactin

levels at 30 and 55 minutes. Following buprenorphine administration (0.3 mg)

and saline, there was a progressive increase in plasma prolactin levels. The

mean increase in plasma prolactin levels at 30 and 55 minutes was

approximately 10 and 25 ng/mL, respectively. The buprenorphine-induced

stimulation of plasma prolactin levels at these times was statistically significant

when compared with baseline values (time 30-Dunnett t=3.103, df=15, p <.01;

time 55-Dunnett t=6.916, df=15, p<.01).

50
FIGURE 3. Plasma prolactin concentration ng/mL X±SE) following

simultaneous administration of 0.3 mg buprenorphine plus saline

(B) or 0.3 mg buprenorphine plus 0.6 (C), 0.45 (D), 0.3 (E), and

0.15 (F) mg naloxone

NOTE: B vs. C, at time 55 (p <.05). B vs. D, at time 55 (p <.05). B vs. E,

nonsignificant. B vs. F, nonsignificant.

SOURCE: Mendelson, J.H.; Mello, N.K.; Teoh, S.K.; Lloyd-Jones, J.G.; and

Clifford, J.M. Naloxone suppresses buprenorphine stimulation of

plasma prolactin. J Clin Psychopharmacol 9(2):105-109, 1989.

Copyright 1989 by Williams & Wilkins.

51
Figure 3 shows that peak prolactin levels that were observed after 0.3 mg of

buprenorphine plus 0.6 mg naloxone (55 minutes) were significantly less than

those found 55 minutes after administration of 0.3 mg buprenorphine and saline

(Dunnett t=2.032, df=35, p <.05). Plasma prolactin values after administration of

0.3 mg buprenorphine plus 0.45 mg naloxone were not significantly different

from prolactin values following administration of 0.3 mg buprenorphine and 0.6

mg naloxone (figure 3). Simultaneous injection of 0.3 mg buprenorphine and

0.45 mg naloxone also resulted in a significant attenuation of buprenorphinestimulated prolactin levels at 55 minutes (Dunnett t=2.02, df=35, p <.05). When

0.3 mg buprenorphine was administered with 0.3 mg naloxone, plasma prolactin

levels were increased slightly, but not significantly, over values observed when

0.3 mg buprenorphine was administered with 0.45 mg naloxone. When 0.3 mg

buprenorphine was administered with 0.3 mg or 0.115 mg naloxone, the

increase in plasma prolactin levels was not significantly different from prolactin

levels following administration of 0.3 rng buprenorphine plus saline. Taken

together, data in figure 3 demonstrate a dose/effect relationship between

naloxone dose and suppression of the increase in plasma prolactin levels

produced by administration of 0.3 mg buprenorphine.

Figure 4 shows plasma naloxone concentrations following IM injection of

0.3 mg buprenorphine and concurrent IM naloxone administration in doses of

0.6, 0.45, 0.3, and 0.15 mg. A linear relationship was found between the dose

of naloxone administered and the concentration of naloxone in plasma.

Figure 5 shows plasma buprenorphine levels following IM administration of

buprenorphine (0.3 mg) plus saline and buprenorphine (0.3 mg) plus 0.6, 0.45,

0.3, and 0.15 mg naloxone. Plasma buprenorphine levels were not affected

significantly by concomitant IM administration of naloxone.

DISCUSSION

Increased plasma prolactin levels found in this study are consistent with

previous reports of increased plasma concentrations of prolactin following

buprenorphine administration to humans (Mendelson et al. 1982; McQuay et al.

1980; Bullingham et al. 1993; Rolandi et al. 1993). The magnitude of prolactin

stimulation following buprenorphine administration (0.3 mg) observed in this

study indicates that buprenorphine is approximately two and one-half times

more potent than an equianalgesic (10 mg) dose of morphine administered

parenterally (Zis et al. 1964). The finding that naloxone significantly inhibited

the prolactin-stimulating effects of buprenorphine in a dose-dependent manner

is consistent with previous reports that concomitant administration of an opiate

antagonist and buprenorphine results in a significant reduction or total blockade

52
FIGURE 4. Plasma naloxone concentration (ng/mL X±SE) following

simultaneous administration of 0.3 mg buprenorphine plus 0.6

(C), 0.45 (D), 0.3 (E), and 0.15 (F) mg naloxone

NOTE: C vs. D, at all times (p <.01). C vs. E, at all times (p <.01). C vs. F, at all

times (p <.01).

SOURCE: Mendelson, J.H.; Mello, N.K.; Teoh, S.K.; Lloyd-Jones, J.G.; and

Clifford, J.M. Naloxone suppresses buprenorphine stimulation of

plasma prolactin. J Clin Psychopharmacol 9(2):105-109, 1989.

Copyright 1989 by Williams & Wilkins.

53
FIGURE 5. Plasma buprenorphine concentration (ng/mL X±S.E.) following

simultaneous administration of 0.3 mg buprenorphine plus saline

(B) or 0.3 mg buprenorphine plus 0.6 (C), 0.45 (D), 0.3 (E), and

0.15 (F) mg naloxone

NOTE: No significant difference between treatments

SOURCE: Mendelson, J.H.; Mello, N.K.; Teoh, S.K.; Lloyd-Jones, J.G.; and

Clifford, J.M. Naloxone suppresses buprenorphine stimulation of

plasma prolactin. J Clin Psychopharmacol 9(2):105-109,1989.

Copyright 1989 by Williams & Wilkins.

54
of buprenorphine-induced opiate-agonist activity (Lewis et al. 1963; Cowan et

al. 1977a, 1977b; Heel et al. 1979; Kubicki and Azcona 1979; Budd 1963).

The efficacy of naloxone for blocking buprenorphine stimulation of prolactin

probably is related to the rate of buprenorphine and naloxone binding in the

central nervous system. Naloxone rapidly binds with the F-opiate receptor,

but buprenorphine has been shown to bind slowly with p-receptors (Budd

1963; Norwich Eaton Pharmaceuticals, Inc., 1985; Boas and Villiger 1965).

Data obtained in this study indicate that concomitant parenteral administration

of naloxone and buprenorphine inhibits the prolactin stimulation observed when

buprenorphine is administered alone. Since prolactin stimulation occurs rapidly

following opioid-agonist administration and is concordant with the rapid

induction of the pharmacologic reinforcing properties associated with opioid

abuse, the authors postulate that naloxone added to buprenorphine parenteral

preparations would reduce the abuse potential of buprenorphine. This would be

particularly important for diminishing the abuse liability of buprenorphine by

persons whose drug-seeking and drug-use behavior is highly motivated by the

prompt, predictable onset of “the rush” following IV drug self-administration

(Mello and Mendelson 1980).

Bigelow and associates (1987) have reported that in “subjects maintained on a

low dose of methadone (30 mg), clinically useful doses of buprenorphine plus

naloxone 0.2 mg produced significant abstinence syndromes which were similar

to those produced by naloxone 0.2 mg alone and which were perceived by

subjects as being quite unpleasant.” Based on these studies, Bigelow and

coworkers (1987) concluded that “combinations of buprenorphine and naloxone

have a low potential for abuse in an opioid-dependent population.” There are

also recent reports that administration of an IM combination of buprenorphine

(0.3 mg) and naloxone (0.2 mg) was as safe and effective in relieving moderate

to severe pain in patients following surgery as 0.3 mg buprenorphine alone

(Vanacker et al. 1986; Rolly et al. 1986). These observations (Bigelow et al.

1987; Vanacker et al. 1986; Rolly et al. 1986) are consistent with data showing

that buprenorphine binds slowly to the p-receptor (Budd 1963; Norwich Eaton

Pharmaceuticals, Inc., 1985; Boas and Villiger 1985). Naloxone binds rapidly to

the p-receptor but has a relatively short duration of action. Thus, the abuse

potential of buprenorphine may be diminished by the addition of naloxone to

buprenorphine preparations.

CONCLUSIONS

The authors conclude that buprenorphine may be an effective and safe

pharmacotherapy for heroin abuse and concurrent heroin and cocaine abuse

for the following reasons:

55
1. Buprenorphine effectively suppresses heroin self-administration.

2. Buprenorphine is reinforcing but does not produce “rush”-like effects.

3. Buprenorphine does not induce significant physical dependence.

4. The possibility of buprenorphine lethal overdose is remote.

5. Buprenorphine does not induce disorders of hormone function that would

increase risk for infectious disease.

6. Buprenorphine may be administered sublingually.

7. Buprenorphine may be combined with naloxone to reduce illicit diversion for

IV use.

8. Buprenorphine may suppress both opiate and cocaine self-administration.

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ACKNOWLEDGMENTS

This research was supported in part by NIDA grants DA-04059, DA-00064,

DA-00101, and DA-02519.

Portions of this report were originally published in “Science,” “American Journal

of Psychiatry,” “Journal of Pharmacology and Experimental Therapeutics,” and

“Journal of Clinical Psychopharmacology” and are reprinted with permission of

the editors.

AUTHORS

Jack H. Mendelson, M.D.

Professor of Psychiatry (Neuroscience)

Nancy K. Mello, Ph.D.

Professor of Psychology (Neuroscience)

Harvard Medical School

Alcohol and Drug Abuse Research Center

Mclean Hospital

115 Mill Street

Belmont, MA 02178

60
Primate Studies of the Behavioral

Pharmacology of Buprenorphine

Nancy K. Mello and Jack H. Mendelson

INTRODUCTION

Buprenorphine, an opioid mixed agonist-antagonist, is a powerful analgesic with

minimal capacity to induce physical dependence (Houde 1979; Jaffe and Martin

1985; Martin 1979). Clinical studies suggest that buprenorphine is potentially

useful for the treatment of opioid dependence (Mello and Mendelson 1980;

Mello et al. 1982; Jasinski et al. 1982, 1983). Buprenorphine, an oripavine

derivative of thebaine, is a congener of etorphine, a potent opioid agonist, and

diprenorphine, an opioid antagonist (Lewis 1974). The basic pharmacology of

buprenorphine has been described elsewhere (Lewis et al. 1983; Cowan et al.

1977a, 1977b; Jacob et al. 1979; Martin et al. 1976). This chapter summarizes

some studies of the behavioral pharmacology of buprenorphine in the primate

model and discusses recent studies that suggest that buprenorphine may be

useful as a pharmacotherapy for the treatment of cocaine abuse as well as

opioid dependence.

Both opiate agonists and opiate antagonists have been used to treat opiate

addiction, and each approach is based on a different rationale (Jaffe 1985).

Opioid agonists such as methadone and its long-acting derivative levo-alphaacetylmethadol (LAAM) produce subjective effects that are similar to heroin’s

and induce cross-tolerance to opioids, attenuating the euphorigenic response

to other opioid drugs (Blaine et al. 1978, 1981; Dole and Nyswander 1965;

Jaffe 1985). Opioid antagonists such as naltrexone antagonize the subjective

and physiological effects of opioids for 24 hours or more (Martin et al. 1973a;

Verebey et al. 1976; Julius and Renault 1976). Clinical research has shown

that naltrexone effectively suppresses heroin self-administration by heroin

addicts (Meyer and Mirin 1979; Mello et al. 1981). Unlike methadone,

naltrexone can be discontinued abruptly without discomfort if a patient wishes

to resume drug use. Naltrexone, however, has no opioid-like agonist effects,

and this probably contributes to the poor patient acceptance of narcotic

antagonist treatment (Meyer and Mirin 1979; Mello et al. 1981). Outpatient

evaluations of naltrexone treatment have shown that most patients tend to

61
discontinue naltrexone within days or weeks (Meyer and Mirin 1979; O’Brien et

al. 1975; Resnick and Washton 1978; Schecter 1980; Crabtree 1984).

Buprenorphine combines the characteristics of both opioid agonist and

antagonist pharmacotherapies for heroin addiction and offers some advantages

over either opioid agonists or antagonists used alone (Mello and Mendelson

1985). For example, unlike methadone, buprenorphine does not produce

severe and protracted withdrawal signs and symptoms in humans (Jasinski

et al. 1978; Mello et al. 1982; Lukas et al. 1984; Fudala et al. 1989).

Buprenorphine is also safer than opioid agonists, since its antagonist

component appears to prevent lethal overdose even at approximately 10 times

the analgesic therapeutic dose (Banks 1979). This characteristic reduces the

possibility of opiate overdose deaths so often associated with illicit methadone

use (Kreek 1978).

The first inpatient clinical studies of subcutaneous (SC) buprenorphine

administration by Jasinski and coworkers (1978) showed that it was equivalent

to naltrexone in the duration of opiate antagonist action (Martin et al. 1973a).

Suprenorphine (8 mg/day SC) blocked the subjective and miotic effects of high

doses of morphine (60 to 120 mg/day) for up to 29.5 hours. More recently,

sublingual buprenorphine maintenance (2, 4, 8, and 16 mg) administration

has been shown to produce a dose-related blockade of a hydromorphone

challenge (Bickel et al. 1988a). Moreover, the buprenorphine blockade of

hydromorphone’s subjective effects persisted for 24 hours (Bickel et al. 1988a).

Buprenorphine also is effective for opiate detoxification (Jasinski et al. 1982,

1983; Bickel et al. 1988b; Kosten and Kleber 1988), and the availability of a

sublingual preparation of buprenorphine further enhances its potential clinical

utility.

Although the pharmacological profile of buprenorphine would predict that it

should be effective in the treatment of opioid dependence, it was important to

determine whether buprenorphine in fact attenuated heroin self-administration

by heroin addicts. The first inpatient evaluation of buprenorphine effects on

heroin self-administration was conducted in the Clinical Behavior Laboratory

of the Harvard-McLean Alcohol and Drug Abuse Research Center (Mello and

Mendelson 1980; Mello et al. 1982). Operant techniques were used to provide

an objective and quantifiable measure of drug-seeking behavior. The operant

paradigm used was similar to that previously employed in a clinical evaluation

of naltrexone (Mello et al. 1981).

Buprenorphine maintenance reduced heroin self-administration by

experienced heroin abusers by 69 to 98 percent. Seven subjects maintained

on buprenorphine treatment (8 mg/day) took significantly less heroin than did

62
seven subjects maintained on buprenorphine placebo (p <.001). A lower

dose of buprenorphine (4 mg/day) also significantly reduced heroin selfadministration in comparison to placebo maintenance (p <.02) and suppressed

overall heroin use by 45 percent. In contrast, placebo buprenorphine subjects

took between 98 and 100 percent of all the heroin available over the 10-day

period of heroin availability. Only two subjects used less than the daily

maximum amount of heroin available and on only two occasions.

Buprenorphine was accepted by the subjects, and tolerance to its opiateagonist side effects developed gradually. Buprenorphine did not suppress

these subjects’ ability to perform an operant task for money. These data

suggest that buprenotphine should be an effective pharmacotherapy for the

treatment of heroin addiction (Mello and Mendelson 1980; Mello et al. 1982).

A more complete description of these clinical studies appears in Mendelson

and Mello (this volume).

BUPRENORPHINE’S EFFECTS ON OPIATE SELF-ADMINISTRATION:

PRIMATE STUDIES

One question of important clinical relevance is the comparative effectiveness

of buprenorphine and methadone for the treatment of opiate dependence.

The authors used a primate drug self-administration model to compare the

effectiveness of buprenorphine and methadone in suppressing the intravenous

(IV) self-administration of two commonly abused opiates, heroin and

hydromorphone (Mello et al. 1988).

Six male macaque monkeys were surgically implanted with chronic indwelling

double-lumen catheters to permit IV drug self-administration. All surgical

procedures were performed under aseptic conditions. One catheter lumen

was used for opiate drug self-administration, and the second lumen was used

for administration of the maintenance treatment drugs, buprenorphine or

methadone. Monkeys were maintained in accordance with Department of

Health and Human Services “Guidelines for the Care and Use of Laboratory

Animals,” and their health status was periodically monitored by a veterinarian.

After a treatment-free baseline of 60 sessions of stable opiate selfadministration, the effects of IV saline control treatment on food and opiate

self-administration were studied for 20 sessions. Subsequently, monkeys

were assigned to treatment with either buprenorphine or methadone. Animals

in each treatment group were equated for drug history insofar as possible. Two

monkeys were studied under both buprenorphine and methadone maintenance

conditions in a single crossover design. However, the toxic effects of high

doses of methadone in the methadone-first group precluded use of a single

crossover design in all subjects (Mello et al. 1988).

63
The effects of methadone and buprenorphine treatment on opiate and food

self-administration were studied over an ascending and a descending dose

series. Doses of each drug were extrapolated from the clinically effective dose

range. However, it was necessary to exceed the clinical dose range of both

buprenorphine and methadone to affect significantly opiate self-administration

by primates. Buprenorphine was studied over a dose range of 0.014 to 0.789

mg/kg/day (equivalent to 1 to 56 mg/day in humans), and each dose was

studied for 20 consecutive sessions. Methadone was studied over a dose

range of 0.179 to 11.86 mg/kg/day (equivalent to 12.5 to 800 mg/day in

humans). Each methadone dose also was studied for 20 sessions each unless

adverse reactions required terminating a high toxic dose of methadone after 1

or 2 days. The severity of adverse reactions to methadone limited the

maximum dose studied in individual monkeys.

Food (1 g banana pellet) and IV drug self-administration, heroin (0.01 and 0.02

mg/kg/injection) or hydromorphone (0.02 mg/kg/injection), were maintained on

a fixed ratio (FR) second-order schedule of reinforcement (FR 4 [VR 16:S]). An

average of 64 responses was required for delivery of each food pellet or drug

injection. Food sessions began at 11 a.m., 3 p.m., 7 p.m., and 11 p.m. each

day, and drug sessions began 1 hour later at 12 noon, 4 p.m., 8 p.m., and

12 p.m. Each drug or food session lasted for 1 hour or until 20 drug injections

or 65 food pellets were delivered. Operant drug and food sessions were run

every day, 7 days a week.

Maintenance drug or saline control solutions were delivered 9 hours after

termination of the last opiate drug session at midnight. This time was chosen to

reduce the possibility that buprenorphine, a mixed agonist-antagonist, would

precipitate opiate withdrawal and discomfort in monkeys that self-administered

high doses of opiates. Buprenorphine, methadone, and saline-control solutions

were administered at 9:30 a.m., 1.5 hours before the first morning opiate selfadministration session at 12 noon The four daily opiate and food sessions were

1.5 to 15 hours after methadone or buprenorphine administration. Treatment

drugs were given at a rate of 1 mL solution every 2 minutes and flushed through

with sterile saline in a volume that exceeded the estimated catheter dead

space. Additional details of the apparatus and procedures have been published

(Mello et al. 1983).

Opiate Self-Administration During Buprenorphine and Methadone

Maintenance Treatment

Buprenorphine significantly suppressed opiate self-administration by macaque

monkeys at doses between 0.282 and 0.675 mg/kg/day, equivalent to 20 to 48

mg/day in humans. Significant suppression of opiate self-administration (p<.05-

64
.001) required 2.5 to 7 times the buprenorphine dose shown to be effective in

human opiate abusers (Mello et al. 1982). In contrast, methadone over a dose

range of 1.43 to 11.86 mg/kg/day failed to suppress opiate self-administration

in four of five monkeys studied. This methadone dose range is equivalent

to 100 to 800 mg/day in humans. Illustrative data showing the effects of

buprenorphine and methadone on opiate self-administration in monkeys

(A389, B205) used in a single crossover design appear in figures 1 and 2.

Monkeys took 43 percent of their total daily opiate injections during the first

daily drug sessions, 2.5 hours after methadone administration. Consequently,

the distribution of opiate self-administration across drug sessions did not

account for the absence of methadone suppression. The authors conclude

that buprenorphine is more effective than methadone in suppressing heroin

administration in the primate model (Mello et al. 1983). These data

demonstrate the feasibility of using the primate drug self-administration model

for the evaluation of new pharmacotherapies for the treatment of opiate

addiction.

Although a controlled clinical study comparing buprenorphine and methadone

has not yet been conducted, these primate data are consistent with clinical

evaluations of buprenorphine (Mello and Mendelson 1980; Mello et al.

1982) and with previous studies of the effects of methadone on opiate selfadministration by opiate addicts (Martin et al. 1973b; Jones and Prada 1977).

Inpatient studies showed that some heroin addicts maintained on 50 to 100 mg/

day of methadone continued to work for hydromorphone (4 mg IV) by riding an

exercycle for 10 miles within 1 hour for approximately 2.5 months (Martin et al.

1973b; Jones and Prada 1975). Martin and coworkers (1973b) concluded that

even at 100 mg/day of methadone, “cross-tolerance is not complete enough

to completely abolish the reinforcing properties of 4 mg of hydromorphone

hydrochloride, which would be equieuphorigenic to approximately 10 mg of

heroin” (p. 294). Outpatient clinical studies also have shown that methadone

is not uniformly effective with all patients and some methadone maintenance

patients continue to use heroin, albeit at a lower level (Chambers and Taylor

1973; Chambers et al. 1973). A diverse pattern of polydrug abuse among

methadone maintenance patients has been well documented (Langrod 1970;

Bourne 1975; Maddox and Elliot 1975; Stimmel et al. 1978).

Methadone has been shown to block heroin self-administration in rhesus

monkeys, but only at doses associated with severe debilitation, depression,

and death (Harrigan and Downs 1981). A methadone dose of 12 to 24 mg/kg/

day suppressed heroin self-administration in one monkey (Harrigan and Downs

1981). However, for lower methadone treatment doses, most investigators

have reported continued opiate self-administration. For example, persistent

opiate self-administration during methadone maintenance was observed in the

65
FIGURE 1. Opiate self-administration during buprenorphine maintenance

*p<.05

**p<.01

***p<.001

NOTE: After a treatment-free baseline (B) of 60 sessions, saline control

treatment (S) was followed by buprenorphine treatment over an

ascending then a descending dose series. Buprenorphine

66
doses (milligrams per kilogram per day) are shown on the lower

abscissa, and the equivalent dose in humans (milligrams per day) is

shown on the top abscissa. Total drug injections (inj) per day for 20

sessions over 5 days (mean±S.E.) are shown on the left ordinate.

Statistically significant changes from the baseline during drug selfadministration are indicated by black stars for the ascending dose

series and open stars for the descending dose series. Significance

levels are shown for the first value or midpoint of a series of similar

values. Monkey A420 lost his catheter (//) during descending

buprenorphine dose 0.226 mg/kg/day and was reimplanted, and

after a 28-day interval, the 0.226 mg/kg/day dose was repeated.

SOURCE: Mello, N.K.; Bree, M.P.; and Mendelson, J.H. Comparison of

buprenorphine and methadone effects on opiate self-administration

in primates. J Pharmacol Exp Ther 225(2):378-386, 1983.

Copyright 1983 by American Society for Pharmacology and

Experimental Therapeutics.

dog (Jones and Prada 1977). Methadone maintenance resulted in an initial

suppression of morphine self-administration (1 mg/kg/injection), which gradually

returned to control levels over 2 weeks and subsequently increased significantly

above premaintenance control levels (Jones and Prada 1977). In the baboon,

a continuous infusion of methadone (8.3 mg/kg/hour) reduced, but did not

eliminate, choices of heroin (0.3-0.96 mg/kg) over food during 10 consecutive

days of observation (Griffiths et al. 1976). Thus, it appears that although

sufficient doses of opiate agonists can temporarily decrease opiate selfadministration (Griffiths et al. 1976; Wurster et al. 1977), extended observations

have shown that opiate self-administration returns to baseline levels through

time (Jones and Prada 1977; Mello et al. 1983).

The buprenorphine dose-related suppression of opiate intake observed is not

consistent with previous studies of the effects of continuous buprenorphine

infusions. For example, Harrigan and Downs (1981) reported that continuous

infusion of 0.020 or 0.040 mg/kg/hour of buprenorphine did not significantly

change morphine self-administration (2, 10, 50,250, and 625 mg/kg/injection)

during 15-minute access periods once every 4 hours. It is difficult to equate

continuous infusions with a single daily bolus drug administration. However,

a continuous buprenorphine infusion of 0.020 to 0.040 mg/kg/hour would be

equivalent to bolus administration of 0.48 to 0.96 mg/kg/day. Significant

suppression of opiate self-administration at lower doses of buprenorphine

(0.336-0.447 mg/kg/day) was observed. Several other procedural differences

limit comparisons between the present study and that of Harrigan and Downs

67
FIGURE 2. Opiate self-administration during methadone maintenance

treatment in monkeys previously studied under buprenorphine

maintenance treatment

*p<.05

**p<.01

***p<.001

NOTE: Saline control treatment (S) was followed by methadone treatment over

an ascending and descending dose series. Methadone doses

(milligrams per kilogram per day) are shown on the lower abscissa, and

the equivalent dose in humans (milligrams per day) is shown on the

top abscissa. Total drug injections per day (mean±S.E.) are shown on

the left ordinate. Each point reflects 20 sessions over 5 days with the

following exceptions: monkey A389—saline was run for 120

sessions over 30 days; monkey B205—saline was run for 60

sessions over 15 days; methadone doses of 2.18 and 2.93 mg/kg/day

were run for 40 sessions over 10 days (the most proximal point is

joined to the preceding and following values by a solid line); and the

68
highest methadone dose was run for only eight sessions over 2 days.

Statistically significant changes from saline control levels are indicated

by open stars for the descending series.

SOURCE: Mello, N.K.; Bree, M.P.; and Mendelson, J.H. Comparison of

buprenorphine and methadone effects on opiate self-administration

in primates. J Pharmacol Exp Ther 225(2):378-386, 1983.

Copyright 1983 by American Society for Pharmacology and

Experimental Therapeutics.

(1981). For example, they used an FR 1 schedule of reinforcement and 15-

minute drug access periods and alternated 3 days of morphine availability with

2 days of methamphetamine and 2 days of saline availability.

Food Self-Administration During Buprenorphine and Methadone

Maintenance Treatment

Food self-administration also was affected differently by buprenorphine and

methadone. Maintenance on buprenorphine at doses of 0.014 to 0.789 mg/kg/

day for more than 6.5 months was not associated with a reduction in food

intake, and two monkeys showed significant increases in food intake at higher

buprenorphine doses. These data confirm previous observations that food

intake increased significantly in monkeys that self-administered up to 3

mg/kg/day of buprenorphine (Mello et al. 1981). Monkeys maintained on

buprenorphine remained generally healthy and alert, and these data further

testify to the safety of daily buprenorphine treatment at high doses over several

months.

Methadone suppressed food intake significantly below baseline in all monkeys

at some point during the course of methadone maintenance treatment. An

opiate-related decrease in food intake has been reported consistently in the

experimental (Cochin et al. 1948; Crowley et al. 1975; Lukas et al. 1988) and

clinical (Isbell 1948) literature. Moreover, methadone-maintained monkeys

appeared very debilitated by the prolonged course of high-dose opiate

exposure. Methadone administration over a dose range of 7.35 to 11.86

mg/kg/day resulted in transient seizures. Profound intoxication and respiratory

depression at the highest doses studied required administration of naloxone

(0.2 mg/kg/injection). It was necessary to limit methadone doses to the

equivalent of 500 to 800 mg/day in humans to prevent methadone-related

lethality. Comparable methadone toxicity has been reported by several other

laboratories (Crowley et al. 1975; Harrigan and Downs 1981; Snyder et al.

1977).

69
BUPRENORPHINE’S EFFECTS ON COCAINE AND FOOD SELFADMINISTRATION: PRIMATE STUDIES

Cocaine abuse has increased among heroin-dependent persons, including

those in methadone maintenance treatment programs (Kosten et al. 1986,

1987a, 1987b; Kaul and Davidow 1981), and has reached epidemic proportions

in the general population (Kozel and Adams 1986). At present, there is no

uniformly effective pharmacotherapy for cocaine abuse (Kleber and Gawin

1984; Gawin and Ellinwood 1988) and the dual abuse of cocaine plus heroin is

a difficult treatment challenge. The opiate agonists methadone and IAAM and

the opiate antagonist naltrexone are useful for the treatment of heroin abuse

(Dole and Nyswander 1965; Blaine et al. 1978, 1981; Meyer and Mirin 1979;

Martin et al. 1973a, 1973b; Mello et al. 1981). But these pharmacotherapies

have not proven useful for combined cocaine and heroin abuse (Kosten et al.

1987a). Although desipramine (a tricyclic antidepressant) reduces cocaine

abuse in some patients (Gawin and Kleber 1984; Tennant and Rawson 1983;

Kosten et al. 1987b; Gawin and Ellinwood 1988), desipramine may stimulate

relapse to cocaine abuse in abstinent patients (Weiss 1988). Treatment with

methadone and desipramine has yielded inconsistent results on cocaine use

by heroin abusers (O’Brien et al. 1988; Kosten et al. 1987b).

The effects of daily buprenorphine treatment on cocaine self-administration by

five rhesus monkeys were examined (Mello et al. 1989, 1990a). Two male and

three female adult rhesus monkeys with a 262±79-day history of cocaine selfadministration were studied. Each monkey was surgically implanted with a

double-lumen silicon rubber IV catheter under aseptic conditions to permit

administration of buprenorphine or saline during each cocaine selfadministration. The IV catheter was protected by a custom-designed tether

system that permits monkeys to move freely. Monkeys worked for food (1 g

banana pellets) and for IV cocaine (0.05 or 0.10 mg/kg/injection) on an FR 4

(VR 16:S) operant schedule of reinforcement. An average of 64 responses was

required for each food pellet or cocaine injection. Food and cocaine were

available during four 1-hour sessions each day. Food sessions began at 11

a.m., 3 p.m., 7 p.m., and 7 a.m.; cocaine sessions began at 12 noon, 4 p.m., 8

p.m., and 8 a.m. Each food or drug session lasted for 1 hour or until 20 drug

injections or 65 food pellets were delivered. The total number of cocaine

injections was limited to 80 per day to minimize the possibility of adverse drug

effects (Johanson et al. 1976). The nutritionally fortified banana pellet diet was

supplemented with fresh fruit, vegetables, biscuits, and multiple vitamins

each day.

Daily buprenorphine treatment (or an equal volume saline control solution) was

administered each day beginning at 9:30 a.m. Buprenorphine and saline were

70
gradually infused at a rate of 1 mL solution every 12 minutes and flushed

through the catheter with sterile saline in a volume that exceeded the catheter

dead space. Buprenorphine was administered at two doses (0.40 and 0.70 mg/

kg/day) that effectively suppressed opiate self-administration in previous studies

in the primate model (Mello et al. 1983). Each dose of buprenorphine and

saline was studied for 15 consecutive days (60 sessions). After 30 days of

treatment, buprenorphine was abruptly discontinued, and daily saline treatment

was resumed.

Cocaine Self-Administration During Buprenorphine and Saline

Maintenance Treatment

Figure 3 shows cocaine and food self-administration during 15 days of

baseline saline treatment and six successive 5-day periods of buprenorphine

treatment. Each of the five monkeys self-administered relatively high doses

of cocaine during baseline saline treatment (2.1 to 4 mg/kg/day; group average

of 3.07±0.17mg/kg/day). This dose of cocaine is comparable to that often

reported by cocaine abusers; 1 to 2 gms of cocaine per week is equivalent

to 2.04 to 4.08 mg/kg/day in a 70-kg human (Mendelson et al. 1988). All

monkeys reduced cocaine self-administration during buprenorphine treatment

(p<.0001) (figure 3). On the first day of buprenorphine treatment, cocaine

self-administration decreased by 50 percent or more in four of the five subjects

(range 50 to 67 percent). Average cocaine self-administration decreased by

49 percent to an average dose of 1.60±.25 mg/kg/day during the first 5 days

of buprenorphine treatment (p<.01). Average cocaine self-administration fell

to 77 and 83 percent below baseline during days 6 to 10 and 11 to 15,

respectively, of buprenorphine treatment. Cocaine self-administration

averaged 0.98±0.11 mg/kg/day during 15 days of buprenorphine treatment

at 0.40 mg/kg/day.

During the second 15 days of buprenorphine treatment at 0.70 mg/kg/day,

cocaine self-administration decreased to between 91 and 97 percent below

baseline levels. Monkeys self-administered an average of 0.19+0.03

mg/kg/day of cocaine. Analysis of data from individual subjects showed that

both the time course and the degree of buprenorphine’s suppression of

cocaine-maintained responding were equivalent in animals that selfadministered relatively high (4 mg/kg/day) and low (2.1 mg/kg/day) doses

of cocaine during the saline baseline treatment period. After abrupt cessation

of 30 days of buprenorphine treatment, cocaine-maintained responding

remained suppressed for at least 15 days in all animals. Individual monkeys

returned to baseline levels of cocaine self-administration at different rates,

ranging from 15 to 58 days (mean 30.5±10 days).

71
FIGURE 3. Buprenorphine suppression of cocaine self-administration: The

effects of single daily infusions of buprenotphine or a saline

control solution on cocaine and food self-administration

*p<.05

**p<.01

72
NOTE: Saline treatment is shown as an open bar and buprenorphine treatment

as a striped bar (0.40 mg/kg/day) and a solid bar (0.70 mg/kg/day).

The number of days that each treatment condition was in effect is

shown on the abscissa. Each data point is the mean±SEM of five

subjects. (A)=the average number of cocaine injections selfadministered; (B)=the average dose of cocaine (mg/kglday) selfadministered; (C)=the average number of food pellets selfadministered. The statistical significance of each change from the

saline treatment baseline as determined by analysis of variance for

repeated measures and Dunnett’s tests for multiple comparisons is

shown by an asterisk.

SOURCE: Mello N.K.; Mendelson, J.H.; Bree, M.P.; and Lukas, S.E.

Buprenorphine suppresses cocaine self-administration by rhesus

monkeys. Science 245:859-862, 1989. Copyright 1989 by

American Association for the Advancement of Science.

The prolonged suppression of cocaine self-administration after termination

of buprenorphine treatment is comparable to clinical reports of delayed onset

of buprenorphine withdrawal signs and symptoms. Peak abstinence signs

and symptoms occurred within 15 to 21 days after abrupt cessation of

buprenorphine (8 mg/day SC) treatment for 54 days (Jasinski et al. 1978).

After 36 days of sublingual buprenorphine treatment (8 mg/day), mild

withdrawal symptoms were reported 3 to 5 days after the last dose of

buprenorphine (Fudala et al. 1989). This sublingual dose is equivalent to 5.3

mg SC (R.E. Johnson, personal communication, June 1988). Differences in

the effective dose of buprenorphine and the duration of treatment as well as the

measures of withdrawal may account for the differences between the two

studies (Jasinski et al. 1978; Fudala et al. 1989). The delay (days or weeks) in

appearance of mild buprenorphine withdrawal signs and symptoms probably

reflects the slow dissociation of buprenorphine from the opiate receptor (Lewis

et al. 1983). Moreover, studies of buprenorphine kinetics in rhesus monkeys

have shown that multiple doses (1.0 mg/kg every 6 hours over 4 weeks)

increased the biological half-life of buprenorphine threefold in comparison to

a single 1.0 mg/kg SC injection (Numata et al. 1981).

Food Self-Administration During Buprenorphine and Cocaine SelfAdministration

Food-maintained responding also was suppressed by 31 percent during the

first 15 days of buprenorphine treatment (0.40 mg/kg/day) (figure 3). During the

second 15 days of treatment, with a higher dose of buprenorphine (0.70 mg/kg/

73
day), food self-administration gradually recovered to average 20 percent below

baseline. Although these changes in food-maintained responding were

statistically significant (p<.05-.01), it is unlikely that they were biologically

significant. There were no correlated changes in body weight, and animals

continued to eat daily fruit and vegetable supplements.

Analysis of the pattern of food self-administration by individual monkeys

indicated that buprenorphine treatment did not change the overall daily

distribution of sessions in comparison to saline treatment. For example,

food intake during the first session at 11 a.m. after buprenorphine treatment

(9:30 a.m. to 10:30 a.m.) was not suppressed in comparison to saline

treatment. Within 3 to 7 days after cessation of buprenorphine treatment

(mean=8.5±2.9 days), four of five animals returned to baseline levels of

food-maintained operant responding. Animals did not appear sedated

during buprenotphine treatment, and activity levels were normal. The authors

conclude that buprenorphine treatment suppressed cocaine-maintained

responding but did not produce a generalized suppression of behavior.

Implications of Buprenorphine’s Suppression of Cocaine SelfAdministration for Drug Abuse Treatment

These data suggest that buprenorphine may be an effective pharmacotherapy

for treatment of cocaine abuse. The primate model for preclinical evaluation

of pharmacotherapies has several advantages, including ensured compliance

with the treatment regimen and no confounding by polydrug abuse. Clinical

evaluation of buprenorphine treatment of cocaine abuse, however, will require

double-blind (buprenorphine vs. placebo) trials with randomized patient

assignment and independent indices of compliance with the treatment regimen

(buprenorphine blood levels) and objective measures of illicit drug use (frequent

drug urine screens). If buprenorphine treatment of cocaine abuse proves to be

clinically efficacious, this would not be a “substitute addiction” with a less toxic

cocaine-like stimulant drug analogous to methadone treatment of heroin

dependence.

These data also suggest that buprenorphine may be potentially valuable for

the treatment of dual addiction to cocaine and heroin because it suppresses

heroin use by heroin addicts (Mello and Mendelson 1980, 1985; Mello et al.

1982). One open clinical trial of buprenorphine treatment is consistent with

the hypothesis that buprenorphine may be efficacious for reduction of cocaine

abuse as well as heroin abuse (Kosten et al. 1989). Opioid-dependent patients

treated with daily sublingual doses of buprenorphine for 1 month (average 3.2

mg/day; range 2-8 mg) had significantly fewer cocaine-positive urines than did

patients treated with methadone (Kosten et al. 1989). If buprenorphine reduces

74
cocaine abuse as well as dual cocaine and heroin abuse, the potential benefits

to society in terms of reduction of drug abuse problems and the associated risks

for human immunodeficiency virus infection are incalculable.

The mechanisms accounting for suppression of cocaine self-administration by

an opioid mixed agonist-antagonist drug are unclear. The relative contribution

of buprenorphine’s opioid agonist and antagonist components to its effects

on cocaine’s reinforcing properties are unknown, but there is considerable

evidence that opioid antagonists such as naloxone and naltrexone do not

suppress cocaine self-administration in primates or in rodents (Woods and

Schuster 1972; Killian et al. 1978; Goldberg et al. 1971; Ettenberg et al.

1982; Carroll et al. 1986). We infer that either buprenorphine’s opioid agonist

component or its opioid agonist-antagonist combination is critical for

suppression of cocaine self-administration. Clinical and primate studies

of opioid agonisteffects on cocaine self-administration are inconsistent.

Methadone treatment did not reduce cocaine-positive urines in heroindependent patients (Kosten et al. 1987a, 1989) but morphine pretreatment

suppressed cocaine self-administration in a dose-dependent manner in squirrel

monkeys (Stretch 1977).

Since cocaine’s reinforcing properties are critically modulated by dopaminergic

neural systems and buprenorphine appears to modify the reinforcing properties

of cocaine, these data suggest an interrelationship between opioid and

dopamine systems (Fischman 1987; Dackis and Gold 1985; Kuhar et al.

1988; Ritz et al. 1987; Woolverton et al. 1984; Woolverton 1986). This

interpretation is consistent with several lines of evidence indicating

comodulatory interactions between endogenous opioid and dopaminergic

systems in brain. Neuroendocrine (Mendelson et al. 1986; Kuljis and Advis

1989; Mello et al. 1990b), neuropharmacological (Ishizuka et al. 1988;

Di Chiara and lmperato 1988) and behavioral (Bozarth and Wise 1981;

Blumberg and lkeda 1978; Shippenberg and Herz 1987) studies suggest

comodulatory interrelationships between dopaminergic and endogenous

opioid system activity. These data suggest the importance of examining

commonalities in the way in which abused drugs maintain behavior leading

to their self-administration (Mello 1983; Di Chiara and lmperato 1986).

COMPARISON OF BUPRENORPHINE’S ACUTE AND CHRONIC EFFECTS

ON FOOD-MAINTAINED RESPONDING

Although chronic buprenorphine administration did not suppress food

self-administration in rhesus monkeys (Mello et al. 1981, 1982, 1983), the

acute administration of buprenorphine usually suppresses food-maintained

responding in other primates (Dykstra 1983; Lukas et al. 1986) and in pigeons

75
(Leander 1983). For example, in squirrel monkeys, acute administration of

buprenorphine over a dose range of 0.0003 to 1.0 mg/kg suppressed foodmaintained responding on a multiple fixed ratio (FR 30) fixed interval (FI 5-

minute) schedule of reinforcement (Dykstra 1983). In baboons, acute

administration of buprenorphine at a dose of 3.2 mg/kg also significantly

suppressed food self-administration maintained on an FR 50 schedule of

reinforcement. At lower doses (0.01-1.0 mg/kg), however, buprenorphine did

not affect food-maintained responding in baboons (Lukas et al. 1986). in

contrast to these findings, fixed-ratio discrimination performance maintained by

food was not affected by acute administration of 3.2 mg/kg of buprenorphine in

food-deprived rhesus and Patas monkeys (Moerschbaecher et al. 1984). There

was no effect of buprenorphine on the rate or the accuracy of responding in this

paradigm (Moerschbaecher et al. 1984). Buprenorphine (0.01-3.2 mg/kg) also

failed to disrupt performance on a multiple schedule involving complex visual

discriminations by food-deprived Patas monkeys (Moerschbaecher et al. 1987).

It is possible that relative food deprivation (i.e., maintenance of animals at 85

percent of free-feeding weight) increased the saliency of food reinforcement in

these discrimination studies. However, no data on the number of banana

pellets earned were presented; accuracy of discrimination performance was

the primary dependent variable (Moerschbaecher et al. 1984.1987). The

procedural differences among these several studies make it difficult to account

for the apparent differences in buprenorphine’s acute effects on foodmaintained performance.

The discrepancy between acute and chronic drug administration data suggests

that although the gradual introduction of buprenorphine does not disrupt

food intake in humans or in primates (Jasinski et al. 1978; Mello et al. 1981,

1982, 1983) isolated single doses of buprenorphine may suppress foodmaintained behavior for the duration of action of the compound (Dykstra 1983;

Lukas et al. 1986). The acute and chronic effects of buprenorphine on foodmaintained responding in macaque monkeys were reexamined (Mello et al.

1985). After food self-administration was stable on an FR 4 (VR 16:S) secondorder schedule, monkeys were given a single SC injection of either saline or

buprenorphine (0.01, 0.03, 0.1, or 0.3 mg/kg) 1 hour before the 11 a.m. food

session. Four food sessions were run each day at 4-hour intersession intervals.

Buprenorphine doses were given in an ascending order. Saline and each dose

of buprenorphine were repeated twice after a 72-hour interval.

Figure 4 shows that pretreatment with low acute doses of buprenorphine

(0.01 and 0.03 mg/kg) did not change the number of food pellets earned or

response rates on an FR 4 (VR 16:S) schedule of reinforcement from saline

treatment levels. Acute administration of higher doses of buprenorphine (0.10

and 0.30 mg/kg) significantly suppressed food self-administration (p<.01).

76
FI GURE 4. The effects of an acute dose of saline or buprenorphine on foodmaintained responding by male macaque monkeys

NOTE: Food self-administration (1 g banana pellet) was maintained on an FR

4 (VR 16:S) schedule of reinforcement that required an average of 64

responses for each food pellet. Saline and buprenorphine doses (0.01-

0.30 mg/kg) are shown on the abscissa. Average numbers of food

pellets earned in four postdrug food sessions distributed over 20 hours

are shown on the left ordinate as black squares. Responses per

second are shown on the right ordinate as open squares. Each data

point represents an average of 32 food self-administration sessions.

SOURCE: Adapted from Mello, N.K.; Bree, M.P.; Lukas, S.E.; and Mendelson,

J.H. Buprenorphine effects on food-maintained responding in

macaque monkeys. Pharmacol Biochem Behav 23:1037-1044,

1985. Copyright 1985 by Pergamon Press plc.

The rate of food-maintained responding also decreased significantly from

saline control levels after acute administration of 0.10 and 0.30 mg/kg of

buprenorphine (p<.01). Moreover, there was a dose-dependent persistence of

buprenorphine’s suppressive effects on food self-administration (p<.02) and on

the rate of food-maintained responding (pc.05). However, after pretreatment

with low doses of buprenorphine (0.01 and 0.03 mg/kg), food-maintained

responding remained slightly (but not significantly) depressed for 48 hours.

Food self-administration was significantly suppressed by an acute dose of

77
0.10 mg/kg of buprenorphine, but the total number of food pellets earned

returned to within 4 percent of the saline control baseline within 48 hours after

buprenorphine administration. However, after pretreatment with the highest

dose of buprenorphine (0.30 mg/kg), food-maintained responding was

suppressed for up to 72 hours (Mello et al. 1985).

The effects of chronic buprenorphine self-administration (0.01-0.10 mg/kg/

injection) and heroin self-administration (0.01-0.10 mg/kg/injection) on foodmaintained responding also were examined (Mello et at. 1985). Four doses of

buprenorphine over a range of 0.01 to 0.10 mg/kg/injection were studied in five

monkeys. All monkeys were not studied at every dose of each drug. Three

doses of heroin over a range of 0.01 to 0.10 mg/kg/injection were studied in

two monkeys. Monkeys were exposed to an ascending series of doses of

buprenorphine and heroin.

Drug and food self-administration were maintained on the same second-order

schedule of reinforcement FR 4 (VR 16:S) for a minimum of 40 sessions over

10 days or until food and drug self-administration were stable. In the

progressive ratio studies, the number of responses required for each drug

injection was increased systematically, but food-maintained responding was

controlled by the same FR 4 (VR 16:S) schedule of reinforcement. The average

response requirement for each drug injection was increased from 64 to 96 to

128 to 160 by increasing the value of the FR component of the second-order

schedule from FR 4 to FR 6 to FR 8 to FR 10, etc. Each increase in the FR

schedule component was run for eight sessions over 2 days. Progressive

increases in the response requirement for drug injections were continued

until the monkey stopped responding for drug for 2 consecutive days.

Chronic buprenorphine self-administration (0.01-0.10 mg/kg/injection) did not

significantly suppress food intake. When average daily doses of buprenorphine

self-administered were three to nine times higher than the highest dose studied

in the acute buprenorphine administration paradigm, there was no suppression

of food-maintained responding. As progressive ratio-response requirements

increased, buprenorphine intake fell to 30 or 40 percent of baseline levels,

but food self-administration remained constant. For example, total daily

buprenorphine intake was more than 0.90 mg/kg/day during baseline and

declined to approximately 0.30 mg/kg/day with no corresponding changes in

food intake. Food intake increased significantly in two monkeys when

buprenorphine self-administration (mg/kg/day) was equivalent to or double the

acute dose that significantly suppressed food intake. At higher doses per

injection (0.10 mg/kg/injection), total daily buprenorphine intake decreased from

more than 2.5 mg/kg/day to approximately 1.5 mg/kg/day with no corresponding

changes in food intake. In one monkey, buprenorphine doses as high as 5 mg/

78
kg/day did not suppress food intake, and gradual decreases in buprenorphine

self-administration were not accompanied by increased food self-administration

(Mello et al. 1985). Similarly, chronic heroin self-administration (0.01,0.05, and

0.10 mg/kg/injection) was not associated with significant changes in food selfadministration.

The most parsimonious explanation of these differences between acute

and chronic effects of buprenorphine on food-maintained responding appears

to be that tolerance develops to buprenorphine’s effects. This interpretation is

necessarily inferential since this study was not designed to measure tolerance

per se. But this hypothesis is consistent with clinical observations that tolerance

to the opioid agonist-like side effects of buprenorphine developed within 21

days (Mello et al. 1982). This is also consistent with other evidence of tolerance

to the behavioral and physiological effects of buprenorphine (Lewis et al. 1983;

Mello et al. 1982). However, a tolerance hypothesis is not consistent with

observations in squirrel monkeys, where repeated administration of 0.01 mg/kg/

day of buprenorphine for 17 days continued to suppress food-maintained rates

of responding (Dykstra 1983). In an effort to assess whether or not tolerance

occurs to buprenorphine’s acute suppressive effects on food-maintained

responding, this issue was reexamined in rhesus monkeys (Lukas et al. 1988).

Analysis of Tolerance to Buprenorphine’s Effects on Food-Maintained

Responding

The time course of the development of tolerance to buprenorphine’s effects on

food-maintained responding was examined by exposing rhesus monkeys to

25 consecutive days of single SC injections of buprenorphine (1.0 mg/kg/

day) (Lukas et al. 1988). Monkeys worked for food (1 g banana pellets) on

a second-order FR 4 (VR 16:S) schedule that required an average of 64

responses for each food pellet. Food was available at 11 a.m., 3 p.m., and 7

a.m., and each session lasted for 1 hour or until 65 food pellets were delivered.

Buprenorphine or saline control injections were given 1 hour before the 11 a.m.

food session.

Figure 5 shows that the first injection of buprenorphine (1.0 mg/kg) significantly

suppressed food-maintained responding and suppression was greatest on the

second day of treatment. Food-maintained responding returned to control

levels within 4 days of buprenotphine treatment and remained at or slightly

above control levels for the next 21 days.

Substitution of saline for buprenorphine was followed by a further increase in

food self-administration and then by a gradual decline over 7 to 10 days. This

was not accompanied by any discernible signs of buprenorphine withdrawal

79
FIGURE 5. Changes in total daily food pellets (mean±S. E.) earned during 25

wnsewtive days of buprenorphine (1.0 mg/kg), diprenorphine

(1.0 mg/kg), or heroin (7.0 mg/kg) administration

NOTE: Each data point represents the percent change from 10 days of saline

control treatment for three monkeys. Monkeys self-administered

between 125 and 224 pellets per day during saline treatment.

Consecutive days are shown on the abscissa. Daily averages are

shown for the first 5 days, and 5-day averages are shown for days 10

through 25.

SOURCE: Adapted from Lukas, S.E.; Mello, N.K.; Bree, M.P.; and Mendelson,

J.H. Differential tolerance development to buprenorphine-,

80
diprenorphine-, and heroin-induced disruption of food-maintained

responding in macaque monkeys. Pharmacol Biochem Behav

30:977-982, 1988. Copyright 1988 by Pergamon Press plc.

(Lukas et al. 1988). These data confirm the hypothesis that tolerance develops

rapidly to buprenorphine’s disruptive effects on food-maintained responding

(Mello et al. 1983). These data are consistent with the interpretation that

tolerance accounts for the reported differences between the acute and chronic

effects of buprenorphine on food-maintained responding (Mello et al. 1985). It

was found that gradual induction of buprenorphine maintenance treatment and

daily buprenorphine administration at doses of 0.014 to 0.789 mg/kg/day over

6 months did not produce suppression of food-maintained responding (Mello et

al. 1983). Similarly, chronic buprenorphine self-administration of 0.3 to above

2.8 mg/kg/day did not suppress food-maintained responding (Mello et al. 1981,

1965).

Comparison of the Effects of Buprenorphine, Diprenorphine, and Heroin

on Food-Maintained Responding

There is an extensive literature indicating that, in general, opiate agonists

increase food intake in several species, whereas opiate antagonists usually

suppress feeding behavior (Morley et al. 1983a, 1983b; Yim and Lowy 1984).

Since buprenorphine is a congener of diprenorphine, a potent opioid antagonist,

and etorphine, an opioid agonist (Lewis et al. 1983) it is a unique compound

for studying opiate effects on food intake. However, it is unclear whether

buprenorphine’s opioid agonist or antagonist effects were primarily responsible

for its acute suppressive effects on food-maintained responding (Mello et al.

1985; Lukas et al. 1988).

Diprenorphine, the antagonist component of buprenorphine (Lewis et al. 1983)

suppresses rates of food-maintained responding (Dykstra 1983; DeRossett

and Holtzman 1984) and decreases body weight in squirrel monkeys (Herman

and Holtzman 1984) but comparable data were not available for rhesus

monkeys. If the acute suppression of food-maintained responding by

buprenorphine does reflect predominantly antagonist effects, this might explain

the duration of buprenorphine’s acute effects. Diprenorphine (1.0 mg/kg) and

buprenorphine (0.1 mg/kg) each suppressed food-maintained responding for 24

to 48 hours in squirrel monkeys (DeRossett and Holtzman 1984). A protracted

suppression of food-maintained responding would be expected, since the opioid

antagonist effects of buprenorphine persist for up to 72 hours, while its opioid

agonist effects persist for about 6 hours (Jasinski et al. 1978; Lewis et al. 1983).

In an effort to clarify the relative contribution of the agonist and antagonist

81
components of opioid mixed agonist-antagonist drugs to effects on foodmaintained behavior, the acute effects of diprenorphine and heroin were

compared to buprenorphine under identical conditions (Lukas et al. 1988).

Diprenorphine (1.0 mg/kg/day) significantly suppressed food-maintained

responding on the first day of treatment (figure 5). Food intake remained

suppressed for 5 days but gradually returned to control levels by day 10.

Food-maintained responding then increased significantly above control levels

between days 15 and 25 of diprenorphine treatment (p<.05). Heroin (1.0 mg/

kg) also decreased food-maintained responding on the first day of treatment.

A slight recovery of food-maintained responding occurred between days 5 and

7 of heroin treatment, but food-maintained responding was significantly below

the saline baseline throughout heroin treatment (p<.01).

Figure 6 shows the rates of tolerance development to buprenorphine, heroin,

and diprenorphine. The linear portion of the time/effect curve was subjected

to regression analysis (Tallarida and Jacob 1979). The regression lines

for buprenorphine and diprenorphine were significantly different from

heroin but were not different from each other. The buprenorphine and

diprenorphine regression lines for recovery of food-maintained performance

were parallel, but the diprenorphine curve was shifted to the right, indicating

that recovery was delayed by 3 days. These data show that the rates of

tolerance development to diprenorphine and buprenorphine were the same.

The 3-day delay in development of tolerance to diprenorphine may result from

the fact that diprenorphine has a shorter duration of antagonist action than does

buprenorphine (DeRossett and Holtzman 1984; Dykstra 1983) and it may

have taken longer for effective drug levels to accumulate in the blood.

The lack of tolerance to heroin is inconsistent with previous observations that

20 days of heroin self-administration did not significantly suppress foodmaintained responding when the total daily intake was 0.18, 1.12, and 1.79

mg/kg (Mello et al. 1985). In that study, however, heroin intake was more

evenly distributed throughout the day across four drug sessions between

noon and midnight. A single bolus dose of heroin (1.0 mg/kg/day) was more

disruptive than a comparable daily dose distributed over 12 hours. The exact

mechanisms of the observed differences in the rate of tolerance development

between buprenorphine, diprenorphine, and heroin are unknown, but it is

likely that one major contributing factor is the difference in pharmacokinetic

properties of these drugs (Lukas et al. 1988).

PREDICTION OF BUPRENORPHINE’S ABUSE LIABILITY

Buprenorphine suppresses opiate self-administration in human heroin addicts

(Mello and Mendelson 1980; Mello et al. 1982) and in a primate model (Mello

82
FIGURE 6. Regression analysis of the rate of recovery from heroin-,

buprenorphine-, and diprenorphine-induced suppression of

food-maintained behavior

NOTE: Only the linear portion of the time-effect curve was analyzed; this

included days 2 to 8 of the heroin and buprenorphine treatment and

days 5 to 11 of diprenorphine treatment.

SOURCE: Adapted from Lukas, S.E.; Mello, N.K.; Bree, M.P.; and Mendelson,

J.H. Differential tolerance development to buprenorphine-,

diprenorphine-, and heroin-induced disruption of food-maintained

responding in macaque monkeys. Pharmacol Biochem Behav

30:977-982, 1988. Copyright 1988 by Pergamon Press plc.

et al. 1983). Recent studies suggest that buprenorphine may also suppress

cocaine self-administration in primates (Mello et al. 1989, 1990a) and reduce

cocaine use by heroin-dependent persons (Kosten et al. 1989). An unresolved

issue affecting clinical deployment of buprenorphine, however, is its abuse

liability relative to other opiates such as methadone and heroin.

It is well established that buprenorphine produces opiate agonist-like

subjective effects comparable to morphine and methadone. A comparison

of the subjective effects of single doses of buprenorphine (0.2-2.0 mg),

morphine (15-40 mg), and methadone (30 mg) revealed similar euphoria and

liking scores on several self-report measures (Jasinski et al. 1978). Moreover,

subjects reported similar degrees of “liking” during chronic buprenorphine

or morphine maintenance (Jasinski et al. 1978). An 8-mg/day dose of

83
buprenorphine produced subjective effects and euphoria equivalent to that

produced by 120 mg/day of morphine (30 mg q.i.d.) or 40 to 60 mg of

methadone (Jasinski et al. 1978). Although SC injection of buprenorphine

did not produce a rapid high or “rush” similar to IV heroin injection,

buprenorphine-maintained subjects did report a generalized feeling of

contentment (Mello and Mendelson 1980; Mello et al. 1982).

Since buprenorphine and other mixed agonist-antagonist drugs have minimal

physical dependence producing capacities, this has refocused attention on the

adequacy of using physical dependence as a criterion for predicting abuse

liability (Woolverton and Schuster 1983). Although it has long been known that

the reinforcing properties of psychomotor stimulants and low doses of opiates

are independent of physical dependence (Schuster and Johanson 1974), the

assumption that opiate abuse is critically modulated by physical dependence

and the avoidance of withdrawal has remained a central concept in drug abuse

liability evaluation (Thompson and Unna 1977; Martin and Jasinski 1977).

The primate drug self-administration model has been shown to be a powerful

tool for evaluating reinforcing efficacy and predicting the abuse potential of

new compounds (Griffiths et al. 1979, 1980; Schuster and Johanson 1974;

Thompson and Unna 1977; Brady and Lukas 1984) and a high concordance

between animal drug self-administration data and subjective reports of opiate

effects has been reported consistently (Griffiths and Balster 1979). However,

there have been relatively few studies of the reinforcing properties of

buprenorphine or other opioid mixed agonist-antagonist drugs (Balster and

Lukas 1983).

Buprenorphine has consistently been shown to be a positive reinforcer in

rhesus monkeys (Woods 1977; Mello et al. 1981; Yanagita et at. 1982;

Young et al. 1984). Woods (1977) was the first to report that substitution of

buprenorphine (0.003-0.10 mg/kg/injection) for codeine (0.32 mg/kg/injection)

maintained responding on an FR 30 schedule of reinforcement. However,

response rates for buprenorphine were lower than response rates for codeine,

morphine, or heroin (Woods 1977). These original findings were recently

confirmed under the same experimental conditions, and buprenorphine

maintained the highest rates of responding at a dose of 0.1 mg/kg/injection

(Young et al. 1984).

It was reported that buprenorphine maintained operant responding on a

second-order FR 3 (VR 16:S) schedule that required an average of 48

responses per injection (Mello et al. 1981). Monkeys self-administered

buprenorphine across a dose range of 0.005 to 0.10 mg/kg/injection and took

significantly more buprenorphine injections than saline (p<.01). Four monkeys

took progressively more buprenorphine (mg/kg/day) as the dose per injection

84
increased from 0.01 to 0.10 mg/kg (Mello et al. 1981). Yanagita and coworkers

(1982) also have reported that buprenorphine was clearly reinforcing at unit

doses of 0.004 mg/kg/injection and above.

Relative Reinforcing Properties of Buprenorphine and Opioid Agonists

Although buprenorphine consistently maintains behavior leading to its

administration, recent studies suggest that it is less reinforcing than other

opioid agonist drugs (Mello et al. 1988a). One way to evaluate the relative

reinforcing efficacy of two compounds is to use a progressive ratio procedure.

The response requirement for each drug injection is progressively increased

until the animal stops responding (i.e., reaches a “breakpoint”).

Progressive ratio performances for buprenorphine with heroin, methadone, and

saline were compared (Mello et al. 1988a). Eight monkeys with a history of

opioid agonist and opioid mixed agonist-antagonist self-administration and two

initially drug-naive monkeys were subjects. Buprenorphine was studied over a

dose range of 0.01 to 0.10 mg/kg/injection and methadone over a dose range

of 0.03, 0.10, and 0.25 mg/kg/injection. Each drug dose was available for 40

sessions over 10 days at the lowest response requirement (FR 4 [VR 16:S]) or

until baseline drug self-administration was stable. Subsequently, the response

requirement for each drug injection was increased by 32 responses every

eight sessions (2 days) until drug self-administration ceased for 2 consecutive

days. The immediately preceding drug-response requirement defined the

breakpoint, or the maximum number of responses that the monkey would emit

for a single drug injection. After the breakpoint at one drug dose was reached,

the monkey was returned to the baseline schedule (FR 4 (VR 16:S]) at the same

dose until drug self-administration resumed. Monkeys then were given access

to another drug dose and run on the baseline schedule until drug selfadministration was stable for 40 consecutive sessions. Response requirements

then were increased progressively as before and continued until the monkey

reached the breakpoint at that dose.

Figures 7a and 7b show progressive ratio data for buprenorphine (0.01-

0.10 mg/kg/injection), heroin (0.01-0.10 mg/kg/injection), and methadone

(0.03-0.25 mg/kg/injection). Both heroin (0.01-0.10 mg/kg/injection) and

intermediate doses of methadone (0.10 mg/kg/injection) appeared to be

significantly more reinforcing than buprenorphine. Monkeys consistently emitted

more responses for heroin and for methadone (0.10 mg/kg/injection) than for

any dose of buprenorphine. In contrast to buprenorphine, the progressive ratio

breakpoint for heroin increased as a function of increased heroin doses per

injection (Mello et al. 1988a). These progressive ratio studies suggest that

buprenorphine is less reinforcing than two opioid agonists that are known to

be abused by humans (Mello et al. 1988a).

85
FIGURE 7a. Percent change in responding for buprenorphine from baseline

control levels as a function of progressive increases in the

number of responses required for each injection

NOTE: The percent change from baseline control levels on an FR 4

(VR 16:S) schedule is shown on the left ordinate. The number

86
of responses required for each drug injection is shown on the

abscissa. The group average progressive ratio breakpoint is

indicated by in each panel. The group average for 0.01 mg/kg/

injection buprenorphine represents five animals; the group average for

0.03 mg/kg/injection buprenorphine represents six animals; the group

averages for 0.05 and 0.10 mg/kg/injection buprenorphine represent

three or four animals, respectively.

SOURCE: Mello et al. 1988a. Copyright 1988 by Elsevier Scientific Publishers

Ireland Ltd.

Relative Reinforcing Properties of Buprenorphine and Other Opioid Mixed

Agonist-Antagonists

The relative reinforcing properties of nalbuphine (Nubain), butorphanol (Stadol),

and pentazocine (Talwin) were compared with saline and buprenorphine in

male rhesus monkeys (Mello et al. 1988b; Yanagita et al. 1982). Yanagita and

coworkers (1982) compared buprenorphine and another opioid mixed agonistantagonist, pentazocine, on a progressive ratio procedure and found that the

breakpoint was lower for buprenorphine (0.015 and 0.06 mg/kg/injection) than

for pentazocine (0.06 and 0.25 mg/kg/injection). These data suggest that

buprenorphine has lower potential for abuse than pentazocine. Progressive

ratio performances for nalbuphine (0.010, 0.032, and 0.100 mg/kg/injection),

butorphanol (0.0010, 0.0032, and 0.0100 mg/kg/injection), pentazocine (0.10,

0.32, and 0.56 mg/kg/injection), and saline were compared. After baseline

drug self-administration was stable, the second-order schedule response

requirement per injection was increased in increments of 64 until the monkey

stopped responding for eight consecutive sessions (Mello et al. 1988b).

All three drugs at each dose maintained more responding and higher

progressive ratio breakpoints than did saline. Group average progressive ratio

breakpoints for butorphanol showed dose-related increases of 576, 1,173, and

1,963 responses per injection. Progressive ratio breakpoints for the highest

dose of butorphanol were higher than for any dose of nalbuphine. The low and

high doses of nalbuphine maintained higher progressive ratio breakpoints

(1,600 and 1,472 responses per injection) than did the intermediate dose of

nalbuphine (618 responses per injection). Group average breakpoints for

pentazocine also showed dose-related increases (864 and 1,824 responses

per injection), and these studies are still in progress. In contrast, group average

breakpoints for saline-maintained responding ranged between 64 and 170

responses per injection. These data suggest that the relative reinforcing

efficacy of each of these three opioid mixed agonist-antagonist drugs is quite

87
FIGURE 7b. Percent change in responding for heroin and methadone from

baseline control levels as a function of progressive increases in

the number of responses required for each injection

NOTE: The percent change from baseline control levels on an FR 4 (VR 16:S)

schedule is shown on the left ordinate. The number of responses

required for each drug injection is shown on the abscissa. The group

average progressive ratio breakpoint is indicated by in each panel.

Each data point for heroin represents an average of three or four

animals. Data points for methadone (0.03 and 0.10 mg/kg/injection)

represent three animals; data for methadone (0.25 mg/kg/injection)

represent one animal.

SOURCE: Mello et al. 1988a. Copyright 1988 by Elsevier Scientific Publishers

Ireland Ltd.

88
similar to those of the others (Mello et al. 1988b). These data obtained in a

primate drug self-administration model are consistent with clinical observations

of pentazocine abuse and predictions of abuse liability of butorphanol and

nalbuphine (Jaffe 1985). Progressive ratio breakpoints for nalbuphine,

butorphanol, and pentazocine were consistently higher than previously reported

for buprenorphine (0.10 mg/kg/injection) or heroin (0.10 mgikg/injection) (522

and 1,067 responses per injection) (Mello et al. 1988a). These data suggest

that these opioid mixed agonist-antagonists may have a greater potential for

abuse than buprenorphine.

Buprenorphine also has proved to be less reinforcing than other opioids and

some opioid mixed agonist-antagonists in baboons and in rhesus monkeys, as

evaluated with a simple drug substitution procedure (Lukas et al. 1983, 1986;

Young et al. 1984). Baboons were trained to self-administer cocaine (0.32 mg/

kg/injection) on an FR 160 schedule of reinforcement. Baboons could earn a

maximum of eight injections per day, and a 3-hour timeout interval was imposed

after each drug injection. The self-administration patterns of codeine and

morphine were compared to four mixed agonist-antagonist drugs (butorphanol,

nalbuphine, pentazocine, and buprenorphine) and one antagonist (naloxone)

and SKF-10047, a prototype sigma agonist. Each of the mixed agonistantagonists-nalbuphine (0.001-1.0 mg/kg/injection), butorphanol (0.0001-0.1

mg/kg/injection), and pentazocine (0.32-10.0 mg.kg/injection)-was selfadministered at higher levels than buprenorphine across a dose range of

0.00032 to 0.32 mg/kg/injection (Lukas et al. 1983, 1986). Moreover, each

mixed agonist-antagonist drug, except buprenorphine, showed a drug selfadministration profile similar to that of codeine (i.e., more injections were selfadministered at higher doses per injection than at lower doses per injection).

These drug self-administration profiles contrast sharply with the relatively flat

dose-response curve observed for buprenorphine in baboons (Lukas et al.

1986).

Similar findings were obtained in rhesus monkeys using drug substitution

procedures with response rate as a measure. Monkeys were trained to selfadminister codeine (0.32 mg/kg/injection) on an FR 30 to 600 seconds in 2 daily

sessions that terminated after 13 infusions or 130 minutes (Young et al. 1984).

The opioid mixed agonist-antagonist butorphanol (0.001-0.0032 mg/kg/injection)

and propriam (0.03-1.0 mg/kg/injection) maintained response rates between

1.25 and 1.5 per second, whereas buprenorphine maintained response rates

that averaged one per second at doses of 0.0032 to 0.01 mg/kg/injection

(Young et al. 1984). In contrast to data in baboons, nalbuphine (0.001-0.32

mg/kg/injection) maintained response rates consistently below one per

second. However, interpretation of data obtained in a substitution procedure

in terms of relative reinforcing efficacy is limited by several problems associated

89
with using response rate as a measure (Schuster and Johanson 1974; Schuster

and Balster 1973).

CONCLUSIONS: THE POTENTIAL USEFULNESS OF BUPRENORPHINE

AS A PHARMACOTHERAPY FOR HEROIN AND COCAINE ABUSE

Ultimately, the abuse potential of any pharmacotherapy must be balanced

against its safety and efficacy relative to other drugs (Mello and Mendelson

1988). Buprenorphine maintenance treatment effectively reduced heroin

self-administration by heroin addicts (Mello and Mendelson 1980; Mello et

al. 1982) and offers some advantages as an analgesic (Houde 1979).

Buprenorphine appears to be as effective as methadone for detoxification of

heroin addicts (Bickel et al. 1988b; Kosten and Kleber 1988). Buprenorphine,

however, has two important advantages over the opiate agonist methadone

as a pharmacotherapy for opiate addiction: (1) Buprenorphine does not

induce significant physical dependence in humans, and consequently,

buprenorphine treatment can be discontinued without severe withdrawal

signs and symptoms (Jasinski et al. 1978; Fudala et al. 1989; Lukas et al.

1984); and (2) the possibility of lethal overdose is remote due to the opiate

antagonist properties of buprenorphine (Lewis et al. 1983; Jasinski et al.

1978; Banks 1979; Mello et al. 1982).

The opiate agonist component of buprenorphine that raises concern about its

potential abuse liability is buprenorphine’s primary advantage over treatment

with the opiate antagonist naltrexone. It is likely that the agonist component of

this opioid mixed agonist-antagonist is important for patient acceptance, since

naltrexone, an equally potent opioid antagonist, has not been widely effective

in the treatment of heroin addiction. It has been very difficult to retain heroin

abusers in naltrexone treatment programs (Julius and Renault 1976; Resnick

and Washton 1978; Meyer and Mirin 1979; Schecter 1980; Crabtree 1984). We

conclude that the safety and potential therapeutic benefits of buprenorphine

probably outweigh the possible risks associated with its abuse potential. To

date, illicit diversion of buprenorphine has been minimal compared to that of

heroin (O’Connor et al. 1988).

However promising buprenorphine appears to be as a pharmacotherapy

for heroin addiction (Mello and Mendelson 1980), dual addiction to heroin

and cocaine (Kosten et al. 1989) and perhaps cocaine abuse per se (Mello

et al. 1989,1990a), it is not a chemical panacea. Even though an effective

pharmacotherapy may antagonize drug effects and improve mood, there is

always the possibility that drug abusers may engage in other forms of addictive

drug use. Drug addiction is a complicated and multiply determined behavior

disorder. It is realistic to anticipate that buprenorphine, and its successor

90
pharmacotherapies, may attenuate drug abuse but probably will not completely

eliminate it.

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ACKNOWLEDGMENT

Preparation of this chapter was supported in part by National Institute on Drug

Abuse grants DA-02519, DA-04059, DA-00101, and DA-00064.

AUTHORS

Nancy K. Mello, Ph.D.

Professor of Psychology (Neuroscience)

Jack H. Mendelson, M.D.

Professor of Psychiatry (Neuroscience)

Harvard Medical School

Alcohol and Drug Abuse Research Center

McLean Hospital

115 Mill Street

Belmont, MA 02178

100
Phase II Clinical Trials of

Buprenorphine: Detoxification and

Induction Onto Naltrexone

Thomas R. Kosfen, Charles Morgan, and Herbert O. Kleber

INTRODUCTION

Pharmacologic treatment strategies for heroin addiction currently employ two

general approaches: detoxification followed by drug-free abstinence and

maintenance treatment with either opioid agonists or antagonists (Cushman

and Dole 1973; Gold et al. 1978; Kleber et al. 1985; Kosten and Kleber 1984;

Resnick et al. 1977). Since the goal of agonist maintenance with methadone

is usually the eventual detoxification to a drug-free state, detoxification from

methadone or heroin to either drug-free or antagonist treatment is a clinically

important treatment strategy. Detoxification techniques have ranged from

methadone-dosage tapering to clonidine substitution and the combination

of clonidine substitution with naloxone (Cushman and Dole 1973; Gold et al.

1978; Kleber et al. 1985; Resnick et al. 1977). Transition to antagonists,

such as naltrexone, has been clinically difficult, however, because naltrexone

introduction must be delayed to allow for an adequate opioid-free interval during

which physical dependence will be lost to avoid precipitating withdrawal (Kosten

and Kleber 1984). Previous work has shown that naltrexone, even at very low

doses (1 mg), will precipitate substantial withdrawal symptoms in patients

discontinued from methadone 18 hours earlier (Charney et al. 1984). Typically,

10 to 14 days must intervene between the last methadone dose and the first

naltrexone dose to avoid precipitating withdrawal (Kosten and Kleber 1984).

As an alternative to this long opioid-free period, during which relapse to

drug abuse is likely, the authors have explored the early introduction of the

antagonist naltrexone (Charney et al. 1981, 1982; Kleber et al. 1987; Vining

et al. 1988). In the initial studies, an attempt was made to introduce very small

doses of antagonist directly after stopping the agonist (Charney et al. 1982;

Kleber et al. 1987). Conceptually, this was an attempt to introduce opioid

antagonism gradually to avoid precipitating withdrawal. Because even low

naltrexone doses precipitated withdrawal, it was necessary to administer

101
clonidine to suppress these symptoms. Opioid-dependent patients detoxified

with clonidine and naltrexone exhibited approximately a 50-percent reduction in

the duration of their acute withdrawal symptoms (Charney et al. 1982; Kleber et

al. 1987; Vining et al. 1988). These studies suggested that recovery from

opioid physical dependency might be accelerated by the introduction of an

opioid antagonist.

Another strategy to accelerate reduction in opioid dependency would be to

introduce a partial opioid agonist that could precipitate mild withdrawal and

at the same time minimize these symptoms by its agonist activity. This

strategy has not been feasible with previously available partial agonists such

as pentazocine, cyclazocine, butorphanol, or nalorphine, since they precipitate

significant withdrawal in morphine-dependent patients and may cause

psychosis in some patients (Jacob et al. 1977; Martin 1967; Martin et al.

1966; Pircio et al. 1976; Woods and Gmerek 1983). A new partial agonist,

buprenorphine, however, showed therapeutic promise because of early work

indicating that it did not precipitate significant withdrawal in methadone- or

morphine-dependent patients (Jasinski et al. 1978, 1984; Mello and Mendelson

1980; Mello et al. 1982).

Buprenorphine is a partial opioid agonist or mixed agonist antagonist that

addicts report does not produce a heroin-like rush (Jasinski et al. 1984).

Buprenorphine doses of 2 to 4 mg have been substituted for 20 to 30 mg of

methadone without precipitating substantial withdrawal symptoms, although

buprenorphine may act as an opioid antagonist at doses as low as 8 mg

(Jasinski et al. 1978; Mello and Mendelson 1980; Mello et al. 1982). After

chronic administration, buprenorphine does not produce significant physical

dependence, as suggested by the minimal withdrawal symptoms that occur

when it is stopped (Dum et al. 1981; Jasinski et al. 1984; Lewis 1986).

Because of these properties, buprenorphine was examined to determine

whether it might facilitate the transition from opioid agonists to antagonists in

a three-step process: (1) buprenorphine substitution for agonists such as

methadone, (2) buprenorphine-induced reduction in physical dependency, and

(3) discontinuation of buprenorphine with rapid introduction of naltrexone.

The design for this study with opioid-dependent patients involved an initial

outpatient protocol followed by an inpatient protocol for patients in the last twothirds of this study. The outpatient protocol included discontinuation of either

heroin or methadone followed by a 30-day trial on a range of buprenorphine

dosages (protocol A). Induction onto naltrexone was attempted in all those

patients who completed 30 days on buprenorphine. For the first one-third of

the subjects, there was an attempt to complete their induction as outpatients,

but because this was generally unsuccessful, a second inpatient protocol was

102
developed. The inpatient protocol (protocol B) began after the 30-day

outpatient buprenorphine maintenance and included blinded discontinuation

of the buprenorphine followed by double-blind placebo-controlled challenges

with either low-dose naltrexone or high-dose naloxone. These two inpatient

challenges carefully compared the capacities of low-dose naltrexone and highdose naloxone to precipitate withdrawal in buprenorphine-maintained patients.

Although the initial challenge studies were done with low-dose naltrexone (1 mg

oral P.O.) to parallel earlier work with naltrexone in methadone-maintained

patients (Charney et al. 1984), the subsequent studies were high-dose

naloxone rather than naltrexone for three reasons. First, previous work with

partial agonists such as butorphanol, nalbuphine, and pentazocine had used

high doses of naloxone to precipitate a withdrawal syndrome after chronic

treatment with these agents, thereby providing some guidelines for its use with

buprenorphine. In these studies with nalbuphine and butorphanol, a withdrawal

syndrome could be precipitated by 4 mg naloxone (Jacob et al. 1977; Jasinski

et al. 1968; Pircio et al. 1976; Woods and Gmerek 1985). With pentazocine, 10

to 15 mg of naloxone was necessary to reverse its agonist as well as dysphoric

effects, whereas up to 16 mg of naloxone did not reverse respiratory depression

associated with buprenorphine (Dum et al. 1981; Jasinski et al. 1978; Kallos

and Smith 1968; Quigley et al. 1984; Kosten et al. 1988, Lewis 1985). Thus,

high doses of naloxone had been given previously to patients treated with these

partial agonists, and it appeared that over 16 mg of naloxone might be needed

with buprenorphine to precipitate any withdrawal.

Second, translating this naloxone dose into an equivalent dose of naltrexone is

not straightforward because the half-life is markedly longer for naltrexone than

for naloxone and because two indicators of antagonist potency—recipitating

withdrawal or blocking exogenous opioids-suggest different relative potencies

of these two medications (Kosten and Kleber 1984; Martin 1967). Precipitation

of withdrawal in opioid-dependent patients can be induced by as little as 0.1

mg of naloxone or 1 mg of naltrexone, while blocking a 25-mg injection of

heroin after antagonist administration requires 1 mg of intravenous (IV)

naloxone or 50 mg of oral naltrexone (Charney et al. 1982, 1984; Kleber

et al. 1987; Vining et al. 1988). These two assessments indicate a tenfold

to fiftyfold relative potency of naloxone over naltrexone, suggesting that

unacceptably large naltrexone doses, theoretically more than 800 mg (50

times 16 mg naloxone), would be required to precipitate significant withdrawal

in buprenorphine-maintained patients. This high-dose naltrexone (above 200

mg daily) has been associated with liver toxicity.

Third, any substantial withdrawal syndrome precipitated by the high-dose

antagonist would last substantially longer with naltrexone than with naloxone

103
(Charney et al. 1982; Kleber et al. 1987; Kosten and Kleber 1984; Resnick et al.

1977). In addition to behavioral ratings of withdrawal symptoms, physiological

(blood pressure) and biochemical (3-methoxy-hydroxyphenethylamine glycol

[MHPG]) responses to antagonist challenge were monitored. Previous work

had demonstrated increases in both blood pressure and plasma-free MHPG, an

index of norepinephrine turnover, during low-dose naltrexone-precipitated

withdrawal in methadone-maintained patients (Charney et al. 1984). Thus,

these two other measurements could be used to provide important objective

correlates of any opioid withdrawal precipitated by naltrexone in buprenorphinemaintained patients.

METHODS

Subjects

Forty-one opioid-dependent patients were entered into the month-long

outpatient protocol A. The patients included 31 males and 10 females with a

mean age of 31 (±SEM 1) years. Of these, 14 patients came from methadone

maintenance at a dose of 25 mg/day, and the other 27 patients were using

street heroin. For those using heroin, opioid addiction was confirmed using

urine toxicology and challenge with naloxone at 0.8 mg intramuscularly (Wang

et al. 1974; Kleber et al. 1985). To qualify for inclusion, these heroin abusers

had to attain a withdrawal score above 35 on the laboratory’s clinician-rated

scale within 15 minutes of naloxone injection. The outpatient withdrawal-rating

scale includes 24 items with 0- to 3-point severity ratings and has a score

range of 0 to 72 (Kosten et al. 1985). An item score of 3 indicates “severe”

withdrawal, and a total score of less than 20 indicates minimal withdrawal.

For the inpatient challenges, a 15-item subscale ranging from 0 to 45 was

used. This shorter subscale allowed more rapid administration and used items

considered more responsive to acute change over the course of the antagonist

challenges.

Of the 41 patients, 18 entered the inpatient protocol B after completion of the

30-day outpatient protocol A. The inpatient protocol included double-blind

challenges with either lowdose naltrexone in 13 patients or high-dose naloxone

in 5 patients. The other 23 patients either dropped out of the outpatient protocol

A before 30 days (n=13) or completed the open outpatient protocol A and

attempted outpatient induction onto naltrexone from buprenorphine (n=10).

The 18 patients entering the inpatient protocol and the 23 other patients were

not significantly different in demographics or percentage from the methadone

maintenance group (26 percent inpatient vs. 39 percent outpatient).

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The findings from the inpatient protocol were compared with those of a

previously published study in which 15 methadone-maintained patients

(mean dose 35 mg daily; range 20 to 65 mg) were given low-dose (1 mg)

oral naltrexone challenges (Charney et al. 1984). These patients included 10

males and 5 females and had a mean age of 31±1 years. The mean duration

of methadone treatment was 3±1 years. Eight other methadone-maintained

patients were given a blinded challenge with placebo, but data were incomplete

on one of them. The seven placebo patients included five males and two

females and had a mean age of 3±1 years.

Study Design

Protocol A: Outpatient. Patients starting buprenorphine treatment were

discontinued from either methadone maintenance or street heroin and within

24 hours of their last dose were started on sublingual buprenorphine at 2 mg,

except for four patients. Two of the four started at 4 mg, and the other two

started at 8 mg in a dosage-induction experiment that examined whether opioid

withdrawal would be precipitated by the higher buprenorphine dosages. Among

the 37 patients starting at 2 mg, a wider range of maintenance dosages was

examined, and after the first 5 days, the maintenance dosages were 2 mg

(n=16), 3 mg (n=14), 4 mg (n=4), and 6 mg (n=3). This was an open trial with

single daily dosing 7 days a week. After the first 5 days, patients remained

on fixed dosages of buprenorphine for days 6 to 30 as outpatients and then

either stopped the buprenorphine as outpatients or entered protocol B. During

this 30-day outpatient trial, withdrawal symptoms were rated daily by a clinician,

and urine toxicologies were obtained twice weekly on a randomized schedule.

For the 12 patients who had been transferred from methadone maintenance

to buprenorphine, urine toxicologies for the 2 months before starting

buprenorphine also were obtained. Two months of urines were used, because

only random weekly urines, rather than twice weekly urines, were obtained in

the methadone program. The rates of cocaine- and opioid-positive urines were

compared for methadone and buprenorphine treatments.

Buprenorphine was discontinued abruptly in an open trial with 10 outpatients

who took buprenorphine for 30 days. Maintenance dosages for these patients

were 2 mg (n=3), 3 mg (n=2), 4 mg (n=3), 6 mg (n=1), and 8 mg (n=1). They

reported few withdrawal symptoms during the 3 to 5 days that the authors were

able to follow them after discontinuation of buprenorphine, but only two (at 2 mg

and 4 mg) took any naltrexone, and they all returned to methadone

maintenance or illicit opioid use.

Protocol B: Inpatient. Following the 30 days on buprenorphine, 18 patients

were hospitalized at the Connecticut Mental Health Center Clinical

105
Neuroscience Research Unit for 4 to 7 days. Upon admission to the hospital,

each patient received a maintenance dose of buprenorphine once daily at 5

p.m. for 3 days. The maintenance doses were 2 mg (n=7), 3 mg (n=8), 4 mg

(n=2), and 6 mg (n=1). The buprenorphine then was discontinued abruptly by

blinded substitution of placebo on day 3 after each patient had completed a

placebo antagonist challenge. In the naltrexone challenge, an oral placebo was

given at 9 a.m. on that day. In the naloxone challenge, an IV placebo was

given instead. The day after buprenorphine placebo substitution, patients were

given a challenge of either active naltrexone (1 mg P.O.) or active naloxone (0.5

mg/kg IV) at 9 a.m. The IV naloxone infusion was given over a 20-minute

period using a 10-mg/mL naloxone solution. Throughout the hospitalization, all

patients received a vanillylmandelic acid exclusion diet (Chamey et al. 1964).

Prior to the naltrexone or naloxone challenge procedure, each patient fasted

overnight for 10 hours and remained in the fasting state during the procedure

until approximately 3 p.m. An IV catheter was placed in the patients arm to

obtain two blood samples during the hour before receipt of naltrexone or

naloxone (baseline) and then every 30 minutes for the next 3.5 hours after

naltrexone or naloxone administration. A separate IV injection site was used

for the IV naloxone infusions. Blood pressure measurements and opioid

withdrawal ratings were obtained at the same time points. Withdrawal during

the inpatient protocol was rated using the 15-item subscale of the 24-item scale,

with items scored from 0 to 3, giving a score range from 0 to 45 (Charney et

al. 1961, 1964). This shorter subscale had been developed in the authors’

earlier methadone-naltrexone challenge study and was adopted

to facilitate comparison between the current study and previous work (Chamey

et al. 1964). The comparison methadone-maintenance patients had been

continued on a stable dose of methadone before admission to the Research

Unit and then had participated in a procedure identical to the 1-mg oralnaltrexone challenges following abrupt discontinuation of their methadone dose

(Charney et at. 1994). Raters and patients were blind as to whether placebo or

naltrexone was administered.

Biochemical Methods: Protocol B

Two 1-mL aliquots of plasma were taken from iced blood samples that were

centrifuged within 2 hours. Assays for MHPG then were conducted on these

duplicate samples using selected ion monitoring with a gas chromatograph/

mass spectrometer (Finnegan Model 3300 series) (Elsworth et al. 1962).

Because of difficulties in finding adequate veins for blood sampling, MHPG

determinations could be made at antagonist challenges for only eight of the

naltrexonechallenged and four of the naloxone-challenged buprenorphine

patients.

106
Data Analysis

For protocols A and B, data analysis induded simple descriptive measures of

treatment retention, withdrawal symptoms, and illicit drug use. Comparisons

were made across buprenorphine dosages as well as between dropouts and

the remaining sample using contingency tables or repeated measures analysts

of variance (ANOVA), as appropriate. To facilitate data analyses, ANOVA-R

of withdrawal ratings in the outpatient trial (protocol A) use ratings from days 2,

5, 8, 11, 14, 17, 20, 23, 26, and 29. For protocol B, withdrawal ratings over a

3-hour period were compared for the naltrexone- and naloxone-challenged

buprenorphine patients and the naltrexone-challenged methadone patients

(TREATMENT type) as well as for the placebo and naltrexone challenges

(CHALLENGE type) using a three-way analysis of covariance (ANCOVA)

(e.g., treatment type by challenge type by time point-repeated measure).

The naltrexone-challenged methadone patients were used as a further

historical comparison group. Mean blood pressures were calculated as

2 (systolic-diastolic)/3+diastolic pressure. Blood pressures and plasma levels

of MHPG were analyzed by determining the peak change in blood pressure or

MHPG for each patient because of considerable variability in the time course

of withdrawal symptoms induced by naloxone in the buprenorphine patients

and by naltrexone in the methadone-maintained patients. The peak changes

in blood pressure and in MHPG were compared for the various groups using

covariance adjustment for baseline differences (ANCOVA).

RESULTS

Outpatient Buprenorphine and Overall Outcome: Protocol A

The 41 opioiddependent patients generally had minimal withdrawal symptoms

while maintained on buprenorphine. Patients had mild withdrawal symptoms

when started on buprenorphine, but this declined over the first 2 weeks on

buprenorphine. The mean score (on the 24-item, 72-point scale) was 18±15

(SD) at day 2 and had declined to 11±9 by day 14 and to 9±8 by day 21.

Maintenance doses of buprenorphine during the course of the trial were

examined using only those patients started at 2 mg (four were started at higher

doses) and categorizing the patients into three groups: 2 mg (n=16), 3 mg

(n=14), and 4 or 6 mg (n=7). Because all three groups were on 2 mg during

the first 5 days, analyses were run using only days 8 through 29. Withdrawal

symptoms for the three DOSE groups were similar for weeks 2 to 4 of the trial,

and no significant DOSE effect was seen. Withdrawal symptoms at day 2

were more intense among patients getting the 2-mg standard induction dose

(18.6±15) than among the four patients started at either 4 mg or 8 mg of

buprenorphine (8±8) (t=2.3; p<.05; one tail), suggesting that higher

107
buprenorphine doses did not precipitate withdrawal. Instead, the starting dose

of 2 mg may have been somewhat low for the patients coming from methadone

maintenance (all at 25 mg) because the 10 methadone patients who started at

2 mg had fairly sustained mild withdrawal symptoms over the first 2 weeks,

while the 27 street heroin addicts showed a decline in symptom levels (repeated

measures ANCOVA, TIME: F=2.9; df=4,35; p<.03) (TREATMENT: F=2.1;

df=1,35; p<.1). At day 2 the methadone and street groups were equivalent (18

vs. 19), but by day 8 the methadone group remained at 18±15, whereas the

street group dropped to 11±8 (t=2.1; df=25; p<.05). The methadone group

remained above the street group at days 11 (18 vs. 11) (t=2.2; p<.03) and 14

(16 vs. 9) (t=2.3; p<.03). Interestingly, the four patients starting above 2 mg,

who had lower levels of withdrawal than the 2-mg patients (see above), had

all come from methadone maintenance, and they had somewhat lower

withdrawal levels throughout the first (mean=13) and second (mean=8)

weeks of buprenorphine treatment. Thus, although these levels of withdrawal

symptoms were mild and generally not related to maintenance doses of

buprenorphine, the patients coming from methadone maintenance appeared

to have a more sustained period of withdrawal adjustment and may have

benefited from a starting dose higher than 2 mg.

During the 30-day outpatient protocol, patients showed good retention and

reduced illicit opioid use. Of the 41 entrants, 29 patients (71 percent) came in

daily and completed this protocol. The mean stay was 25±8 days, and several

of the 12 dropouts left due to circumstances unrelated to the medication (e.g.,

unexpected job transfer) or to illicit drug abuse. Illicit opioid use for the patients

completing treatment declined from 33 percent of urines in week 1 to 19 percent

in week 4 and was not related to dosage of buprenorphine. For the dropouts,

illicit opioid use remained at 50 percent of urines through week 3, and both

dropouts in week 4 were using illicit opioids. For the whole trial, the percentage

of illicit opioid urines was greater among dropouts (51 percent) than among

those remaining in treatment (27 percent) (t=2.3; p<.03) and there was an

inverse correlation between days in treatment and number of illicit urines

(r=.34; p<.03) (more illicit urines with fewer days in treatment).

Demographic comparisons and overall outcome for the various maintenance

dosages of buprenorphine are shown in table 1. None of the outcomes,

including retention for 30 days, percentage of urines positive for illicit opioid

use, taking at least one dose of naltrexone, and being maintained on naltrexone

for at least 2 weeks, were significantly different among the dosage groups.

Although the rate of successful naltrexone maintenance appears to be best with

a 3-mg dose of buprenorphine (22 percent vs. 7 percent and 0 percent), this is

an artifact of the allocation of patients to naloxone challenges compared with

naltrexone challenges. All naloxone-challenge patients had been maintained at

108
TABLE 1. Sample characteristics and global outcome by maintenance dose

of buprenorphine (n=41)

Buprenorphine Dose

Characteristic 2 mg 3 mg 4,6,8 mg All

Sample size 16 14 11 (6,3,2) 41

Males (%) 69 79

Age (years±SD) 31±7 29±6

From “street” (%) 69 70

Outcomes

Stay 30 days (%) 63 70

Opiate use (%) 37 27

Take naltrexone (%) 50 50

Naltrexone>2 weeks (%) 6 22

91 77

33±7 31±7

55 68

82 71

37 33

46 49

0 10

NOTE: No differences were statistically significant.

3 mg of buprenorphine, and this naloxone procedure, rather than dose of

buprenorphine, seemed generally more effective at eventual naltrexone

induction. The patients who received a high-dose naloxone challenge were

successful at being maintained on naltrexone. This success appeared to result

from the tolerance of these patients to a rapid increase in naltrexone dosage

from 6 mg to full 50 mg over the 24 to 36 hours after the withdrawal from highdose naloxone had resolved (within 4 to 5 hours). During this rapid induction

onto naltrexone, patients had trouble sleeping and one had vague muscle

aches, but none showed severe signs of withdrawal. Thus, the high-dose

naloxone enabled a very rapid detoxification from buprenorphine. These

challenges are addressed in more detail below.

Another interesting finding among these patients was a remarkably low level

of cocaine abuse. Overall, these patients on buprenorphine had a 3-percent

rate of cocaine urine toxicologies (SD=2 percent), which is substantially less

than the 30- to 40-percent rates that are found in the authors’ methadonemaintenance program.

When the 12 patients who had been on this methadone maintenance program

were examined before starting buprenorphine, the six patients who had been

abusing cocaine demonstrated a dramatic reduction in cocaine use on

buprenorphine, as shown in figure 1.

109
FIGURE 1. Plot of rates of cocaine-positive urine toxicologies (cocaine urines

per 100) in 12 patients switched from methadone maintenance to

buprenorphine protocol for 1 month

NOTE: Each symbol represents one patient, except for the large diamond

representing the six cocaine nonabusers.

Only one patient did not stop completely, and this patient showed a 50-percent

reduction in use. When asked why they had stopped abusing cocaine, the

patients reported less pleasure from cocaine and, specifically, dysphoric "crash"

symptoms after its use. These crash symptoms had been ameliorated in the

past by “speedball” use of opioids such as heroin or methadone along with the

cocaine. Apparently, this speedball effect was blunted by the use of

buprenorphine.

inpatient Antagonist Challenges: Protocol B

Of the 18 inpatients given antagonist challenges, 13 received naltrexone and 5

received naloxone. None of the 13 patients on buprenorphine had marked

differences in their responses to 1 mg of oral naltrexone as compared to their

responses to placebo. In contrast, naltrexone (1 mg) induced substantial

withdrawal symptoms in 13 of 15 methadone-maintained patients in an earlier

study (Charney et al. 1984). Significant increases in withdrawal symptoms were

110
induced in five buprenorphine patients by high-dose naloxone infusions (0.5

mg/kg IV) (mean weight=746 kg). This naloxone dose (mean=35 mg) is about

100 times the dose usually needed to precipitate withdrawal in methadone- or

heroin-dependent subjects and is about 50 times greater than the 0.8-mg dose

that precipitated withdrawal in the heroin-dependent patients before they started

on buprenorphine 30 days earlier.

The withdrawal symptoms (and standard errors) for the two buprenorphine

groups are shown in figure 2 along with the methadone group response to

1 mg naltrexone for comparison. The placebo responses for the three different

conditions were indistinguishable from the 1-mg naltrexone response in the

buprenorphine group (n=13) and were omitted for clarity. .

The withdrawal symptoms among the buprenorphine patients were

significantly greater for the naloxone-challenged (0.5 mg/kg) than for the

naltrexone-challenged (1 mg) patients (TREATMENT type), as shown by

FIGURE 2. Plot of opioid-withdrawal symptoms for patients maintained on

buprenorphine and given either naltrexone 1 mg P.O. or naloxone

0.5 mg/kg (mean=35 mg) IV and for methadone-maintained

patients given naltrexone 1 mg P.O.

NOTE: Because placebo challenges for all three groups did not differ from

buprenorpine with naltrexone, they are not shown for clarity. The

mean scores standard errors are plotted.

111
main effects (TREATMENT: F=10.5; df=1,32; p<.003) (CHALLENGE: F=2.7;

df=1,32; p<.05, one tail) and interaction with TIME or the repeated measure

(TREATMENT X CHALLENGE X TIME: F=7.0; df=5,160; p<.0001). The

comparison of withdrawal seventy scores among the methadone and two

buprenorphine groups (TREATMENT type) also was highly significant for

main effects (TREATMENT: F=18.7; df=2,52; p<.0001) (CHALLENGE:

F=20.5; df=1,52; p<.001) and for TIME interaction (TREATMENT X

CHALLENGE X TIME: F=5.8; df=10,260; p<.0001). As figure 2 shows, the

withdrawal response for the naloxone-challenged buprenorphine patients was

substantially less than that for the naltrexone-challenged methadone patients.

The placebo challenge responses in the methadone and both buprenorphine

groups were not significantly different from each other or from the naltrexone

challenge in the buprenorphine patients. The withdrawal symptom severity was

not related to either dose of buprenorphine or methadone vs. ‘street” induction

onto buprenorphine.

Before giving the active naltrexone challenge, the baseline plasma-free MHPG

levels were not significantly different among the two buprenorphine (3.3±0.6 ng/

mL and 3.6±0.7 ng/mL) and methadone groups (3.1±0.9 ng/mL), as shown in

table 2.

TABLE 2. The effect of naltrexone- or naloxone-precipitated opiate

withdrawal on plasma-free MHPG levels in buprenorphine- and

methadone-maintained patients

MHPG (ng/mL±SD)

Treatment Group Number Baseline Peak

Buprenorphine

Naltrexone

Placebo

Naloxone

Placebo

8 3.3±0.6 3.5±O.7

8 3.2±0.9 3.6±0.8

4 3.6±0.7 3.7±0.7

4 3.5±0.8 3.9±1.0

Methadone

Naltrexone

Placebo

15 3.1±0.9 4.0±1.2

7 3.9±0.6 4.4±0.7

NOTE: Significant differences are indicated in text.

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The peak increase in plasma MHPG, however, was significantly greater for the

methadone (0.9 ng/mL) than for either the naltrexone-challenged (0.2 ng/mL) or

the naloxone-challenged (0.1 ng/mL) buprenorphine groups. Using ANCOVA

(covariance) to adjust for baseline levels, the overall F ratio was 54 (df=6,45;

p<.0001), with significant CHALLENGE (F=4.6; df=1,45; p<.04), TREATMENT

type (methadone and two buprenorphine groups) (F=8.6; df=2,45; p<.001), and

interaction effects (F=5.0; df=2,45; p<.01). The major source of this MHPG

interaction was that the buprenorphine patients showed lesser MHPG

responses to active challenge than to placebo, while the methadone patients

showed greater responses to active challenge than to placebo.

Among the buprenorphine-maintained patients, a significant change in blood

pressure was induced by the naloxone but not by the naltrexone challenge

compared to placebo challenge. Because the baseline mean blood pressures

ranged from 93 to 104 mm Hg, as shown in table 3, covariance adjustments

were used for comparisons. Using ANCOVA to compare the two

CHALLENGES for the three TREATMENTS gave an overall F ratio of 12.4

(df=6,57; p<.0001), with significant TREATMENT (F=11.4; df=2,57) and

CHALLENGE (F=11.5; df=1,57) effects but no significant interaction.

TABLE 3. The effects of naltrexone- and naloxone-precipitated opiate

withdrawal on mean standing blood pressure in buprenorphineand methadone-maintained patients

Mean Blood Pressure ±SD)

Treatment Group Number Baseline Peak Differ

Buprenorphine

Naltrexone

Placebo

Naloxone

Placebo

13 96.7±10.5 106.6±10.5 9.9

13 93.3 ± 8.9 102.0±10.3 8.7

5 94.8 ± 4.8 105.3 ± 7.0 10.5

5 104.7±14.0 102.3 ± 8.7 -2.4

Methadone

Naltrexone

Placebo

15 103.5±11.7 117.1±8.6 13.6

7 101.3 ± 9.1 105.9 ± 9.2 4.6

NOTE: Significant differences are indicated in text.

113
The difference between the placebo and naloxone challenges for the

buprenorphine patients (2.4-mm drop for placebo and 10.5-mm rise for

naloxone) was substantially greater than the difference for the naltrexonechallenged buprenorphine patients (8.7-mm rise for placebo and 9.9-mm rise

for naltrexone) and equivalent to the difference for the methadone patients

(4.6-mm rise for placebo and 13.6-mm rise for naltrexone). Thus, the blood

pressure changes were consistent with the differences in withdrawal symptoms

among the three TREATMENT groups.

DISCUSSION

This study showed that heroin addicts or methadone-maintained patients can

be transferred onto the partial opioid agonist buprenorphine for a 1 -month

outpatient program with good retention, minimal withdrawal symptoms, and a

reduction in illicit opioid and cocaine use. The reduction in cocaine abuse was

particularly striking and may offer a potential new treatment for this serious

addiction. The optimal dose of buprenorphine for outpatient treatment or for

the transition to naltrexone appears to be quite flexible within the sublingual

range of 2 to 8 mg, and dosing may be quite similar to that with methadone

maintenance in which wide individual variations are common. Based on the

good retention and limited illicit drug use, buprenorphine clearly holds promise

as a treatment agent for opioid addicts.

Following a month on buprenorphine, patients can be given low doses of the

opioid antagonist naltrexone (1 mg) without precipitating withdrawal symptoms

or increases in blood pressure and norepinephrine turnover, as reflected by

plasma MHPG levels. When given to patients maintained on the pure agonist

methadone, the same dose of naltrexone precipitated substantial withdrawal

symptoms and increases in blood pressure and MHPG levels. Withdrawal can

be precipitated in buprenorphine patients using high-dose IV naloxone (0.5

mg/kg), but this withdrawal syndrome is less intense than that produced by

even low-dose naltrexone in methadone-maintained patients. More importantly,

naltrexone maintenance can be rapidly initiated after the naloxone-precipitated

withdrawal without precipitating further withdrawal symptoms. These findings

suggest an attenuation of opioid physical dependence by the limited antagonist

activity of buprenorphine, since these buprenorphine patients had been

dependent on the opioid agonists methadone or heroin before starting

buprenorphine. In several previous reports, this group and others have shown

that opioiddependent patients can be switched from the pure agonists to

buprenorphine with minimal withdrawal symptoms (Kosten and Kleber 1988;

Jasinski et al. 1978, 1984) but systematic examination of the transition from

buprenorphine to a pure antagonist has not been previously reported.

114
Two concepts seem important in explaining the authors’ findings concerning

antagonist challenge in the buprenorphine patients—the higher opioid receptor

affinity of buprenorphine compared with commonly prescribed antagonists and

antagonist resetting of receptor mechanisms from an opioid-dependent to an

opioid-naive state.

Whereas naltrexone has a greater affinity for the p-receptor than does

methadone or heroin, buprenorphine is an unusual partial agonist in apparently

binding more tightly than naltrexone to these receptors (Neil 1984; Lewis 1985).

This difference in affinity has been offered as an explanation for naloxone’s

inability to precipitate withdrawal in buprenorphine-maintained animals (Kosten

et al. 1988; Lewis 1985). Thus, one reason low-dose naltrexone probably

produced minimal withdrawal was the inability of this pure antagonist to displace

buprenorphine, while the highdose naloxone worked by the law of mass action

to occupy enough of the receptors long enough to precipitate withdrawal.

The capacity of opioid antagonists to actively reset receptor mechanisms,

thereby decreasing physical dependence, also may contribute to the minimal

withdrawal response exhibited by the naloxone-challenged patients when

they were rapidly inducted onto naltrexone over a 36-hour period. Previous

studies have shown that coadministration of opioid agonists with antagonists

inhibited the development of physical dependency or accelerated recovery

(Cochin and Mushlin 1976). Also, clinical studies with rapid donidine

naltrexone detoxification found that giving the antagonist naltrexone to opioiddependent patients can compress the abstinence syndrome into a relatively

brief period (Chamey et al. 1982; Kleber et al. 1987; Vining et al. 1988).

Antagonist exposure appears to actively reset relevant receptor mechanisms,

not only attenuating the development of physical dependence, but also

reversing receptor changes and receptor coupling to second messengers

induced during physical dependence on opioids (Aceto et al. 1977; Bardo

et al. 1983; Cochin and Mushlin 1976; Collier et al. 1983; Krystal et al. 1989;

Rothman et al. 1986; Zukin and Tempel 1986). Buprenorphine may have

induced some receptor resetting during the month of treatment. Clearly, some

mild withdrawal was produced by buprenorphine over the first 1 or 2 weeks

after the transition from the pure agonists, and less severe withdrawal, minimal

MHPG elevation, and a relatively small blood pressure increase compared

with that found in the methadone patients were precipitated by the high-dose

naloxone.

Buprenorphine in this dosage range, however, has predominantly agonist

activity, as suggested by neuroendocrine assessments (Rolande et al. 1983;

Mendelson et al. 1982). Using cortisol, growth hormone, prolactin, and

luteinizing hormone as markers, it has been concluded that the pattern

115
of hormonal response to acute and repeated dosing of buprenorphine is

consistent with an agonist rather than antagonist profile (Rolande et al. 1983;

Mendelson et al. 1982; Brown et al. 1978). This agonist profile is consistent

with the easy transition from methadone to buprenorphine. Further work

may explore the neuroendocrine profile of buprenorphine after a month of

treatment, since previous studies have involved only several days of treatment.

Perhaps with longer treatment, buprenorphine accumulates, resulting in more

antagonist activity, as has been shown acutely in animals given much higher

dosages of buprenorphine (Cowan et al. 1977; Lewis 1985). A definitive test

of the antagonist hypothesis could best be obtained using an antagonist with a

higher receptor affinity than buprenorphine, but such a drug is not available.

Clinically, previous studies have shown that buprenorphine withdrawal may

be substantially less severe than withdrawal from pure agonists, such as

methadone (Jasinski et al. 1984). Since a major problem with methadone

maintenance treatment for opioid abuse has been the continuation of

substantial withdrawal symptoms following attainment of a drug-free state,

buprenorphine may offer a method for minimizing the withdrawal symptoms

that follow detoxification from maintenance treatment (Cushman and Dole

1973; Kosten and Kleber 1988). Furthermore, patients may start naltrexone

more readily after buprenorphine and thereby have a greater chance of

remaining drug free (Kosten and Kleber 1984). The endogenous opioid

system may indeed be set closer to normal baseline functioning when

chronically exposed to the partial antagonist buprenorphine rather than to

the pure agonist methadone. The rapid detoxification from buprenorphine

with high-dose naloxone seems to offer an exciting possibility of stabilizing

buprenorphine-treated patients on naltrexone within a day, and the low abuse

of cocaine while they are on buprenorphine suggests that patients with

combined addiction may have an ideal treatment available. Both treatment

issues deserve more careful evaluation in future studies.

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ACKNOWLEDGMENT

Support was provided by National Institute on Drug Abuse grants DA-00112

(TRK) and DA-04060.

AUTHORS

Thomas R. Kosten, M.D.

Associate Professor

Charles Morgan, M.D.

Assistant Professor

Herbert D. Kleber, M.D.

Professor

Psychiatry Department

Yale University School of Medicine

27 Sylvan Avenue

New Haven, CT 06519

119
Development of Buprenorphine for the

Treatment of Opioid Dependence

Rolley E. Johnson and Paul J. Fudala

INTRODUCTlON

The only available morphine-like agent currently approved by the Food and

Drug Administration for the treatment of opioid dependence is methadone.

Methadone is given orally to substitute for illicit opioids, thereby preventing

symptoms of withdrawal and helping individuals to maintain abstinence from

illicit drugs (Greenstein et al. 1984; Higgins et al. 1986; U.S. Department of

Health and Human Services 1988). Other drugs that have been extensively

studied for the maintenance, detoxification, or abstinence treatment of opioid

addicts include I-alpha-acetylmethadol (LAAM), clonidine, propoxyphene, and

naltrexone.

The Addiction Research Center (ARC) has had an active research program

for nearly 50 years studying these and other pharmacotherapies (U.S.

Department of Health, Education, and Welfare 1978) some of which have

demonstrated potential utility as treatment agents for opioid dependence.

This research has included studies of agonists such as methadone (Isbell

et al. 1948; Martin et al. 1973a; Nutt and Jasinski 1974; Wikler 1977a, 1977b),

LAAM (Fraser and lsbell 1952) and propoxyphene (Jasinski et al. 1977);

antagonists like nalorphine (Wikler et al. 1953; Fraser 1957; Martin and

Gorodetzky 1965), naloxone (Jasinski et al. 1967) naltrexone (Martin et al.

1973b), and cyclazocine (Martin et al. 1965, 1966); and mixed agonists/

antagonists, including propiram (Jasinski et al. 1971) butorphanol (Jasinski

et al. 1975) pentazocine (Jasinski et al. 1970), nalbuphine (Jasinski and

Mansky 1972), and buprenorphine (Jasinski et al. 1978). Since the original

study of buprenorphine by Jasinski and colleagues (1978) additional studies

have been conducted by investigators at ARC to characterize further the

pharmacologic, pharmacodynamic, and pharmacokinetic properties of

buprenorphine and to assess its utility in the treatment of opioid dependence.

Phase I inpatient studies were conducted to evaluate different doses and

routes of administration and the agonist and antagonist properties of

buprenorphine; phase II studies were conducted to assess the utility of

120
buprenorphine in outpatient populations. Results from these earlier phase I

and II studies are summarized in this chapter to provide a chronology of the

development of buprenorphine and to provide the information that formed the

basis for a dose-scheduling investigation-the major focus of this report.

EARLY PHASE I AND II STUDIES

Determination of Route of Administration

Jasinski and colleagues (1982) reported the results of single-dose studies

comparing the oral (P.O.) and sublingual (SL) routes of administration to

the subcutaneous (SC) route. They found the onset, time to peak, and duration

of effect to be similar among the three routes of administration. For sublingually

and subcutaneously administered buprenorphine, onset of action for physiologic

and behavioral effects was evident within 0.5 to 1 hour, with peak effects for

these measures occurring between 1 and 4 hours (figure 1).

Duration of these effects was similar for both SL and SC routes and may

persist for 24 hours (Jasinski et al. 1978, 1989). Orally administered

buprenorphine had one-fifth the potency (figure 2) and sublingually

administered buprenorphine had two-thirds the potency of buprenorphine

given subcutaneously. Given the low relative potency of oral buprenorphine

and the desire not to use a parenteral dosage form in treatment, the SL route

was determined to be the most appropriate for chronic administration.

Determination of the Antagonist Properties of Buprenorphine

Buprenorphine has been shown to precipitate an opioid-withdrawal

syndrome in nonhuman primates (Aceto 1984). The use of buprenorphine

as a detoxification or maintenance agent requires the substitution of

buprenorphine for heroin, methadone, or other opioids. To determine the

potential for buprenorphine to precipitate a withdrawal syndrome in opioiddependent humans, the intensity of opioid-withdrawal signs and symptoms

was measured following the administration of SL buprenorphine (0, 2, and

4 mg) and intramuscular (IM) naloxone (0.5 mg) under double-blind, doubledummy procedures to six subjects maintained on a mean methadone dose

of 38 mg (Jasinski et al. 1983). The possibility of precipitating an opioidwithdrawal syndrome was increased by administering buprenorphine or

naloxone 3 hours following the last methadone dose. Although only naloxone

precipitated a significant withdrawal syndrome, there was a trend (which

followed the onset and time course of buprenorphine effects) toward increased

physiologic withdrawal signs as the dose of buprenorphine was increased

(figure 3). These data suggested that initial doses of 2 mg, and probably

121
FIGURE 1. Mean change from baseline (pupil diameter) and mean scores on the MBG and PCAG subscales of the

ARC lnventory

NOTE: Responses were measured over 72 hours following the administration of buprenorphine or placebo. Each

point represents the mean value of 10 subjects.
FIGURE 2. Mean change from baseline (pupil diameter) and mean scores on the MBG, LSD, and PCAG subscales

of the ARC lnventoty

NOTE: Responses were measured over 24 hours following the administration of buprenorphine or placebo. Each

point represents the mean value of 10 subjects.

SOURCE: D.R. Jasinski and R.E. Johnson, unpublished data
4 mg, of buprenorphine could be used without precipitating a withdrawal

syndrome.

Determination of the Ability of Buprenorphine to Substitute for Heroin and

Methadone

Following the study of buprenorphine-precipitated withdrawal, studies were

initiated to substitute buprenorphine in morphine- and methadone-dependent

individuals. Results of these studies indicated that 2 mg of subcutaneously

administered buprenorphine produced no change in self-reported sickness

during the transition from morphine (15 mg, 4 times daily), while the transition

from methadone (54 mg daily) to buprenorphine was associated with a mild to

moderate withdrawal syndrome of shorter duration than that seen following

untreated withdrawal from methadone (Jasinski and Johnson, unpublished

observations).

Determination of an Appropriate Dosage for Treatment

Bickel and colleagues (1988a) compared the effectiveness of buprenorphine

(2 mg SL) to that of methadone (30 mg P.O.) in a 90-day outpatient

detoxification study. In this study, IM hydromorphone injections (0 and

6 mg) were administered while subjects were maintained on the above

doses of buprenorphine or methadone to assess each drug’s blockade of

hydromorphone-induced physiologic and subjective effects. Hydromorphone

produced greater pupillary constriction and subject-reported “drug liking”

(figure 4) in the buprenorphine group compared with the methadone group.

Although previous reports had indicated that subcutaneously administered

buprenorphine produced maximal agonist effects at a dose of 2 mg (Jasinski

et al. 1982) data from this study indicated that a higher buprenorphine dose

(providing more opioid blockade) would be required if buprenorphine were

to be an effective treatment agent. These results led to another study to

assess further the opioid-blocking properties of buprenorphine. This study

was conducted with five subjects who were maintained on ascending doses of

2, 4, 8, and 16 mg of sublingually administered buprenorphine for 2 weeks

(Bickel et al. 1988b). Hydromorphone doses of 0, 6, and 12 mg (6 and

18 mg cumulatively) were administered intramuscularly within 24 hours of

the last dose of buprenorphine. Results from this study indicated that an SL

buprenorphine dose of 8 mg was required to provide sufficient blockade of

subject-reported “high” (figure 5), “drug effect,” and responses on an opioidagonist adjective-rating scale following hydromorphone administration.

124
FIGURE 3. Buprenorphine vs. naloxone-mean 3-hour totals (from six

subjects) for Himmelsbach scores (bottom) and subject-reported

sickness (top)

NOTE: For Himmelsbach scores, the histograms show the relative contribution

of each component to the total score.

SOURCE: R.E. Johnson and D.R. Jasinski, unpublished data

125
FlGURE 4. Effects of a 6-mg hydromorphone challenge on subject-rated drug

liking shown for subjects treated with 2 mg buprenorphine

administered sublingually (n=15; unfilled bars) and 30 mg

methadone administered orally (n=16; filled bars)

NOTE: Data are from two observations made after hydromorphone

administration and show change from predrug baseline values.

Brackets indicate SE.

SOURCE: Bickel, W.K.; Stitzer, M.L.; Bigelow, G.E.; Liebson, I.A.; Jasinski,

D.R.; and Johnson, R.E. A clinical trial with buprenorphine:

Comparison with methadone in the detoxification of heroin addicts.

Clin Pharmacol Ther 43:72-78, 1988a. Copyright 1988 by C.V.

Mosby Company (St. Louis).

Determination of an Appropriate Dose Schedule for Treatment

Introduction. With the knowledge that buprenorphine was effective

sublingually and could substitute for heroin in heroin-dependent individuals

and that an 8-mg dose was necessary to achieve adequate blockade of

effects from other opioids, a multicomponent, interlaboratory inpatient study

128
FIGURE 5. Effects of cumulative hydromotphone doses on subject-rated high measured on an analog scale, with

subjects chronically maintained on ascending doses of buprenorphine

NOTE: The variability bars represent ± 1 SEM. B indicates challenge effects of a dose of hydromorphone that did

differ significantly (planned comparisons) from effects of that dose at the 2-mg buprenorphine maintenance

dose. H between two dose points indicates challenge doses not significantly different (planned comparisons)

from each other.

SOURCE: Bickel, W.K.; Stitzer, M.L.; Bigelow, G.E.; Liebson, I.A.; Jasinski, D.R.; and Johnson, R.E. Buprenorphine:

Dose-related blockade of opioid challenge effects in opioid dependent humans. J Pharmacol Exp Ther

247:47-53, 1999b. Copyright 1998 by American Society for Pharmacology and Experimental

Therapeutics (Davis).
was undertaken to (1) assess a rapid dose-induction procedure for the use of

buprenorphine in heroin-dependent individuals; (2) compare the efficacy of oncedaily to every-other-day dosing of buprenorphine; (3) characterize the withdrawal

syndrome associated with the abrupt termination of buprenorphine; (4) evaluate

the ability of buprenorphine to block the subjective and physiologic effects of

hydromorphone; and (5) evaluate the rate of relapse to illicit opioid use following

the termination of buprenorphine. Dependent variables included physiologic

and subject- and observer-reported behavioral measures, as well as

pharmacokinetic, neuroendocrine, electroencephalographic, and medical

safety parameters.

Methods. The study was conducted in male heroin addicts, ages 26 to 45

years, using a randomized, double-blind, parallel-group design. Inclusion

criteria included (1) three consecutively collected urine samples positive for

opioids, (2) a current self-reported period of heroin addiction of at least 4

months, (3) self-reported heroin use of $50 to $200 per day, (4) self-reported

number of intravenous (IV) heroin injections of at least two per day, and (5)

physical examination and self-reported history consistent with heroin addiction.

Subjects with active cardiovascular or hepatic disease, those who tested positive

for the human immunodeficiency virus antibody, or those presenting more than

one urine sample positive for methadone were excluded.

Buprenorphine, in a 30-percent (v/v) aqueous ethanol solution, was administered

sublingually in a 1-mL volume; buprenorphine placebo consisted of the vehicle

solution only. Hydromorphone HCI and naloxone HCI doses were prepared in

sterile saline for injection at concentrations of 0, 2, and 4 mg and 0, 3, 6, and

12 mg, respectively. Initially, doses were prepared in a volume of 2 mL. When

it became evident that all doses could not be administered by the IV route, the

injection volume was decreased to 1 mL to facilitate IM administration.

The study was conducted in three phases (figure 6). In phase 1 (days 1

through 18), all subjects received ascending buprenorphine doses of 2 ,4,

and 8 mg over the first 3 days and were maintained on 8 mg daily for the

next 15 days. In phase 2 (days 19 through 36), subjects in group 1

continued to receive buprenorphine daily, while subjects in group 2 received

buprenorphine on even-numbered study days and placebo on odd-numbered

study days. In phase 3 (days 37 through 56) all subjects received only

buprenorphine placebo and were discharged from the research ward on day

57. Hydromorphone challenges were conducted on days 16 through 18 and

31 through 36. For challenges given in phase 2, hydromorphone doses were

randomly administered to subjects in group 1 over the 6-day challenge period;

however, for subjects in group 2, active hydromorphone doses were randomized

128
FIGURE 6. Timeline for the study

NOTE: The numbers below each study day indicate the dose of buprenorphine HCI (0, 2, 4, or 8 mg) that subjects

in each group received on a particular day. Days on which subjects received hydromorphone or naloxone

challenges are also indicated.

SOURCE: P.J. Fudala and R.E. Johnson, unpublished data
to days when subjects received buprenorphine placebo. All naloxone challenges

were randomly administered on days 53 through 56.

Subscales of the ARC Inventory, observer- and subject-reported drug-effect

questionnaires, and a withdrawal-symptom questionnaire were used to rate

signs and symptoms of acute and opioid withdrawal effects. Whereas

physiologic and behavioral measures were assessed multiple times daily

throughout the study, other parameters (e.g., neuroendocrine or

electroencephalographic assessments) were assessed at appropriate

times that would not violate the blind of the study.

Results.

Dose Induction. Subject-reported "overall sickness" and “level of withdrawal”

were significantly greater on day 1 than on any other day (Fudala et al.

1988) (figure 7). No differences were observed among the other 3 days,

and no differences between days were noted for observer-reported "subject

withdrawing."

Subject-reported “drug liking,” “drug effects,” and “overall well-being" and MBG

(euphoria) scale scores increased following buprenorphine administration,

whereas "overall sickness" and LSD (dysphoria) and PCAG (apathetic sedation)

scats scores decreased. Observer-reported "subject’s liking for drug," "signs

of drug effect," and “how subject feels" also increased after buprenorphine

administration and followed the same time course as those of comparable

subject-reported measures. The peak increase or decrease for each measure

occurred between 2 and 4 hours following buprenorphine administration. The

responses for each measure at 23 hours after buprenorphine administration

were approximately equal to those observed one-half hour following drug

administration. Eleven of sixteen behavioral measures normally sensitive to

opioid withdrawal effects decreased following buprenorphine administration,

but none was significantly different with respect to changes between days.

Increased supine pulse rate, which could be an opioid-withdrawal effect, was

greatest on day 4. Pupillary constriction was greatest on days 3 and 4, when

the highest doses of buprenorphine were given, which is consistent with a

morphinelike effect. Urinary excretion data indicated that all subjects were

below the 300-ng/mL positive cutoff level for opioid equivalents by day 4.

Results from this phase of the study indicated that heroin-dependent individuals

coult be rapidly inducted onto buprenorphine without precipitating an opioidwithdrawal syndrome.

130
FIGURE 7. Mean responses for subject-reported “overall sickness” (left.) and “level of withdrawal” (right)

NOTE: Responses were measured over 23 hours following buprenorphine administration on each of the first 4 study

days. Each point represents the mean value of 11 to 19 subjects.
Everyday vs. Every-Other-Day Dosing. The same subscales and

questionnaires from the dose-induction phase were used to measure signs and

symptoms of acute drug and opioid withdrawal effects. On the days that

subjects in group 2 received no drug, LSD scale scores and reports of

symptoms, including muscle cramps and backaches, painful joints and weak

knees, and runny noses, all increased. On the days that both groups received

buprenorphine, subjects in group 2 reported greater “drug liking,” “drug effect,”

and “good effect” compared with group 1 (table 1).

TABLE 1. Multiple contrasts performed on measures that showed a

significant group by day interaction during the everyday- vs.

every-other-day-dosing comparison phase of the study

Pupils

Self-Reports

Group 1 Odd Days

Even Days vs. Odd Days Group 1 vs. Group 2

NS F=50 (2>1)

LSD

Liking

Drug effect

Good effect

Urge for opiate

Overall discomfort

NS

NS

NS F=39.2 (2>1)

F=38 (2>1)

F=19.3 (2>1)

NS F=22.4 (1>2)

NS N S

NS F=43.6 (2>1)

Pupils

Group 2

Even Days vs. Odd Days

F=66.4 (O>E)

Even Days

Group 1 vs. Group 2

NS

Self-Reports

LSD F=21.6 (O>E) NS

Liking F=95.9 (E>O) F=13.6 (2>1)

Drug effect F=62.7 (E>O) F=12 (2>1)

Good effect F=82.1 (E>O) F=13.8 (2>1)

Urge for opiate F=27 (O>E) F=15.9

Overall discomfort F=38.3

 (1>2)

(O>E) NS

NOTE: All significant F(1,187)>3.84

SOURCE: P.J. Fudala and R.E. Johnson, unpublished data

132
Subject-reported responses on the withdrawal symptom questionnaire

remained constant between days 19 and 30 and baseline (days 14 and 15)

for group 2 and decreased from baseline for group 1. Observer-reported

withdrawal was generally higher for group 2 and lower for group 1 during this

period. There were no differences between groups across days for any

physiologic measure except pupil diameter. Pupillary constriction followed

buprenorphine administration; however, on nondrug days, the pupils of

subjects in group 2 dilated.

Data from several behavioral and physiologic measures normally sensitive

to opioid withdrawal symptomatology revealed differences between the two

groups. The changes observed were not clinically significant, as evidenced by

small changes reported by both subjects and observers and by the fact that no

subject discontinued his participation during this phase of the study. Results of

this phase of the study indicated that buprenorphine dosed on an every-otherday schedule was associated with reports of mild opioid withdrawal symptoms.

Abrupt Withdrawal of Buprenorphine. Data from seven subjects who did not

receive therapeutic intervention for withdrawal signs and symptoms indicated

that peak withdrawal effects occurred between 3 and 5 days following the last

buprenorphine dose, with group 1 reporting greater effects than group 2. Peak

responses of subjects in group 2 occurred earlier than in group 1 for subjectreported “level of withdrawal” and “overall discomfort” and for observer-rated

“subject withdrawing” (figure 8). The withdrawal-symptom questionnaire did

not indicate significant differences between the two groups, and peak scores

occurred 5 days following the last buprenorphine dose. Changes in responses

generally returned to baseline within 10 days; however, subjects in group 1

experienced greater decreases in self-reported sleep than did those in group

2, and sleep did not return to baseline within 13 days. Thus, chronically

administered buprenorphine, when abruptly terminated, produced mild-tomoderate opioid-withdrawal symptoms that required little or no therapeutic

intervention.

Hydromorphone and Naloxone Challenges. Subjects completed self-report

questionnaires at 0.5, 1, 2, and 4 hours after hydromorphone and naloxone

administration. Observer-reported questionnaires were completed at these

same times and at 1.5 hours post-challenge drug. Physiologic measures

were assessed at 0.5 hours predrug and at 0.5, 1, 1.5, 2, and 4 hours postdrug.

In the first hydromorphone challenge, there were no significant treatment

effects for any subject-reported or physiologic measure. There were significant

effects for observer-reported “drug effect,” “high,” and “drug liking.” In the

second hydromorphone challenge, there were significant treatment effects for

133
FIGURE 8. Mean responses for observer-reported “subject withdrawing” (left) and subject-reported "level of

withdrawal” (middle) and “overall discomfort” (right)

NOTE: Responses were measured for 16 days following the last dose of buprenorphine (given on study day 36).

Only data from subjects who received no therapeutic intervention for withdrawal signs and symptoms are

included.

SOURCE: R.E. Johnson and P.J. Fudala, unpublished data
subject-reported “overall well-being,” for observer-reported “how subject feels,”

and for subject- and observer-reported measures of “drug effect,” “high,” and

“drug liking.” Scores on the LSD scale were lower following hydromorphone

than after placebo administration. In this challenge, hydromorphone produced

greater pupillary constriction in group 2 than in group 1; no change in any

other physiologic parameter was noted. In the naloxone challenge, no

significant effects were observed for any of the measures assessed.

The challenge doses of hydromorphone and naloxone were originally

planned to be administered through an IV catheter that was also used for

metabolic and neuroendocrine portions of this study. Due to the subject

population’s abuse of their veins, however, the veins of only six subjects

were suitable for catheter insertion. Two of these subjects completed all

three challenges by the IV route. Four and three subjects completed the

first and second hydromorphone challenges, respectively, by the IV route.

Statistical analyses were not performed on their data. For subjects in group

2 who were administered hydromotphone intravenously in the second

challenge, however, clinically significant effects were observed on measures

of subject-reported “drug liking,” MBG scale scores, and pupillary constriction.

This trend was not observed in similarly treated subjects in group 1 or in

subjects in either group who were given hydromorphone intramuscularly in

either challenge.

Results from the second hydromorphone (IM) challenge could be interpreted

to mean that there were no differences between everyday and every-other-day

dosing of buprenorphine or that even once-daily dosing of buprenorphine did

not provide sufficient blockade of the effects of hydromorphone at the doses

tested. The magnitude of these effects was small, however, suggesting limited

clinical significance.

Since IV administration is the preferred route of illicit opioid abusers,

increases in subjective measures of “liking” and MBG scale scores in subjects

who received IV hydromorphone along with the withdrawal symptomatology

observed in group 2 during every-other-day dosing suggest that buprenorphine

at the dosage tested should be administered no less often than once daily.

Results of the naloxone challenge tests indicated that no physical dependence

was evident 17 days after cessation of chronic buprenorphine administration.

Postdischarge Followup. Subjects were followed for 4 weeks after discharge

from the research ward. They returned twice weekly, with a minimal interval

of 1 day between visits, to provide urine samples and receive aftercare (e.g.,

referrals for abstinence counseling and vocational training). The urine samples

of only 2 of 15 subjects were negative for opioids or other drugs of abuse. One

of these subjects, however, was incarcerated after the second visit.

135
Pharmacokinetic, Neuroendocrine, Electroencephalographic, and Medical

Safety Parameters. Preliminary data from the pharmacokinetic portion of

the study indicated that during the dose-induction phase, buprenorphine

equivalents in the urine increased, whereas opioid equivalents decreased.

Data from two subjects (figure 9) showed plasma levels ranging from

approximately 6 to 7 ng/mL when buprenorphine was dosed once daily.

Plasma buprenorphine levels from the subjects given the drug every other

day appeared to be about half of those observed during daily dosing. Following

abrupt termination of buprenorphine, plasma levels decreased below the 1-ng/

mL sensitivity level of the assay within 3 days.

Data from four subjects indicated that plasma testosterone levels increased

compared with controls following the withdrawal of buprenorphine (figure 10).

No changes were observed in levels of cortisol, prolactin, luteinizing hormone,

thyroid-stimulating hormone, or growth hormone for these subjects.

FIGURE 9. Plasma levels of buprenorphine equivalents from two subjects

who received buprenorphine every day or every other day

between study days 19 and 36

NOTE: Both subjects received buprenorphine daily prior to study day 19 and

placebo after study day 36.

SOURCE: E.J. Cone, P.J. Fudala, and R.E. Johnson, unpublished data

136
FIGURE 10. Mean plasma testosterone levels from four subjects while they

were receiving buprenorphine (study days 18 and 19) or after

drug administration was discontinued (study day 50)

NOTE: Controls (n=25) were nontreated individuals with no history of opiate

abuse. Testosterone levels were measured from 50 mL of unextracted

plasma by radioimmunoassay (ICN Biomedical Inc., Carson, CA).

SOURCE: E.M. Dax, P.J. Fudala, J.H. Jaffee, and R.E. Johnson, unpublished

data

Spontaneous electroencephalogram (EEG) recordings at four electrode sites

were obtained from 16 subjects on days 15, 17, 20, 30, 34,37, 39, 44, 47, and

56. During the placebo-substitution phase of the experiment, an immediate

decrease in alpha power and a delayed gradual increase in alpha frequency

occurred at the posterior electrode. Changes in characteristics of EEG alpha

rhythm are characteristic of opioid withdrawal and have been reported after the

discontinuation of buprenorphine (Lukas et al. 1984). There were no significant

EEG differences between the experimental groups in any phase of the study.

There were no differences between groups with respect to subject-reported side

effects that could be considered “probable” or “possible.”1

Probable side effects

137
included constipation and sedation; possible side effects induded headache,

nausea and other gastrointestinal distress, and dizziness.

SUMMARY

Data from these studies indicate that buprenorphine is efficacious in treating

opioid dependence. It was possible to induct heroin addicts rapidly onto

buprenotphine without precipitating an opioid withdrawal syndrome.

A daily 8-mg SL dosage was sufficient to maintain individuals without producing

reports of withdrawal symptoms. When buprenorphine was administered at

the above dose every other day, however, mild withdrawal symptoms were

reported, and responses to challenges with intravenously given hydromorphone

appeared greater than when the challenges were given intramuscularly. From

these results, the authors conclude that buprenorphine at this dose should be

administered on a daily basis. These results are now being applied to a phase

II outpatient clinical trial comparing buprenorphine with methadone.

NOTE

1. To classify a side effect as either probable or possible, it was necessary

that the effect meet all of the criteria for a specific categorization as follows:

Probable-(l) reasonable temporal sequence; (2) well-known response

pattern; (3) confirmed by dechallenge; and (4) could not be explained

by known characteristics of the subject’s clinical state or other therapy

administered to the subject. Possible-(l) reasonable temporal sequence;

(2) known or suspected response pattern; and (3) could not be reasonably

explained by known characteristics of the subject’s clinical state or other

therapy administered to the subject (Karch and Lasagna 1975).

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ACKNOWLEDGEMENTS

Drs. Edward Cone, Elizabeth Dax, Jack Henningfield, Ronald Herning, Jerome

Jaffe, W. Robert Lange, and Wallace Pickworth and Mr. Frederick Snyder

contributed to the design and analysis of the various component portions of the

study assessing the determination of an appropriate dose schedule for the use

of buprenorphine in the treatment of heroin-dependent individuals.

AUTHORS

Rolley E. Johnson, Pharm.D.

Assistant Professor

Department of Psychiatry and Behavioral Sciences

Behavioral Pharmacology Research Unit

Johns Hopkins University School of Medicine

Bayview Research Campus

4940 Eastern Avenue

Baltimore, MD 21224

Paul J. Fudala, Ph.D.

Deputy Chairman

National Institute on Drug Abuse/VA Mental Disorders Medications

Development Center

Research Assistant Professor of Pharmacology in Psychiatry

Center for Studies of Addiction

University of Pennsylvania School of Medicine

3900 Chestnut Street

Philadelphia, PA 19104-6178

141
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U.S. Department of Commerce

Springfield, VA 22161

(703) 487-4650

For information on availability of NIDA Research Monographs 1 through 70

(1975-1986) and others not listed, write to NIDA, Community and Professional

Education Branch, Room 10A-54, 5600 Fishers Lane, Rockville, MD 20657.

142
71 OPIATE RECEPTOR SUBTYPES AND BRAIN FUNCTION. Roger M.

Brown, Ph.D.; Doris H. Clouet, Ph.D.; and David P. Friedman, Ph.D., eds.

GPO out of stock NTIS PB #89-151955/AS $31

72 RELAPSE AND RECOVERY IN DRUG ABUSE. Frank M. Tims, Ph.D.,

and Carl G. Leukefeld, D.S.W., eds.

GPO Stock #017-024-01302-1 $6 NTIS PB #89-151963/AS $31

73 URINE TESTING FOR DRUGS OF ABUSE. Richard L. Hawks, Ph.D., and

C. Nora Chiang, Ph.D., eds.

GPO Stock #017-024-01313-7 $3.75 NTIS PB #89-151971/AS $23

74 NEUROBIOLOGY OF BEHAVIORAL CONTROL IN DRUG ABUSE.

Stephen I. Szara, M.D., D.Sc., ed.

GPO Stock #017-024-01314-5 $3.75 NTIS PB #89-151989/AS $23

75 PROGRESS IN OPIOID RESEARCH. PROCEEDINGS OF THE 1986

INTERNATIONAL NARCOTICS RESEARCH CONFERENCE. John W.

Holaday, Ph.D.; Ping-Yee Law, Ph.D.; and Albert Herz, M.D., eds.

GPO out of stock NCADI out of stock

Not available from NTIS

76 PROBLEMS OF DRUG DEPENDENCE, 1986: PROCEEDINGS OF THE

48TH ANNUAL SCIENTIFIC MEETING, THE COMMITTEE ON PROBLEMS

OF DRUG DEPENDENCE, INC. Louis S. Harris, Ph.D., ed.

GPO out of stock NCADI out of stock

NTIS PB #88-208111/AS $53

77 ADOLESCENT DRUG ABUSE: ANALYSES OF TREATMENT

RESEARCH. Elizabeth R. Rahdert, Ph.D., and John Grabowski, Ph.D., eds.

GPO Stock #017-024-01348-0 $4 NCADI out of stock

NTIS PB #89-125488/AS $23

78 THE ROLE OF NEUROPLASTICITY IN THE RESPONSE TO DRUGS.

David P. Friedman, Ph.D., and Doris H. Clouet, Ph.D., eds.

GPO out of stock NTIS PB #88-245683/AS $31

79 STRUCTURE-ACTIVITY RELATIONSHIPS OF THE CANNABINOIDS.

Rao S. Rapaka, Ph.D., and Alexandros Makriyannis, Ph.D., eds.

GPO out of stock NTIS PB #89-109201/AS $31

143
80 NEEDLE SHARING AMONG INTRAVENOUS DRUG ABUSERS:

NATIONAL AND INTERNATIONAL PERSPECTIVES. Robert J. Battjes,

D.S.W., and Roy W. Pickens, Ph.D., eds.

GPO out of stock NTIS PB #88-236138/AS $31

81 PROBLEMS OF DRUG DEPENDENCE, 1987: PROCEEDINGS OF THE

49TH ANNUAL SCIENTIFIC MEETING, THE COMMITTEE ON PROBLEMS

OF DRUG DEPENDENCE, INC. Louis S. Harris, Ph.D., ed.

GPO Stock #017-024-01354-4 $17 NTIS PB #89-109227/AS

Contact NTIS for price

82 OPIOIDS IN THE HIPPOCAMPUS. Jacqueline F. McGinty, Ph.D., and

David P. Friedman, Ph.D., eds.

GPO out of stock NTIS PB #88-245691/AS $23

83 HEALTH HAZARDS OF NITRITE INHALANTS. Harry W. Haverkos, M.D.,

and John A. Dougherty, Ph.D., eds.

GPO out of stock NTIS PB #89-125496/AS $23

84 LEARNING FACTORS IN SUBSTANCE ABUSE. Barbara A. Ray, Ph.D.,

ed.

GPO Stock #017-024-01353-6 $6 NTIS PB #89-125504/AS $31

85 EPIDEMIOLOGY OF INHALANT ABUSE: AN UPDATE. Raquel A. Crider,

Ph.D., and Beatrice A. Rouse, Ph.D., eds.

GPO Stock #017-024-01360-9 $5.50 NTIS PB #89-123178/AS $31

86 COMPULSORY TREATMENT OF DRUG ABUSE: RESEARCH AND

CLINICAL PRACTICE. Carl G. Leukefeld, D.S.W., and Frank M. Tims, Ph.D.,

eds.

GPO Stock #017-024-01352-8 $7.50 NTIS PB #89-151997/AS $31

87 OPIOID PEPTIDES: AN UPDATE. Rao S. Rapaka, Ph.D., and Bhola N.

Dhawan, M.D., eds.

GPO Stock #017-024-01366-8 $7 NTIS PB #89-158430/AS $45

88 MECHANISMS OF COCAINE ABUSE AND TOXICITY. Doris H. Clouet,

Ph.D.; Khursheed Asghar, Ph.D.; and Roger M. Brown, Ph.D., eds.

GPO Stock #017-024-01359-5 $11 NTIS PB #89-125512/AS $39

89 BIOLOGICAL VULNERABILTY TO DRUG ABUSE. Roy W. Pickens,

Ph.D., and Dace S. Svikis, B.A., eds.

GPO Stock #017-022-01054-2 $5 NTIS PB #89-125520/AS $23

144
90 PROBLEMS OF DRUG DEPENDENCE 1988: PROCEEDINGS OF THE

50TH ANNUAL SCIENTIFIC MEETING, THE COMMITTEE ON PROBLEMS

OF DRUG DEPENDENCE, INC. Louis S. Harris, Ph.D., ed.

GPO Stock #017-024-01362-5 $17

91 DRUGS IN THE WORKPLACE: RESEARCH AND EVALUATION DATA.

Steven W. Gust, Ph.D., and J. Michael Walsh, Ph.D., eds.

GPO Stock #017-024-01384-6 $10 NTIS PB #90-147257/AS $39

92 TESTING FOR ABUSE LIABILITY OF DRUGS IN HUMANS. Marian W.

Fischman, Ph.D., and Nancy K. Mello, Ph.D., eds.

GPO Stock #017-024-01379-0 $12 NTIS PB #90-148933/AS $45

93 AIDS AND INTRAVENOUS DRUG USE: FUTURE DIRECTIONS FOR

COMMUNITY-BASED PREVENTION RESEARCH. C.G. Leukefeld, D.S.W.;

R.J. Battjes, D.S.W.; and Z. Amsel, D.Sc., eds.

GPO Stock #017-024-01388-9 $10 NTIS PB #90-148941 /AS $39

94 PHARMACOLOGY AND TOXICOLOGY OF AMPHETAMINE AND

RELATED DESIGNER DRUGS. Khursheed Asghar, Ph.D., and Errol De

Souza, Ph.D., eds.

GPO Stock #017-024-01386-2 $11 NTIS PB #90-148958/AS $39

95 PROBLEMS OF DRUG DEPENDENCE 1989: PROCEEDINGS OF THE

51 ST ANNUAL SCIENTIFIC MEETING, THE COMMITTEE ON PROBLEMS

OF DRUG DEPENDENCE, INC. Louis S. Harris, Ph.D., ed.

GPO Stock #017-024-01399-4 $21 NTIS PB #90-237660/AS $67

96 DRUGS OF ABUSE: CHEMISTRY, PHARMACOLOGY, IMMUNOLOGY,

AND AIDS. Phuong Thi Kim Pham, Ph.D., and Kenner Rice, Ph.D., eds.

GPO Stock #017-024-01403-6 $8 NTIS PB #90-237678/AS $31

97 NEUROBIOLOGY OF DRUG ABUSE: LEARNING AND MEMORY. Lynda

Erinoff, Ph.D., ed.

GPO Stock #017-024-01404-4 $8 NTIS PB #90-237686/AS $31

98 THE COLLECTION AND INTERPRETATION OF DATA FROM HIDDEN

POPULATIONS. Elizabeth Y. Lambert, M.S., ed.

GPO Stock #017-024-01407-9 $4.75 NTIS PB #90-237694/AS $23

99 RESEARCH FINDINGS ON SMOKING OF ABUSED SUBSTANCES.

C. Nora Chiang, Ph.D., and Richard L. Hawks, Ph.D., eds.

GPO Stock #017-024-01412-5 $5 NTIS PB #91-141119 $23

145
100 DRUGS IN THE WORKPLACE: RESEARCH AND EVALUATION DATA.

VOL. II. Steven W. Gust, Ph.D.; J. Michael Walsh, Ph.D.; Linda B. Thomas,

B.S.; and Dennis J. Crouch, M.B.A., eds.

GPO Stock #017-024-01458-3 $8

101 RESIDUAL EFFECTS OF ABUSED DRUGS ON BEHAVIOR. John W.

Spencer, Ph.D., and John J. Boren, Ph.D., eds.

GPO Stock #017-024-01426-7 $6 NTIS PB #91-172858/AS $31

102 ANABOLIC STEROID ABUSE. Geraline C. Lin, Ph.D., and Lynda Erinoff,

Ph.D., eds.

GPO Stock #017-024-01425-7 $8 NTIS PB #91-172866/AS $31

103 DRUGS AND VIOLENCE: CAUSES, CORRELATES, AND

CONSEQUENCES. Mario De La Rosa, Ph.D.; Elizabeth Y. Lambert, M.S.;

and Bernard Gropper, Ph.D., eds.

GPO Stock #017-024-01427-3 $9 NTIS PB #91-172841/AS $31

104 PSYCHOTHERAPY AND COUNSELING IN THE TREATMENT OF

DRUG ABUSE. Lisa Simon Onken, Ph.D., and Jack D. Blame, M.D., eds.

GPO Stock #017-024-01429-0 $4 NTIS PB #91-172874/AS $23

105 PROBLEMS OF DRUG DEPENDENCE, 1990: PROCEEDINGS OF THE

52ND ANNUAL SCIENTIFIC MEETING, THE COMMITTEE ON PROBLEMS

OF DRUG DEPENDENCE, INC. Louts S. Harris, Ph.D., ed.

GPO Stock #017-024-01435-4 $22

106 IMPROVING DRUG ABUSE TREATMENT. Roy W. Pickens, Ph.D.; Carl

G. Leukefeld, D.S.W.; and Charles R. Schuster, Ph.D., eds.

GPO Stock #017-024-01439-7 $12 NTIS PB #92-105873

Paperback $50 Microfiche $19

107 DRUG ABUSE PREVENTION INTERVENTION RESEARCH:

METHODOLOGICAL ISSUES. Carl G. Leukefeld, D.S.W., and William J.

Bukoski, Ph.D., eds.

GPO Stock #017-024-01446-0 $9 NTIS PB #92-160985

Paperback $35 Microfiche $17

108 CARDIOVASCULAR TOXICITY OF COCAINE: UNDERLYING

MECHANISMS. Pushpa V. Thadani, Ph.D., ed.

GPO Stock #017-024-01446-0 $7 NTIS PB #92-106608

Paperback $35 Microfiche $17

146
109 LONGITUDINAL STUDIES OF HIV INFECTION IN INTRAVENOUS DRUG

USERS: METHODOLOGICAL ISSUES IN NATURAL HISTORY RESEARCH.

Peter Hartsock, Dr.P.H., and Sander G. Genser, M.D., M.P.H., eds.

GPO Stock #017-024-014451 $4.50 NTIS PB #92-106616

Paperback $26 Microfiche $12.50

110 THE EPIDEMIOLOGY OF COCAINE USE AND ABUSE. Susan Schober,

Ph.D., and Charles Schade, M.D., M.P.H., eds.

GPO Stock #017-024-01456-7 $11 NTIS PB #92-14624-0

Paperback $43 Microfiche $17

111 MOLECULAR APPROACHES TO DRUG ABUSE RESEARCH: VOLUME I.

Theresa N.H. Lee, Ph.D., ed.

Not for sale at GPO NTIS PB #92-135743

Paperback $35 Microfiche $17

112 EMERGING TECHNOLOGIES AND NEW DIRECTIONS IN DRUG

ABUSE RESEARCH. Rao S. Rapaka, Ph.D.; Alexandros Makriyannis, Ph.D.;

and Michael J. Kuhar, Ph.D., eds.

GPO Stock #017-024-01455-9 $11

113 ECONOMIC COSTS, COST-EFFECTIVENESS, FINANCING, AND

COMMUNITY-BASED DRUG TREATMENT. William S. Cartwright, Ph.D.,

and James M. Kaple, Ph.D., eds.

Not for safe at GPO NTIS PB #92-155795

Paperback $35 Microfiche $17

114 METHODOLOGICAL ISSUES IN CONTROLLED STUDIES ON EFFECTS

OF PRENATAL EXPOSURE TO DRUG ABUSE. M. Marlyne Kilbey, Ph.D., and

Khursheed Asghar, Ph.D., eds.

GPO Stock #017-024-01459-1 $12 NTIS PB #92-146216

Paperback $43 Microfiche $17

115 METHAMPHETAMINE ABUSE: EPIDEMIOLOGIC ISSUES AND

IMPLICATIONS. Marissa A. Miller, D.V.M., M.P.H., and Nicholas J. Kozel, M.S.,

eds.

GPO Stock #017-024-01460-5 $4

116 DRUG DISCRIMINATION: APPLICATIONS TO DRUG ABUSE

RESEARCH. Richard A. Glennon, Ph.D.; Torbjörn UC. Järbe, Ph.D.; and

Jerry Frankenheim, Ph.D., eds.

GPO Stock #017-024-01470-2 $13

147
117 METHODOLOGICAL ISSUES IN EPIDEMIOLOGICAL, PREVENTION,

AND TREATMENT RESEARCH ON DRUG-EXPOSED WOMEN AND THEIR

CHILDREN. M. Marlyne Kilbey, Ph.D., and Khursheed Asghar, Ph.D., eds.

GPO Stock #017-024-01472-9 $12

118 DRUG ABUSE TREATMENT IN PRISONS AND JAILS. Carl G.

Leukefeld, D.S.W., and Frank M. Tims, Ph.D., eds.

GPO Stock #017-024-01473-7

119 PROBLEMS OF DRUG DEPENDENCE 1991: 53RD ANNUAL

SCIENTIFIC MEETING, THE COMMITTEE ON PROBLEMS OF DRUG

DEPENDENCE, INC. Louis S. Harris, Ph.D., ed.

GPO Stock #017-024-01474-5 $22

120 BIOAVAILABILITY OF DRUGS TO THE BRAIN AND THE BLOODBRAIN BARRIER. Jerry Frankenheim, Ph.D., and Roger M. Brown, Ph.D., eds.

148
DHHS Publication No. (ADM) 92-1912

Alcohol, Drug Abuse, and Mental Health Administration

Printed 1992