Benzodiazepines:

A Review of Research Results, 1980

Editors:

Stephen I. Szara, M.D., D.Sc.

Jacqueline P. Ludford, M.S.

National Institute on Drug Abuse

NIDA Research Monograph 33

A RAUS Review Report

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Benzodiazepines:

A Review of Research Results, 1980
ACKNOWLEDGMENT

This monograph is based upon papers and discussion from the RAUS

Review Conference on Benzodiazepines, held September 12, 1980, in

Rockville, Maryland. Arrangements for the conference, sponsored

by the Division of Research, National Institute on Drug Abuse,

were made by CDP Associates, Inc., Rockville, Maryland 20852,

under NIDA contract No. 271-79-3636.

COPYRIGHT STATUS

The chapter entitled "Benzodiazepines: Clinical Use Patterns,"

by Karl Rickels, M.D., is adapted from copyrighted material and

therefore may be under copyright. It is used with the permission

of Raven Press, New York. Before reproducing, readers are advised

to determine its copyright status or to secure permission of the

copyright holder. The table and figures in that chapter are copyrighted as noted in the text and are reproduced herein with permission. Further reproduction is prohibited without specific permission of the copyright holders. All other material in this

volume is in the public domain and may be used or reproduced without permission from the Institute or the authors. Citation of the

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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; Alcohol, Drug Abuse, and Mental

Health Administration; Public Health Service; or the Department of

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The U.S. Government does not endorse or favor any specific commercial product or commodity. Trade or proprietary names appearing

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essential in the context of the studies reported herein.

Library of Congress catalog card number 81-600106

DHHS publication number (ADM)81-1052

Printed 1981

NIDA Research Monographs are indexed in the Index Medicus. They

are selectively included in the coverage of BioSciences Information Service, Chemical Abstracts, Current Contents, Psychological

Abstracts, and Psychopharmacology Abstracts.

i v
Preface

The Research Analysis and Utilization System (RAUS) is designed to

serve four functions:

Collection and systematic classification of findings of all

intramural and extramural research supported by the National

Institute on Drug Abuse (NIDA);

Evaluation by scientific peers of the latest research findings;

Regular dissemination of findings to researchers in the

field and to administrators, planners, instructors, and

other interested persons:

Provision of a feedback mechanism to NIDA staff and planners so that administration and monitoring of the NIDA

research program reflect the very latest knowledge gleaned

from research in the field.

Since there is a limit to the number of research findings that can

be intensively reviewed annually, four subject areas are chosen each

year and subjected to a thorough review. The reviewers, distinguished scientists in the selected field, are provided with copies

of all pertinent literature and reports from NIDA-funded research.

They are invited to add to this any information derived from their

own research and that of colleagues not funded by NIDA. Each

reviewer writes a state-of-the-art paper in his or her particular

subject area. These papers make up a RAUS Review Report in the NIDA

Research Monograph series.

Additionally, an evaluative meeting is held for presentation of the

papers and exchange of ideas among the scientists and with NIDA

staff. This meeting has sometimes been referred to as the "therefore"

meeting: Here is our position: therefore, where are we going next,

and where should further research lead? Should we alter our path?

Step up NIDA support because new needs have arisen or new developments hold special promise? Discussions at the meeting and the

specific recommendations of the experts in the field provide a basis

upon which NIDA evolves its plans for future research.

V
In Fiscal Year 1980 the abuse liability of the benzodiazepines was

chosen as an area for RAUS review. The subject was ripe for

review because much conflicting information was circulating among

scientists and clinicians about the abuse liability of the highly

popular "tranquilizers"; because of pronounced public interest,

as reflected by the Congress and the press; and because of a perceived need by NIDA for objective evaluation of research on the

benzodiazepines.

The reviewers were invited to discuss:

The basic biochemistry and neuroanatomy underlying

the question of the abuse potential of benzodiazepines, including the existence and sites of

receptors involved;

Studies on self-administration in animals and humans;

Carryover effectiveness, rebound insomnia, and performance effects;

Clinical use patterns and their relationship to

misuse and abuse;

Dependence on benzodiazepines.

The results of these reviews are presented in this monograph. The

review meeting was chaired by Dr. William Martin, of the University

of Kentucky, former Director of the Addiction Research Center, in

Lexington, Kentucky. Dr. Edward Truitt, of Northeast Ohio College

of Medicine, summarized the reviews and discussions. Dr. Stephen

Szara, Chief, Biomedical Branch, NIDA Division of Research, served

as moderator and directed the scientific discussion.

Jacqueline P. Ludford, M.S.

Coordinator

Research Analysis and Utilization System

v i
Contents

Preface

Jacqueline P. Ludford . . . . . . . . . . . . . . . . . .

Introduction

Stephen I. Szara . . . . . . . . . . . . . . . . . . . .

Benzodiazepines: Biochemistry to Function

John F. Tallman . . . . . . . . . . . . . . . . . . . . .

The Benzodiazepine Receptor: Anatomical Aspects

Michael J. Kuhar . . . . . . . . . . . . . . . . . . . .

Benzodiazepine Self-Administration in Animals and Humans:

A Comprehensive Literature Review

Roland R. Griffiths and Nancy A. Ator . . . . . . . . . .

Benzodiazepine Dependence Studies in Rodents

William R. Martin and L. F. McNicholas . . . . . . . . .

Benzodiazepines: Clinical Use Patterns

Karl Rickels . . . . . . . . . . . . . . . . . . . . . .

Benzodiazepine Hypnotics: Carryover Effectiveness,

Rebound Insomnia, and Performance Effects

Anthony Kales . . . . . . . . . . . . . . . . . . . . . .

Dependence on Benzodiazepines

Leo E. Hollister . . . . . , . . . . . . . . . . . . . .

Benzodiazepines: Executive Summary and Discussion

Edward B. Truitt, Jr. . . . . . . . . . . . . . . . . . .

Benzodiazepines: Biochemistry to Function . . . . 84

The Benzodiazepine Receptor: Anatomical Aspects . 85

Benzodiazepine Self-Administration . . . . . . . 86

Benzodiazepine Dependence Studies in Rodents . . . 87

Benzodiazepines: Clinical Use Patterns . . . . . . 88

Benzodiazepine Hypnotics: Carryover Effectiveness,

Rebound Insannia, and Performance Effects . . . . 89

Dependence on Benzodiazepines . . . . . . . . . . 90

General Discussion . . . . . . . . . . . . . . . . . 91

RAUS Summary of New Directions for Research

Jacqueline P. Ludford and Stephen I. Szara. . . . . . . .

Participants, RAUS Review Conference on Benzodiazepines . . .

List of NIDA Research Monographs . . . . . . . . . . . . . .

v

1

4

12

22

37

43

61

70

83

93

96

97

vii

Introduction

Stephen I. Szara, M.D., D.Sc.

The benzodiazepines represent a class of drugs that are widely

prescribed and used as so-called "minor tranquilizers." At the

latest count, in 1979 alone, 62.3 million prescriptions for minor

tranquilizers were filled (National Prescription Audit 1979).

Because of the sheer volume of traffic in these drugs, if there is

a potential for misuse and abuse, it is inevitable that a potential

also exists for creation of a public health problem.

When widespread clinical use of benzodiazepines began some 20 years

ago, they were considered to have a relatively large margin of

safety and they were prescribed quite liberally. Very soon, however, some adverse reactions started to appear, and by the mid-70's

concerns about the potential problems of abuse of the newly developed congeners of benzodiazepines prompted the National Institute

on Drug Abuse (NIDA) to convene a technical review to discuss the

need for new methodologies to assess the abuse potential of these

drugs. That meeting took place in 1976 at the Addiction Research

Center in Lexington, Kentucky, under the chairmanship of Dr. William

Martin (NIDA 1976).

Since then two major developments have occurred that are specifically related to NIDA's interest in benzodiazepines. The first was

the discovery of specific binding sites for benzodiazepines in the

brain in 1977 by Squires and Braestrup (1977) and by Mohler and

Okada (1977) and the emergence of a plausible hypothesis to explain

how benzodiazepines may interact with normal brain function. Biochemical research on benzodiazepine receptors in brain and their

relation with neurotransmitter mechanisms has developed rapidly tom

become one of the most active areas of psychopharmacology. If

dependence develops, as some clinicians feel it does under certain

circumstances, the obvious question arises Whether or not the receptors are in some way involved in this phenomenon.

The second major development is social and political. I am referring to the 1979 hearing by the Senate Subcommi ttee on Health and

Scientific Research that became known as the "Valium hearing,"

focused on the "growing and very serious public health problem"

1
of which the American people may not be aware. Senator Edward M.

Kennedy, subcommittee chairman, pointed out: "If you require a

daily dose of Valium to get through each day, you are hooked and

you should seek help."

The hearings resulted in a predictable aftereffect: a flood of

testimonials in the media about adverse reactions and dependence,

and congressional inquiries to various agencies. These appear to

have created a climate which may lead to a reassessment of present

scheduling policies towards this class of drugs. For this reason, as

well as from a purely scientific perspective, NIDA has become involved,

especially since NIDA plays a role as one of the Federal agencies Supplying scientific data on abuse potential and dependence liability.

When we look at NIDA's program, as most of the contributors to this

monograph were asked to do, we find that our research has been

limited to a relatively few projects, and most of these have struggled

to solve the methodological problems in obtaining reliable, reproducible data on dependence liabilities of benzodiazepines. Furthermore,

we are faced with the fact that the pharmacological laboratories are

producing new and different kinds of benzodiazepines faster than our

researchers are able to catch up in determining their abuse potentials,

based on experimental animal data.

These considerations, among others, have led us to convene this

meeting so that NIDA can have the benefit of "cross-fertilization"

of basic scientists on the one hand and clinical scientists on the

other. By taking a look at the receptor research and pharmacokinetic

data as well as at the clinical experience with the various benzodiazepines, we may come up with some new suggestions on how to improve

our knowledge base so that we will be ready to supply reliable

information for the process of public health decisionmaking.

In the course of this discussion, we hope that new ideas for research

will be generated as each of us becomes aware of new data, new observations, and new experience in fields other than that of our own

focus. We also hope that these discussions may lead to a better

understanding of actions of these drugs and ultimately contribute

to better and safer use of benzodiazepines.

REFERENCES

Mohler, H., and Okada, T. Benzodiazepine receptor: demonstration

in the central nervous system. Science, 198:849-851, 1977.

National Institute on Drug Abuse. Final Report on NIDA's Technical

Review on Methodology for Determining and Assessing Abuse Potential

of Benzodiazepines (Contract No. 271-75-1139). Rockville, MD: the

Institute, September 1976.

National Prescription Audit, 1979. I.M.S. America, Ltd. Ambler,

PA, 1979.

2
Squires, R., and Braestrup, C. Benzodiazepine receptors in rat

brain. Nature, 266:732-734, 1977.

U.S., Congress, Senate, Committee on Labor and Human Resources,

Subcommittee on Health and Scientific Research hearings. Use and

Misuse of Benzodiazepines. 96th Cong., 1st sess., Sept. 10, 1979.

3
Benzodizepines: Biochemistry

to Function

John F. Tallman, Ph.D.

PROPERTIES OF DIFFERENT BINDING SITES

Peripheral Versus Central

The high affinity and stereospecific binding sites for benzodiazepines in brain seem to represent the places where benzodiazepines

exert their pharmacological effects. This conclusion is based upon

the high degree of correlation between the ability of an extensive

series of benzodiazepines to displace binding of [

3H]diazepam from

the high-affinity sites in brain and their activity in a number of

behavioral tests including conflict, muscle relaxant, and anticonvulsant tests (Braestrup and Squires 1978). One of the most

potent benzodiazepines is clonazepam, 5-(o-chloropenyl)-1, 3--dihydro7-nitro-2H-1,4-benzodiazepine-2-one; clonazepam is also a potent

displacer of [

3H]diazepam binding to brain specific sites (Braestrup

et al. 1977; Braestrup and Squires 1977; Möhler and Okada 1977a,b).

At the other end of the spectrum of potency is R05-4864, 7-chloro1,3-dihydro-l-methyl-5-(pchlorophenyl)-2H-l,4-benzodiazepine-2-one,

which does not have central behavioral effects and is inactive in

displacing [

3H]diazepam from the high-affinity sites in brain

(Braestrup et al. 1977). The lack of potency of RO5-4864 is particularly striking because it is quite similar to diazepam, differing

from diazepam only by possessing a p-chloro substituent.

Initial investigations of the binding of [

3H]diazepam indicated that

specific high-affinity binding of [

3H]diazepam could be obtained not

only to brain but also to several peripheral tissues including

kidney (Braestrup et al. 1977). The sites on the kidney cells,

although possessing a high affinity for [

3H]diazepam, showed a different pharmacological spectrum from the brain site. R05-4864 is

a rather potent displacer of [

3H]diazepam binding; in contrast,

clonazepam is much weaker. Thus, although peripheral tissues possess

high-affinity sites for diazepam, they seem to be different from the

central sites.

In addition to the kidney, the "peripheral sites" seem to be on cultured cells of various types, including those of presumptive neuronal

origin (Guidotti et al. 1979; Strittmatter et al. 1979; Syapin and

Skolnick 1979). Both rat astrocytana (Syapin and Skolnick 1979)

and neuroblastoma (Guidotti et al. 1979; Strittmatter et al. 1979;

4
Chang et al., in press) cells possess a large number of these peripheral sites-they do not possess the clonazepam displaceable binding.

The nature and biological significance of this peripheral binding site

is obscure; it is interesting to note that this site may activate

phospholipid methylation either directly or indirectly (Strittmatter

et al. 1979). The existence of such peripheral binding sites for

Valium is not only of academic interest. Much of the literature about

drug levels following single doses and chronic administration of

Valium would indicate that these receptors should be occupied following single doses and chronic administration of Valium would indicate

that these receptors should be occupied following clinical use of

Valium (Peskar and Spector 1973). Thus, a number of investigations

into the nature and function of the peripheral site are in order, if

only because some side effects of Valium may be mediated through

this site.

One of the early issues that investigators examined was the cellular

localization of the central type of receptor. Although initial

reports indicated a neuronal localization (Braestrup and Squires

1977); Mohler and Okada 1977a,b), subsequent reports (Chang et al.

1979; Henn and Henke 1978) supported a glial localization. These

reports used kainic acid lesioning or tissue culture; in the case

of the kainic acid lesioning experiments, it became clear that a

sufficient degeneration period was necessary before neuronal membrane

fractions containing sites from lesioned animals could be degraded.

If such a period is observed, degeneration studies support a neuronal

localization for the binding sites (Chang et al., in press).

Recently, a nuclear benzodiazepine binding site was described in brain

(Bosmann et al. 1980). This site has lower affinity for the benzodiazepine [

3H]flunitrazepam than the cell membrane binding site; however,

clonazepam is far more potent in displacing binding than R05-4864

(unpublished) indicating that the nuclear site has properties similar

to the membrane binding site.

Multiple Central Receptors

In addition to the distinction between peripheral and central receptors, some investigators have also examined the possibility that

multiple central sites may exist based on thermostability studies

(Squires et al. 1979). These earlier studies did not consider the

newly described nuclear sites. Additionally, several triazolopyridazines displace binding of [

3H]diazepam with properties indicating

that they are displacing binding from a heterogeneous set of sites

(Hill coefficient ~0.5) (Squires et al. 1979). Such methods indicate that multiple sites may exist in brain but are not conclusive.

It is not known whether these multiple sites would be genetically

distinct or vary in their association with other membrane proteins

such as a GABA recognition unit (see article by M. Kuhar and associates, this volume). By this criterion of heat denaturation, two

such sites are said to exist in cerebral cortex and one site in

cerebellum (Lippa et al., in press). Additionally, a recent paper

5
indicates microheterogeneity of benzodiazepine receptors as measured

in different brain regions on sodium dodecyl sulfate gels (Sieghart

and Karobath 1980).

MODULATION OF CENTRAL BENZODIAZEPINE BINDING SITES

Understanding the mechanism of action of Valium at central sites

demands an understanding of the modulation of the central receptor

complex of proteins. It now is clear that both the affinity of the

Valium receptor and the number of receptors is under pharmacological

control, and it is important to relate this biochemical control to a

behavioral function.

Affinity Changes

The early (primarily electrophysiological) literature is strongly in

favor of an interaction between the benzodiazepines and GABA (Tallman et al. 1980; Gallager 1978). Initial binding studies did not

indicate the presence of such an interaction (Braestrup et al. 1977;

Mohler and Okada 1977a); subsequently, we (Gallager et al. 1978;

Tallman et al. 1978, 1979) and others (Tallman et al. 1980) have

obtained definitive evidence that the central benzodiazepine binding

site can interact with a GABA recognition site. When GABA, muscimol,

and other GABAergic agonists occupy this site, the affinity of the

benzodiazepine binding site for [

3H]diazepam is enhanced. This

enhancement is seen in all preparations that contain clonazepam

displaceable benzodiazepine binding.

The magnitude of GABA-enhancement depends on the ability to remove

the large amounts of endogenous GABA present in brain membrane preparations and on the region of the brain chosen for study (Karobath and

Sperk 1979). It is not yet clear whether the regional distribution

reflects altered proportions of GABA receptors and benzodiazepine

sites or different amounts of residual GABA. Regionally altered

proportions of high-affinity GABA binding proteins and benzodiazepine

sites are indicated by autoradiographic studies (Young and Kuhar

1980). The contribution of nuclear binding sites to these regional

distributions has not been studied, and it is not clear if multiple

benzodiazepine sites may be defined upon their interaction or lack

of interaction with GABA.

Most GABA agonists enhance the affinity of central benzodiazepine

sites. Two compounds, isoguvacine and THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-3-ol), behave in an anomalous fashion. Isoguvacine is a partial agonist for GABA by the criterion of enhancement

of [

3H]diazepam binding and will decrease muscimol activation of

binding to the isoguvacine level (Braestrup et al. 1979b; KrogsgaardLarsen and Johnston 1978); THIP, on the other hand, does not enhance

binding of [

3H]diazepam, reverses muscimol activation of benzodiazepine

binding (like bicuculline), and yet appears to be an agonist (Braestrup

et al. 1979b). Neither isoguvacine nor THIP protects the benzodiazepine site from heat denaturation, a property both GABA and muscimol

possess (Squires et al. in press). Among other explanations, it seems

6
possible that THIP in particular may possess agonistic properties at

a GABA receptor that is not coupled with a benzodiazepine site and

may indicate that several different GABA receptors exist in brain

(Krogsgaard-Larsen et al. 1980). The difficulties in detecting and

separating multiple GABA receptors have been discussed in great

detail recently (DeFeudis 1978; Nistri and Constanti 1979).

Lesion experiments also support the close interaction of GABA sites

and benzodiazepine sites. Following kainic acid lesion of the striatonigral GABAergic pathway, an apparent increase in the number of GABA

receptors in the substantia nigra was noted without changes in the

affinity for the ligand (Waddington and Cross 1978). Concurrent with

this short-term denervation supersensitivity in nigral GABA receptors,

no change in the number of benzodiazepine sites was noted under these

experimental conditions. The affinity response of the benzodiazepine

sites to occupancy of the GABA receptor shows a shift to the left in

the GABA dose-response curve (indicating a GABAergic supersensitivity)

(Biggio et al. 1979). Thus the lesion studies support the interdependence of GABA and the benzodiazepines.

The affinity of central sites for [

3H]diazepam is also enhanced by a

pyrazolo(3,4-6)pyridine called SQ65,396 (Beer et al. 1979; Williams

and Risley 1979). Although initially thought to be via a GABAergic

mechanism (Williams and Risley 1979), SQ65,396 now has been said to

be a direct allosteric modifier of binding based upon studies with

soluble binding sites (A. Lippa, personal communication). This

compound may be a prototype for an interesting series of anxiolytic

agents; it does not seem to be an effective anticonvulsant (Beer et

al. 1979).

Another agent that affects benzodiazepine binding by affinity change

is pentylenetetrazole (and its analogues). They seem to block GABA

enhancement of benzodiaxepine binding but not basal levels. This

blockage seems to be correlated to their convulsant properties (Paul

et al., in press).

In addition to the pharmacological agents, certain anions such as

chloride, iodide, nitrite, and thiocyanate have been shown to enhance

the affinity of central binding sites for [

3H}diazepam (Costa et al.

1979a,b). This effect is separate from the GABA enhancement and is

additive to it. The possibility that SQ65,396 interacts at this site

has not been examined. Recently, the action of SQ65,396 has been

shown to be reversible by picrotoxin, an agent which acts at the

chloride ionophore (Supavilai and Karobath 1979).

Binding Site Number Changes

One of the early reports on alterations in central binding sites

indicated a rapid and transient increase in the number of binding

sites following either electrically or chemically induced seizures

(Paul and Skolnick 1978). What is remarkable about this finding is

the rapid increase and rapid decrease in the binding sites; most

central nervous system receptors show alteration over a period of

7
days rather than minutes. The magnitude of this effect is approximately 15 percent; but it is interesting to note that only 20 to 30

percent of the benzodiazepine sites must be occupied to fully protect

against seizures (Lippa et al. 1979). Thus, increases of this magnitude (or affinity changes) probably possess physiological significance.

The anticonvulsant agent diphenylhydantoin can also rapidly elicit a 20

to 30 percent increase in the number of benzodiazepine binding sites

following pretreatment in vivo (Gallager et al. 1980). This increase

is dose-dependent and is elicited in the range of diphenylhydantoin's

anticonvulsant properties. The exposure of new sites for [

3H]diazepam

is transient, and within a few hours the binding returns to control

levels. In addition to the increase in the number of sites, the

diphenylhydantoin treatment enhances the electrophysiological properties of the benzodiazepines but does not alter the response to GABA.

Accordingly, it is still possible to obtain GABA enhancement of

benzodiazepine binding in membranes prepared from diphenylhydantointreated animals. It is not known yet what chronic diphenylhydantoin

will do to adult animals; however, pretreatment of pregnant rats has

been shown to decrease the number of central binding sites in offspring during early postnatal life (Gallager and Mallorga 1980). 'Ibis

decrease is transient and can be correlated to increased susceptibility to seizures. Diphenylhydantoin does not increase binding of

[

3H]diazepam in vitro.

Another compound, EMD 28422 (N6-[2-(4-chlorophenyl)-bicyclo-2.2.2.

octyl-(3)]-adenosine), which is a purine derivative, also elicits

an increase in the number of benzodiazepine binding sites without a

change in affinity. This effect was noted both in vivo (Speth et al.

1979) and in vitro (P. Skolnick, in preparation), and has been correlated to anticonvulsant properties of this molecule (Skolnick et al.,

in press). In the presence or absence of GABA or chloride, the

magnitude of the effect was the same (about 20 to 30 percent new

sites). In spite of the lack of effects of GABA upon the unmasking,

the GABA antagonist, bicuculline, is capable of blocking the effects

of EMD 28422, indicating a possible permissive role for the GABA

receptor in the rapid modulation of the benzodiazepine binding site.

EFFECT OF CHRONIC DRUG TREATMENTS ON BENZODIAZEPINE RECEPTORS

The clinical and basic literature is not clear concerning the chronic

effects of the benzodiazepines. One recently published study seriously underplays the potential hazards of the benzodiazepines (Marks

1978), particularly when contrasted to a recent critical report of the

Institute of Medicine (National Academy of Sciences 1979). Clearly,

this is an area that needs much more clinical investigation and

laboratory studies.

At the receptor level, chronic (several weeks, not months) administration of high doses of benzodiazepines leads to a modest decrease

in the apparent number of binding sites in brain (Rosenberg and Chin

1979; Chin and Rosenberg 1978; Braestrup et al. 1979a). However,

another study did not find this decrease (Möhler et al. 1978). The

cleanest study to date (J.N. Crawley et al., in preparation) indicates

8
that the potency of the benzodiazepine administered may affect the

result. Clonazepam binding and chlordiazepoxide binding were compared,

and the investigators found that clonazepam gave a much larger decrease

than chlordiazepoxide; clonazepam is much more potent.

Behaviorally, depending on the animal test used, there are small or no

effects on anti-pentylenetetrazole activity of the benzodiazepines

(Lippa et al. 1978), but tolerance seems to develop to the effects of

benzodiazepines on strychnine- or bicuculline-induced seizures (Lippa

et al. 1978). Overt tolerance does not develop to the anticonflict

effects of the benzodiazepines (J.N. Crawley, personal communication).

A factor in all of this may be the low fractional occupancy necessary

to elicit the full biological effects of the benzodiazepines (Lippa

et al. 1979). Thus, a certain amount of redundancy may exist in the

benzodiazepine system.

CONCLUSIONS

I have attempted to update the current picture about the functioning

of the benzodiazepines in vivo. Much important work remains to be

done to correlate the biochemical with the behavioral effects of the

benzodiazepines and to relate them to the clinical situation.

REFERENCES

Beer, B., Klepmer, C., Lippa, A., and Squires, R.F. Pharmacol Biochem

Behav, 9:849, 1979.

Biggio, G., Corda, M., Lombetti, C., and Gessa, G. Eur J Pharmacol,

58:215, 1979.

Bosmann, H.B., Penney, D.P., Case, K.R., and Averill, K. Proc Natl Acad

Sci, 77:1195, 1980.

Braestrup, C.,

Braestrup, C.,

Braestrup, C.,

1977.

Braestrup, C.,

Braestrup, C.,

331, 1979b.

Chang, R.S.L.,

1979.

Chang, R.S.L.,

and Squires, R.F. Proc Natl Acad Sci, 74:3805, 1977.

and Squires, R.F. Br J Psychiatry, 133:249, 1978.

Albechtsen, R., and Squires, R.F. Nature 269:702,

Nielsen, M., and Squires, R.F. Life Sci, 24:347, 1979a.

Nielsen, M., Larsen, P.K., and Falch, E. Nature 280:

Tran, V.T., and Snyder, S.H. Soc Neurosci Abst:#1632,

Tran, V.T., and Snyder, S.H. Brain Res, in press.

Chin, T.H., and Rosenberg, H. Life Sci, 23:1153, 1978.

Costa, T., Rodbard, D., and Pert, C.B. Nature 277:315, 1979a.

9
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AUTHOR

John F. Tallman, Ph.D.

Biological Psychiatry Branch

National Institute of Mental Health

Bethesda, Maryland 20014

11
The Benzodiazepine Receptor:

Anatomical Aspects

Michael J. Kuhar, Ph.D.

INTRODUCTION

A site in brain tissue that has the properties of a relevant and

pharmacologically active benzodiazepine (BZ) receptor has been

identified by binding techniques (Squires and Braestrup 1977; Mohler

and Okada 1977; Tallman et al. 1980). Thus it is possible to study

molecular and anatanical mechanisms of BZ drugs more extensively

than before. This report will focus on the anatomical localization

of BZ receptors and their significance.

Biochemical studies have shown that the BZ receptors are unevenly

distributed in brain regions (Squires and Braestrup 1977; Mohler and

Okada 1977, 1978; Braestrup et al. 1977; Speth et al. 1978). Phylogenetic studies suggest that the BZ receptors appear relatively late

in evolution (Nielsen et al. 1978). Overall, these results strongly

suggest that the receptor is not some simple, universal constituent

of neuronal membranes, but rather a unique entity specially involved

in certain brain regions (and therefore certain physiological functions) and possibly associated with a unique, endogenously-occurring

"active" compound such as a neurohormone (Marangos et al. 1979;

Tallman et al. 1980). Hence, anatanical studies of the BZ receptor

are necessary for a full understanding of the action of BZ drugs.

The usefulness of anatomical studies of receptors for providing

insights to mechanisms of drug actions has been demonstrated in the

cases of, for example, the opiate receptor (Atweh and Kuhar 1977),

and the alpha-adrenergic receptor (Young and Kuhar 1980b).

NEURONAL VERSUS NON-NEURONAL LOCALIZATION

An obvious first issue is whether the BZ receptor is localized to

neurons in the brain or to various non-neuronal elements or to both.

While some initial studies suggested a non-neuronal localization,

recent data indicate a neuronal localization. Injection of kainic

acid, a toxin specific for intrinsic neurons (Coyle et al. 1978),

results in a loss of BZ receptor at a time when degeneration is

thought to be complete (Sperk and Schlogl 1979). Electron microscopic

autoradiographic studies show that the BZ receptors are associated

with synapses (Mohler et al. 1980). In the caudate nucleus and putamen from brains of patients with Huntington's disease characterized

12
by a neuronal cell loss in these regions, there was a significant

reduction of BZ receptors (Mohler and Okada 1978). In the cerebella

of mutant mice having a loss of neurons there was a reduction of

BZ receptors (Lippa et al. 1978; Skolnick et al. 1979; Speth and

Yamamura 1979). All of these findings, as well as the observed

close interaction between GABA receptors, potential chloride channels,

and BZ receptors (Tallman et al. 1980), are strongly supportive of

a neuronal localization of the receptor. However, it seem difficult

to rule out the possibility that some receptors in the brain may

be non-neuronal (Henn and Henke 1978). There are BZ binding sites

in the kidney, liver, lung, and some tissue culture cell lines, but

they do not have pharmcological properties associated with anxiolytics (Tallman et al. 1980) and their significance is not understood.

REGIONAL LOCALIZATION IN BRAIN--INSIGHTS TO DRUG ACTION

Biochemical studies in several species showed that cerebral and cerebellar cortical and limbic areas had relatively high levels of BZ

receptors (Squires and Braestrup 1977; Mohler and Okada 1977; Braestrup et al. 1977; Speth et al. 1978). Other areas tended to have

lower, sometimes much lower, levels. The high levels in cortical

areas may be unique among receptor distributions. The receptors in

limbic areas may be important for the anxiolytic actions of the drugs.

Light microscopic autoradiographic studies of receptors are useful

because they provide great sensitivity in measurement and a high

degree of anatomical resolution (Kuhar 1978; Young and Kuhar 1979a).

Accordingly, the distribution of BZ receptors was examined in the

brains of humans and animals by microscopic methods. In agreement

with the biochemical studies, there were striking regional variations

in receptor densities that, in some cases, were species-dependent.

The light microscopic studies involved labeling receptors in vitro in

mounted tissue sections and generating autoradiograms by the apposition of emulsion-coated coverslips (Young and Kuhar 1979a,b).

In rat brain, receptor density was high in the cerebral cortex, the

molecular layer of the cerebellum, parts of the limbic system,

olfactory bulb, hypothalamus, substantiae gelatinosae of the spinal

trigeminal nucleus, and spinal cord. White matter areas showed

negligible levels of receptor. In human tissues, there was also a

striking absence of BZ receptor in white matter. In the human cerebellum, there was a high density of receptors in association with both

the granule cell layer and the molecular layer. In the cerebral

cortical areas, there were variations in the autoradiographic grain

densities. For example, in the calcarine cortex, BZ receptors were

highest in layers III, IVa, and IVc. In mice, the distribution was

quite similar to that found in the rat. An interesting species difference was found in the cerebellum where there was a high density

of BZ receptors in the molecular layer of mice and rats, but compared

with the human tissues, there was a markedly reduced level of BZ

receptors in the granule cell layer (Young and Kuhar 1979b, 1980a).

The receptor distributions in the rat have been presented schematically on stereotaxic drawings (Young and Kuhar 1980a).

13
In agreement with biochemical reports (Began et al. 1980; Howells et

al. 1979), autoradiographic studies showed high densities of BZ

receptors in the rat retina (Young and Kuhar 1979b). They were found

highly localized to the inner plexiform and ganglion cell layers while

a few receptors were also present in the inner nuclear layer.

Following the administration of BZ drugs, a variety of physiological

effects are observed (Greenblatt and Shader 1974; Haefely et al. 1980).

It is interesting, but admittedly speculative, to relate brain regions

containing high densities of BZ receptors with physiological functions

known to be altered by BZ administration. One must be cautious in

assuming connections between brain regions laden with high densities

of receptors and clinical drug effects, because it is possible that

brain regions with rather low levels of receptor may also be critical

for clinical effects. Also, species differences are likely to be

significant as well. However, it seems that some relationships

between brain areas with high receptor levels and certain drug effects

are striking. For example, anxiety is a complex function possibly

involved with the limbic system that has been implicated as an anatomical area related to emotion and its physiologic, behavioral, and

endocrinological sequelae. The circuitry is complex and involves a

number of brain areas including the hippocampus, amygdala, hypothalamus, frontal cortex, and other associated areas (Papez 1937).

It has been speculated that the antianxiety action of BZ drugs is due

to suppression of the limbic system. Spontaneous and evoked activity

of the hippocampus, amygdala, and related structures are profoundly

depressed by BZ administration (see Young and Kuhar 1980a and Haefely

et al. 1980 for references). The amygdala may be especially important for certain actions of BZ drugs because behavioral studies

involving direct injection into the amygdala have revealed potent

effects. Direct injection of diazepam into the anterior amygdaloid

nucleus showed anticonvulsant effects in that it resulted in an

elevated pentylenetetrazol (PTZ) threshold for appearance of spike

activity in the EEG; and also elevated the threshold of limbic system

after discharges. Thus, it seems that the anterior amygdaloid nucleus

could be particularly important for the anticonvulsant effects of

diazepam (which is an antianxiety model) as the dorsal hippocampus

did not show such effects (Nagy and Decsi 1979). In another similar

study using a "conflict situation" model for anxiety it was found

that the direct intra-amygdala application of diazepam produced an

antianxiety effect (Nagy et al. 1979). In the receptor distribution

studies, high densities of BZ receptors were found in much of the

limbic system, including parts of the amygdaloid complex, hippocampal formation, pyriform cortex, medial septal nuclei, and hypothalamus. The anatomical results suggest more specifically the parts

of the limbic system important for BZ anxiolytic effects. For

example, only certain amygdaloid nuclei (centralis, medialis, and

lateralis) contain high levels of receptors.

Benzodiazepines are also used extensively as anticonvulsants. They

have been shown to prevent the spread of seizures from the cortex,

thalamus, and limbic structures (Haefely et al. 1980). The high

level of BZ receptors in the cortex and limbic structures suggests

that the drug action at receptors in these areas could directly

14
prevent the spread of seizures. It is also interesting to hypothesize

a relationship between receptors in the reticular formation with the

muscle relaxant action of the drugs, receptors in the lateral hypothalamus with the appetite stimulation effects, and receptors in the

cerebellum with the ataxia and incoordination observed with high

intake of the drugs.

Thus, one can make a number of interesting associations between

anatomical distributions of BZ receptor and physiological effects of

the drugs. However, it is recognized that these associations are only

new hypotheses and their validity will rest on future experiments.

Nevertheless, these studies seem to provide some suggestions and directions for future experiments. There are also many other areas of

the brain having high levels of BZ receptors, and no one is aware of

the significance of these areas (for example, the receptors in the

retina and superior colliculus).

MULTIPLE BZ RECEPTORS

While early studies indicated the presence of only a single homogenous

class of BZ receptor sites, more recent evidence has suggested the

existence of at least two pharmacologically, biochemically, and functionally distinct receptor sites. Experiments demonstrating multiple

BZ receptors have involved heat inactivation experiments as well as

pharmacological studies with a novel series of triazolopyriazines

(TPZ) (Squires et al. 1979; Williams et al. 1980; Lippa et al. 1979a,

1980). Hofstee's analysis of the ability of several TPZ drugs to

displace BZ receptor binding from rat brain cortical synaptosomal

membrane fragments yielded curvilinear plots that could be resolved

into two components. The data suggested at least two populations of

BZ receptors, one with a high affinity site for TPZ and another with

low affinity for TPZ. These sites varied in their relative proportions

in the various brain regions (Lippa et al. 1980). Since pharmacological and behavioral studies of TPZ drugs have demonstrated activity

in tests believed predictive of anxiolytic activity without much of the

accompanying sedation and ataxia produced by benzodiazepines (Lippa

et al. 1979a, b), and since the TPZ-sensitive BZ receptors appear to

have a unique regional distribution, it might be supposed that an

understanding of those regions containing high densities of BZ receptors

with a high affinity for TPZ would provide some clue about brain

regions critical for anxiolytic activity as opposed to side effects

of the benzodiazepines. Biochemical experiments suggested that the

cerebellum contained mostly "type 1" receptors (the subclass of BZ

receptors for which TPZ's have a high affinity) while the hippocampus

and cortex contain both type 1 and "type 2" (the subclass of BZ

receptors having a low affinity for TPZ drugs) receptors (Lippa et

al. 1980). Light microscopic autoradiographic studies of the distribution of the two types of receptors have confirmed and extended the biochemical experiments (Young et al. 1981). Areas with high densities

of BZ receptors with a high affinity for TPZ drugs include the cerebellum, globus pallidus, and parts of the cerebral cortex. Areas

having BZ receptors with a low affinity for the drugs include the

superficial layer of the superior colliculus, the caudate-putamen,

and parts of the dentate gyrus.

15
Since type 1 receptors may be more related to the antianxiety action

of benzodiazepines, it was of interest to note whether type 1 receptors were found in parts of the limbic system including the hippocampus, amygdala, and frontal cortex. It is interesting that these

areas were not the most enriched in type 1 receptors overall, but

substantial amounts of type 1 receptors were observed in some parts

of these areas. In the hippocampal formation, for example, receptors

in the dentate gyrus were resistant to TPZ drugs while binding in

the hippocampus proper was affected by them. The frontal cortex

appearedtohave a mixture of both type l and type 2 receptors,

although type 1 receptors appeared to predominate in lamina IV.

Thus, if the TPZ-related receptors are in fact related to the antianxiety action of the drugs, then only certain anatomical pathways

within these brain regions may be involved in the complex symptomatology known as anxiety. However, as stated earlier, additional

experiments on the mechanism of anxiety and effects of TPZ will be

necessary before these ideas can be accepted. These notions must be

considered with additional caution since there are important regional

and species differences as described above and extrapolation of data

from rat brain to human tissues may not be valid. Also, while TPZ

drugs show "antianxiety" action in animal model studies, they have

not yet been shown to have such action in humans. Nevertheless, the

clear demonstration that there are two types of BZ receptors with

very different regional distributions in rat brain will help to

explain the physiological differences between benzodiazepines and

TPZ drugs and point out target sites in the brain for additional

studies of the two apparently different receptors. Whether the two

receptors are biochemically and structurally different or whether

the differences are due to environmental or allosteric effects cannot

be determined from these data. However, receptor purification techniques have suggested the presence of multiple molecular weight

forms of the BZ receptors (Sieghart et al. 1980).

ELECTRON MICROSCOPIC LOCALIZATION OF RECEPTOR

A serious limitation of the biochemical as well as the light microscopic studies of receptor distributions is the lack of ultrastructural resolution. Because the resolution of the light microscope is

limited, it is not possible to associate the receptors with specific

membranes in brain regions, but only to associate receptors with

brain regions in a fairly generalized fashion. Accordingly, ultrastructural studies at the electron microscopic level are very important and, presumably, this area will receive a great deal of attention

in the future. A recent electron microscopic autoradiographic study

of BZ receptors provided evidence that the receptors are associated

with synaptic contacts (Mohler et al. 1980). The study utilized

flunitrazepam in a radiolabeled form, which not only binds to the

BZ receptor but also can be used as a photoaffinity label to produce

a covalent labeling of the receptor. The cellular and subcellular

localization of BZ receptors was analyzed in autoradiographs of

photolabeled brain slices. It was found that 55 percent and 74

percent of the grains in cerebral and cerebellar cortex slices respectively were associated with synaptic contacts (because of the method

of analysis, the regions of synaptic contacts include nerve endings

16
and adjacent postsynaptic and glial structures). This large fraction

of grains is much higher than would occur on the basis of random

chance and it is clear that the BZ receptor is associated in some way

with synaptic contacts. It is possible that BZ receptors are associated with other structures as well. One cannot absolutely rule

out an association of some BZ receptors with glial structures in

synaptic areas or even distinguish between presynaptic and postsynaptical localizations because of the limited resolution of electron

microscopic autoradiography. The investigators felt that their

observed distributions were at least compatible with the association

of benzodiazepine receptors with GABAergic transmission (Mohler et

al. 1980).

In a study combining the electron microscopic autoradiographic localization of BZ receptors and the immunocytochemical localization of

glutamic acid decarboxylase, it was found that a large fraction of BZ

receptors were associated with GABAergic terminals (Mohler and

Richards, personal communication). However, BZ receptors were apparently more widespread than the terminals containing the enzyme.

Thus, it was suggested that all BZ receptors are not associated with

GABA receptors. Light microscopic data could be interpreted to be

in agreement (Young and Kuhar 198Ob; Palacios et al. 1980). However,

the precise relationship between BZ receptors and GABAergic transmission is not yet totally understood, although it is well known that

BZ drugs have a profound effect on GABAergic transmission (Haefely

et al. 1980, Costa et al. 1975).

Because of the limited resolution of autoradiography, even at the

electron microscopic level, additional techniques will be necessary

to more precisely localize benzodiazepine receptors in tissues. Perhaps electron microscopic immunocytochemical studies will be useful

for this, and they are feasible if antibodies to the receptor can be

produced.

FUTURE DIRECTIONS -- THE BENZODIAZEPINE (BZ) RECEPTOR

Since anatomical studies are so important for understanding several

aspects of BZ drug action, work in this and related areas will continue to be fruitful. Specific topics that could be explored further

are fairly obvious and include the following:

1. More detailed light microscopic mapping of receptor locations in

animal models (rat and monkey) and also in human tissues. Receptor distribution in brain is very basic information and should

be studied. Techniques for accomplishing this are adequate and

available.

2. Identification of endogenous ligand(s). In other words, why is

the BZ receptor in the brain and what is its normal significance

in the absence of BZ drug?

17
3. Electron microscopic localization of BZ receptors. The location

of the receptor needs to be studied by high resolution methods.

Perhaps the most promising is an immunocytochemical approach.

Thus, isolation and purification of, and production of antibodies

against BZ receptors is an important goal.

4. Functional anatanical studies. In other words, which brain areas

are most critical for therapeutic effects? Perhaps behavioral

studies combined with direct micro-injections of drug into discrete brain areas is the best approach.

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20
ACKNOWLEDGMENTS

The author acknowledges support of RCDA Type II Award MH00053 and

DA00266 and a grant from F. Hoffmann-La Roche.

AUTHOR

Michael J. Kuhar, Ph.D.

Department of Neuroscience

The Johns Hopkins University

School of Medicine

725 N. Wolfe Street

Baltimore, Maryland 21205

21
Benzodiazepine SelfAdministration in Animals and

Humans: A Comprehensive

Literature Review

Roland R. Griffiths, Ph.D., and Nancy A. Ator, Ph.D.

One approach to studying drug abuse has been the development of

experimental paradigms for controlled investigations of drug selfadministration in laboratory animals and humans. Such experimental

models can provide various types of information relevant to drug

abuse, including comparative information about the relative efficacy

with which different drugs maintain drug self-administration. The

validity of this approach is supported by the good correspondence

between those drugs that are self-administered by laboratory animals

and those self-administered and abused by man (Griffiths and Balster

1979; Griffiths et al. 1980a). The purpose of this paper is to

review the current status of the scientific literature on benzodiazepine self-administration. The first two sections review the

animal and human data, respectively. The final section summarizes

major findings and outlines directions for future research on

benzodiazepine self-administration.

ANIMAL STUDIES

Experimental studies with nonhuman primates and rats have examined

self-administration of a variety of benzodiazepines via the intravenous, intragastric, and oral routes. As a whole, these studies

show that a number of the benzodiazepines can sustain responding at

rates higher than vehicle but that the efficacy of the benzodiazepines in maintaining self-administration behavior is generally less

than for other sedative-hypnotic drugs (e.g., barbiturates, ethanol)

with which they have been compared.

Nonhuman Primates

Studies of benzodiazepine self-administration in nonhuman primates

have employed the intravenous (I.V.) and intragastric (I.G.) routes,

and the majority have been conducted with rhesus monkeys. The

animals are prepared with indwelling catheters that are connected

to infusion pumps. An injection typically depends on the animal's

pressing a lever, which activates the pump to deliver a drug dose.

Rates of self-injection of drug can be compared with rates of selfinjection of the vehicle to determine whether drug reinforcement

is demonstrated.

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Yanagita and Takahashi (1973) investigated self-administration of

three benzodiazepines (chlordiazepoxide, 1 mg/kg I.V., 10 mg/kg

I.G.; diazepam, 0.4 mg/kg I.V.; oxazolam, 10 mg/kg I.G.). Groups

of rhesus monkeys first had saline available for up to 2 weeks and

then drug available for at least 4 weeks. Drug injections depended

on a single lever press response and were continuously available

24 hours per day. Though complete data are not presented, it appears

that diazepam maintained more self-administration than the other two

drugs. Three of four drug-naive monkeys initiated lever pressing

and maintained rates above those maintained by saline (20 to 25

injections per 24 hours resulting in a mean daily dose of 8 to 10

mg/kg). Mean daily intake of chlordiazepoxide was 10 to 20 mg/kg I.V.

and 100 mg/kg I.G. (i.e., regardless of route of self-administration,

the monkeys pressed the lever approximately 10 times in 24 hours).

Unfortunately no saline control data were presented. Although I.G.

self-administration of chlordiazepoxide continued longer than 8

weeks, daily intake via the I.V. route declined after 4 weeks (to

two to four injections per day). No data were reported on levels

of oxazolam intake, except that two of four monkeys initiated

responding but did not show "high intake." The report concluded

that diazepam was "moderately reinforcing," and that chlordiazepoxide

and oxazolam were 'mildly reinforcing."

Using the same procedures, Yanagita and his colleagues also investigated I.G. self-administration of two other benzodiazepines: Sch

12041 (7-chloro-1, 3-dihydro-5 phenyl-l-(2,2,2-trifluoroethyl)-2 H1,4-benzodiazepine-2-one) (Yanagita et al. 1975) and ID-540 (l-methyl5(o-fluorophenyl)-7-chloro-1,3-dihydro-2 H-1, 4-benzodiazepine-2-one)

(Yanagita and Kiyohara 1976). None of the four monkeys selfadministered Sch 12041 at a dose of 20 mg/kg above the levels maintained by water. When the dose was decreased to 5 mg/kg, three of

the four monkeys increased rates of self-administration to levels

greater than those maintained by the higher dose. Whether the levels

were reliably higher than maintained in the water control condition

is not clear due to variability in the water data. The authors

concluded that the reinforcing effect of Sch 12041 was "positive

but weak." The report on ID-540 is available in English in abstract

form only. One of four self-administration-experienced monkeys was

said to have self-administered the drug (taking about 10 injections

per day at doses of 0.25 and 1 mg/kg).

Using procedures similar to those described above, Altshuler and

Phillips (1978) found that rhesus monkeys with I.G. catheters did

not self-administer diazepam but did self-administer chlordiazepoxide.

Unfortunately, no information on dose, length of exposure, drug

history, or vehicle controls permits assessment of this experiment.

Two studies of I.V. diazepam self-administration initially maintained

responding of rhesus monkeys at a high rate with codeine reinforcement

(0.05 mg/kg) and substituted doses of diazepam or saline. Hoffmeister

(1977) showed that the number of injections of diazepam (0.005 to 0.05

mg/kg) was less than for codeine but higher than for saline at all

but the highest dose, with the 0.05 mg/kg dose maintaining the highest

rate of self-injection. Increasing the number of responses required

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per injection of that dose produced a monotonic decrease in number of

injections. In contrast Hackett and Hall (1977) failed to find

response rates above those maintained by saline when diazepam doses

(0.05 to 0.04 mg/kg) were substituted for codeine. The reason for

the difference in results is unclear, and lack of complete procedural

description (i.e., specification of response requirement and session

duration) in the Hoffmeister report makes further methodological

comparisons impossible.

Johanson and Balster (1978) summarized several unpublished studies

that evaluated the I.V. self-administration of two benzodiazepines

in rhesus monkeys using drug substitution procedures. In these

studies doses of a test compound were substituted for a dose of drug

(e.g., cocaine or codeine) already maintaining self-administration.

Self-administration was rated as positive if the test drug maintained

a greater number of injections than vehicle for at least one dose

in more than half of the monkeys studied. According to these

criteria, self-administration results were positive with flurazepam

and equivocal with chlordiazepoxide (positive results were obtained

in one laboratory while negative results were obtained in another).

Griffiths et al. (1981) extended the study of I.V. benzodiazepine

self-administration to a different procedure and primate species.

Baboons were trained to respond to a lever which produced cocaine

injections (0.32 mg/kg) for the 160th response. A 3-hour time-out

(a period during which drug was not available) followed each injection, permitting a maximum of eight injections per day. A range

of doses (e.g., 0.01 to 17.8 mg/kg) of each of a number of benzodiazepines and the vehicles alone were substituted for 12 to 15

days with a return to the cocaine reinforcement condition preceding

each substitution. The highest rate of self-injection was obtained

with midazolam, an ultra-short-acting benzodiazepine. Doses ranging

between 1.0 and 10.0 mg/kg were self-administered above saline levels

in all five baboons tested and, in several animals, were self-administered at levels comparable to that of cocaine control. The other

benzodiazepines (diazepam, clonazepam, clorazepate, flurazepam, and

medazepam) all sustained some self-administration--average injections

per day maintained by drug exceeded levels maintained by the vehicle

for at least two baboons at one or more doses.

One study employed a procedure designed to induce self-administration

of chlordiazepoxide by manipulation of environmental conditions and

exposure to the drug. Findley et al. (1972) trained two rhesus

monkeys to press a lever under a complex choice procedure in which

I.V. injections of either drug or saline occurred after meeting a

shock-avoidance response requirement. Initial selection of the drug

option over the saline option was promoted by pairing a lower shockavoidance response requirement with the drug option. Initial exposure

to the drug was further assured by presenting the shock-avoidance/

drug-choice trials automatically every 3 (or 4) hours, but the monkeys

could produce them more frequently by pressing a separate lever.

Drug dose was varied between approximately 0.5 to 2.0 mg/kg chlordiazepoxide. Evidence of drug reinforcement included increasing frequency

of trial initiation by the monkeys and the more frequent choice of

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the drug option over the saline option. The influence of the initial

pairing of the drug option with the lower shock-avoidance requirement

seemed not to persist, since, when the same drug dose later was made

available in both options, choice of each became 50 percent.

A number of the studies cited above compared responding maintained by

benzodiazepines with responding maintained by other drugs under the

same procedures and, in some cases, in the same animals. In these

studies the percentage of animals self-administering the drug, the

rate of drug self-administration, or drug choice performance are

taken as indicators of the relative reinforcing efficacy of the drug.

These studies showed that benzodiazepines as a class are more efficacious than some drugs, including chlorpranazine (Altshuler and

Phillips 1978; Griffiths et al. 1981; Hoffmeister 1977; and Yanagita

and Takahashi 1973), imipramine, haloperidol, or perphenazine

(Hoffmeister 1977). The studies also showed, however, that benzodiazepines were clearly less efficacious than a range of other drugs,

including pentobarbital (Altshuler and Phillips 1978; Griffiths et

al. 1981; Hoffmeister 1977; Yanagita and Takahashi 1973), alcohol

(Hoffmeister 1977; Yanagita and Takahashi 1973), amobarbital (Griffiths et al. 1981), secobarbital (Findley et al. 1972; Griffiths

et al. 1981), and cocaine (Altshuler and Phillips 1978; Griffiths

et al. 1981; Hoffmeister 1977). On the whole, these data suggest

that benzodiazepines can be considered to be moderately reinforcing.

Rats

The majority of benzodiazepine self-administration studies with rats

have employed the oral route, while only three studies have examined

intravenous or intragastric drug delivery. Davis et al. (1978)

reported in abstract form that both I.G. and I.V. self-administration

of chlordiazepoxide (0.1 to 1.0 mg/kg) occurred at rates higher than

those maintained by saline. The authors noted that higher numbers

of injections were obtained with the I.V. route. Götestam (1973)

investigated I.G. self-administration of medazepam (2.5 to 10.0 mg/kg)

in groups of rats, each having saline or a different drug dose available 24 hours a day. Over 6 days of drug availability, the mean

number of injections per day increased, with the greatest increase

at the 10.0 mg/kg dose and the least for the saline group. A final

study by Walton and Deutsch (1978) investigating I.G. and oral selfadministration provided no evidence for the reinforcing effects of

diazepam (0.25 to 1.0 mg/ml). It is possible that these negative

results reflect procedural limitations of the study. The rats were

deprived of fluid for 23 hours at the time of each daily session

and each dose was in effect for only two sessions. In addition,

the drug vehicle was a 3 percent ethanol solution, a concentration

that was consumed in another study at greater volumes than water by

drug-naive rats of the same species as those used by Walton and

Deutsch (Veale and Myers 1969).

The remainder of the studies with rats to be discussed involved oral

drug self-administration (i.e., the drug was added to drinking water),

and all but one involved self-administration of chlordiazepoxide.

Because of problems inducing rats to consume oral drug solutions

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(e.g., Wolf et al. 1978), several studies have employed conditions of

forced chlordiazepoxide intake by making the drug solution (0.2 or

0.5 mg/ml chlordiazepoxide) the only fluid available (Harris et al.

1968; Kamano and Arp 1965; Stolerman et al. 1971). Drug preference

was then tested by presenting the rats with a choice of water and the

drug solution in the home cage. In all three studies a history of

forced chlordiazepoxide intake was not sufficient to induce a higher

proportion of total fluid to be taken as drug solution on choice days.

In fact, other data suggest that forced consumption of a nonpreferred

drug solution may actually decrease the probability of that solution's

being preferred in a choice test (cf. Veale and Myers 1969).

A number of other experimental manipulations have been investigated

as means of inducing higher oral benzodiazepine intake. It is well

established that rats that receive food pellets intermittently in a

daily session will exhibit excessive levels of water intake immediately post-pellet (cf. Sanger and Blackman 1978). This paradigm

(schedule-induced polydipsia) has been used to generate consumption

of chlordiazepoxide solutions (Jacquet and Stokes 1975; Sanger 1977).

Sanger (1977) provided some evidence for the reinforcing effects of

chlordiazepoxide. The group of rats that had 0.1 mg/ml chlordiazepoxide available drank a slightly higher volume than the group having

only water available, and volume consumed decreased when water was

substituted for drug. Rats having 0.4 mg/ml chlordiazepoxide available consumed less than that of the water group, and volume increased

when water was substituted for the drug solution. Jacquet and Stokes

(1975) also reported schedule-induced drinking of chlordiazepoxide

solutions, but the limited information (given in an abstract) does

not provide evidence for the reinforcing properties of the drug.

Some studies have manipulated remote environmental contingencies

thought to produce stress in an effort to determine whether this

would result in increased intake of chlordiazepoxide. Rats were

provided chlordiazepoxide solutions in the home cage and were

submitted to supposedly aversive conditions in daily sessions in

separate chambers. Exposure to shock-avoidance trials, inescapable

shock conditions (Kamano and Arp 1965) and operant extinction (i.e.,

lever presses ceased to produce food reinforcement; Harris et al.

1968) failed to increase drug consumption in the home cage.

Another experimental manipulation employed by Harris et al. (1968)

apparently was more successful in modulating chlordiazepoxide intake.

Following 25 days of daily sessions in which food pellets depended

on licking a tube containing chlordiazepoxide (0.5 mg/ml), rats drank

more drug solution during a choice condition in the home cage than

prior to training and more than another group of rats following a

25-day period in which drug solution was the only fluid available.

This result is particularly interesting since, under the latter

condition, total drug intake was two to three times greater. Food

deprivation was not a confounding factor, since all rats in this

experiment were maintained at 85 percent of ad libitum weight throughout all conditions.

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Although the question of whether a history of self-administration of

other drugs will increase the subsequent likelihood of benzodiazepine

self-administration has not been investigated systematically, one

study provides some data suggestive of this possibility. Amit et al.

(1973) found that rats that showed high daily alcohol intake for an

extended period of time later drank a greater proportion of total

daily fluid as a diazepam solution (0.06 mg/ml) in a choice condition

with water than either drug-naive rats or rats that had consumed less

alcohol per day.

Few of the rat studies reviewed above have attempted to directly

compare the self-administration of benzodiazepines with other drugs

(Davis et al. 1978; Götestam 1973; Harris et al. 1968; Stolerman

et al. 1971). The lack of adequate dose manipulations, in particular, makes any conclusion about relative drug reinforcing efficacy

hazardous. The study by Davis et al. (1978) provides some suggestive

evidence that chlordiazepoxide may be a less efficacious reinforcer

than d-amphetamine: rats that had failed to self-administer I.V.

chlordiazepoxide (0.25 mg/kg) subsequently acquired self-administration behavior when d-amphetamine (0.25 mg/kg) was substituted.

Overall, studies of benzodiazepine self-administration in rats provide only limited evidence for drug reinforcement. Several studies

have demonstrated benzodiazepine intake over vehicle control levels

intravenously (Davis et al. 1978), intragastrically (Davis et al.

1978; Götestam 1973), and orally (Amit et al. 1973; Sanger 1977).

The remaining studies reviewed either failed to demonstrate drug

reinforcement or did not experimentally address the question of drug

reinforcement per se. The limited research with rats to date comparing benzodiazepines to other drug classes provides no basis for

drawing meaningful conclusions about the reinforcing efficacy of the

benzodiazepines relative to other drugs.

HUMAN STUDIES

A variety of different experimental approaches in treatment and

laboratory settings has provided information about the reinforcing

properties of benzodiazepines in various subject populations,

including normal student volunteers, patients with insomnia, alcoholics, psychiatric patients, and volunteers with histories of

sedative drug abuse. As a whole, these studies demonstrate that

benzodiazepines maintain self-administration; however, their efficacy

as reinforcers appears to depend on the subject population studied

and the conditions of drug availability.

Rothstein et al. (1976) investigated self-administration of medication in a group of alcoholic patients who were treated in an outpatient clinic setting. The study involved 108 patients who were

followed for at least 1 year while receiving free prescriptions

for various tranquilizers (95 percent chlordiazepoxide; 4 percent

diazepam; 1 percent phenothiazine). Patients were instructed to

use the medication as needed for relief of anxiety, but urged to

take as little as possible. Daily self-administration doses of

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the most commonly used drug, chlordiazepoxide, ranged between 10 to

200 mg. Eighty-six percent of the total patient group reported not

taking their prescribed drug every day, while 50 percent went without

the drug for more than 30 days during the study period. In the group

of patients studied, overall drug intake apparently remained relatively stable (17 percent of patients increased intake; 14 percent

decreased intake, and 7 percent stopped using the drug during the

study period). Clinical evidence of abuse or misuse (e.g., exceeding

prescribed dose range or using the drug as an alcohol substitute)

was seen in 5 percent of the patients. The authors concluded that

benzodiazepine use in alcoholics appears quite safe.

Kryspin-Exner and Demel (1975) described a series of three studies

involving benzodiazepine self-administration by alcoholic and drugabuse patients in a treatment context. In the first, alcoholics in

a supervised outpatient setting were given prescriptions for benzodiazepines for a period of at least 4 weeks (mean observation time

was 1 year). Characteristics of dependence, including a tendency

toward increased doses and corresponding psycho-organic deficit

symptoms were shown by 3.6 percent of the 111 patients given chlordiazepoxide and 2.3 percent of the 302 patients given diazepam. Of

the 11 patients, 7 had histories of abusing sedatives or analgesics

in addition to alcohol. In a second study, the double-blind selfadministration of diazepem (5 mg/tablet) or placebo was studied in

a group of hospitalized male alcoholics who did not have histories

of abusing drugs other than alcohol. All patients had abstained

from alcohol for approximately 7 days prior to the study. They

were told that medication was important for treatment of their withdrawal symptoms and that they could take up to 10 tablets a day.

patients were assigned to either placebo (N=23) or diazepam (N=24)

and the study was conducted for a 32-day period. Under these conditions, relatively low levels of self-administration occurred

(average of 1.7 tablets per patient per day) with no significant

difference between diazepam and placebo. In a final study, 20

patients with histories of abuse of hypnotic drugs were placed on

a canbination of four tranquilizers (oxazepam, lorazepam, diazepam

and nitrazepam) at almost unrestricted doses. The authors noted

that within a few weeks 8 of the 20 patients became dependent on

the tranquilizers that were originally prescribed for therapeutic

purposes. These studies emphasize the potential importance of a

patient's history in determining levels of benzodiazepine selfadministration. Patients with histories of abusing sedatives or

analgesics may be more likely to misuse benzodiazepines than

patients with histories of abusing only alcohol.

Winstead et al. (1974) encouraged all patients admitted to a 16-bed

general psychiatric ward to request diazepam (10 mg) when necessary

(prn), every 4 hours. patients were told to seek medication from

staff if they felt unusually tense, anxious, or worried. Over the

6-month study period 83 patients participated. patients differed

greatly in their tendency to request medication--27 percent sought

none, and requests were made on an average of only once every 3

days. The characteristics correlated with drug taking were anxiety,

being female, being white, and having an elevated psychasthenia

28
scale on the MMPI. Although within-subject analysis indicated that

drug taking decreased over the duration of the hospital stay, drug

taking for the entire ward increased over the 6-month study period.

The authors suggest that this increase may be attributable to au

increasingly favorable staff attitude toward minor tranquilizer use

that developed over the study. The authors concluded that when

diazepam was made freely available, psychiatric patients of all

diagnoses sought it for the appropriate indication of anxiety, and

most used it conservatively.

Jick et al. (1966) and Fabre at al. (1976) used a procedure for

assessing drug preference while evaluating the efficacy of various

benzodiazepine hypnotics in outpatients with insomnia. The two

drugs being compared were identically packaged and labeled as either

Drug A or Drug B. One drug was administered on a double-blind basis

in random order on the first night, with the comparison drug given

on the second night. Patients subsequently were asked to express

their preference for Drug A or Drug B, or, alternatively, indicate

that they had no preference. Fourteen to thirty-five patients participated in each preference comparison. Using such procedures Jick

et al. (1966) showed that the benzodiazepine hypnotic flurazepam (7-

chloro-1 [2-diethylaminoethyl]5-[2-fluorophenyl]-1,3-dihydro-2H-l,

4 benzodiazepine-2-one dihydrochloride) was preferred to placebo in

two separate experiments. In a third experiment, no difference in

preference was obtained when 15 mg flurazepam was compared with l00 mg

secobarbital. Using similar procedures, Fabre et al. (1976) reported

that the benzodiazepine triazolam (0.5 mg) was clearly preferred to

placebo. In subsequent paired comparisons, 0.5 mg triazolam also

was found to be preferred to 500 mg chloral hydrate and 30 mg flurazepam. Overall, these studies show that the reinforcing effects

(as indicated by a verbal preference measure) of hypnotic benzodiazepines can be demonstrated under conditions that may favor the selfadministration of sedative drugs (i.e., at night in people complaining

of insomnia).

Johanson and Uhlenhuth (1978) used a paired preference procedure,

somewhat similar to that described above, to assess choice between

diazepam and placebo and diazepam and d-amphetamine. Normal student

volunteers participated in sessions involving drug administration in

the morning. Each experiment consisted of nine sessions, three per

week. During the initial four sampling sessions, the subjects were

given an opportunity to experience the effects of the two drugs that

were dispensed blind in different colored capsules. During the five

subsequent choice sessions subjects were instructed to choose between

the two colors, and their choice determined which they received.

Eight to 11 subjects participated in each paired comparison. The

results indicated that there was no preference between placebo and

2 mg diazepam, but placebo was preferred to both 5 and 10 mg diazepam.

d-Amphetamine (5 mg) was preferred to diazepam (2 mg). Overall, the

study provides no evidence for the reinforcing properties of diazepam

in normal volunteers.

29
A series of studies conducted at Baltimore City Hospitals examined

diazepam and pentobarbital self-administration in male volunteer

subjects with histories of sedative drug abuse (Bigelow et al. 1976;

Griffiths et al. 1976, 1979). Subjects lived on a residential

research ward and were required to ride a stationary exercise bicycle

in order to obtain a maximum of 20 ingestions of drug during daily

sessions. When dose of drug was varied under blind (Griffiths et

al. 1979) or nonblind (Griffiths et al. 1976) conditions, the number

of ingestions taken increased as dose increased with both pentobarbital (30 to 90 mg/ingestion) and diazepam (2 to 20 mg/ingestion).

Furthermore, increases in the response requirement to obtain drug

(Bigelow et al. 1976), or increases in the minimum time period

imposed between the availability of successive drug ingestions

(Griffiths et al. 1976) produced decreases in the number of ingestions consumed for both pentobarbital and diazepam. These results

show that diazepam and pentobarbital are similar to the extent that

they both maintain self-administration and that they are similarly

responsive to manipulation of dose, response requirement, and minimum

interingestion interval.

Several of the studies conducted at Baltimore City Hospitals provided

some information about the reinforcing efficacy of diazepam relative

to other drugs having sedative properties. Griffiths et al. (1979)

directly compared the self-administration of pentobarbital (30 or 90

mg/ingestion), diazepam (10 or 20 mg/ingestion), chlorpromazine (25

or 50 mg/ingestion) or placebo under double-blind conditions. In

this study a drug was made available for 5 to 15 consecutive days and

the order of exposure to different drugs was mixed. A maximum of

10 ingestions was available during a 7.5 hour session each day. On

the first day of drug availability ingestions were available upon

request of the subject, provided that 15 minutes had elapsed since

the last dose was dispensed. After the first day subjects were

required to obtain each ingestion of drug by riding a stationary

exercise bicycle for 15 minutes. Although all three drugs produced

subjective effects and observable signs of sedative intoxication,

the drugs were associated with different amounts of self-administration. With the exception of one idiosyncratic subject, chlorpromazine was similar to placebo in that it did not maintain selfadministration. Both diazepam and pentobarbital maintained selfadministration with the higher dose of each associated with higher

average levels of self-administration than the lower dose. The high

dose of pentobarbital was associated with higher levels and more

regular self-administration than was the high dose of diazepam. A

subsequent set of experiments (Griffiths et al. 1980b) provided more

information about the relative reinforcing efficacy of diazepam in

comparison to pentobarbital by using a choice procedure in which

subjects were given repeated opportunities to choose between two

available drug alternatives. In this study drug-free days alternated

with drug administration days. Following experimenter-scheduled

exposures to the test drugs under double-blind conditions, subjects

were given repeated opportunities to choose between two available

drug alternatives. In Experiment 1, pentobarbital (200 to 900 mg)

produced dose-related increases in subject- and observer-rated drug

30
effects, and subjects generally chose higher pentobarbital doses

over lower doses. In Experiment 2, diazepam (50 to 400 mg) produced

only modest elevations in drug effect ratings and subjects did not

consistently choose higher doses over lower doses. In Experiment 3,

400 mg pentobarbital and 200 mg diazepam produced subject and observer

drug effect ratings of similar magnitude while placebo produced

negligible effects. All subjects chose pentobarbital over placebo

and diazepam over placebo on all occasions; all subjects chose pentobarbital over diazepam on the majority of choice trials. Overall,

these studies conducted in subjects with histories of sedative drug

abuse suggest that the reinforcing efficacy of diazepam is greater

than that of chlorpromazine, but less than that of pentobarbital.

CONCLUSIONS AND FUTURE DIRECTIONS

In spite of methodological limitations described below, the literature on animal and human studies reviewed in the preceding sections

provides remarkably similar assessments of the overall efficacy of

the benzodiazepines in maintaining self-administration behavior.

The experimental reports indicate that benzodiazpines can serve as

reinforcers in both animals and humans, although the precise conditions for demonstrating these reinforcing effects are not clear. To

the extent that the benzodiazepines maintain self-administration,

they are more efficacious than drugs such as chlorpromazine, which

have not been shown to maintain self-administration in animals or

humans. However, both animal and human data show that benzodiazepines

are less efficacious in maintaining self-administration behavior than

classic drugs of abuse such as pentobarbital. The inescapable conclusion is that benzodiazepines, as a class, appear to be modest reinforcers. This conclusion is compatible with the fact that, although

there are a number of reports describing human abuse of the benzodiazepines, the abuse liability of these compounds is generally considered to be relatively low (Marks 1978).

Drawing more specific conclusions about the self-administration of

benzodiazepines at this time must be tempered by the recognition that

the present data base is at a very preliminary stage of development.

Many of the animal and human reports reviewed should be viewed as

pilot studies, since they lack experimental thoroughness or methodological rigor. For instance, many of the animal benzodiazepine selfadministration studies investigated only one dose level (e.g., Amit

et al. 1973; Harris et al. 1968; Kamano and Arp 1965; Stolerman et al.

1971; Yanagita and Takahashi 1973) and others have not provided adequate descriptions of methods and/or results (e.g., Davis et al. 1978;

Jacquet and Stokes 1975; Hoffmeister 1977; Altshuler and Phillips

1978). In the human research, lack of appropriate controls in some

of the reviewed studies would suggest that these reports should most

properly be viewed as clinical descriptions rather than experimental

evaluations. For instance, the results of several reports purporting

to show that benzodiazepine self-administration is quite modest in a

treatment context would have been greatly strengthened by appropriate

double-blind placebo or inactive medication controls (Kryspin-Exner

and Demel 1975, Experiment 1; Rothstein et al. 1976; Winstead et al.

31
1974). Clearly, given the preliminary nature of these studies, future

research investments could be profitably placed in further rigorous

studies of animal and human benzodiazepine self-administration.

Both animal and human research suggest that the likelihood of selfadministering benzodiazepines may depend on the history of the subject

population examined. In the single relevant animal study to date,

Amit et al. (1973) presented evidence suggesting that oral diazepam

intake in rats was greater in animals with histories of self-administering other drugs than in drug-naive rats. In human research, the

nonblind studies conducted in a therapeutic context (Kryspin-Exner

and Demel 1975) suggest that patients with histories of abusing

sedatives or analgesics may be at substantially greater risk for

developing abusive patterns of benzodiazepine self-administration

than patients without such histories. Among the studies conducted

with double-blind placebo controls, several studies with alcoholics

or normals (Johanson and Uhlenhuth 1978; Kryspin-Exner and Deme1

1975, Experiment 2) failed to show any reinforcing properties of

diazepam, in contrast to other double-blind studies with sedative

abuser subjects that clearly demonstrated reinforcing effects with

diazepam (Griffiths et al. 1979, 1980b). Future research with both

animals and humans should provide more basic experimental and epidemiological information on drug history and other population differences

as potential determinants of benzodiazepine self-administration.

In addition, possible pharmacological and physiological mechanisms

that may underlie these differences should be explored.

The results of several of the animal and human studies underscore the

potential importance of environmental conditions as a determinant of

the reinforcing efficacy of benzodiazepines. In a study of oral

chlordiazepoxide self-administration in rats, Harris et al. (1968)

found that pairing drinking with obtaining food reinforcement was

sufficient to induce a higher drug intake in a choice situation.

The contribution of other contextual variables to benzodiazepine

self-administration was suggested but not demonstrated experimentally

by the results of other animal studies (e.g., Findley et al. 1972;

Sanger 1977). In human research, the only studies to suggest that

benzodiazepines were reinforcers in nonabuser subjects were those

of Jick et al. (1966) and Fabre et al. (1976) whose research showed

preference for hypnotic benzodiazepines over placebo under conditions

in which the drug was dispensed at night to subjects complaining of

insomnia. It seems likely that these subjects would not have preferred the drug if it had been dispensed in the morning, as was the

procedure in the preference study by Johanson and Uhlenhuth (1978).

Such findings emphasize that the reinforcing efficacy of a drug

should not be considered apart from the context of drug availability.

It seems quite possible that such contextual modulation is particularly important to the establishment of abusive patterns of drug

use with drugs showing only modest reinforcing efficacy in the

laboratory, such as nicotine, caffeine, or benzodiazepines. Future

animal and human research should explore more fully the environmental

and situational conditions (for example, experimentally-induced

stress) that may modulate the reinforcing efficacy of benzodiazepines.

32
Only one of the reviewed studies attempted a systematic comparison

of compounds within the benzodiazepine class (Griffiths et al. 1981).

That study compared the intravenous self-administration of six

benzodiazepines in baboons, and showed that the ultra-short-acting

benzodiazepine, midazolam, was more efficacious in maintaining selfadministration than compounds with longer durations of action. Future

research in animals and humans should provide more canparative data

about the reinforcing efficacy of different benzodiazepines. In these

studies particular attention should be given to differences in rates

of absorption (cf. Bliding 1974) and duration of action (cf. Griffiths

et al. 1981) as properties that may covary with reinforcing efficacy.

The animal research reviewed on oral or intragastric self-administration of benzodiazepines has been quite limited in scope. Interpretation of results of oral benzodiaxepine self-administration studies

in rats is particularly problematic, especially since levels of drug

intake rarely exceeded those of the water controls (Amit et al. 1973;

Sanger 1977), and assessment of more than one drug concentration was

rare. Since the oral route is the most common route by which benzodiazepines are abused in man, and because solubility problems may

compromise some of the results of the intravenous route in animals,

future research investments should be made into the development of

good animal models of oral and intragastric benzodiazepine selfadministration. Such models should be used to provide comparative

information about drug reinforcing efficacy both within and between

relevant pharmacological classes.

Finally, it should be noted that it has been beyond the purview of

this review to examine the data concerning the consequences of benzodiazepine self-administration. Clearly, a balanced view of the abuse

liability of the benzodiazepines must consider the consequences of

use as well as the reinforcing efficacy of these compounds. Notable

adverse effects of benzodiazepine self-administration include memory

deficits (e.g., Clarke et al. 1970; Ghoneim et al., in press), and

sensory/motor impairment (e.g., McNair 1973; Wittenborn 1979), along

with possible subtle adverse changes in mood and behavior (e.g.,

Griffiths et al. 1980b; Hendler at el. 1980). Future animal and

human research should determine the magnitude and prevalence of such

effects through a range of therapeutic and abused dose levels.

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of drugs by the primate. In: Ho, B.T., Richards, D.W., III, and

Chute, D.L., eds. Drug Discrimination and State Dependent Learning.

New York: Academic Press, l978. pp. 263-280.

Amit, Z., Corcoran, M.E., Charness, M.E., and Shiggal, P. Intake of

diazepam and hashish by alcohol preferring rats deprived of alcohol.

Physiol Behav, 10:520-527, 1973.

Bigelow, G., Griffiths, R.R., and Liebson, I. Effects of response

requirement upon human sedative self-administration and drug-seeking

behavior. Pharmacol Biochem Behav, 5:681-685, 1976.

33
Bliding, A. Effects of different rates of absorption of two benzodiazepines on subjective and objective parameters. Eur J Clin

Pharmacol, 7:201-211, 1974.

Clarke, P.R.F., Eccersley, P.S., Frisby, J.P., and Thornton, J.A.

The amnesic effect of diazepam (Valium). Br J Anaesth, 42:690-697,

1970.

Davis, W.M., Smith, S.G., and Werner, T.E. Variables influencing

chlordiazepoxide self-administration behavior in rats. Fed Proc,

37:828, 1978.

Fabre, L.F., McLendon, D.M., and Harris, R.T. Preference studies of

triazolam with standard hypnotics in out-patients with insomnia. J

Intern Med Res, 4:247-254, 1976.

Findley, J.D., Robinson, W.W., and Peregrino, L. Addiction to

secobarbital and chlordiazepoxide in the rhesus monkey by means of

a self-infusion preference procedure. Psychopharmacologia (Berlin),

26:93-114, 1972.

Ghoneim, M.M., Mewaldt, S.P., Berie, J.L., and Hinrichs, J.V. Memory

and performance effects of single and three-weeks' administration

of diazepam. Psychopharmacology, 73:147-151, 1981.

Götestam, K.G. Intragastric self-administration of medazepam in rats.

Psychopharmacologia (Berlin), 28:87-94, 1973.

Griffiths, R.R., and Balster, R.L. Opioids: Similarity between

evaluations of subjective effects and animal self-administration

results. Clin Pharmacol Ther, 25:611-617, 1979.

Griffiths, R.R., Bigelow, G.E., and Henningfield, J.E. Similarities

in animal and human drug taking behavior. In: Mello, N.K., ed.

Advances in Substance Abuse: Behavioral and Biological Research.

Greenwich, CT: JAI Press, Inc., 1980a. pp. l-90.

Griffiths, R.R., Bigelow, G., and Liebson, I. Human sedative selfadministration: Effects of interingestion interval and dose. J

Pharmacol Exp Ther, 197:488-494, 1976.

Griffiths, R.R., Bigelow, G., and Liebson, I. Human drug selfadministration: Double-blind comparison of pentobarbital, diazepam,

chlorpromazine and placebo. J Pharmacol Exp Ther, 210:301-310, 1979.

Griffiths, R.R., Bigelow, G.E., Liebson, I., and Kaliszak, J.E.

Drug preference in humans: Double-blind choice comparison of pentobarbital, diazepam, and placebo. J Pharmacol Exp Ther, 2l5:649-

661, 1980b.

Griffiths, R.R., Lucas, S., Bradford, L.D., Brady, J.V., and Snell,

J.D. Self-injection of barbiturates and benzodiazepines in baboons.

Psychopharmacology, submitted, 1981.

34
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Clinical Toxicology. Amsterdam: Excerpta Medica, 1977. pp. 308-

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Harris, R.T., Claghorn, J.L., and Schoolar, J.C. Self-administration

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Hendler, N., Cimini, C., Ma, T., and Long, D. A comparison of cognitive impairment due to benzodiazepines and to narcotics. Am J

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Hoffmeister, F. Assessment of the reinforcing properties of stimulant

and depressant drugs in the rhesus monkey as a tool for the prediction

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Johanson, C.E., and Balster, R.L. A summary of the results of a drug

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pp. 68-85.

Kamano, D.K., and Arp, D.J. Chlordiazepoxide (Librium) consumption

under stress conditions in rats. Int J Neuropsychiatry, 1:189-192,

1965.

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treatment of mixed drug abuse. Int J Clin Pharmacol, 12:13-18, 1975.

Marks, J. The Benzodiazepines--Use, Overuse, Misuse, Abuse. Baltimore: University Park Press, 1978.

McNair, D. Antianxiety drugs and human performance. Arch Gen

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Long-term use in alcoholism. Ann NY Acad Sci, 273:381-384, 1976.

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Sanger, D.J. Schedule-induced drinking of chlordiazepoxide solutions

by rats. Pharmacol Biochem Behav, 7:1-6, 1977.

Sanger, D.J., and Blackman, D.E. The effects of drugs on operant

behavior: In: Blackman, D.E., and Sanger, D.J., eds. Contemporary

Research in Behavioral Pharmacolcgy. New York: Plenum Press, 1978.

pp. 239-387.

Stolerman, I.P., Kumar, R., and Steinberg, H. Development of morphine

dependence in rats: Lack of effect of previous ingestion of other

drugs. Psychopharmacology, 20:321-336, 1971.

Veale, W.L., and Myers, R.D. Increased alcohol preference in rats

following repeated exposures to alcohol. Psychopharmacologia

(Berlin), 15:361-372, 1969.

Walton, N.Y., and Deutsch, J.A. Self-administration of diazepam by

the rat. Behav Biol, 24:533-538, 1978.

Winstead, D.K., Anderson, A., Eilers, M.K., Blackwell, B., and

Zaremba, A.L. Diazepam on demand. Arch Gen Psychiatry, 30:349-351,

1974.

Wittenborn, J.R. Effects of benzodiazepines on psychomotor performance. Br J Clin Pharmacol, 7:61S-67S, 1979.

Wolf, G., Jacquet, Y., and Carol, M. Test for oral and postingestional factors mediating differential acceptability of morphine,

methamphetamine, and chlordiazepoxide drinking solutions. Psychopharmacology, 60:101-102, 1978.

Yanagita, T., and Kiyohara, H. Drug dependence potential of ID-540

tested in rhesus monkeys. Preclin Rep, 2:187-194, 1976.

Yanagita, T., Oinuma, N., and Takahashi, S. Drug dependence potential

of Sch-12041 7 chloro-1 3-dihydro-5-phenyl-l-2 2 2-trifluoroethyl-2

H-l 4 benzodiazepine-2-one evaluated in the rhesus monkey. Preclin Rep,

1:231-235, 1975.

Yanagita, T., and Takahashi, S. Dependence liability of several

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185:307-316, 1973.

ACKNOWLEDGMENT

Preparation of this manuscript was supported in part by National

Institute on Drug Abuse grants DA-01147 and DA-01022 and National

Research Service Award DA-05157.

AUTHORS

Roland R. Griffiths, Ph.D., and Nancy A. Ator, Ph.D.

The Johns Hopkins University School of Medicine

720 Rutland Avenue, Baltimore, Maryland 21205

36
Benzodiazepine Dependence

Studies in Rodents

William R. Martin, Ph.D., and L. F. McNicholas, Ph.D.

GENERAL ISSUES

Drug dependency has several dimensions related to drug needs. Drug

abusers may have hereditary, congenital, or induced need for certain

drugs. These needs maybe related to personality disorders. Alcoholics, narcotic abusers, and polydrug users have abnormal psychometric profiles and prevailing affective disorders as a group.

Several types of drugs of abuse, including narcotic analgesics,

amphetamines, and barbiturates, have been shown to produce subject

states of well-being that are polarly opposite to hypophoria and

depression. These feelings of well-being improve self-image. Martin

et al. (1973) found that feelings of hypophoria were part of the

protracted abstinence syndrome. Thus chronic drug ingestion may induce a drug need. Finally, the abstinence syndrome has been thought

to create both a physiologic and a psychologic need. Drug dependence

thus has several dimensions.

Animal research on dependence on barbiturates, sedative-hypnotic drugs,

and antianxiety drugs has focused to a large extent on physiologic

dependence as manifested by withdrawal convulsion and deliriun and,

to a lesser degree, on their reinforcing properties. Lesser attention has been paid to those aspects of abstinence symptoms and their

associated physiologic mechanisms responsible for discomforting

symptoms which may give rise to and perpetuate drug-seeking behavior

once the important connection between the drug-related relief of the

abstinence discanfort and drug ingestion has been established. In

trying to establish methodologies for identifying these various properties of abused drugs, each of these aspects of dependence must be

considered.

Theantianxietyproperty of the benzodiazepines has been assessed

using inhibition of operant behavior. The literature on the effect

of benzodiazepines on conditioned avoidance responsing has been

recently reviewed by Haefly (1978). The extent to which this important therapeutic action of the benzodiazepines contributes to their

dependence-producing effect is not known. As will be discussed subsequently, the ability of oxazepam to decrease conditioned inhibition

of bar-pressing behavior persists with chronic administration.

37
A very limited amount of work has been done in assessing the physical

dependence-producing properties of the benzodiazepines, and none to

determine if chronic intoxication produces a drug need during or

following the abstinence syndrome in the rat. Further, a detailed

description of the benzodiazepine abstinence syndrome in the rat has

not been made.

EFFECTS OF CHRONIC ADMINISTRATION OF BENZODIAZEPINES

Randall et al. (1961) administered large doses (10, 100, and 1,000

mg/kg) of diazepam in food to rats for a B-week period and reported

a large reduction in food consumption, loss of weight, and a debilitated (unthrifty) appearance. There were no abnormal laboratory

observations. Margules and Stein (1968) studied the effect of the

chronic daily administration of oxazepam (20 mg/kg) on lever pressing

for food and its inhibition by foot shock punishment in the rat.

Oxazepam depressed bar pressing and decreased foot shock inhibition

of bar pressing. Tolerance developed to oxazepam's inhibition of bar

pressing but not to its ability to disinhibit the effect of punishment.

Sansone (1979) found that when chlordiazepoxide (5 and 10 mg/kg) was

administered for 5 days to rats, the increase in motor activity seen

with these doses was enhanced, while some tolerance to the motor

depressant actions of 20 and 30 mg/kg was seen.

SELF-ADMINISTRATION

Götestam (1973) found that rats would self-administer medazepam and

morphine by the intragastric route. Rats would not spontaneously

consume (drink) chlordiazepoxide or neprobamate-containing solution

when offered in a free choice situation or in a free choice situation

after forced consumption. Bats would consume these drugs when they

had to drink them to obtain food (Harris et al. 1968). Bats participating in a shock avoidance or an unavoidable shock experiment did

not consume more chlordiazepoxide solution than they did under a nonstressful condition (Kamano and Arp 1965). Diazepam decreased alcohol

consumption in naive rats but not in rats previously dependent on

alcohol (Ferko et al. 1979). Stolerman et al. (1971) found that

forced ingestion of chlordiazepoxide in drinking water of rats for

20 days resulted in a progressive increase in the amount consumed

(26.3 to 34.0 mg/kg). Chronic ingestion of chlordiazepoxide in

drinking water did not affect the quantity of chlordiazepoxide ingested

when it was offered in a choice situation in which the rat had the

opportunity of ingesting either water or a chlordiazepoxide solution.

Prior chronic ingestion of chlordiazepoxide did not affect the consumption of a morphine solution in either a choice situation or when

the rats were given access to the morphine solution as their only

source of drinking water.

PHYSICAL DEPENDENCE

The dependence-producing properties of the benzodiazepines have received little attention until recently. Fraser and Jasinski (1977),

in their review, report on experimental methods for measuring physical

38
dependence on minor tranquilizers only in the dog (meprobamate) and

monkey (meprobamate, diazepam, and chlordiazepoxide). Hollister et al.

(1961, 1963) reported on experimentally induced physical dependence

with chlordiazepoxide and diazepam in man. Following withdrawal of

chlordiazepoxide from 12 subjects who had received 300 to 600 mg/day,

the following symptoms and signs of withdrawal were observed: depression (6 subjects), seizures (2), twitching (l), insomnia (2), loss of

appetite (4), agitation (3), and a worsening of their psychosis. Some

of these signs appeared by the second day and persisted through the

ninth day of withdrawal (Hollister et al. 1961). One seizure and

other withdrawal signs were seen in 6 of 13 patients in which the dose

of diazepam was increased to 120 mg/day.

Yanaura et al. (1975) allowed rats to ingest diazepam mixed with food.

The rats were offered a choice of food containing 0.05 and 0.1 percent

diazepam or 0.1 and 0.2 percent. The low-dose group consumed 60 to

90 mg/kg/day of diazepem, while the high-dose group consumed 110 to

115 mg/kg/day of diazepam. These dose levels did not impair growth

or decrease food intake. When the rats were abruptly withdrawn after

7 days of treatment, they lost some weight and food intake was curtailed. Phenobarbital in food prevented the decrease in food intake

and loss of weight. Diazepam also suppressed the decrease in food

intake and weight loss in abstinent phenobarbital-treated rats.

EXPERIMENTAL STUDIES OF SEDATIVE-HYPNOTICS AND ANTIANXIETY

DRUGS IN THE GASTRIC FISTULA RAT

We are conducting studies in the gastric fistula rat to identify

pharmacologic parameters that are associated with the dependenceproducing capacity of drugs used as sedatives and for the treatment

of sleep disorders, which could lead to the development of safe,

effective agents of low abuse potential.

We have selected the gastric fistula preparation because it allows

ready acute and chronic dosing of rats with water-insoluble drugs.

Drug-containing capsules can be placed directly into the stomach.

Using this preparation it has been possible to conduct crossover

studies with sedative-hypnotic drugs and to obtain valid potency

estimates on two measures: behavioral depression (using a Behavioral

Rating Scale, BRS) and depression of respiratory rate. In our first

study, pentobarbital, secobarbital, methaqualone, diazepam, and

chloral hydrate were compared using four- to eight-point assays.

Valid potency estimates were obtained between pentobarbital, secobarbital, and methaqualone for both behavioral depression and depression of respiratory rate. Secobarbital and pentobarbital were found

to be equi-potent while methaqualone was l/4 to l/5 as potent as

pentobarbital. Valid assays were not obtained between pentobarbital

on the one hand and diazepam or chloral hydrate on the other. The

diazepam BRS dose response line had a shallower slope than the pentobarbital dose response line, and a ceiling was encountered at the

40 mg/kg dose level. Eighty mg/kg of diazepam did not produce a

greater depression than did 40 mg/kg. Diazepam did not depress the

respiratory rate in doses up to 80 mg/kg. The chloral hydrate BRS

dose response line had a steeper slope than that of pentobarbital;

however, it did not depress respiration.

39
In another series of studies, we have investigated the interaction

between alcohol and pentobarbital, chloral hydrate, or diazepam. In

these studies it was found that diazepam modestly enhanced alcohol

depression (BRS) to a degree greater than could be attributed to

additivity, whereas alcohol and pentobarbital were additive. Alcohol

and chloral hydrate were less than additive.

PENTOBARBITAL DEPENDENCE IN THE RAT

Since the pioneering work of Seevers in the dog and Isbell (1950) in man,

demonstrating that seizures and delirium tremens were important signs

of abstinence in barbiturate-dependent dogs and man, much work has

been directed to the study of these phenomena. However, in the classic

paradigm of drug seeking behavior, it can be questioned whether these

two phenanena are related to a drug need or are early and important

factors in drug seeking behavior of sedative-hypnotics and antianxiety

drugs.

We are studying physical dependence on pentobarbital and diazepam in

the rat with the end of measuring seizure incidence and type, signs

that could be indicative of murine delirium as well as other signs

of abstinence, and to determine their time course. At the present

time our data, which are preliminary, have been most thoroughly analyzed

for dependence on pentobarbital in the rat. Rats that have been

prepared with a gastric fistula have been made dependent on pentobarbital by administering pentobarbital-containing capsules into the

stomach through the fistula. The stabilization dose levels have

ranged from 227 mg/kg/day (ca 20 mg qid) to 500 mg/kg/day (ca 40 mg

qid) at approximately equal intervals. Rats have been maintained at

these dose levels for 4 months. These doses make most of the animals

ataxic and cause loss of righting reflex 40 to 50 percent of the time.

Rats maintained their body weight. In some animals it is necessary

to curtail food intake to maintain body weight at approximately 300 gm.

Signs of abstinence have been studied from 8 to 48 hours following

withdrawal. The signs of abstinence that have been noted during this

period are (1) an early hyperphagia, followed by a decrease in food

intake which becomes apparent 12 to 16 hours after the onset of

abstinence, and (2) a decrease in body weight, which also becomes

manifest at 12 to 16 hours after abstinence and is maximal from 24

to 32 hours after withdrawal. Pupillary diameter and body temperature are not markedly changed during withdrawal. Convulsions have

appeared in some animals (4/8) 13 to 15 hours after withdrawal.

Other signs of abstinence identified include head and body tremors,

wet dog shakes, twitches and jerks, prolonged tremors, poker tail,

stiff-legged walking, and teeth chattering. Most of these signs

of abstinence appear or are apparent within 8 hours after withdrawal

and gradually diminish thereafter. Some signs are still present

some 40 hours after withdrawal. We are in the process of attempting

to determine the relative contribution of these various signs of

abstinence to the withdrawal syndrome. It appears that the withdrawal syndrome of pentobarbital is a complex one. Parts of it have

a rapid onset, which may be correlated with the onset of drug-seeking

40
behavior. The loss of weight and appetite are later phenomena,

appearing approximately 1 day following the above-described signs of

abstinence.

Rats have been made dependent on 80 to 100 mg/kg/day of diazepam administered 4 times daily intragastrically for over 35 days. Preliminary

data on abstinence signs present from the 8th through the 40th hour

indicates that the rats exhibited a progression of changes. From the

8th to the 20th hour of abstinence, the rats exhibited increased activity and wet dog shakes. In addition these rats exhibited a poker

tail and lost weight, signs which were present by the 8th hour and

persisted through the 40th hour. An increase in head and body tremor

as well as body twitches or spasms, jerks, and hostility was seen

by the 20th hour of abstinence and persisted through the 40th hour.

From the 25th through the 40th hours of abstinence, violent and

explosive awakening and turning movements were seen. These movements

were rapid and propelled the rats to the top or side of the observation cage. Between these episodes the rats would sleep or exhibit

fixed posture and staring. One rat showed rapid turning and biting

movements and vocalized while turning.

CONCLUSIONS

There is only a small amount of information concerning benzodiazepine

dependence in the rat. Although benzodiazepines will decrease conditioned avoidance responding, adverse circumstances do not seem to give

rise to increased ingestion. Other problems related to dependence

that can be dealt with experimentally are (1) the relative agonistic

actions of the different benzodiazepines; (2) the characterization of

their dependence-producing ability, including whether they produce

protracted abstinence or not; (3) identification of signs of abstinence that are predictors of drug seeking behavior; and (4) the

relative threat of the abstinence syndrome to health.

The rat certainly is an economic species in which these assessments

can be made. The rat has been extensively used in operant studies.

It now appears that rats dependent on pentobarbital and diazepam have

an abstinence syndrome rich in signs. The gastric fistula rat allows

the ready enteric administration of the water-insoluble benzodiazepines.

The viability of this preparation is such that a variety of crossover

and dependence studies can be conducted, which should allow the efficient generation of quantitative data of relatively low variability.

REFERENCES

Ferko, A.P., Bobyock, E., and Chernick, W.S. A study on diazepam and

post-withdrawal drinking on ethanol solutions in rats. Toxicol Appl

Pharmacol, 50:355-363, 1979.

Fraser, H.F., and Jasinski, D.R. The assessment of the abuse potentiality of sedative/hypnotics (depressants) (Methods used in animals

and man). Drug Addiction I. Section I, Chapter 2. Handb Exp

Pharmacol, 45/I:589-612, 1977.

41
Götestam, K.G. Intragastric self-administration of medazepam in

rats. Psychopharmcologia, 28:87-94, 1973.

Haefly, W.E. Behavioral and neuropharmacological aspects of drugs

used in anxiety and related states. In: Lipton, M.A., DiMascia, A.,

and Killam, K.F., eds. Psychopharmacology: A Generation of Progress.

New York: Raven Press, 1978.

Harris, R.T., Claghorn, J.I., and Schoolar, J.C. Self administration

of minor tranquilizers as a function of conditioning. Psychopharmacologia, 13:81-88, 1968.

Hollister, L.E., Bennet, J.L., Kimbell, I.J., Savage, C., and Overall,

J.E. Diazepam in newly admitted schizophrenics. Dis Nerv Syst, 24:

746-750, 1963.

Hollister, L.E., Motzenbecker, F.P., and Degan, R.O. Withdrawal

reactions from chlordiazepoxide ("Librium"). Psychopharmacologia,

2:63-68, 1961.

Isbell, H. Addiction to barbiturates and the barbiturate abstinence

syndrome. Ann Intern Med 33:108- , 1950.

Kamano, D.K., and Arp, D.J. Chlordiazepoxide (Librium) consumption

under stress conditions in rats. Int J Neuropsychiatry, 1:189-192,

1965.

Margules, D.L., and Stein, I. Increase of "anxiety" activity and

tolerance of behavioral depression during chronic administration of

oxazepam. Psychopharmacologia, 13:74-80, 1968.

Martin, W.R., Jasinski, D.R., Haertzen, C.A., Kay, D.C., Jones, B.E.,

Mansky, P.A., and Carpenter, R.W. Methadone--a reevaluation. Arch

Gen Psychiatry, 28:286-295, 1973.

Randall, L.O., Heise, G.A., Schallet, W., Bagdon, R.E., Banziger, R.,

Boris, A., Moe, R.A., and Abrams, W.B. Pharmacological and clinical

studies on valium (TM). A new psychotherapeutic agent of the benzodiazepine class. Curr Ther Res, 3:405-425, 1961.

Sansone, M. Effects of repeated administration of chlordiazepoxide

on spontaneous locomotor activity in mice. Psychopharmacologia, 66:

109-110, 1979.

Stolerman, I.P., Kumar, R., and Steinberg, H. Development of morphine

dependence in rats: Lack of effect of previous ingestion of other

drugs. Psychopharmacologia, 20:321-336, 1971.

Yanaura, S., Tagashira, L., and Suzuki, T. Physical dependence on

morphine, phenobarbital and diazepam in rats by drug-admixed food

ingestion. Jpn J Pharmacol, 25:453-463, 1975.

AUTHORS

William R. Martin, Ph.D., and L. F. McNicholas, Ph.D.

Department of Pharmacology, University of Kentucky, Lexington, KY 20406

42
Benzodiazepines: Clinical Use

Patterns

Karl Rickels, M.D.

INDICATIONS FOR BENZODIAZEPINE USE

Research conducted over many years has shown that nonpsychotic anxious

patients respond best to anxiolytics if they suffer primarily from

emotional and somatic symptoms of anxiety, and less from depression

and interpersonal problems (Rickels 1978).

Benzodiazepines are usually not very effective in clear-cut depressions, in anxiety associated with schizophrenia, in agitation

associated with chronic brain syndrome, and in phobic and obsessivecompulsive disorders. Indications for benzodiazepines, using DSM III

Diagnostic Criteria (American Psychiatric Association 1980), are

generalized anxiety disorder, atypical anxiety disorder, anticipatory

anxiety, panic disorder, posttraumatic anxiety, adjustment disorder

with anxious mood, several somatization disorders, formerly described

as psychophysiological reactions, and, finally, many nonpsychotic

anxiety reactions not clearly diagnosable according to the DSM III,

such as anxiety in patients who have been told of the need for a

coronary bypass operation, anxiety in cancer patients, or anxiety

present with or triggered by many physical illnesses.

Many social phobias, in fact, while possibly improving more with

behavioral therapy or with imipramine than with the benzodiazepines,

do respond, to some extent at least, to treatment with benzodiazepines.

Anxiety is perceived as a subjective feeling of heightened tension

and diffused uneasiness, defined as the conscious and reportable experience of intense dread and foreboding, conceptualized as internally

derived and unrelated to external threat. It is not merely fear

because it lacks a specific object. It is a painful dread of situations that covertly symbolize unconscious conflict and impulses.

The many symptoms of anxiety are attributable to the fact that anxiety,

more than any other type of emotional disorder, can induce widespread

physiologic changes. Anxiety is perceived as a threat arising primarily from within, triggering somatic and visceral responses through

the autonomic nervous system and the hypothalamic-pituitary-endocrine

system (Lader 1974). Frequently some remembrance of a past threat,

triggered by some unrecognized present situation, signals a feeling

tone and somatic responses of the past fearful state.

43
Anxiety can be partly bound by such mechanisms as phobias, obsessions,

and conversions, or it can be diverted into the soma, leading to somatization. In fact, pure anxiety states are relatively-rare because

such syndromes as depression, hysteria, hypochondriasis, somatization,

phobias, and obsessional thinking are often concomitantly present.

Anxiety can be operationally defined in term of scores on various

patient- or physician-completed checklists and rating scales.

While the use of anxiolytics in the above-mentioned nonpsychotic

anxiety states is well established, the relatively high use pattern,

both in and out of the hospital, of benzodiazepines, particularly

diazepam, in nonanxious patients suffering from physical disorders,

particularly cardiovascular, raises the question of whether or not

the use of anxiolytics in such medical disorders is appropriate.

Despite several small short-term studies (Dunbar et al. 1971; Benson

197l; Hackett and Cassem 1972), no good scientific data are presently

available to support or refute the prophylactic use of anxiolytic

agents for the prevention of a second heart infarct or for the prolongation of expected lifespan.

One could theorize that since anxiety and stress may lead to increased

triglyceride and cholesterol levels, and also to a facilitation of

platelet clotting, anxiolytics given prophylactically may indeed

increase the lifespan of such cardiac patients. In fact, it may be

worthwhile to consider a national multicenter study to test such a

hypothesis, particularly in light of recent reports indicating that

aspirin may exert no beneficial effects in such patients (Horwitz

1980).

APPROPRIATE EMPLOYMENT OF ANXIOLYTIC TREATMENT

It must be emphasized that antianxiety agents work symptomatically,

not etiologically. They do not, for example, directly affect the

psychodynamic and environmental factors responsible for emotional

problems; they do not, at least in a direct sense, affect the basic

personality attributes of the patient. By relieving the symptoms

of anxiety and tension, however, these drugs may render a patient

less miserable and better able to cope with intrapsychic and extrapsychic stress. Antianxiety agents may also facilitate problemsolving and the deconditioning and reconditioning of emotional

responses.

For the achievement of good therapeutic results, antianxiety agents

must be prescribed appropriately. The physician who uses these

agents for the achievement of unobtainable goals rather than for

symptomatic relief, or as a vehicle of rejection rather than within

the context of a supportive relationship, will see only a few beneficial effects. In other words, drugs must be prescribed for the

right reasons. Equally important for achieving good results is that

the physician be knowledgeable about the antianxiety agents he uses.

Even if prescribed for the right reasons, the wrong agent, or the

right agent given in the wrong treatment regimen, will not prove

helpful to the patient (Rickels 1978).

44
Drug treatment should be employed only when warranted by the patient's

degree of disability or discomfort, and should be primarily symptomoriented. Duration of treatment should be influenced by duration of

symptoms. Thus, many acutely anxious patients may require treatment

for only a few days or weeks, as their complaints are often shortlived and of a situational nature. Within these acutely anxious

patients, the main function of drug treatment is generally to render

the patient less miserable until the anxiety attack runs its course.

Short-term treatment, however, may well prove inadequate for more

chronically ill anxious patients. In fact, it seems likely that many

chronically anxious patients are currently being treated inadequately

and for too short a period of time.

It is the opinion of the author that many anxious patients simply need

a more protracted course of pharmacologic treatment than is generally

provided. For some, even a form of maintenance treatment similar to

that of diabetics receiving insulin or hypertensive patients receiving

antihypertensive medication may be necessary. In fact, this type of

maintenance treatment with antianxiety agents is frequently being provided by the primary care physician, even though no research data

seem to be available to support or refute such a treatment strategy.

Finally, some chronically anxious patients need a small crutch or

support in order to cope with life, and an occasional pill is much

less expensive and time-consuming for the patient than seeing a

psychiatrist for many years. If such a patient's functioning capacity

decreases, more rigorous psychiatric treatment should be seriously

considered.

NONSPECIFIC FACTORS PREDICTING IMPROVEMENT WITH ANXIOLYTICS

Clinical experience indicates that drug response in anxiety appears

to be influenced by many factors above and beyond those associated

with the pharmacology of the medication the patient receives:

improvement often occurs spontaneously; any effort at treatment, no

matter how small, may produce at least some placebo response; and

any doctor-patient contact may result in some change in clinical

status (Uhlenhuth et al. 1969).

The isolation of the most important nonspecific factors that influence

drug treatment response in neurotic anxiety, and the evaluation of

the nature and extent of their impact, represent a complex and challenging research undertaking. For the past 15 years the Psychopharmacology Research Group at the Department of Psychiatry of the University

of Pennsylvania has devoted considerable effort to this particular

research area.

From this research, a certain pattern of relationships between nonspecific factors and response to treatment with anxiolytics has

emerged. Table 1 summarizes some of these relationships; it gives

only those nonspecific factors that have been replicated rather

consistently in research conducted by this research group or in

research conducted by others (Rickels 1978). Of particular interest

is that such predictors as more realistic aspirations toward mental

45
health, high ego strength, low hostility, and better social advantage

are also good predictors for psychotherapy outcome.

Table 1

Predictors of Improvement with Anxiolytics

Physician Attributes

Warmth

Liking patient

Feeling comfortable with patient

Positive attitude toward drugs

Believing patient has good prognosis

Patient Personality

Characteristics

More verbal intelligence

More canpliance

More realistic treatment goals

High ego strength

Low verbal hostility

Low acquiescence

Neurotic Psychopathology

More severe somatization

Less severe obsessioncompulsion

Less severe interpersonal

sensitivity

More severe anxiety

Social Advantage

More education

Higher occupational level

Higher socioeconomic class

More marital stability

Treatment Orientation

Realizes problems are emotional

rather than somatic

Expects drug treatment

Prior Treatment

Characteristics

Treated with fewer prior

psychiatric drugs

Better response to prior

psychiatric drugs

Less severe depression

from: Rickels, K. Use of antianxiety agents in anxious outpatients.

Psychopharmacology, 58:1-17. ©1978, Springer-Verlag.

BENZODIAZEPINE USE PATTERNS

The benzodiazepines are some of the most widely used drugs in medicine.

Data based on prescription audits (Balter 1975; Blackwell 1975;

National Prescription Audit 1979; DHEW 1980) indicate that psychotropic drug use peaked in 1973 and has declined slightly during the

past few years, probably as a result of the negative publicity the

benzodiazepines received (figure 1). Data based on a variety of surveys in the United States and Europe provide convincing evidence that

psychotropic drugs, including the benzodiazepines, are used rather

conservatively (Parry et al. 1973; Balter 1973; Mellinger et al. 1978;

Uhlenhuth et al. 1978; Hesbacher et al. 1976; Bergman et al. 1979;

Idanpään-Heikkalä 1977). A more detailed description of these and

other surveys has been given elsewhere (Rickels, in press).

46
Figure 1

Antianxiety Drug Prescriptions Filled in U.S. Drug Stores

1973 - 1978
Survey data certainly support an interpretation of conservative use

of psychotropic drugs including the anxiolytics. Many more individuals suffer from significant degrees of psychic distress than take

psychotherapeutic drugs.

We may therefore conclude that (1) psychotropic drugs are conservatively used and possibly even underused at times; (2) patient attitudes express doubts concerning the morality of drug use and are

associated with traditional stoic values; (3) little support is

provided for a "self-indulgent consumer" interpretation of drug use

(Balter 1973); and (4) the majority of physicians are conservative

and rather astute in their psychotropic drug-prescribing habits.

It should be stated that it is also true that a minority of physicians

do over- and underprescribe psychotherapeutic drugs, and that some

physicians may prescribe drugs irrationally, for unobtainable goals

(Rickels 1978). It is also true that patients, particularly alcoholics and addiction-prone individuals, may at times overuse benzodiazepines (Hollister 1977a; Kielholz 1973).

No clear-cut scientific evidence exists either supporting or refuting

the use of benzodiazepines in patients suffering from medical disorders such as cardiovascular or gastrointestinal illnesses without

concomitant anxiety, i.e., for prophylactic use in these illnesses,

and therefore such use cannot at present be regarded as either appropriate or inappropriate.

TOXICITY AND DRUG ABUSE

The benzodiazepines are remarkably safe substances. Their major side

effect is sedation; if initially present, it tends either to disappear

or, at least, to subside in intensity with time and/or as a result of

dosage adjustment. An interesting phenomenon of the anxiolytics is

that tolerance develops swiftly for their sedative but not for their

antianxiety effects. Because of the possible occurrence of early

sedative (frequently dose-related) side effects, physicians should

start patients on a low dosage and increase the dosage fairly quickly.

We need to warn patients to exercise caution when driving or using

heavy machinery should they feel drowsy.

As with any type of sedative drug, the addition of other sedating

substances such as antihistamines, many of which are available over

the counter, and particularly alcohol, may lead to increased sedation.

While the combination of alcohol in small quantities, i.e., one or

two drinks, with a normal dose of a benzodiazepine (e.g., 20 to 30

mg/d of diazepam) does not produce much of a problem, the overuse

of either or both may produce serious consequences.

In view of the wide use of the benzodiazepines, particularly diazepam,

it is not surprising that they are frequently overused, either accidentally or intentionally. Many such cases are seen in hospital

emergency rooms (Hollister 1977a; Peterson and Chambers 1975). But

serious intoxication and death caused solely by benzodiazepine overdose are most unusual. Personally, I am not aware of any death that

48
has been clearly demonstrated to be caused solely by benzodiazepine

intake. Multiple drugs are involved in most instances in which death

occurs from benzodiazepine overdose. A similar opinion has been

expressed by many experts in the field (Greenblatt and Shader 1974).

Benzodiazepine overuse is nearly always complicated by alcohol abuse

and/or other drug intake.

One of the most extensive reviews of the use, overuse, and misuse of

the benzodiazepines in the United Kingdom has been reported recently

by Marks (1978). He estimated that in 1976, of the total British

population, 75 percent or more used alcohol, 50 percent used tobacco,

but only 12 percent used psychotropics, excluding the barbiturates.

Thus, such abuse substances as alcohol and tobacco that have had

rather serious medical consequences were used much more frequently

than were the psychotropic drugs. This finding closely agrees with

that of the national survey in the United States reported by Parry

and his colleagues (1973).

Marks also reviewed death rates per 100,000 adults; he estimated that

alcohol led to 27 deaths, tobacco to 250, and psychotropic drugs,

excluding barbiturates, to only 3. Such data reflect a remarkably

safe record for the psychotropic drugs, and particularly for the

benzodiazepines, inasmuch as Marks' statistics included not only

anxiolytics but also antidepressants and neuroleptics. Marks concluded that it was impossible to kill oneself with benzodiazepines

alone, but that a combination of benzodiazepines with other sedatives,

particularly alcohol, may well be deadly. A more extensive discussion of toxicity and abuse of benzodiazepines can be found elsewhere

(Rickels, in press).

Thus, we can conclude that the benzodiazepines are extremely safe

drugs and that intentional or accidental overuse of benzodiazepines

alone will rarely have severe consequences, a finding which contrasts

markedly with the findings for other centrally acting agents. In

hospital emergency rooms, the frequent mention of benzodiazepines as

drugs ingested either accidentally or used in suicide attempts is

not only an indication of their general availability but, in the

opinion of many, a blessing. If benzodiazepines were not available,

the individuals overusing them would be taking barbiturates or other

central nervous system drugs, drugs that have much more serious

consequences when overused. The combination of benzodiazepines with

other sedatives, including antihistamines and/or alcohol, should be

avoided because such combinations, particularly when abused, may lead

to serious medical consequences including death.

PHYSIOLOGICAL DEPENDENCE

Considering their widespread use, physiological dependence upon the

benzodiazepines, frequently hard to differentiate from a return of

anxiety symptomatology after withdrawal, has been reported remarkably

rarely. Most reports are anecdotal and often involve patients taking

medication in much higher than the recommnended dosages and for long

periods of time.

49
One of the earliest studies assessing the addictive potential of

benzodiazepines was conducted by Hollister et al. (1961). This study

demonstrated clearly that some patients, who received chlordiazepoxide

(100 to 600 mg/d) for several months and were then abruptly withdrawn

from the medication, suffered clear-cut withdrawal symptoms, which

included convulsions in three instances. About 10 years later, Covi

et al. (1973) compared sudden discontinuation effects in two groups

of anxious patients; one group was treated with an anxiolytic for

10 weeks and the other group was treated for 20 weeks. The authors

observed more evidence of distress after withdrawal in those patients

treated for 20 weeks than in those treated for 10 weeks. No seizures

or muscular fasciculations were observed.

A number of individual case reports have appeared in the literature

describing withdrawal reactions occurring after the abrupt withdrawal

of benzodiazepines, particularly diazepam, the most widely prescribed

anxiolytic (Winokur et al. 1980). All these case reports were uncontrolled and are frequently anecdotal. Hollister (1977b) noted in his

reply to Preskorn and Denner's (1977) report of three psychotic

episodes occurring after withdrawal from diazepam, that for each of

these three cases there existed another equally plausible explanation.

Winokur and his associates reported what is probably the first wellcontrolled, double-blind case study of withdrawal reactions in a

patient who had been on therapeutic dosages (15 to 20 mg/d) of

diazepam for 6 years. (See figure 2.) Withdrawal reaction occurred

1 to 2 days after switching from diazepam to a placebo. The symptoms

were completely reversed by reinstitution of diazepam treatment and

then slowly decreased over time during placebo treatment in the supportive environment of a clinical research center. Although neither

psychotic episodes nor convulsions occurred, the patient was disturbed by the withdrawal symptoms. They included extreme anxiety

and irritability, tremulousness, perspiration, nausea, constipation,

Figure 2. Diazepam Withdrawal

From: Winokur et al. Withdrawal reaction from long-term, low-dosage administration of

diazepam. Arch. General Psychiatry, 37:101-105. ©1980, American Medical Association.

50
difficulty in urination, headaches, insomnia, and intermittent

hypersensitivy to auditory and olfactory stimuli.

Very few other systematic data regarding the possible incidence of

withdrawal reactions with benzodiazepine treatment or the possible

facilitating events that may provoke these reactions are presently

available. Yet, most clinicians agree that the higher the patient's

daily dosage and the longer the patient has been continuously on

medication, the greater the possibility for the development of at

least a mild withdrawal reaction. But even after many years of

benzodiazepine therapy, patients treated with therapeutic doses do

not seem to develop seizures upon cessation of treatment.

NIMH/UNIVERSITY OF PENNSYLVANIA DIAZEPAM MAINTENANCE STUDY

Because of the lack of data regarding the value of long-term treatment

with benzodiazepines and about the possible incidence of both return

of symptoms and withdrawal reactions that may occur after abrupt

discontinuation of medication, a large-scale NIMH-supported study was

initiated several years ago by our group at the University of Pennsylvania (USPHS Grant MH-08957-16). The study involves chronically

anxious patients who are being treated with daily dosages of 20 to

40 mg diazepam for up to 6 months.

Preliminary Results

Preliminary results indicate that:

Patients who dropped out while on diazepam did so primarily

because of improvement; no tolerance to diazepam's anxiolytic

effect.

Patients experienced maximal improvement during the initial 4 to

6 weeks of treatment; no additional improvement occurred over

the entire maintenance phase (figure 3). Thus, the study showed

that maintenance of chronic anxious patients was necessary to

continue the level of improvement.

A most important finding for clinicians was that early response

(during the first week of treatment) was a very strong predictor

of B-week improvement (figure 4). Patients who improved during

the first week of treatment continued to show excellent improvement subsequently, whereas those showing no improvement during

the first week had a very poor chance of improving later.

About 40 percent of all patients showed a clear-cut pattern of

return of symptoms when switched to a placebo; the symptoms

usually returned slowly over a 2- to 4-week period. But 60

percent of all patients stayed well when changed to a placebo,

thus indicating no need for long-term diazepam treatment.

Of 100 patients who were switched abruptly from diazepam treatment

to placebo, only 11 reported some type of withdrawal reaction.

Of these 11, 6 experienced transient reactions that lasted only

a few days at the most. On followup, patients made such statements as: "For a few days I felt like I did when I stopped

51
Figure 3

Improvement as a Function of Initial Psychopathology and Duration of Treatment

From: Rickels, K. Benzodiazepines: Use and misuse. In: Klein, D. F., and Rabkin, J., eds.

Anxiety: New Research and Changing Concepts. pp. 1-26. ©1981, Raven Press, New York.
Figure 4

Percent of Patients Very Much or Much Improved

at Treatment Endpoint

as a Function of One Week Improvement

From: Rickels, K. Benzodiazepines: Use and misuse. In: Klein, D. F., and Rabkin, J., eds.

Anxiety: New Research and Changing Concepts. pp. 1-26. © 1981, Raven Press, New York.

53
smoking." "For a few days I slept restlessly and dreamt a lot."

"For a few days I felt a little tense." None of these patients

had any increased symptmatology or any signs of withdrawal

reactions when seen by their physician after 1 or 2 weeks on

placebo and none of them needed further treatment.

Five patients suffered from clear-cut withdrawal reactions that

included gastrointestinal symptoms, lethargy, tremulousness, weakness, insomnia, and anxiety. These reactions began within 2 days,

peaked at about 5 to 7 days, and then abated during the next 7 to 10

days without any further treatment. Figure 5 gives a schematic presentation of the difference in time between a return of symptom and

the occurrence of physiological withdrawal reactions. Two of the five

patients with clear-cut withdrawal reactions had been on chlorazepate

for 8 months and on oxazepam for 5 years, respectively, prior to participating in the study. Three patients reported no prior psychotropic

drug use but admitted to king fairly heavy social drinkers. Since

there is cross-tolerance between alcohol and diazepam, these three

withdrawal reactions occurring after 4 months of diazepam treatment

in patients with no prior psychotropic drug use may be related to

their alcohol intake. No patient experienced seizures, psychotic

reactions, or muscle fasciculations.

This study thus lends support to the clinical impression that abrupt

withdrawal of anxiolytic medication should not be instituted in

patients who have been regularly treated for 4 months or longer

without discussing with the patient the possibility of a withdrawal

reaction or a temporary return of symptoms and the several ways of

dealing with such phenomena. It should be emphasized that withdrawal symptoms after abrupt termination of medication have also

been reported with other psychotropic drugs including the tricyclic

antidepressants (Kramer et al. 1961). More recently, withdrawal

reactions have been reported for such nonpsychotropic medications

as beta-adrenergic blockers and other antihypertensive agents

(Garbus et al. 1979).

The recent findings (Tallman et al. 1980) that specific benzodiazepine receptors exist in certain parts of the brain may help to

explain why some patients who have been treated for long periods of

time with benzodiazepines and then have medication abruptly discontinued may have temporary withdrawal reactions. The implication of

the receptor theory is that human beings must have a built-in

calming and anticonvulsive chemical substance, i.e., an endogenous

ligand, which has not yet been discovered. We can speculate that

such endogenously produced ligands are suppressed during benzodiazepine treatment. Consequently, abrupt discontinuation of longterm treatment may not allow for an immediate availability of enough

endogenous ligands to replace the benzodiazepines at the receptor

sites.

The pharmacokinetic properties of most benzodiazepines (i.e., a long

half-life, active metabolites, accumulation in the blood and tissues,

and anticonvulsant properties) may help to explain why benzodiazepines

are only rarely associated with serious withdrawal phenomena and have

54
Figure 5

Schematic Time Course Graph:

Return of Symptoms vs Withdrawal Reactions

After Abrupt Diazepam Withdrawal

From: Rickels, K. Benzodiazepines: Use and misuse. In: Klein, D. F., and Rabkin, J., eds.

Anxiety: New Research and Changing Concepts. pp. l-26. ©1981, Raven Press, New York.
a low dependency-producing potential. Additional reasons for the

rare observation of clear-cut physiological withdrawal reactions may

be the short-term use of these drugs by most patients; their frequent

use on an as-needed basis (Rickels 1978; Winestead et al. 1974); and

the almost universal practice, recommended by physicians and practiced

by patients, of discontinuing benzodiazepine use gradually.

AREAS OF FURTHER EXPLORATION

The addiction potential of different benzodiazepines, assessed by

incidence, type, and intensity of acute withdrawal reactions

produced by abrupt cessation of medication, should be studied as

a function of drug dosage and treatment duration. Patient characteristics including personality attributes, prior drug use,

history of alcoholism, and predisposition toward or history of

substance dependence also should be studied in this context.

Attempts should be made to identify appropriate and inappropriate

indications for long-term benzodiazepine treatment.

The phenomena of drug withdrawal and the most appropriate means

of coping with such phenomena also need further investigation.

Gradual medication withdrawal will most likely be the least painful

for the patient; but it is probably also true that abrupt withdrawal is not dangerous, even if possibly rather uncomfortable

for most patients.

Sociological studies are needed to investigate long-term benzodiazepine uses in order to provide information regarding how

these drugs are being actively utilized (Tessler et al. 1978).

Other studies may want to identify patients in family practice

who are emotionally distressed, and then record their drug-taking

behavior. Such surveys would enable the investigator to determine

which types of anxious patients are treated with benzodiazepines

and which are not; which patients are treated for short and which

for long periods of time; and which factors other than level of

anxiety may determine drug-prescribing behavior as well as actual

drug taking.

Further studies should address the effects of benzodiazepines on

memory, cognition, and performance, to mention only a few of the

many psychological parameters to be studied. Patients suffering

from varying degrees of anxiety and treated for varying lengths

of time with drug or placebo should be included. Nonanxious

individuals may serve as controls.

The role of benzodiazepines in physical illness should be assessed

in greater detail.

Use of benzodiazepines in the elderly is of particular importance,

and pharmacokinetics should play an important role in these

investigations.

56
Patients who have been on therapeutic dosages of benzodiazepines

for various periods of time (e.g., 3 months, 6 months, 1 year,

3 years) could be obtained from family practice networks such as

our own. Attempts to withdraw medication should be made under

controlled conditions. Subgroups of patients, treated for varying

lengths of time, should be withdrawn at different rates: one

subgroup withdrawn slowly with gradually reduced dosages, e.g.,

one-fourth dosage reduction every 2 weeks; another subgroup withdrawn abruptly, receiving placebo in the same dosages as the

patients on medication. If these latter patients should develop

disturbing or severe withdrawal reactions with which they cannot

cope, they could be placed again on benzodiazepines and withdrawn gradually. Those patients who cannot be withdrawn on an

outpatient basis should be placed in a clinical research center

(Winokur et al. 1980) in an academic setting and be withdrawn

under closely supervised conditions. An attempt should be made

to clearly define withdrawal reactions, which frequently occur

early after termination of drug treatment, and further differentiate them from the slow return of symptoms that may well occur

in many chronic anxious patients.

Some of the most important nondrug factors that may influence the

occurrence of a withdrawal reaction of patients on a given benzodiazepine should also be investigated. These factors should

include prior history of drug taking, both over-the-counter and

prescription medications, to assess accurately the prior use,

if any, of cross-tolerant substances including alcohol.

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N.J. Withdrawal reaction from long-term, low-dosage administration

of diazepam. Arch Gen Psychiatry, 37:101-105, 1980.

Winstead, D.K., Anderson, A., Eilers, M.K., Blackwell, B., and Zaremba,

A.L. Diazepam on demand. Arch Gen Psychiatry, 30:349-351, 1974.

59
AUTHOR

Karl Rickels, M.D.

Professor of Psychiatry and Pharmacology and

Director, Psychopharmacology Research and Treatment Unit

Department of Psychiatry

University of Pennsylvania

Philadelphia, Pennsylvania 19104

NOTE: This paper is based primarily upon a paper presented at the

Annual Meeting of the American Psychopathological Association,

Washington, D.C., March 1980, and to a lesser degree upon a paper

presented at the Annual Meeting of the American Psychiatric Association, San Francisco, California, May 1980.

The American Psychopathological Association paper has been published under the title, "Benzodiazepines: Use and Misuse," in

Anxiety: New Research and Changing Concepts D.F. Klein and

J. Rabkin, editors, © 1981, Raven Press, New York. This adaptation is published with their permission.

60
Benzodiazepine Hypnotics:

Carryover Effectiveness, Rebound

Insomnia, and Performance Effects

Anthony Kales, M.D.

Since insomnia is frequently a long-term or chronic condition, sleeping

pills are often prescribed for lengthy intervals. One study has shown

that over 40 percent of all prescriptions for sleeping pills extend for

periods longer than 3 months (Kales et al. 1975). Yet most clinical

trials of hypnotic drugs have evaluated the effects of only 1 to 3

nights of drug administration. In addition, they have not provided

comprehensive profiles of degree and duration of effectiveness and with

drawal effects.

Sleep laboratory studies, because of their precise and objective measurements, are being used more frequently to evaluate hypnotic drugs.

These studies have enabled researchers to establish comprehensive profiles of benzodiazepine drugs and to provide clinicians with detailed

information regarding drug efficacy, duration of effectiveness, and

effects on sleep architecture. For example, in contrast to traditional

clinical studies, in which effectiveness has usually been evaluated

for only one to several nights, the designs of certain sleep laboratory

studies have enabled investigators to evaluate the continued effectiveness of hypnotic drugs. In addition, the use of consecutive-night

designs in the evaluation of baseline, drug administration, and withdrawal conditions has allowed for the detection of such withdrawal

effects as carryover effectiveness and rebound insomnia (Guidelines

1977). Finally, the demonstration of pharmacokinetic differences

among short-, intermediate-, and long-acting benzodiazepine drugs has

provided direction for the investigation of possible effects on daytime

performance.

CARRYOVER EFFECTIVENESS

To date, only two benzodiazepine hypnotics (flurazepam and quazepam,

the latter an investigational hypnotic) have been shown to provide

carryover of effectiveness during the first few nights following drug

withdrawal. When the short- and intermediate-ten efficacies of nine

different hypnotic drugs were compared in the sleep laboratory, a

considerable loss of effectiveness was observed for each of the drugs

except flurazepam (Kales et al. 1977). Furthermore, a summary of six

separate studies of flurazepam in our laboratory showed that while

flurazepam improved sleep on the first night of administration, it did

not reach peak effectiveness until the second and third consecutive

drug nights (Kales et al. 1976a). In addition, values for total wake

time continued to be significantly lower than baseline for the first 2

61
nights following withdrawal. These findings of a carryover of effectiveness over the first few nights of drug administration and during

the first few nights following withdrawal were corroborated by another

sleep laboratory study that assessed the long-term (4 weeks) effectiveness of flurazepam (Dement et al. 1978).

Quazepam, in an intermediate-term (2-week) sleep laboratory study, was

found to be effective with continued use, to become increasingly

effective over the first several nights of use, and to have a carryover of effectiveness after withdrawal (kales et al. 1980). As with

flurazepam, peak effectiveness was reached on the second and third

drug nights, and sleep was significantly improved over baseline on

the first night following withdrawal.

Since flurazepam and quazepam have the same long-acting metabolite (N

desalkyl flurazepam) (Kaplan et al. 1973), the carryover effectiveness

has been considered to reflect the gradual buildup and elimination of

this metabolite. However, other drugs with long-acting metabolites,

such as diazepam, have not been shown to demonstrate carryover effectiveness. Thus, carryover effectiveness may be related to high blood

levels of active metabolites, but also to the specific hypnotic

efficacy of the compound.

Carryover effectiveness can provide a number of clinical advantages as

well as disadvantages. An advantage of carryover effectiveness, for

example, is the potential for including drug-holiday periods in the

course of therapy. In addition, the continuation of improved sleep

(compared to baseline) for the first and, possibly, second nights of

withdrawal facilitates withdrawal from the drug (Kales et al. l976a).

Carryover effectiveness can be disadvantageous, however, because of

its potential to cause decrements in daytime performance. The area

of benzcdiazepine-induced decrements in performance is discussed

later in this paper.

REBOUND INSOMNIA

A number of short- and intermediate-acting benzodiazepine drugs have

been shown to cause rebound insomnia--a worsening of sleep difficulty

beyond baseline levels-following their withdrawal (Kales et al. 1978,

1979). This phenomenon is unique to benzodiazepines because it occurs

after administration of only single doses of drugs taken for short-term

periods, and it is not accompanied by a REM rebound. Furthermore, its

occurrence may be independent of the degree of effectiveness at the

time of withdrawal. The question of whether rebound insomnia occurs

at all with long acting benzodiazepines needs to be evaluated in studies

that include extended withdrawal periods.

To date, rebound insomnia has been shown to follow the abrupt withdrawal of fosazepam (Allen and Oswald 1976), triazolam (Roth et al.

1976; Vogel et al. 1975, 1976), temazepam (Bixler et al. 1978; Mitler

et al. 1975), lorazepam (Globus et al. 1974), lormetazepam (Oswald et

al. 1979), nitrazepam (Adam et al. 1976), and flunitrazepam (Bixler

et al. 1977). It has not been reported to follow withdrawal of

62
flurazepam or diazepam. These two groups of benzodiazepine drugs

differ primarily in the duration of the half-lives of the parent

compounds and their metabolic products (Mitzler et al. 1977). The

half-lives of fosazepam (4 hours), triazolam (4.5 hours), temazepam

(4 to 10 hours), lormetazepam (9.9 hours), and lorazepam (9 to 22

hours) are short, and the half-lives of nitrazepam and flunitrazepam

(about 24 hours) are intermediate, when compared with those of diazepam

(20 to 50 hours) and flurazepam (47 to 100 hours) (Allen and Oswald

1976; Mitzler et al. 1977; Breimer 1977; Shader and Greenblatt 1977;

Wendt 1976; Humpel et al., in press).

The relationship between the half-lives of these benzodiazepines and

the occurrence of rebound insomnia following their withdrawal can be

interpreted in light of the presence of specific benzodiazepine receptors in human brain tissue (Mohler and Okada 1977). 'Ibis discovery

suggests that substances that normally occupy these receptors may

exist in the brain, and that the production of these endogenous substances may be regulated by concentrations of the ligand and feedback

mechanism. Production of endogenous, benzodiazepine-receptor ligands

would decrease if active, exogenous benzodiazepine drugs or metabolites

were introduced. We have proposed that abrupt withdrawal of benzodiazepine drugs with relatively short half-lives could therefore result

in rebound insomnia because of a lag in the production and replacement

of endogenous, benzodiazepine-receptor ligands (kales et al. 1978,

1979). If Benzodiazepines with long-acting metabolites were withdrawn,

however, effects on the benzodiazepine receptors would be less abrupt

because the endogenous ligands would be partially restored before the

active metabolites of the exogenously administered drugs were

completely eliminated.

Although rebound insomnia has not been reported to follow the withdrawal of flurazepam and diazepam after relatively short periods of

use, this syndrome could appear after periods of withdrawal longer

than those evaluated in these studies (kales et al. 1978, 1979). The

lack of rebound insomnia with flurazepam and diazepam suggests that

this syndrome may occur less frequently following withdrawal of longacting benzodiazepines as compared with short-acting and intermediateacting benzodiazepines when these drugs have been used in low doses

for relatively short periods (kales et al. 1978, 1979).

It is likely that an analogue of rebound insomnia occurs when certain

short-acting or intermediate-acting benzodiazepine tranquilizers are

taken during the day (kales et al. 1979). As these drugs' durations

of action are exceeded, anxiety may rise above baseline levels, causing

a condition that we call rebound anxiety (kales et al. 1979). This

hypothesis is supported by results of one study in which the withdrawal

of fosazepam was associated with a significant increase above baseline

in ratings of anxiety (Allen and Oswald 1976). The paucity of reports

of rebound anxiety following withdrawal of short-term use of benzodiazepines, or of rebound anxiety during benzodiazepine administration,

may be explained by the similarity between any withdrawal symptoms and

the original clinical complaints. Neither the patient nor physician

may attribute the symptoms to drug withdrawal. In fact, the patients

63
themselves may see these symptoms as justifying their need for continuing the drug therapy.

PERFORMANCE DECREMENTS

The effects of benzodiazepine hypnotics on daytime performance have

recently received considerable attention (Institute of Medicine 1979).

One study has shown that repeated use of flurazepam in insomniac subjects may have a cumulative effect on motor behavior; reaction time

increased with flurazepam administration (Church and Johnson 1979).

Similar effects were noted in another investigation (Salkind and

Silverstone 1975). Still another group reported performance decrements

in noninsomniac volunteers following flurazepam administration (Saario

and Linnoila 1976), although they did not find that flurazepam produced

similar effects in insanniac patients (Linnoila et al. 1980). Instead,

they found that insomniac patients tended to perform at a lower level

and with greater individual variability than noninsomniac subjects.

Finally, flurazepam was shown to cause an impairment in vigilance that

persisted throughout 3 weeks of drug administration (Oswald et al.

1979). In a study of over 2,000 patients, the side effects associated

with flurazepam administration were found to be related to dosage and

patient age (Greenblatt et al. 1977). Adverse reactions consisted

primarily of unwanted residual drowsiness and usually occurred within

the first 3 days of administration. In all cases, patients recovered

spontaneously or after the dose was reduced or discontinued (Greenblatt

et al. 1977). These data strongly suggest that patients taking longacting benzodiazepines should be clearly cautioned about the potential

for impaired daytime performance.

There have been few studies on the effects of short-acting benzodiazepines on daytime performance. One study evaluated the effects of

triazolam on daytime mood and performance by assessing subjects at

3.5 hours, 10 hours, and 22.5 hours after drug administration (Roth

et al. 1977). The data demonstrated a dose-related decrement in

performance at the 3.5 hour time point, but there were no significant

performance decrements at subsequent time points (Roth et al. 1977).

Lorazepam has also been shown to cause dose-related decreases in

motor coordination (Bell et al. 1973), but no studies have reported

the duration of these effects. Further studies are needed to characterize the effects of short-acting benzodiazepine hypnotic drugs on

daytime performance.

MEMORY IMPAIRMENT

Certain benzodiazepines are known to cause anterograde amnesia (Greenblatt and Shader 1974). This effect has been reported most often with

lorazepam, but also has been found with other benzodiazepines such as

bromazepam, diazepam, and flunitrazepam. Though anterograde amnesia

may be beneficial when these drugs are used as premedicants in surgery,

endoscopy, or cardioversion, it may pose serious problems when they

are used for their hypnotic effects. From the standpoint of safety,

then, it would be preferable that a benzodiazepine not induce amnesia

when taken orally as a tranquilizer or hypnotic (Greenblatt and Shader

1974).

64
The frequency of reports of anterograde amnesia varies among the different benzodiazepines and appears to be related to dose and route of

administration (Greenblatt and Shader 1974). For example, while anterograde amnesia often results from intraveneous administration of

diazepam, it is much less frequent with intramuscular administration

of the drug and appears to be rare with oral administration.

The actual incidence and characteristics of anterograde amnesia produced by oral administration of benzodiazepine drugs have not been

well-established. Most current information is limited to anecdotal

reports rather than objective, controlled studies. In one controlled

study of flunitrazepam, 2 mg, and secobarbital, 100 mg, anterograde

amnesia followed oral administration of flunitrazepam (Bixler et al.

1979). Amnesia has also been reported to fol1ow oral administration

of 5 mg of lorazepam (Elliot et al. 1975). Similarly, anterograde

amnesia has been reported in patients taking triazolam, 0.5 mg (Kales

et al. 1976b). It should be kept in mind that amnesia and memory

impairment are likely to be under-reported because of the nature of

the symptoms.

Since hypnotics are often taken l/2 to 1 hour before bedtime, there

also may be a decrement in memory retrieval of information acquired

before sleep onset. Further studies are needed to evaluate the

various benzodiazepines' potentials for inducing anterograde impairment of memory following oral administration. The persistence of

anterograde amnesia with continued use of a given drug also needs to

be assessed.

FUTURE RESEARCH DIRECTIONS

A number of the proposed research objectives have already been discussed in the text of the paper. In this section, however, specific

aspects of these objectives are raised.

Carryover Effectiveness

Studies are needed to evaluate the relationship of carryover effectiveness and benzodiazepine pharmacokinetics more comprehensively.

Is the carryover of effectiveness observed with quazepam and flurazepam

a function of their pharmacokinetics? Does this occur with other

long-acting benzodiazepines, such as diazepam, chlordiazepoxide, or

chlorazepate? Since the blood !evels of N desalkyl flurazepam are

sufficient to cause improved sleep induction and maintenance for 2

days following drug withdrawal, why do the side effects and symptoms

of daytime drowsiness usually diminish by the end of 3 days of consecutive use?

Rebound Insomnia

Does rebound insomnia occur following withdrawal of all benzodiazepines, regardless of their length of action? Does the occurrence

of rebound insomnia have any predictive value for the potential of

particular benzodiazepines to produce drug dependency? How long does

65
rebound insomnia last, and is there a relation between the duration

of drug administration and the duration of subsequent withdrawal

phenomena? Is rebound insomnia indicative of a general rebound syndrome that would include rebound anxiety? Can gradual drug withdrawal

decrease the severity of rebound insomnia What are the benzodiazepine ?

receptor correlates that might underly the development of rebound

insomnia?

Performance and Memory

To what extent do all benzodiazepine hypnotics impair daytime performance? Are the potential performance decrements reported with longacting benzodiazepine hypnotics greater than those seen in benzodiazepines taken as daytime anxiolytics? How long do performance levels

remain decreased? Since performance has been reported to improve

following withdrawal of short-acting benzodiazepines, is this indicative of a hyperactive withdrawal state, and what is its clinical

significance?

What is the relative incidence of memory impairment caused by longacting as opposed to short-acting benzodiazepines taken in oral-dose

form? Is the incidence of amnesia caused by benzodiazepine hypnotics

higher in elderly patients compared with young adults? Does tolerance

develop quickly to the effects of drugs on memory? What receptormediated events could account for these effects?

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use: Sleep laboratory evaluation. J Clin Pharmacol, 18:110-118, 1978.

Bixler, E.O., Scharf, M.B., Soldatos, C.R., Mitsky, D.J., and Kales, A.

Effects of hypnotic drugs on memory. Life Sci, 25:1379-1388, 1979.

Breimer, D.D. Clinical phamnacokinetics of hypnotics. Clin Pharmacokinet 2:93-109, 1977.

66
Church, M.W., and Johnson, L.C. Mood and performance of poor sleepers

during repeated use of flurazepam. Psychopharmacol, 61:309-316, 1979.

Dement, W.C., Carskadon, M.A., Mitler, M.M., Phillips, R.L., and

Zarcone, V.P. Prolonged use of flurazepam: A sleep laboratory study.

Behav Med, 5(10):25-31, 1978.

Elliot, H.W., Navarro, G., Kokka, N., and Nomof, N. Early phase I

evaluation of sedatives, hypnotics or minor tranquilizers. In:

Kagan, F., Harwood, T., Rickles, K., Rudzik, A., and Sorer, H., eds.

Hypnotics: Methods of Development and Evaluation. New York: Spectrum

Publications, 1975. pp. 87-105.

Globus, G., Phoebus, M.A., Humphries, J., Boyd, R., Gaffney, D., and

Gaffney, S. The effect of lorazepam on anxious insomniacs' sleep as

recorded in the home environment. J Clin Pharmacol, 14:192-201, 1974.

Greenblatt, D.J., Allen, M.D., and Shader, R.I. Toxicity of high-dose

flurazepam in the elderly. Clin Pharmacol Ther, 21:355-361, 1977.

Greenblatt, D.J., and Shader, R.I. Benzodiazepines in Clinical

Practice. New York: Raven Press, 1974. pp. 204-205.

Guidelines for the Clinical Evaluation of Hypnotic Drugs. DHEW Pub No.

(FDA) 78-3051. Washington, D.C.: Superintendent of Documents, U.S.

Government Printing Office, 1977.

Humpel, M., Nieuweboer, B., Milius, W., Hanke, H., and Wendt, H. The

pharmacokinetics and biotransformation of the new benzodiazepine lormetazepam in humans. II. Radioimmunological determinations in plasma

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Clin Pharmacol Ther, 18:356-363, 1975.

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and Schweitzer, P.K. Quazepam, a new benzodiazepine hypnotic:

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and Dement, W.C. Long-term effectiveness of temazepam 30 mg. h.s.

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of the effects of flurazepam 30 mg and triazolam 0.5 mg on the sleep

of insomniacs. Psychopharmacol, 47:81-86, 1976.

68
Vogel, G., Thurmond, A., Gibbons, P., Edwards, K., Sloan, K.B., and

Sexton, K. The effect of triazolam on the sleep of insomniacs.

Psychopharmacologia, 41:65-69, 1975.

Wendt, G. Schicksal des hypnotickums Flunitrazepam im menschlichen

Organismus. In: Hugin, W., Hossli, G., Gemperle, M., eds. Bisherige

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Intensivetherapie. Easel, Switzerland: Roche Publications, 1976.

AUTHOR

Anthony Kales, M.D.

Sleep Research and Treatment Center and

Department of Psychiatry

The Pennsylvania State University College of Medicine

Hershey, Pennsylvania 17033

NOTE: Martin B. Scharf, Ph.D., attended the review conference and

presented the paper in Dr. Kales' absence.

69
Dependence on Benzodiazepines

Leo E. Hollister, M.D.

The benzodiazepines and related compounds are a rapidly expanding

group of drugs. For some years, diazepam has been the most widely

prescribed drug in most of the developed countries of the world,

with its close relative, chlordiazepoxide, also retaining a high

degree of use. Success has brought canpetition, first with oxazepam

and clorazepate dipotassium; more recently with lorazepam, prazepam,

and others. It is difficult to determine how much these drugs are

used as hypnotics, even though they are not specifically promoted

as such. Flurazepam is the only benzodiazepine promoted solely as

a hypnotic, but it may soon have competition from a chemically

close relative, triazolam. One benzodiazepine, clonazepam, is

promoted as an anticonvulsant. Many other benzodiazepines are in

clinical use in countries other than the United States.

Most benzodiazepines share a common pharmacological spectrum: sedative, hypnotic, muscle relaxant, and anticonvulsant actions. Their

major differences are based on their pharmacokinetics. The larger

group (chlordiazepoxide, diazepam, clorazepate dipotassiun, and

prazepam) is composed of drugs that produce long-lived metabolites,

most notably nordiazepam. The smaller group (oxazepam and lorazepam)

is composed of drugs that produce no metabolites and thus can be

rapidly inactivated. Whether or not differences in plasma disappearance rates are important for determining clinical indications for

these drugs, or for their potential for creating dependence, is

still uncertain.

CURRENT USE PATTERNS OF BENZODIAZEPINES

Prescriptions for antianxiety drugs in the United States during 1976

were distributed as follows: benzodiazepines accounted for 78 percent, long-acting barbiturates for 12 percent, and meprobamate for

10 percent (National Prescription Audit 1976). The total number of

prescriptions for antianxiety drugs had remained virtually constant

during the preceding 5 years.

Prescriptions for hypnotics in the United States during 1976 were

distributed as follows: flurazepam accounted for 51 percent, shortacting barbiturates for 22 percent, and the remaining 27 percent

were accounted for by the so-called "nonbarbiturate" hypnotics

(National Prescription Audit 1976). Total prescriptions for hypnotics declined by about 31 percent during the preceding 5 years.

70
Quite possibly the overall decline may represent some use of antianxiety drugs as hypnotics, an interchangeable clinical application.

The best epidemiologic study of the use of antianxiety drugs is now

several years old. As the number of prescriptions for these drugs

has probably declined during the intervening period, the findings of

this study probably still reflect current patterns. In 1971, households chosen by usual sampling techniques in the United States, as

well as in nine European countries, were asked about their use of

antianxiety drugs (Balter et al. 1974). The two major questions

were whether any adult member (over age 18 years) had used such a

drug in the preceding 12 months and if so, whether the use had been

for as long as 1 month. The highest overall use of antianxiety

drugs was in Belgium, where 16.8 percent of adults queried had used

such a drug on at least one occasion in the preceding year; only 9.7

percent answered positively to this question in Spain. Other data

from the United States indicated a figure of 15 percent. One month

or more of chronic use of these agents followed a similar pattern

with a maximum of 8.6 percent and a minimum of 3.4 percent of adults

using these drugs in this manner. In the United States such use was

reported by 6 percent of those surveyed. Those persons who had used

them were quite positive in their opinions about the benefits derived;

77 percent claiming substantial benefit."

What emerged from these data was the remarkable fact that medical use

of sedative-hypnotics is not out of hand, but seems to have stabilized

at a reasonable level. Further, despite vast cultural, political,

and economic differences between developed countries, use of these

agents is remarkably comparable within a rather narrow rank. This

use pattern suggests that a relatively small proportion of the population perceives a need for these drugs and benefits from their use.

Further analysis of the data from this survey indicates that physicians prescribe these drugs in a medical model, the rate of prescription increasing proportionally to the degree of "life stress" or

"psychic distress" reported by the patients (Mellinger et al. 1978).

Actually, the number of persons with high levels of stress was

considerably greater than the number who take drugs, indicating that

many persons are able to cope with stress without the use of drugs

at all.

TOLERANCE TO AND DEPENDENCE ON BENZODIAZEPINES

Tolerance

All sedative drugs, regardless of class, may produce some degree of

tolerance and dependence. These phenomena are observed with most

drugs only when they are used chronically and usually when doses are

large. Drugs differ in the degree to which tolerance develops over

time, the degree to which dependence may occur as a function of multiples of the usual therapeutic dose, and the degree to which tolerance

develops in various pharmacological actions.

71
Tolerance implies that increasing amounts of drug are required to

maintain equal pharmacological effects. Tolerance is almost a

requisite for development of physical dependence. Several types of

tolerance are recognized. Metabolic tolerance signifies an increased

ability of the body to dispose of the drug during continuing exposure

to it. Phenobarbital and meprobmate induce drug-metabolizing enzymes

that increase their own metabolic as well as that of many other drugs,

so that tolerance quickly develops. The benzodiazepines also stimulate drug-metabolizing enzymes, but less so than the other two types

of drugs. Pharmacodynamic tolerance indicates a change in the sensitivity or numbers of receptors or cellular membrane macromolecules,

upon which the drug acts. It may also include alterations in intracellular responses such as the rate of synthesis or release of neurohormones. Finally, psychic or behavioral tolerance may develop;

persons using these drugs are able to compensate for certain

deficits in function while maintaining other desired effects. The

concept of "immune" tolerance, due to formation of antibodies to a

drug, is controversial and is not pertinent to the drugs under

consideration. In the case of benzodiazepines, tolerance seem most

rapidly developed to the sedative actions of the drugs and much less

likely to other pharmacological actions.

Dependence

Psychic dependence is related somewhat to tolerance and is a requisite for physical dependence, yet it is separate from either. It

signifies some reward to users in terms of euphoria, greater confidence, or less depression, so that they are impelled to continue its

use without interruption. Not all drugs to which psychic dependence

develops are associated with tolerance or physical dependence.

Cocaine, for instance, produces strong psychic dependence, but in

man shows little evidence of tolerance or physical dependence. Benzodiazepines undoubtedly produce psychic dependence.

Physical dependence refers to a time-related syndrome that develops

when a subject who has been overusing a drug suddenly stops taking

it or sharply reduces its dose. Physical dependence on sedativehypnotic drugs resembles that from alcohol, so that withdrawal reactions are called "alcohol-barbiturate" types. They consist of

alterations of consciousness (delirium), neuromuscular irritability

(tremors and seizures), and vegetative disturbances (vaniting,

sweating, tachycardia). The syndrome of deliriun tremens is well

known from alcohol but can be mimicked by withdrawal of sedativehypnotics (Mellinger et al. 1978).

Animal Studies

Several studies have indicated that, under the proper experimental

conditions, the benzodiazepines may produce tolerance in animals.

The development of tolerance to chlordiazepoxide in the rat was

demonstrated using the conditioned avoidance-escape response (Matsuki

excretion of 14C-labeled chlordiazepoxide were also found in rats

and Iwamoto 1966). Increased rates of tissue disappearance and

made tolerant to chlordiazepoxide, suggesting a degree of metabolic

72
tolerance (Hoogland et al. 1966). The development of tolerance to

chlordiazepoxide in rats and mice was also shown by a variety of

pharmacologic tests (Goldberg et al. 1967). Acute tolerance to

diazepam was shown using the linguomandibular reflex in the cat

(Barnett and Fiore 1971). Similar tolerance was observed in the cat

using the anterior tibia1 flexor reflex or the EEG; amplitude as the

test response. Rats developed tolerance toward the depressant action

of oxazepam after three to four doses, while the disinhibitory action

on punished behavior did not show tolerance (Margules and Stein 1968).

Similar observations were reported following lorazepam administration

(Stein and Berger 1971). Short-term treatment of rats with flurazepam

reduced the spontaneous activity and unmasked the disinhibitory effect

(Cannizzaro et al. 1972).

Psychic dependence may be construed as reflecting the reinforcing

properties of the drug, that is, the extent to which subjects maintain

self-administration. Studies with rhesus monkeys showed that pentobarbital was more effective than diazepam in maintaining self-administration, while chlorpranazine did not maintain self-administration

(Yanagita and Takahashi 1973). Similar relationships have been found

in self-administration studies in man, using polydrug abusers as

subjects (Griffiths et al., submitted).

Evidence for physical dependence has been less clear. Rats reduced

their liquid intake when forced to drink water containing chlordiazepoxide, and later, when given a free choice, the animals returned to

pure water with no evidence of either addiction or tolerance (Harris

et al. 1968). However, when rats were conditioned to drink an aqueous

solution of chlordiazepoxide in order to obtain food pellets, after

25 days of conditioning the animals preferred the chlordiazepoxide

solution rather than pure water. When a 0.5 mg/ml aqueous solution

of chlordiazepoxide was made freely available to rats, none developed

dependence upon the drug (Stolerman et al. 1971).

Monkeys with an indwelling intravenous catheter were forced to choose

between the self-infusion of chlordiazepoxide solution or saline. The

animals exposed to a 24-hour continuous experimental procedure preferred chlordiazepoxide over saline. However, the animals addicted

to chlordiazepoxide preferred intravenous secobarbital when offered

a choice of the two drugs (Findley et al. 1972). In another series

of experiments, daily intravenous administration of chlordiazepoxide,

diazepam, or oxazolam to monkeys produced physical dependence. However, during this experiment, the animals were not heavily depressed

and did not exhibit marked withdrawal signs (Yanagita and Takahashi

1973).

The evidence available indicates that both tolerance and physical

dependence can be developed with the benzodiazepines in animals under

the proper experimental conditions, but it is more difficult to accomplish with the benzodiazepines than with the barbiturates.

73
Human Studies

Benzodiazepines may have been taken by more persons than any other

prescribed drug. This extensive medical use has provided innumerable

opportunities for misuse by every conceivable type of stable and

unstable person. Consequently, it would be expected that instances

of misuse and abuse should be recorded. The question is whether the

number of such instances is excessive relative to the degree of use.

Production of physical dependence on benzodiazepines was first done

experimentally in 1961, not long after chlordiazepoxide was marketed.

Ten of eleven patients treated for several weeks or months with daily

doses of 300 to 600 mg, 8 to 20 times the usual therapeutic dose,

experienced new symptoms and signs after being abruptly switched to

placebos without their knowledge. Depression, agitation, insomnia,

loss of appetite, and nausea appeared between 2 and 8 days after withdrawal. Two patients had seizures, one at 7 days after withdrawal,

the other after 8 days. A third patient, not in the experimental

study, had a seizure 12 days after discontinuation of treatment with

a daily dose of 300 mg. The difference between the withdrawal syndrome from chlordiazepoxide as compared with that from short-acting

barbiturates, or drugs such as meprobamate, is that it was both

milder and more attenuated than the acute explosive withdrawal

reaction seen with the short-acting drugs (Hollister et al. 1961).

Another study employed large doses of diazepam for the treatment of

schizophrenic patients. Clinical signs of withdrawal reaction were

seen in 6 of 13 patients abruptly switched to placebos after daily

doses of 120 mg, or about 8 times the usual therapeutic dose. One

patient had a major seizure on the eighth day of withdrawal (Hollister

et al. 1963). In other cases, the diazepam withdrawal reaction was

mild and attenuated.

Clinical Reports of Dependence

Since these early experimental studies in man, a number of clinical

reports of spontaneous dependence on benzodiazepines has appeared.

As might be expected from their use pattern, the majority of these

were concerned with chlordiazepoxide or diazepam. The reports in the

literature through most of 1978 have been reviewed (Marks 1978).

Slightly more than 402 individual patients have been reported to be

dependent on benzodiazepines. The majority of these patients were

dependent in the context of concurrent abuse of alcohol and other

drugs. Only 56 cases of physical dependence were specifically noted,

the vast majority of patients being assumed to have only psychic

dependence. Based on the results of this extensive survey of the

literature, the author, previously biased towards finding a significant abuse problem, came to the following conclusions:

Physical dependence upon a benzodiazepine can be produced in man

if given in excessive doses over a prolonged period, particularly

to patients with unstable personalities.

74
The dependence risk factor is low and certainly less than that

of the other commonly used sedatives and anxiolytics.

The risk factor and the dangers to society are of such a low

order that no extension of controls is necessary.

In the interest of good medical care and to minimize the risks

of dependence, patients should be thoughtfully selected for

benzodiazepine administration, and drug therapy should be discontinued as soon as it is therapeutically practical to do so.

The frequency of dependence was found to be somewhat higher in another

study. Over a 2-year period in the Stockholm area, 55 persons, the

majority women, were found to be dependent on sedative-hypnotic drugs.

Twenty-two were dependent only on benzodiazepines. Most patients

were highly nervous, had been under previous psychiatric treatment,

and had much accompanying somatic illness. Overuse had gone on for

several years prior to their hospital admission, after which 40 percent showed some signs of physical dependence (Allgulander 1978).

Swedish women, as judged by the epidemiologic study mentioned earlier,

have the highest rate of use of antianxiety drugs, with 21.5 percent

of women surveyed using them.

PHARMACOKINETIC CONSIDERATION IN WITHDRAWAL REACTIONS

One is faced with a paradox that despite the unprecedented use of the

benzodiazepines over a long period of time, reports in the medical

literature are relatively few and the picture of dependence is rather

mild. It should be remembered that the withdrawal syndrome from drugs

such as chlordiazepoxide and diazepam is quantitatively different than

from shorter-acting drugs, such as secobarbital sodium. Withdrawal

symptoms and signs often are not evident until the third day following

cessation of the drug and at that time they resemble the symptom

initially being treated: nervousness, irritability, and insomnia.

It is quite likely many patients construe these symptoms as a recrudescence of those for which they originally took the drug. Either

by resting taking the drug they had taken before, or taking another

sedative, or taking alcohol, they are able to abort the incipient

withdrawal reaction. Others may endure the complete withdrawal

reaction without realizing what is wrong. The peak symptoms from

withdrawal of these long-lived drugs occurs at about the fifth day

after cessation of the drug and almost all symptoms and signs disappear by the eighth or ninth day. Thus, the milder and attenuated

withdrawal syndrome from these drugs may be missed, something unlikely

to occur with the abrupt and severe withdrawal reaction from shortacting drugs such as meprobarmate or secobarbital sodiun.

The general rule, then, is that drugs with a plasma disappearance

rate of between 6 and 24 hours are most likely to show severe withdrawal reactions, while those with effective disappearance rates (of

parent drug as well as active metabolites) of 36 hours or more are

likely to have a mild but longer withdrawal syndrome. Drugs with a

very slow disappearance rate, such as phenobarbital, may protect

against the development of a withdrawal syndrome, which is dependent

75
upon the rate of decline of plasma and tissue concentrations of drug.

Few sedative-hypnotics to reach the market have plasma disappearance

rates below 6 hours. Tybamate is such a drug, with a plasma halflife of 3 hours or less. It is impossible to give this drug in an

ordinary divided dose schedule in such a way as to maintain continually high levels of the drug (Shelton and Hollister 1967). Accordingly, physical dependence on this drug is virtually unknown. These

relationships between plasma half-life and the intensity of the

withdrawal syndrome from various drugs are shown schematically in

figure 1.

Dependence on Therapeutic Doses of Benzodiazepines

Normally one associates withdrawal reactions to sedatives or other

drugs with excessive doses over substantial time periods. It may

very well be that the interaction is between dose and time so that

as the latter becomes longer the dose becomes less. Discontinuation

of chlordiazepoxide 45 mg/day in patients who had been treated with

this dose for several months produced minor withdrawal symptoms that

seemed clearly to be distinguishable from mere return of anxiety.

Subsequently, a number of other cases of withdrawal from therapeutic

doses of diazepam have been reported, most of which are included in

the review of such reports mentioned above (Marks 1978). A patient

who had been treated with 30 to 45 mg/day of diazepam for 20 months,

which was suddenly stopped, showed a clearcut withdrawal reaction.

Precipitous weight loss and orthostatic tachycardia accompanied the

typical dysphoria of withdrawal, which occurred between the fifth

and ninth days after discontinuation of the drug (Pevnick et al.

1978). In other cases, the withdrawal reaction under these circumstances has been markedly protracted, though mild. An even more

extreme example of a protracted withdrawal reaction followed withdrawal of phenobarbital after 30 years of chronic use. Almost 7

months of treatment were required to stabilize the patient (Epstein

1980).

The concept of dependence from sedative drugs given at therapeutic

doses is still relatively new. The mechanism of action is not clear.

One might speculate that in the case of drugs that act on receptors,

such as the benzodiazepines, prolonged use may cause subsensitivity

of receptors. When the drug is withdrawn, the response to any endogenous ligand might be reduced. Further, the possibility exists that

patients who require these drugs on a continuing basis could be deficient in such endogenous ligands. Thus, such patients might not be

protected against sudden withdrawal of the drug as well as others.

Of course, all of this speculation has no substantial evidence as

yet to support it.

PRESENT CLINICAL IMPLICATIONS OF BENZODIAZEPINE DEPENDENCE

Whatever the extent of dependence on these drugs, and whatever the

relationship to dose and time of treatment, there seem to be little

doubt that benzodiazepine dependence should be avoidable in the

majority of instances. Some relatively simple rules about the use

76
Figure 1

Intensity of withdrawal reaction

Postulated relationship between severity of withdrawal reaction and

plasma disappearance rate of sedative drug.

77
of these drugs would help to avoid many of the potential problem.

Among these are the following:

One must use these drugs only when symptoms of anxiety create

either considerable discomfort or disability. If the patient can

cope without drugs or with nondrug treatments, that is fine. While

benzodiazepines are of proven value in actual muscle spasm, they

need not be used for all acute strains with spasm. Heat and

aspirin may be as effective, if not actually better.

One must constantly assess whether the drug is efficacious. A

beneficial effect will usually be evident within a week or so, if

it is going to be obtained at all. Failure of an anxious patient

to respond should alert one to other diagnostic possibilities.

One cannot justify the continued use of any drug if no benefit

is obtained.

One should contract with the patient in advance for brief periods

of treatment. Disabling anxiety is often episodic, which is why

clinical experiments to prove these drugs against placebo axe

sometimes disappointing. One should tailor treatment to the course

of the illness, which generally allows for brief episodes of

treatment.

One should expect that drugs of this type will be abused by persons

with a prior history of drug or alcohol abuse. The majority of

instances of abuse of these drugs are in precisely such patients.

Other classes of antianxiety agents, such as sedative antihistamines, may be more suitable for drug-abusing patients, as these

drugs are noxious when large doses are taken.

When these drugs have been used for long periods of time, even

though doses may have been in the usual therapeutic range, discontinuation of drug should be gradual.

SUMMARY

Dependence is probably less frequent with current use of benzodiazepines than was the case when barbiturates were the primary sedativehypnotic drugs. Dependence still occurs, both in the context of

other types of drug abuse as well as solely in medical treatment.

The withdrawal syndrome produced by most of these drugs is mild and

attenuated, seldom leading to any serious consequences. The preponderance of reports of physical dependence on benzodiazepines involve

diazepam or chlordiazepoxide, a proportion that reflects their rate

of use. The short-acting derivatives, lorazepam and oxazepam, also

produce a similar withdrawal reaction. It is unlikely that any

other members of the class would be less likely to produce dependence.

Benzodiazepine dependence is a largely avoidable problem.

78
FUTURE RESEARCH DIRECTIONS

All the questions that need to be asked will not be proposed, nor

will those proposed be highly original. If they have merit, it is

that they may be answered without too much difficulty or expense.

1. A simple animal model of physical dependence is badly needed.

Although the dog, and to a lesser extent, the cat, have been

useful, these animals require a great deal of maintenance and

have long lives. A model in some small animal would be most

helpful. Already some investigators believe that they can show

a replicable syndrome of physical withdrawal in rats. Such a

model might be highly useful for answering two pertinent

questions:

a. What factors determine "low-dose" dependence? What is the

minimum period required for exposure to such doses to

produce physical dependence? Does the degree of dependence

increase in a linear fashion with increased time of exposure? What proportion of animals develops such a syndrome?

In answering these questions, it is essential that animals

be exposed to the drug on a continuing basis that is not

labor intensive. Gavage feeding is not especially useful

and has risks when used over the long periods required.

Addition of drug in small amounts to feed might be the

most expeditious way to provide sustained drug exposure.

NIDA might wish to contract with feed producers to see if

various benzodiazepines can be incorporated into feed so

that it is still acceptable to the animals and so the dose

per day is appropriate. To assure that doses used in

animals are appropriate to the nature of the problem in

man, plasma concentrations of drug should be monitored

to assure that they are comparable to those expected from

similar low-dose exposure in man. Ratings of the withdrawal

syndrome should be done blindly.

b. Do the kinetics of the various drugs influence the develop

ment of physical dependence? Clinical evidence suggests

that withdrawal reactions following over-use of these drugs

may be more rapid in onset and more severe following shortacting drugs than after long-acting drugs, where reactions

are slower in onset, milder in degree, but longer in

duration. Such relationships could be most expeditiously

studied in an animal model. The range of 1,4- or 1,5-

benzodiazepine plasma half-lives is such that one could

explore withdrawal reactions from drugs with half-lives as

short as 2 to 3 hours to those with half-lives greater than

100 hours. It is possible that ultra-short or ultra-long

acting drugs might be less likely to produce signs of

physical dependence.

79
2.

3.

4.

5.

6.

Does the fact that benzodiazepines react with specific "receptors"

in the brain make them different from other types of sedatives

in their predilection for producing physical dependence? Studies

in animals should determine the changes in the number, the affinity, and the responses of benzodiazepine receptors following

various types of exposure to benzodiazepines. Is sub-sensitivity

during treatment a factor?

What is the reinforcing value of low doses of drugs? Most prior

studies have used relatively high doses and compared one class,

such as sedatives, against another, such as phenothiazines. To

show that the latter drugs are aversive is like shooting fish in

a barrel. What we need to know is whether reinforcement differs

between various types of sedatives or within certain classes,

and whether this phenomenon can be demonstrated at so-called

"therapeutic doses." Is it possible that different absorption

kinetics of benzodiazepines alter reinforcement?

How often does low-dose physical dependence occur clinically and

what characteristics of patients might predict such reactions?

Rather, should one organize systematic studies that would, under

blind conditions, abruptly withdraw patients from benzodiazepines

and observe the effects produced? Apparently enough patients are

interested in caning off benzodiazepines to make such studies

possible and ethical. The problem is that those who feel the

need to discontinue the drug may not be a representative sample.

But there are ways to manage that.

How many patients abuse benzodiazepines? Although patients vary

considerably in the plasma concentrations of drug that they

achieve following any given daily dose, we now have enough

experience to be able to set a reasonable limit on what one

might expect from a given dose. Periodic monitoring of plasma

concentrations of drug during treatment would provide possibly

the most objective way to determine which patients may be

abusing the drugs by taking more than prescribed. Permission

to draw blood samples (perhaps without the reason being given)

should be made a condition of treatment to assure that not only

the good patients will comply with the study. This use of plasma

concentrations might be their most practical application.

Can physicians be educated to use benzodiazepines better without

being so frightened of their use that patients will be deprived

of the well-established benefits? Several approaches to education of physicians should be set up and compared, using some predetermined operational criteria for success.

REFERENES

Allgulander, C. Dependence on sedative and hypnotic drugs: A comparative clinical and social study. Acta Psychiatr Scand, (Suppl.

270):1-102, 1978.

80
Balter, M.B., Levine, J., and Manheimer, D.I. Cross-national study

of the extent of antianxiety/sedative drug use. N Engl J Med, 290:

769-774, 1974.

Barnett, A., and Fiore, J.W. Acute tolerance to diazepam in cats and

its possible relationship to diazepam metabolism. Eur J Pharmacol,

13:239-243, 1971.

Cannizzaro, G., Nigito, S., Provenzano, P.M., and Vitikova, T.

Modification of depressant and disinhibitory action of flurazepam

during short term treatment in the rat. Psychopharmacology, 26:173-

184, 1972.

Covi, L., Lipman, R.S., Pattison, J.H., Derogatis, L., and Uhlenhuth,

E.H. Length of treatment with anxiolytic sedatives and response to

their sudden withdrawal. Acta Psychiatr Scand, 49:51-64, 1973.

Epstein, R.S. Withdrawal symptoms from chronic low-dose barbiturates.

Am J Psychiatry, 137:107-108, 1980.

Findley, J.D., Robinson, W.W., and Peregrino,L. Addiction to secobarbital and chlordiazepoxide in the rhesus monkey by means of selfinfusion preference procedure. Psychopharmacology, 26:93-114, 1972.

Goldberg, M.E., Manian, A.A., and Efron, D.H. A canparative study

of certain pharmacologic responses following acute and chronic administration of chlordiazepoxide. Life Sci, 6:481-491, 1967.

Griffiths, R.R., Bigelow, G., and Liebson, I. Human drug selfadministration. Double-blind comparison of pentobarbital, diazepam,

chlorprarazine and placebo. J Pharmacol Exp Ther, submitted.

Harris, R.T., Claghorn, J.L., and Schoolar, J.L. Self-administration

of minor tranquilizers as a function of conditioning. Psychopharmacology, 13:81-88, 1968.

Hollister, L.E., Bennett, J.L., and Kimbell, I., Jr., Savage, C.,

and Overall, J.E. Diazepam in newly admitted schizophrenics. Dis

Nerv Syst, 24:746-750, 1963.

Hollister, L.E., Motzenbecker, F.P., and Degan, R.O. Withdrawal

reactions from chlordiazepoxide (Librium). Psychopharmacologia, 2:

63-68, 1961.

Hoogland, D.R., Miya, T.S., and Bousquet, W.F. Metabolism and tolerance studies with chlordiazepoxide-2-14C in the rat. Toxicol Appl

Pharmacol, 9:116-123, 1966.

Margules, D.L., and Stein, L. Increase of "antianxiety" activity and

tolerance of behavioral depression during chronic administration of

oxazepam. Psychopharmacology, 13:74-80, 1968.

Marks, J. The Benzodiazepines: Use, Misuse, Abuse. Lancaster,

England: MTP Press, Ltd., 1978. pp. 111.

81
Matsuki, K., and Iwamoto, T. Development of tolerance to tranquilizers in the rat. Jpn J Pharmacol, 16:191-197, 1966.

Mellinger, G.D., Balter, M.B., Manheimer, D.I., Cisin, I.H., and

Parry, H.I. Psychic distress, life crisis, and use of psychotherapeutic medications. National household survey. Arch Gen Psychiatry,

35:1045-1052, 1978.

National Prescription Audit, 1976.

Pevnick, J.S., Jasinski, D.R., and Haertzen, C.A. Abrupt withdrawal

from therapeutically administered diazepam. Arch Gen Psychiatry, 35:

995-998, 1978.

Shelton, J., and Hollister, L.E. Simulated abuse of tybamate in man:

failure to demonstrate withdrawal reactions. JAMA, 199:338-340, 1967.

Stein, L., and Berger, B.D. Psychopharmacology of 7-chloro-5-(Ochlorophenyl)-l,3-dihydr-3-hydroxy-24-1,4-benzodiazepin-2-one

(lorazepam) in squirrel monkey and rat. Arzneim Forsch, 21:1072-

1078, 1971.

Stolerman, I.P., Kumar, R., and Steinberg, H. Development of morphine

dependence in rats. Lack of effect of previous ingestion of other

drugs. Psychopharmacology, 20:321-336, 1971.

Yanagita, T., and Takahashi, S. Dependence liability of several

sedative-hypnotic agents evaluated in monkeys. J Pharmacol Exp Ther,

185:307-316, 1973.

AUTHOR

Leo E. Hollister, M.D.

Professor of Medicine, Psychiatry, and Pharmacology

Stanford University School of Medicine and

Veterans Administration Medical Center

Palo Alto, California 94304

82
Benzodiazepines: Executive

Summary and Discussion

NOTE: Dr. Leo Hollister's paper was not presented orally, but copies were distributed to

the participants at the meeting. Drs. Richard

Shader and David Greenblatt, who spoke on the

metabolism and pharmacokinetics of benzodiazepines but did not submit a paper for this monograph, participated in the discussions. Their

comments are incorporated in the appropriate

summaries of discussions and new research

directions.
Benzodiazepines: Executive

Summary and Discussion

Edward B. Truitt, Jr., Ph.D.

EXECUTIVE SUMMARY

Benzodiazepines: Biochemistry to Function

. . . John F. Tallman

Dr. Tallman began with the important question of whether the binding

of benzodiazepines to receptors in the brain to produce such diverse

effects as anticonvulsant, muscle relaxant, anxiolytic, and sedativehypnotic actions represents a continuum of actions at different levels

or an action on discrete areas or receptors in the brain. Neurophysiologists have shown benzodiazepines to produce enhancement of

the action of the inhibitory neurotransnitter GABA on cerebral neurons,

an effect blocked by the stimulant picrotoxin. Not all GABA receptors

interact with diazepam and not all actions of diazepam are necessarily

mediated through GABA receptors. Much evidence points to the presence

of multiple receptors for diazepam in the brain with different characteristics as well as differences from the peripheral receptors for

diazepam, which may be associated with diazepam side effects. There

are many important areas of research into chronically produced

changes in the number and sensitivity of benzodiazepine receptors.

Complete (100%) occupancy may not be necessary to produce antiseizure

effects, and prolonged protection may occur without full occupancy.

Tallman speculated on the nature of endogenous ligands that might

occupy the benzodiazepine receptors normally, including such candidates as the purine compounds hypoxanthine and inosine, a betacarboline derivative of tryptophane identified by Braestrup, nicotinamide, and an endogenous peptide.

DISCUSSION

Discussion of Dr. Tallman's presentation centered on the possibility

that diphenylhydantoin enhancement of benzodiazepine receptor sensitivity may relate to occupancy by endogenous ligands of the purine

type, particularly an action of methylxanthines such as caffeine or

theophylline. Other drugs that are known to interact with GABA

include alcohol and barbiturates. The latter may act on benzodiazepine receptors that are blocked by picrotoxin, but there are

wnvulsant barbiturates that confound this idea. The most important

aspect of benzodiazepine receptors may be the small but important

changes produced by chronic diazepam administration.

84
EXECUTIVE SUMMARY

The Benzodiazepine Receptor: Anatomical Aspects

. . . Michael J. Kuhar

A site in brain tissue that has the properties of a relevant and

pharmacologically active benzodiazepine receptor has been

identified by binding techniques. Thus it is possible to study

molecular and anatomical mechanisms of benzodiazepine drugs more

extensively than before. This report focuses on the anatanical

localization of benzodiazepine receptors and their significance.

Biochemical studies have shown that the benzodiazepine receptors are

unevenly distributed in brain regions. Phylogenetic studies suggest

that the benzodiazepine receptors appear relatively late in evolution.

Overall, these results strongly suggest that the receptor is not

some simple, universal constituent of neuronal membranes, but

rather a unique entity specially involved in certain brain regions

(and therefore certain physiological functions) and possibly associated with a unique, endogenously occurring "active" compound such

as a neurohormone. Hence, anatanical studies of the benzodiazepine

receptor are necessary for a full understanding of the action of

benzodiazepine drugs. The usefulness of anatomical studies of

receptors for providing insights to mechanism of drug actions has

been demonstrated in the cases of, for example, the opiate receptor

and the alpha-adrenergic receptor.

DISCUSSION

Discussion of Dr. Kuhar's presentation focused on localization, as

did his talk. Central receptors are of more interest than the

peripheral ones. Fluorescent antibody reactions would localize

receptors better than autoradiographic techniques with the light

microscope. Spinal cord receptors have been identified but the

muscle relaxant action is probably supraspinal. Dr. Kuhar was

asked about localization in areas of the cortex other than the

occiput. Patterns are similar in the supraspinal and sensory cortex

areas in the rat, but human studies have not been done. Dr. Kuhar

concluded the discussion by emphasizing the differences in mechanism

of action between benzodiazepines and the sedative hypnotic drugs

such as barbiturates and alcohol. Whereas sedatives and hypnotics

act directly on both inhibitory and excitatory neurons, the benzodiazepine drugs act indirectly through potentiating the actions of an

endogenous inhibitory substance, GABA.

85
EXECUTIVE SUMMARY

Benzodiazepine Self-Administration in Animals and Humans:

A Comprehensive Literature Review

. . . Roland R. Griffiths and Nancy A. Ator

One approach to studying drug abuse has been the development of

experimental paradigms for controlled investigations of drug selfadministration in laboratory animals and humans. Such experimental

models can provide various types of information relevant to drug

abuse, including comparative information about the relative efficacy

with which different drugs maintain drug self-administration. The

validity of this approach is supported by the good correspondence

between those drugs that are self-administered by laboratory animals

and those self-administered and abused by man. This paper reviews

the current status of the scientific literature on benzodiazepine

self-administration. The first two sections review the animal and

human data, respectively. The final section summarizes major

findings and outlines directions for future research on benzodiazepine self-administration.

DISCUSSION

In a brief discussion of his paper, Dr. Griffiths pointed out the

need to discuss the consequences, such as memory effects, of selfadministered doses of benzodiazepines. Considerable variation in

sensitivity to diazepam and pentobarbital exists among drug abusers

and sedative-hypnotic users regarding the occurrence of ataxia and

euphoria. The setting in which the drugs are tested is important.

Shorter acting benzodiazepines such as midazolan are more readily

self-administered in baboons, although this property may depend upon

rapid absorption as well as fast metabolism. Some animals will show

self-administration only during periods of stress.

86
EXECUTIVE SUMMARY

Benzodiazepine Dependence Studies in Rodents

. . . William R. Martin and L.F. McNicholas

There is only a mall amount of information concerning benzodiazepine

dependence in the rat. Although benzodiazepines will decrease conditioned avoidance responding, adverse circumstances do not seem to give

rise to increased ingestion. Other problems related to dependence

that can be dealt with experimentally are (1) the relative agonistic

actions of the different benzodiazepines; (2) the characterization of

their dependence-producing ability, including whether they produce

protracted abstinence or not; (3) identification of signs of abstinence that are predictors of drug seeking behavior; and (4) the

relative threat of the abstinence syndrome to health.

The rat certainly is an economical species in which these assessments

can be made. The rat has been extensively used in operant studies.

It now appears that rats dependent on pentobarbital and diazepam have

an abstinence syndrome rich in signs. The gastric fistula rat allows

the ready enteric administration of the water-insoluble benzodiazepines. The viability of this preparation is such that a variety

of crossover and dependence studies can be conducted, which should

allow the efficient generation of quantitative data of relatively

low variability.

DISCUSSION

In the discussion of Dr. Martin's paper, it was noted that his observed

pattern of withdrawal symptoms following diazepam dependence in the

rat resembled that for serotonin receptor hypersensitivity. It was

suggested and he agreed that the study of withdrawal patterns should

recognize that these symptoms follow a discernible pattern. This

occurs for the study of receptors also and may be related to cycles in

the production of an endogenous ligand acting on the receptor.

87
EXECUTIVE SUMMARY

Benzodiazepines: Clinical Use Patterns

. . . Karl Rickels

Tracing the patterns of benzodiazepine use in a clinical setting,

Dr. Rickels noted a flattening or slight decline in the use of these

drugs in the United States from 1973 to 1978. The proper use of antianxiety drugs in various psychotic and nonpsychotic states is well

described in the Diagnostic and Statistical Manual of Mental Disorders

of the American Psychiatric Association (DSM-III). However, the widespread use of anxiolytic drugs both in and out of the hospital in

nonanxious patients suffering from physical and particularly cardiovascular disorders raises the question of whether these drugs have

any appropriate treatment or prophylactic benefit such as the prevention of reinfarct or effects on stress-induced contributory factors

such as increased triglycerides, cholesterol, or platelet aggregation.

Rickels described the appropriate use of benzodiazepines and criticized

the widespread physician misprescribing practices of overuse as well

as underuse. Many nonspecific factors involving the physician's and

the patient's personalities affect the optimum use of mild tranquilizers. Benzodiazepines are remarkably safe drugs when used alone and

most adverse reactions involve alcohol or multiple drugs.

Physiological dependence at recommended therapeutic doses is rare

and it is difficult to distinguish withdrawal symptoms from return of

the original symptoms. In a largestudy of 100 chronically anxious

patients continued on 20 to 40 mg diazepam for up to 6 months,

Rickels proved that improvement is inversely related to symptom intensity and that most patients plateau in about 4 to 6 weeks. An early

good response during the first week is the best indicator of long-term

improvement. Only 11 of the 100 patients suffered withdrawal reactions

upon abrupt termination of the drug, and 6 of these were mild and

lasted only a few days. Three of the remaining five reactions may have

been partly related to alcohol use. This report lends support to the

clinical impression that anxiolytic medication should not be stopped

abruptly after prolonged treatment.

DISCUSSION

The discussion pointed out the need to know which endogenous ligands

acting on the benzodiazepine receptor may be depressed by long-term

therapy. Also, the usefulness of propranolol and other peripherally

acting symptomatic therapy should be studied for use in withdrawal

reactions. Indicators of the induction of increased drug metabolism

such as the ratio of drug to metabolite and a high rate of decline

in blood levels have not been studied well but may be predictive of

withdrawal reactions. The inverse relationship between half-life and

severity of withdrawal is a testable hypothesis with currently

available drugs. Differences betweenmen and women in withdrawal

reactions are not evident, but women have a menstrual cycle variation

in their response to benzodiazepines.

88
EXECUTIVE SUMMARY

Benzodiazepine Hypnotics: Carryover Effectiveness, Rebound

Insomnia, and Performance Effects

. . . Anthony Kales

Sleep laboratory studies offer greater precision and objectivity than

other methods frequently used to evaluate hypnotic drugs. Since

insomnia is frequently a long-term or chronic condition, sleep studies

can examine the effectiveness of benzodiazepine drugs over longer

periods and measure withdrawal and carryover effects as well.

Carryover effectiveness has been shown for only two benzodiazepine

drugs, flurazepam and quazepam (the latter drug is a new investigational hypnotic). Since both drugs have the same long-acting metabolite (N desalkyl flurazepam), the carryover effectiveness has been

considered to reflect the gradual buildup and elimination of this

metabolite. However, other drugs with long-acting metabolites have

not shown carryover effects, so the hypnotic efficacy of the metabolite must be important. The advantages and disadvantages of carryover effectiveness were compared.

Rebound insomnia, a worsening of sleep beyond the original baseline

condition, occurs with some benzodiazepine drugs with short or

moderate duration of action, but has not yet been found with longacting compounds. Kales proposes that rebound insomnia occurs

because of a lag in the regeneration of an endogenous ligand that

normally occupies the receptor and is suppressed by benzodiazepine

drugs.

Decrements in daytime performance and memory impairment are two important side effects of benzodiazepine drug administration. Drowsiness

and impaired performance the following day are related to dose, age,

and long duration of benzodiazepine action. Anterograde amnesia has

been reported anecdotally but has not been well studied.

DISCUSSION

In the discussion of this paper, Dr. Martin B. Scharf explained the

reasons for disagreement with Dr. Hartse and her colleagues, in

Science magazine, over the existence of rebound insomnia--foliowing

use of some benzodiazepines, and stated the belief that it is related

to short-acting benzodiazepines. Subjective evaluation of sleep

quality is as important or more important than objective EEG; data,

and subjectively the subjects with rebound insomnia feel they sleep

badly, in agreement with objective data. Rebound insomnia after

benzodiazepine use differs basically from barbiturate rebound insomnia in that there is no rapid eye movement (REM) increase. Benzodiazepines apparently do not increase the density of eye movements

during REM rebound as do the barbiturates and glutethimide.

89
EXECUTIVE SUMMARY

Dependence on Benzodiazepines

. . . Leo E. Hollister

Dr. Hollister reviewed current use patterns of benzodiazepine drugs

and pointed out how the use of sedative-hypnotic drugs has plateaued

recently at a reasonable level. Tolerance occurs with benzodiazepine

drugs most rapidly to the sedative actions of the drugs and probably

much less to other pharmacological actions. Both metabolic and pharmacodynamic tolerance occurs with benzodiazepine drugs. Dependence

of both the psychic and physical types can be demonstrated for benzodiazepine drugs in animals, but is more difficult to accomplish than

with the barbiturates.

After an extensive review of the literature on human dependence,

Hollister came to the following conclusions:

1. Physical dependence upon benzodiazepine drugs can be produced

in man if the drugs are given in excessive doses over a prolonged period, particularly to patients with unstable personalities.

2. The dependence risk factor is low and certainly less than for

other commonly used sedatives and hypnotics.

3. The risk factor and the dangers to society are of such a low

order that no extension of controls is necessary.

4. For better medical care and minimal risk of dependence,

patients should be thoughtfully selected for benzodiazepine

therapy and the drug should be discontinued as soon as it is

therapeutically practical to do so.

Hollister noted a remarkable inverse correlation between drug halflife in the plasma and severity of withdrawal reactions. Prolonged

administration also pranotes severe withdrawal effects. His concluding principles for benzodiazepine use are:

1. Use only for anxiety producing considerable discomfort or

disability.

2. Continuously assess efficacy and discontinue if ineffective.

3. Contract with the patient for brief periods of treatment

because anxiety is usually episodic.

4. Expect benzodiazepine abuse from patients with a history of

drug or alcohol abuse and use other classes of drugs for

sedation such as antihistamine drugs for these patients.

5. When these drugs have been used for long periods of time,

discontinuation of drug should be gradual.

90
GENERAL DISCUSSION

Dr. Szara acknowledged in the discussion that the DAWN data on

street abuse of drugs have been criticized and have been only

partially validated. There is a need for better data on abuse of

benzodiazepines, since some persons do not consider their use of

these drugs as abuse, depending on how the question is phrased.

General discussion followed about how better understanding of benzodiazepine receptors could lead to better clinical use of benzodiazepine drugs and less abuse. Development of a partial agonist was

suggested as a possible means of preventing abuse.

Caffeine was named as a general antagonist for benzodiazepines and

it was suggested that excess caffeine consumption may be related to

attempts by the user to curb benzodiazepine carryover effects.

Combined abuse of benzodiazepine-type drugs with methadone was

described. Diazepam is useful in neonatal opiate withdrawal,

although clonidine is more effective.

The relationship between benzodiazepines and opiates should be examined

further because naloxone antagonizes some diazepam depressant actions.

Meprobamate may interact weakly with benzodiazepine receptors. Other

interactions might be identified among the group of drugs termed interneuronal blocking agents. Benzodiazepine drugs are the choice for

treating phencyclidine (PCP) overdose.

Further interest was expressed in the ratio of desmethyl diazepam to

diazepam as an index of the induction of benzodiazepine metabolism

and its possible relationship to the severity of withdrawal. Many

variables characterize the degree of response to benzodiazepine drugs

as well as rate of metabolism including blood levels, patient personality, physician-patient relations, plasma binding, lipid compartments,

prior drug history, etc.

Long-term changes in the benzodiazepine receptor should be studied,

but these studies are difficult because residual drug must be removed

from the receptors before assay. Many other nonspecific factors such

as heating, seizures, diphenylhydantoin, and other treatments can

change receptor binding.

The discussion concluded with this summary by Dr. Martin:

1. Benzodiazepine drugs include many very useful drugs that do

have the potential for abuse, but the abuse is of a modest

nature since these drugs are less abusable than previously

used tranquilizers and hypnotics such as barbiturates.

2. The true size of the public health problem owing to abuse of

these drugs is still not established, but there is cause for

concern.

91
3. Proper use of these drugs for their indications and better

understanding of their phamacokinetics are needed by physicians.

4. Many physicians are using benzodiazepine drugs incorrectly,

sometimes overprescribing and sometimes underprescribing them

as a result of adverse publicity, even when a clear-cut indication

for their use exists.

5. Better understanding is needed of their basic mode of action and

complexities of use in order to develop improved drugs with

better selectivity.

92
RAUS Summary of

New Directions for Research

Jacqueline P. Ludford, M.S., and Stephen I. Szara, M.D., D.Sc.

Future benzodiazepine research should, first and foremost, be

methodologically strong and rigorous. Future investigations need to

be based on sound experimental and epidemiological data, and there

is much work to be done in developing such data for

benzodiazepines. Much of the research already performed has been

methodologically flawed and is open to some question.

Some areas of special interest for NIDA might include:

A. Receptor Studies

1 . Detailed light microscopic mapping of receptor locations in

animals and also in human tissues. Such information is

basic to further studies; techniques are now available to

accomplish this goal.

2. Identification of endogenous ligands. The implication of

benzodiazepine receptors in the brain is that endogenous

benzodiazepine-like substances must exist in the body and

may contribute to modulation of behavior.

3. Location of receptors as studied by high resolution

methods. The most promising method appears to be the

immunocytochemical approach; thus isolation, purification,

and production of benzodiazepine antibodies is an important

goal.

4. Psychopharmacological experiments to explore which areas of

the brain are responsible for which effects. Of special

interest should be to relate benzodiazepine receptor

occupancy to the reinforcing effects of the drug.

B. Abuse Liability Studies

1. Systematic comparative behavioral. study examining different

compounds within the benzodiazepine class. Study of

93
2.

3.

4.

dose-response relationship, and comparative effects of

long-acting vs. short-acting benzodiazepines.

Self-administration studies, both animal and human, which

take into account the environment and characteristics of

the population being studied. Future research should

include information about drug history, including over-thecounter, prescription, and illicit drugs, and environmental

factors including drug availability and stress as well as

the contribution of contextual variables such as food,

nicotine, and caffeine. Patient characteristics,

especially age, sex, and obesity, should be considered.

Investigations of the role of various drug combinations in

altering the reinforcing properties of benzodiazepines.

Commonly used drugs, such as alcohol, caffeine, aspirin,

antihistamines, etc., should be explored in this context.

Study of the personality traits, settings, and physician

attitude interactions which may be related to benzodiazepine abuse.

C. Clinical Studies

1. More detailed exploration of the abstinence syndrome. Can

there be a protracted abstinence syndrome with benzodiazepines? What are the physical signs of dependence? What is

the nature and prevalence of low-dose dependence clinically, both in psychiatric and general medical practice

patients, and what characteristics might predict such

reactions? What is the minimum period of exposure to produce physical dependence at a given daily dosage? Does the

degree of dependence increase in linear fashion with

increased time of exposure? To what extent is it a clinical problem?

2. Investigations of the pharmacokinetics of differing kinds

of benzodiazepines, particularly in the elderly and in

those with physical impairments. Do the kinetics of the

various drugs influence the development of physical

dependence? What is the significance of the ratio of

diazepam to desoxydiazepam, for example, and how is this

related to withdrawal symptoms?

3. In studying the rebound phenomena following withdrawal of

benzodiazepines, is it predictive of dependency? Is it

associated with rebound anxiety? What are the determinants? How long does it last?

4. Is there cross-tolerance and/or interaction between benzodiazepines and opiates? There are striking overlaps in

receptor areas, and benzodiazepines are sometimes used with

methadone by patients to get a “boost.” What are the

94
implications for drug abuse treatment and for the common

practice of prescribing benzodiazepine with opioids for

pain?

5. Food strongly affects absorption. Since the user loses the

peak effect if he takes a "tranquilizer" shortly after a

big meal he may, for example, increase the dose at bedtime

and wake up with continued drug effect ("hangover") the

next day. This is an interesting clinical observation that

needs to be explored by further research.

95
Participants

RAUS REVIEW CONFERENCE ON BENZODIAZEPINES

National Institute on Drug Abuse

Rockville, Maryland

September 12, 1980

REVIEWERS

William R. Martin, Ph.D., Chair

University of Kentucky

Lexington, Kentucky 20506

David J. Greenblatt, M.D.

Tufts University

School of Medicine

Boston, Massachusetts 02111

Roland R. Griffiths, Ph.D.

The Johns Hopkins University

School of Medicine

Baltimore, Maryland 21205

Michael J. Kuhar, Ph.D.

The Johns Hopkins University

School of Medicine

Baltimore, Maryland 21205 GUESTS

Karl Rickels, M.D.

Hospital of the University

of Pennsylvania

Philadelphia, Pennsylvania 19104

Martin B. Scharf, Ph.D.

Pennsylvania State University

College of Medicine

Hershey, Pennsylvania 17033

Richard I. Shader, M.D.

Tufts University

School of Medicine

Boston, Massachusetts 02111

John F. Tallman, Ph.D.

National Institute of

Mental Health

Bethesda, Maryland 20014

SUMMARIZATION

Edward B. Truitt, Jr., Ph.D.

Northeast Ohio

College of Medicine

Rootstown, Ohio 44272

MODERATOR

Stephen I. Szara, M.D., D.Sc.

National Institute on Drug Abuse

Rockville, Maryland 20857

RAUS COORDINATOR

Jacqueline Ludford, M.S.

National Institute on Drug Abuse

Rockville, Maryland 20857

Roger Cadieux

Judith Lawrence, Ph.D., DEA

Robert C. Nelson, M.S., FDA

Edward C. Tocus, Ph.D., FDA

Frank J. Vocci, FDA

NIDA STAFF

Jack Blaine, M.D.

Monique Braude, Ph.D.

Roger Brown, Ph.D.

Dorynne Czechowicz, M.D.

James A. Ferguson, D.V.M.

James D. Lawrence

Marvin Snyder, Ph.D.

Heinz Sorer, Ph.D.

96
monograph series

While limited supplies last, single copies of the monographs may

be obtained free of charge from the National Clearinghouse for

Drug Abuse Information (NCDAI). Please contact NCDAI also for

information about availability of coming issues and other

publications of the National Institute on Drug Abuse relevant to

drug abuse research.

Additional copies may be purchased from the U.S. Government

Printing Office (GPO) and/or the National Technical Information

Service (NTIS) as indicated. NTIS prices are for paper copy.

Microfiche copies, at $3.50, are also available from NTIS.

Prices from either source are subject to change.

Addresses are:

NCDAI

National Clearinghouse for Drug Abuse Information

Room lOA-53

5600 Fishers Lane

Rockville, Maryland 20857

GPO NTIS

Superintendent of Documents National Technical Information

U.S. Government Printing Office Service

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1 FINDINGS OF DRUG ABUSE RESEARCH. Not available from NCDAI.

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2 OPERATIONAL DEFINITIONS IN SOCIO-BEHAVIORAL DRUG USE RESEARCH

1975. Jack Elinson, Ph.D., and David Nurco. Ph.D., eds. Not

available from NCDAI.

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3 AMINERGIC HYPOTHESES OF BEHAVIOR: REALITY OR CLICHE? Bruce J.

Bernard, Ph.D., ed.

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4 NARCOTIC ANTAGONISTS: THE SEARCH FOR LONG-ACTING PREPARATIONS.

Robert Willette, Ph.D., ed.

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5 YOUNG MEN AND DRUGS: A NATIONWIDE SURVEY. John A. O'Donnell,

Ph.D., et al. Not available from NCOAI.

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6 EFFECTS OF LABELING THE "DRUG ABUSER": AN INQUIRY. Jay R.

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7 CANNABINOID ASSAYS IN HUMANS. Robert Willette, Ph.D., ed.

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8 Rx: 3x/WEEK LAAM - ALTERNATIVE TO METHADONE. Jack Blaine, M.D.,

and Pierre Renault, M.D., eds.

Not available from GPO NTIS PB #253 763/AS $12.50

9 NARCOTIC ANTAGONISTS: NALTREXONE PROGRESS REPORT. Demetrios

Julius, M.D., and Pierre Renault, M.D., eds.

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10 EPIDEMIOLOGY OF DRUG ABUSE: CURRENT ISSUES. Louise G. Richards,

Ph.D., and Louise B. Blevens, eds. Examines methodological issues

in surveys and data collection. Not available from NCDAI.

GPO Stock #017-024-00571-1 NTIS PB #266 69l/AS $20

11 DRUGS AND DRIVING. Robert Willette, Ph.D., ed. Reviews

research on effects of drugs on psychomotor performance, focusing

on measures of impairment by different drugs at various levels.

Not available from NCDAI.

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12 PSYCHODYNAMICS OF DRUG DEPENDENCE. Jack D. Blaine, M.D., and

Demetrios A. Julius, M.D., eds. Theoretical and clinical papers

concerned with the intrapsychic determinants of drug addiction.

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13 COCAINE: 1977. Robert C. Petersen, Ph.D., and Richard C.

Stillman, M.D., eds. Reports the extent and limits of current

knowledge about cocaine, its use and misuse.

GPO Stock #017-024-00592-4 NTIS PB #269 175/AS $17

14 MARIHUANA RESEARCH FINDINGS: 1976. Robert C. Petersen, Ph.D.,

ed. Technical papers on which the 6th Marihuana and Health report

to Congress was based.

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15 REVIEW OF INHALANTS: EUPHORIA TO DYSFUNCTION. Charles Wm.

Sharp, Ph.D., and Mary Lee Brehm, Ph.D., eds. Review of inhalant

abuse, including an extensive bibliography.

GPO Stock #017-024-00650-5 NTIS PB #275 798/AS $26

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16 THE EPIDEMIOLOGY OF HEROIN AND OTHER NARCOTICS. Joan Dunne

Rittenhouse, Ph.D., ed. Task Force report on research

technologies and implications for studying heroin-narcotic use.

GPO Stock #017-024-00690-4 NTIS PB #276 357/AS $18.50

17 RESEARCH ON SMOKING BEHAVIOR. Murray E. Jarvik, M.D., Ph.D.,

et al., eds. Includes epidemiology, etiology, consequences of

use, and approaches to behavioral change. From a NIDA-supported

UCLA conference.

GPO Stock #017-024-00694-7 NTIS PB #276 353/AS $27.50

18 BEHAVIORAL TOLERANCE: RESEARCH AND TREATMENT IMPLICATIONS.

Norman A. Krasnegor, Ph.D., ed. Theoretical and empirical studies

of nonpharmacologic factors in development of drug tolerance.

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19 THE INTERNATIONAL CHALLENGE OF DRUG ABUSE. Robert C. Petersen,

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deal with drug issues of particular interest worldwide.

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20 SELF-ADMINISTRATION OF ABUSED SUBSTANCES: METHODS FOR STUDY.

Norman A. Krasnegor, Ph.D., ed. Techniques used to study basic

processes underlying abuse of drugs, ethanol, food, and tobacco.

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21 PHENCYCLIDINE (PCP) ABUSE: AN APPRAISAL. Robert C. Petersen,

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clinicians and researchers assessing what is known about the

problem of PCP abuse.

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22 QUASAR: QUANTITATIVE STRUCTURE ACTIVITY RELATIONSHIPS OF

ANALGESICS, NARCOTIC ANTAGONISTS, AND HALLUCINOGENS. Gene

Barnett, Ph.D.; Milan Trsic, Ph.D.; and Robert Willette, Ph.D.;

eds. Reports from an interdisciplinary conference on the

molecular nature of drug-receptor interactions. Not available

from NCDAI.

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23 CIGARETTE SMOKING AS A DEPENOENCE PROCESS. Norman A.

Krasnegor, Ph.D., ed. Discusses factors involved in the onset,

maintenance, and cessation of the cigarette smoking habit.

Includes an agenda for future research.

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24 SYNTHETIC ESTIMATES FOR SMALL AREAS: STATISTICAL WORKSHOP

PAPERS AND DISCUSSION. Joseph Steinberg, ed. Papers from a workshop cosponsored by NIDA and the National Center for Health Statistics on a class of statistical approaches that yield needed

estimates of data for States and local areas. Not available from

NCDAI.

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99
25 BEHAVIORAL ANALYSIS AND TREATMENT OF SUBSTANCE ABUSE. Norman

A. Krasnegor, Ph.D., ed. Papers present commonalities and

implications for treatment of dependency on drugs, ethanol, food,

and tobacco.

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26 THE BEHAVIORAL ASPECTS OF SMOKING. Norman A. Krasnegor, Ph.D.,

ed. Reprint of the behavioral section of the 1979 Report of the

Surgeon General on Smoking and Health; introduction by editor.

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27 PROBLEMS OF DRUG DEPENDENCE, 1979: PROCEEDINGS OF THE 41ST

ANNUAL SCIENTIFIC MEETING, THE COMMITTEE ON PROBLEMS OF DRUG

DEPENDENCE, INC. Louis S. Harris, Ph.D., ed. Not available from

NCDAI.

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28 NARCOTIC ANTAGONISTS: NALTREXONE PHARMACOCHEMISTRY AND

SUSTAINED-RELEASE PREPARATIONS. Robert Willette, Ph.D., and

Gene Barnett, Ph.D., eds. Papers report research on sustainedrelease and long-acting devices for use with the narcotic antagonist naltrexone.

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29 DRUG ABUSE DEATHS IN NINE CITIES: A SURVEY REPORT. Louis A.

Gottschalk, M.D., et al. Epidemiologic study providing data on

drug-involved deaths and procedures for their investigations.

Not available from NCDAI.

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30 THEORIES ON DRUG ABUSE: SELECTED CONTEMPORARY PERSPECTIVES.

Dan J. Lettieri, Ph.D.; Mollie Sayers; and Helen Wallenstein

Pearson, eds. Volume presents summaries of the major contemporary theories of drug abuse by each of 43 leading theorists.

GPO Stock #017-024-00997-1 Not available from NTIS

31 MARIJUANA RESEARCH FINDINGS: 1980. Robert C. Petersen, Ph.D.,

ed. The text of the 8th Marijuana and Health report to Congress

and the background scientific papers on which this summary report

was based.

GPO Stock #017-024-01010-3 NTIS PB #80-215171 $18.50

32 GC/MS ASSAYS FOR ABUSED DRUGS IN BODY FLUIDS. Rodger L. Foltz,

Ph.D.; Allison F. Fentiman, Jr., Ph.D.; and Ruth B. Foltz. A

collection of methods for the quantitative analysis of several

important drugs of abuse by the technique of gas chromatographymass spectrometry.

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34 PROBLEMS OF DRUG DEPENDENCE, 1980: PROCEEDINGS OF THE 42ND

ANNUAL SCIENTIFIC MEETING, THE COMMITTEE ON PROBLEMS OF DRUG

DEPENDENCE, INC. Louis S. Harris, Ph.D., ed. Comprehensive

assemblage of ongoing research on drug abuse, addiction, and new

compounds.

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35 DEMOGRAPHIC TRENDS AND DRUG ABUSE, 1980-1995. Louise G.

Richards, Ph.D., ed. Estimates of probable extent and nature of

nonmedical drug use, 1980-1995, based on age structure and other

characteristics of U.S. population.

GPO Stock #017-024-01087-1

36 NEW APPROACHES TO TREATMENT OF CHRONIC PAIN: A REVIEW OF MULTIDISCIPLINARY PAIN CLINICS AND PAIN CENTERS. Lorenz K.Y. Ng, M.D.,

ed. A sharing of ideas among active practitioners in the treatment of pain.

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101