National Institute on Drug Abuse

RESEARCH

MONOGRAPH SERIES

Integrating Behavioral

Therapies With

Medications in the

Treatment of Drug

Dependence

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

150

Integrating Behavioral Therapies

With Medications in the Treatment

of Drug Dependence

Editors:

Lisa Simon Onken, Ph.D.

Jack D. Blaine, M.D.

John J. Boren, Ph.D.

NIDA Research Monograph 150

1995

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES

Public Health Service

National Institutes of Health

National Institute on Drug Abuse

5600 Fishers Lane

Rockville, MD 20857
ACKNOWLEDGMENT

This monograph is based on the papers from a technical review on

“Integrating Behavioral Therapies With Medications in the Treatment of

Drug Dependence” held on June 11- 11, 1993. The review meeting was

sponsored by the National Institute on Drug Abuse.

COPYRIGHT STATUS

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For any other use, the copyright holder’s permission is required. All

other material in this volume except quoted passages from copyrighted

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permission from the Institute or the authors. Citation of the source is

appreciated.

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

necessarily reflect the opinions or official policy of the National Institute

on Drug Abuse or any other part of the U.S. Department of Health and

Human Services.

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

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

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

context of the studies reported herein.

National Institute on Drug Abuse

NIH Publication No. 95-3899

Printed 1995

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

selectively included in the coverage of American Statistics Index,

BioSciences Information Service, Chemical Abstracts, Current Contents,

Psychological Abstracts, and Psychopharmacology Abstracts.
Contents

Medications and Behavioral Therapies: The Whole May Be Greater

Than the Sum of the Parts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

Lisa Simon Onken, Jack D. Blaine, and John J. Boren

Enhancing the Effectiveness of Methadone Using Psychotherapeutic

Interventions .............................................. 5

Charles P. O’Brien, George E. Woody, and A. Thomas McLellan

Integrating Psychotherapy and Pharmacotherapy for Cocaine

Dependence: Results From a Randomized Clinical Trial . . . . . . . . .

Kathleen M. Carroll, Bruce J. Rounsaville, Charla Nich, Lynn

Gordon, and Frank Gawin

Can Psychotherapy Rescue Naltrexone Treatment

of Opioid Addiction? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Bruce J. Rounsaville

Strategies To Maximize the Efficacy of Naltrexone for Alcohol

Dependence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Stephanie S. O‘Malley

19

37

53

Disulfiram (Antabuse) Contracts in Treatment of Alcoholism . . . . . . . 65

Timothy J. O’Farrell, John P. Allen, and Raye Z. Litten

Combining Behavioral Therapy and Pharmacotherapy for Smoking

Cessation: An Update . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92

John R. Hughes

Integrating Psychological and Pharmacological Treatment of Dually

Diagnosed Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110

Roger D. Weiss, Shelly F. Greenfield, and Lisa M. Najavits

Combining Pharmacotherapy With Psychotherapy for Substance Abusers

With Borderline Personality Disorder: Strategies for Enhancing

Compliance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129

Marsha M. Linehan

iii
Integration of Behavioral and Pharmacological Treatments for

Panic Disorder: Implications for the Treatment of Substance

Dependence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143

Michael W. Otto, Murk H. Pollack, Susan G. Ball, and

Jerrold F. Rosenbaum

Some Methodological Comments . . . . . . . . . . . . . . . . . . . . . . . . . . . 167

Kenneth I. Howard

Comments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170

Stephen T. Higgins

iv
Medications and Behavioral

Therapies: The Whole May Be

Greater Than the Sum of the Parts

Lisa Simon Onken, Jack D. Blaine, and John J. Boren

It is no revelation that drug dependence is a complex problem with

behavioral, cognitive, psychosocial, and biological dimensions and may

be treated with behavioral therapy (including behavior therapy,

psychotherapy, and counseling), and, where available, pharmacotherapy.

Drug use can be reduced behaviorally with appropriate manipulation of

reinforcements within the environment (Higgins et al. 1993). Continued

improvements over time in drug use can be initiated by cognitivebehavioral psychotherapies to modify cognitions that perpetuate drug use

(Carroll et al., submitted for publication), and a reduced likelihood of

relapse has been engendered by specialized training approaches

(Rohsenow et al., in press). Methadone, of course, has long been

recognized as an effective pharmacotherapy to reduce opiate use, and its

biological mechanism of action is well understood.

Even though a complete understanding of drug dependence must address

behavioral, psychosocial, cognitive, and biological issues, an effective

treatment for an individual need not, in all cases, do so. Sometimes no

treatment is necessary, as is evidenced by the veterans of Vietnam who

tested positive for heroin while in Vietnam but showed no sign of

addiction after returning home (Robins 1993). Many a baby boomer who

experienced the drug culture of the late sixties and early seventies can

attest to knowing more than a few seemingly addicted individuals who,

without treatment, are now drug-free, upstanding members of the

community.

Where treatment is required, integrated behavioral and pharmacological

treatment is not always possible, practical, or necessary. For example,

except for opiate, alcohol, and nicotine dependence, no medications exist.

When behavioral treatments are the only treatments available, of course,

there is no integration to be done. Even where medications exist, many

individuals will not take them, and some individuals may be able to

conquer their drug dependence with behavioral interventions alone.

Finally, there may be compelling reasons to administer medication in the

1
absence of any behavioral or psychosocial services. Although

controversial, some have argued that in this era of AIDS, methadone

alone may be preferable to no treatment at all for a subgroup of opiateaddicted individuals awaiting more comprehensive treatment or as an

initial step in a harm reduction approach.

So why a monograph on “Integrating Behavioral Therapies With

Medications in the Treatment of Drug Dependence”? Two concepts

drove this monograph and the technical review that led to this

monograph. First, appropriate behavioral interventions can potentially

interact effectively with medications, enhancing their effects. From the

earliest days of methadone maintenance, Dole and Nyswander (1965)

stressed the importance of combining psychosocial services with

methadone, and there has been ample literature since then to support this

point of view (Grabowski et al. 1993; McLellan et al. 1993; Stitzer et al.

1993). Similarly, behavioral interventions alone are sometimes

insufficient to treat many drug abusers effectively, and it is believed that

medications, whether for concomitant mental or physical disorders or for

drug abuse per se, have a potential for improving the effect of behavioral

treatments. One function of this monograph is to review the literature to

date on combined behavioral and pharmacological treatments for drug

dependence. The ultimate goal of this monograph is to shed light on the

questions of when and how behavioral and pharmacological therapies for

drug dependence can be integrated for optimal treatment outcome.

The participants in the technical review who spawned this monograph

included the scientific editors of this monograph and Drs. Kathleen

Carroll, John Docherty, Stephen Higgins, Kenneth Howard, John

Hughes, Marsha Linehan, Charles P. O’Brien, Timothy O’Farrell,

Stephanie O’Malley, Michael Otto, Bruce Rounsaville, and Roger Weiss.

The technical review was held on June 10 and 11, 1993, preceding the

annual College on Problems of Drug Dependence meeting in Toronto.

The thoughts expressed at this meeting follow. It is hoped the

contributions to this monograph will stimulate innovative research on the

integration of pharmacological and behavioral therapies.
REFERENCES

Carroll, K.M.; Rounsaville, B.J.; and Nich, C. “One Year Follow-Up of

Psychotherapy and Pharmacotherapy for Cocaine Abuse: Evidence for

Continued Improvement After Psychotherapy.” Manuscript submitted

for publication.

Dole, V.P., and Nyswander, M.E. A medical treatment for

diacetylmorphine (heroin) addiction. JAMA 193:646-650, 1965.

Grabowski, J.; Rhoades, H.; Elk, R.; Schmitz, J.; and Creson, D.

Clinicwide and individualized behavioral interventions in drug

dependence treatment. In: Onken, L.S.; Blaine, J.D.; and Boren, J.J.,

eds. Behavioral Treatments for Drug Abuse and Dependence.

National Institute on Drug Abuse Research Monograph 137. DHHS

Pub. No. (ADM)93-3684. Washington, DC: Supt. of Docs., U.S.

Govt. Print. Off., 1993.

Higgins, S.T.; Budney, A.J.; Bickel, W.K.; Hughes, J.R.; Foerg, F.; and

Badger, G. Achieving cocaine abstinence with a behavioral approach.

Am J Psychiatry 150:5, 1993.

McLellan, A.T.; Amdt, I.O.; Metzger, D.S.; Woody, G.E.; and O’Brien,

C.P. The effects of psychosocial services in substance abuse treatment.

JAMA 269:1953-1959, 1993.

Robins, L. Vietnam veterans’ rapid recovery from heroin addiction: A

fluke or normal expectation. Addiction 88:1041-1054, 1993.

Rohsenow, D.J.; Monti, P.M.; and Abrams, D.B. Psychosocial

assessment and coping skills treatment for cocaine abuse: Preliminary

results, In: Tims, F.; Blaine, J.D.; Onken, L.S.; and Tai, B., eds.

Treatment of Cocaine Dependence: Outcome Research. National

Institute on Drug Abuse Research Monograph. Washington, DC: Supt.

of Docs., U.S. Govt. Print. Off., in press.

Stitzer, M.L.; Iguchi, M.Y.; Kidorf, M.; and Bigelow, G.E. Contingency

management in methadone treatment: The case for positive incentives.

In: Onken, L.S.; Blaine, J.D.; and Boren, J.J., eds. Behavioral

Treatments for Drug Abuse and Dependence. National Institute on

Drug Abuse Research Monograph 137. NIH Pub. No. (ADM) 93-

3684. Washington, DC: Supt. of Docs., U.S. Govt. Print. Off., 1993.

3
AUTHORS

Lisa Simon Onken, Ph.D.

Research Psychologist, Clinical and Experimental Therapeutics Branch

Jack D. Blaine, M.D.

Chief, Clinical and Experimental Therapeutics Branch

John J. Boren, Ph.D.

Chief, Behavioral Pharmacology Branch

National Institute on Drug Abuse

5600 Fishers Lane

Rockville, MD 20857
Enhancing the Effectiveness of

Methadone Using

Psychotherapeutic Interventions

Charles P. O’Brien, George E. Woody, and A. Thomas McLellan

INTRODUCTION

The advent of maintenance treatment afforded the possibility that

psychotherapeutic interventions could be applied to the problems of

opiate addicts. Prior to methadone, heroin addicts showed little interest

in psychotherapy. Attendance at drug-free outpatient programs was (and

is) very irregular, and even the promise of free psychotherapy produced

few takers and little evidence of efficacy (Nyswander et al. 1958). The

availability of methadone in the early 1970s made heroin addicts

available for psychotherapy, but there was controversy as to whether

methadone, either for pharmacological or symbolic reasons, prevented

engagement in psychotherapy (Boume 1975, pp. 1 l-l 2; Karkus 1973).

There was also the perception that most heroin addicts had an antisocial

personality and thus were not amenable to psychotherapy.

There has been great progress in this area over the past two decades.

Much more is known about how to apply psychotherapy and who is

likely to respond. This chapter is a selective summary of some of the

significant studies that have led to this present state of knowledge in this

area. Not all studies are included, but the representative examples

illustrate the difficulties of studies in this population as well as what has

been learned that can be applied by the clinician working in a methadone

program.

CONTINUOUS MEASURES OF PRETREATMENT STATUS AND

OUTCOME

It is obvious that patients are not likely to be “cured” by the addition of

psychotherapy to methadone treatment. Thus, outcome by improvement

must be measured relative to the patient’s status at the beginning of

treatment. To do this, measures of change must be used that are sensitive

and that also take into account the many nondrug variables that impact on

5
the results of treatment. The Addiction Severity Index (ASI) was

developed to assess a wide range of problem areas, and it is now in use

around the world as both a clinical and research tool (McLellan et al.

1980). Using the ASI, differences can be documented among patients in

such areas as medical, psychiatric, employment, family, and legal

problems. These factors are important in themselves, and they

significantly influence the response to any kind of treatment for drug

dependence. Thus, while studies of methadone treatment have the

advantage of urine tests as one objective measure of outcome, even this

unbiased, objective measure of drug use will be affected by the status of

the patient in several nondrug abusers. These nondrug factors are

particularly important in comparing the results of studies involving

different populations. Generally, better educated patients with more

stable family, employment, and social situations have a better prognosis

no matter what type of treatment is used.

Another variable that should be addressed in studies of psychotherapeutic

interventions to enhance the effectiveness of methadone is the dose of

methadone. Many programs use doses that are too low to stabilize the

patient, to reduce drug craving, or to diminish the effects of injected

heroin by cross-tolerance. The survey of 12 methadone programs by Ball

and Ross (1991) showed a wide range across programs in average dose,

and a strong negative correlation with the frequency of opiate-positive

urines. For example, patients receiving less than 39 mg daily had a

3 1 percent probability of heroin use during the 30 days prior to

evaluation; for those receiving 60 to 79 mg the probability was only

6 percent, and only 2 percent of those receiving 80 to 100 mg used heroin

during the prior 30 days. While it is generally accepted that dose

requirements may vary among patients, some treatment programs have

adopted the philosophy that lower doses are preferable. The Ball and

Ross data as well as more than 10 studies in the United States and the

world indicate that this philosophy is associated with higher rates of

supplementation by street heroin. Thus, in order to study the effects of a

psychotherapeutic intervention such as psychotherapy or contingency

contracting among methadone patients, it is first necessary to be certain

that all patients in the study are receiving an adequate dose of methadone.

FAMILY THERAPY

One of the earliest controlled studies of psychotherapy in methadone

patients was conducted at the University of Pennsylvania/Veterans

6
Administration (VA) program in Philadelphia, involving structural family

therapy (Stanton et al. 1982). Structural family therapy was reasonably

well defined, and the therapists were all experienced and supervised by

leaders in the family therapy field. The subjects were heroin addicts in

methadone treatment who were regularly involved with their families of

origin. The patients were randomly assigned to one of four treatment/

control conditions: family therapy with monetary reward to all family

members for clean urines from the index patient; family therapy with no

rewards for clean urine; family meetings to watch a control video (travel

to other cultures) with the same monetary reward for clean urines; and

methadone with individual counseling (standard treatment). The

monetary reward was $5 per clean urine in the mid 1970s which was the

equivalent of about $15 in current dollars. This may have been the

earliest report of a study using monetary rewards for clean urines. The

results indicated a significant effect for the groups randomly assigned to

family therapy whether or not they received monetary rewards. The

order of success at l-year followup was family therapy with reward,

family therapy without reward, family movie with reward, and standard

treatment. The results were evident on measures of use of opiate and

nonopiate drugs, but not on work-school performance or alcohol use.

Although the controlled study of family therapy produced positive

results, the technique lacked practical appeal to the experienced busy

therapists in the program. It was extremely difficult to engage these

families in therapy. It took many personal appeals on the part of the

therapists to get the therapy started. Thus, in practice, family therapy has

been reserved for those patients who have significant family problems

and whose families are willing to enter therapy. Despite this caveat,

family therapy remains a useful option, and it is helpful to have at least

one therapist on the staff who has special training in this area.

INDIVIDUAL PSYCHOTHERAPY

Individual psychotherapy is of interest because of clinical observations

that some drug users begin the use of heroin and other drugs in an effort

to decrease symptoms of a psychiatric disorder. While many studies have

shown that more than 60 percent of patients in methadone treatment have

psychiatric diagnoses in addition to opiate dependence, it is not clear

whether these disorders began before or after the initiation of drug abuse.

These “dual diagnosis” patients could be appropriate candidates for

psychotherapy if it were available. At issue is the funding of methadone

7
programs at a level sufficient to provide for professionally trained

psychotherapists. The largest study that addressed the efficacy of

psychotherapy as compared to counseling by nonprofessional therapists

involved two different kinds of psychotherapy (Woody et al. 1983). The

first type of therapy, cognitive behavioral (CB) therapy, is an active,

directive, time-limited system of psychotherapy that focuses on

uncovering automatic thoughts and assumptions underlying problematic

behavior. Techniques include making lists, homework, role playing, and

other cognitive and behavioral methods. A CB treatment manual for

opiate addiction was developed for the study and eventually was

published as a book (Beck et al. 1993).

The other type of therapy used in the study was supportive-expressive

(SE) therapy. It is analytically oriented and nondirective, and its goals

are to help the patient identify and work through problematic relationship

themes. A manual for this type of therapy also was developed and

published as a book (Luborsky 1984). Drug counseling (DC) also was

operationalized, and a manual was written. The major focus of DC is on

identifying specific practical problems, encouraging cessation of drug

use, and providing external services rather than dealing with intrapsychic

processes. All three types of treatment were administered according to

their respective manuals, and therapists met weekly with a supervisor to

monitor adherence to the specific techniques. Sessions were taped and

rated by independent judges for compliance with the characteristics of

each treatment.

The subjects were 110 methadone patients beginning a new course of

treatment. They were randomly assigned to DC alone or DC plus either

SE or CB. Thus, all patients received DC, but two-thirds received

professional psychotherapy in addition to counseling. The results showed

that patients in all three groups showed improvement across most

outcome measures, but those randomly assigned to psychotherapy

showed more and larger gains than those receiving DC alone (Woody et

al. 1983). The most significant psychotherapy effects were demonstrated

in the patients with significant psychiatric problems in addition to opiate

dependence. Patients with severe psychiatric problems receiving DC

alone showed little or no improvement. In contrast, patients in this

category assigned to either SE or CB showed significant gains in many

areas in addition to less use of heroin and other illegal drugs (Woody et

al. 1984). The dose of methadone functioned as a dependent variable

because patients and their counselors could ask for a raise if the patients

were not doing well. This process resulted in the DC patients getting

8
more dose increases and thus a higher methadone dose than the

professional therapy groups. Ancillary medications such as antidepressants could be prescribed when necessary by psychiatrists not

involved in the psychotherapy. Such prescriptions were needed

significantly less often by patients in the two psychotherapy groups.

There were few significant outcome differences between SE and CB

therapy groups. SE patients showed more improvement in psychological

functioning and employment, while CB patients showed more

improvement with legal problems.

While the above study showed clear benefits for the addition of

psychotherapy to methadone treatment, another large study (n = 72)

failed to show an effect using short-term interpersonal psychotherapy

(IPT) (Rounsaville et al. 1983). There were, however, major differences

in the organization of the two studies. While Woody and colleagues used

psychotherapists as members of the staff who were readily available at

the methadone site, Rounsaville used therapists who were compensated

by the hour as methadone patients kept appointments at their private

offices. Only 5 percent of their eligible patients agreed to participate, and

50 percent of these completed treatment. Woody and colleagues found

that 60 percent of their patients were interested in the study and

60 percent of these became engaged in treatment. It appeared that having

the psychotherapy study central to the clinic was an important factor in

patient engagement and retention.

Subsequently, the authors’ group has completed two additional studies of

psychotherapy in methadone patients. One utilized SE therapy as a

comparison with cue extinction for methadone patients. The rationale for

the extinction procedure is contained in the rich literature demonstrating

both in animals and in humans that opiates and several other drugs of

abuse are capable of producing conditioned reflexes that persist after

cessation of drug taking (O’Brien 1975; O’Brien et al. 1977; Wikler

1973). It was found that conditioned responses can be elicited in opiate

addicts even when they are maintained on methadone (McLellan et al.

1986). When presented with stimuli previously associated with the use of

heroin, many methadone-treated patients report craving for opiates and

exhibit physiological arousal consistent with opiate withdrawal signs. It

is difficult to demonstrate experimentally that this phenomenon actually

provokes drug taking, but based on the strength and prevalence of their

responses, and the clinical reports of patients, it was postulated that

extinguishing or reducing these responses might improve the clinical

outcome of patients in methadone treatment (Childress et al. 1986a,

9
1986b). Stabilized methadone patients were randomly assigned to SE

alone, extinction plus SE, counseling alone, or counseling plus extinction.

As in the original psychotherapy study (Woody et al. 1983), the patients

receiving professional psychotherapy with or without extinction showed

significantly more improvement on the ASI than the group receiving only

extra drug counseling.

A third study of psychotherapy in methadone patients has recently been

completed in two methadone programs in the Philadelphia community

(Woody et al. 1994). An objective of this study was to determine

whether the effectiveness of psychotherapy with patients showing

psychiatric symptoms could be demonstrated in community methadone

programs not as richly staffed as the University of Pennsylvania/VA

program. The design of this study also was more balanced than in the

original study. Newly admitted methadone maintenance patients were

randomly assigned to standard drug counseling plus either SE or an

additional counselor so that all patients received equivalent attention from

a helping person. The findings are in the process of being published

elsewhere, so details will not be included. It can be reported, however,

that the setting was less organized than in the University of

Pennsylvania/VA setting and less conducive to a study of psychotherapy.

About 40 percent of urine tests were positive for opiates, but there was

inconsistent feedback about positive urines to patients since the basic

treatment required only one urine test per month. Study patients had’

weekly urine tests, but the results were not available to clinic staff. In

this setting, the patients randomly assigned to SE treatment still showed

significantly greater improvement than those assigned to the counseling

control group in the areas of drug use, employment, and psychiatric

symptoms. There was a trend toward lower methadone doses in the

psychotherapy group. The magnitude of the positive changes was

approximately as great as those seen in studies conducted in the authors’

clinic; however, the major advantages for the psychotherapy group were

not achieved until the 12-month followup point (6 months after the end of

the therapy). These findings are interpreted as showing a positive though

transient effect of adding the second counselor to the control group. The

improvements produced by the professional psychotherapy were more

lasting, and thus there were greater differences between psychotherapy

and control groups at 12 months than at 6 months.

10
CONTINGENCY CONTRACTING

The treatment of drug dependence has a distinct advantage over treatment

in most other areas because an objective measure of progress is

available-the urine test. While there are limits to the information gained

from urine testing by itself, it does provide accurate evidence of recent

drug use. Urine testing is quite practical in methadone programs because

patients come to the clinic regularly and urines, monitored by direct

observation or by temperature checks, can be collected. Most methadone

programs have had rules requiring negative urine tests for abused drugs

as a contingency for receiving take-home doses of methadone since the

programs began in the late 1960s and early 1970s. Unfortunately, the

consequences of the positive urine tests are generally distant in time from

the behavior and often not consistently applied. In order to save money,

methadone programs are obtaining fewer urine tests (eight per year

required) and not incorporating the results into the counseling sessions.

A number of studies have experimentally examined the effects of

contingent reinforcement of clean urines. Rapid monetary reinforcement

of clean urines was applied in the mid 1970s for the family therapy study

discussed above (Stanton et al. 1982), but no significant effects of the

payments to family members and to index patients were observed. More

recently there have been a series of controlled studies using contingency

contracting based on urine test results that have resulted in at least

temporary behavior change. Stitzer and colleagues (1992) used takehome privileges for methadone patients as the reinforcement for 2

consecutive weeks of drug-free urines. The contingent procedure

produced more individuals with at least 4 consecutive weeks of

abstinence (32 percent versus 8 percent) than the control group that

received take-home doses independent of urine tests. When

nonresponders in the noncontingent group were switched to the

contingency, 28 percent achieved abstinence. The best predictor of

success in this procedure was low baseline levels of drug use. Other

researchers have reported similar results using take-home doses of

reinforcers for abstinence (Milby et al. 1978). These studies strongly

support the clinical practice of rewarding patients with take-home doses

when they produce clean urines. The 2-week period used in the study

allows more flexibility and is likely to be more effective than the 3-month

waiting period for take-home doses required by most programs.

Supplementation of methadone dose by nonopiate drugs such as cocaine

and benzodiazepines also has been addressed by contingency contracting.

11
Contingent take-home doses of methadone have been used successfully to

reduce benzodiazepine supplementation (Iguchi et al. 1988; Stitzer et al.

1982). Temporary abstinence from benzodiazepines was observed in

about 50 percent of the patients during the 12- to 20-week contingent

take-home period. In the recent study by Stitzer and colleagues (1992)

noted above, unprescribed use of benzodiazepines and cocaine responded

equally to the contingency condition. Magura and colleagues (1988),

using take-home doses as the reinforcer, found no overall differences

between the percentage of positive urines between the contingency and

precontingency periods and between the contingency and

postcontingency periods. This group concluded that contracting had a

favorable, though transient effect, only on noncocaine-abusing

methadone patients.

The problem of cocaine abuse among methadone patients was the focus

of a recent study by Silverman and colleagues (1994) using vouchers

exchangeable for retail items as a reinforcer. This is the contracting

system developed by Higgins and colleagues (1991) to achieve

abstinence in primary cocaine addicts. Silverman provided vouchers to 19

methadone patients contingent on cocaine-negative tests. A matched

control group was yoked to the contingent group and thus received the

same number of vouchers, but not contingent on their behavior. Cocaine

use was substantially reduced in the contingent group, but not in the

control group over an 8-week period. Although the reinforcement of

using vouchers for clean urines is more appealing than reinforcement

with cash, there remain substantial practical obstacles to the general

employment of this technique for publicly funded methadone programs.

Dose of methadone also has been used as a reinforcer. For example,

Stitzer and colleagues (1986) reported that polydrug supplementation

could be reduced when methadone dose was increased as a reward for

drug-free urines and when methadone dose was decreased as a

consequence of drug-positive urines. During a study of ambulatory

methadone detoxification, Higgins and colleagues (1986) gave patients

the option to increase their methadone dose by up to 20 mg contingent

upon opiate-free urines. Another group had the option to similarly

increase their dose on a noncontingent basis. Only the contingent group

showed suppression of opiate use outside of the methadone program.

There are practical problems in using methadone dose increases as a

reward and decreases as a form of punishment. First, it seems at odds

with the concept that patients on methadone should receive an adequate

12
dose to produce physiological stability, to reduce or eliminate craving for

opiates, and to produce cross-tolerance to street opiates such that their

effects are drastically diminished. This concept is supported by the Ball

and Ross (1991) data showing the inverse relationship between dose and

frequency of urines positive for opiates. According to these data, patients

with positive urines whose doses are in the lower range should be

increased to the 60 to 100 mg range to see if the higher dose eliminates

the problem. Using extra methadone as a reward for clean urines would

seem to reinforce the use of methadone as a euphorigenic substance and

thus highlight its potential for abuse. Punishing dirty urines by dose

reductions might make the problem worse if the patient actually “needed”

a higher dose.

There also are ethical issues involved, as discussed by Nolimal and

Crowley (1990). While these investigators noticed improvement during

the first month of a contract involving dose reductions for positive urines,

the effect faded in the second and third months. Of their 14 patients, 5

continued abuse and were terminated from methadone treatment.

Termination from treatment also was a consequence of other studies

using dose reduction as a contingency (Dolan et al. 1985; Saxon et al.

1993). This outcome is especially problematic in view of the

accumulating evidence that even suboptimal methadone treatment is

associated with protection from HIV infection (Metzger et al. 1993) and

probably from other infections. Thus, forced termination from

methadone for patients who are not disruptive to the program, but whose

only infraction is some degree of continued opiate use, is ethically

debatable.

Contingency contracting also has been used to address another common

problem among patients in methadone treatment, that of alcohol abuse

and alcoholism. Liebson and colleagues (1978) used methadone as a

reinforcer to obtain disulfiram ingestion by severely alcoholic methadone

patients. Of course, disulfiram blocks the metabolism of alcohol resulting

in acetaldehyde production and a very unpleasant reaction when any

alcohol is ingested. The protocol worked so well for Liebson and

colleagues that it was used as the prototype for a large multiclinic trial of

the treatment of alcoholic methadone patients (Ling et al. 1983). In the

large sample, there were no differences between those randomly assigned

to disulfiram or placebo. It appeared that focusing on the drinking

behavior with breathalyzer tests and a contingency contract was enough

to suppress drinking behavior in most of the methadone patients whether

or not they actually received active disulfiram. Of course, use of the

13
breathalyzer alone has the advantage of not exposing the patient to the

potential side effects of disulfiram ingestion.

DO COUNSELING AND PSYCHOTHERAPY ADD ANYTHING

TO METHADONE?

The funding of public methadone programs naturally is limited, and there

is always pressure to treat more patients for less money. Counseling and

psychotherapy are relatively expensive components of methadone

programs; thus it is reasonable to ask whether they are necessary. A

study that directly addresses these questions was conducted in

Philadelphia (McLellan et al. 1993), where patients in methadone

treatment on a minimum of 60 mg were randomly assigned to one of

three treatment conditions. The minimal contact group received

methadone alone with no required counseling. Specific requests for

information, referral, or dose change were dealt with as needed. The

group randomized to standard treatment met weekly with their counselors

and more often as needed. The group assigned to enhanced treatment

had, in addition to sessions with their counselors, access to psychiatric

treatment, as well as employment and family therapy sessions. In reality,

few of the minimal contact patients could be given as little treatment as

the protocol proposed. Sixty-nine percent of the minimal contact patients

had to be “rescued” from the study because of eight consecutive positive

urines. This “safety net” was included in the protocol for ethical reasons

since the patients randomized to minimal contact were receiving less than

standard care. On virtually all outcome measures including drug use,

psychological status, family problems, and other factors on the ASI, there

was a dose-response relationship between amount of psychosocial and

ancillary services and improvement. Since there was no nontreatment,

the study could not address how much benefit there was in methadone

alone as compared to the use of heroin on the street. It did demonstrate

clearly, however, that the benefits of methadone were much greater for

the patients receiving standard weekly counseling sessions and

significantly greater still for patients randomized to the enhanced therapy

condition.

SUMMARY

There is consistent evidence that the efficacy of methadone can be

enhanced by psychotherapeutic interventions. For individual

14
psychotherapy, the increased efficacy is most demonstrable among

methadone patients also suffering from psychiatric disorders. Patients

with severe psychiatric problems generally show little response to drug

counseling alone. There is no evidence of a consistent advantage of one

type of psychotherapy over another. Contingency contracting using takehome doses of methadone to reinforce drug-free urines has been shown to

be effective, at least over the short term. Rewarding clean urines by

vouchers exchangeable for retail items is supported by a growing

experimental database, although practical issues remain for publicly

funded methadone programs. The use of methadone dose as a reinforcer

has shown some efficacy, but there are both ethical and conceptual

problems. Finally, while there are likely to be some benefits from simply

administering methadone alone in the most economical way, the available

evidence clearly shows that a relatively minor investment in counseling,

individual psychotherapy, or contingency contracting can result in major

improvements in the results of this medication.

REFERENCES

Ball, J.C., and Ross, A. The Effectiveness of Methadone Maintenance

Treatment. New York: Springer-Verlag, 1991.

Beck, A.T.; Wright, F.D.; Newman, C.F.; and Liese, B.S. Cognitive

Therapy of Substance Abuse. New York: Guilford Press, 1993.

Boume, P.G. Methadone: Benefits and Shortcomings. Washington, DC:

Drug Abuse Council, Inc., 1975.

Childress, A.R.; McLellan, A.T.; and O’Brien, C.P. Abstinent opiate

abusers exhibit conditioned craving, conditioned withdrawal and

reductions in both through extinction. Brit J Addict 81:655-660,

1986b.

Childress, A.R.; McLellan, A.T.; and O’Brien, C.P. Conditioned

responses in a methadone population: A comparison of laboratory,

clinic and natural setting. J Subst Abuse Treat 3:173-179, 1986a.

Dolan, M.P.; Black, J.L.; Penk, W.E.; Robinowitz, R.; and DeFord, H.A.

Contracting for treatment termination to reduce illicit drug use among

methadone maintenance treatment failures. J Consult Clin Psychol

53(4):549-551, 1985.

Higgins, S.T.; Delaney, D.D.; Budney, A.J.; Bickel, W.K.; Hughes, J.R.;

Foerg, F.; and Fenwick, J.W. A behavioral approach to achieving

initial cocaine abstinence. Am J Psychiatry 148(9):1218-1224, 1991.

15
Higgins, S.T.; Stitzer, M.L.; Bigelow, G.E.; and Liebson, I.A. Contingent

methadone delivery: Effects on illicit opiate use. Drug Alcohol

Depend 17(4):311-322, 1986.

Iguchi, M.Y.; Stitzer, M.L.; Bigelow, G.E.; and Liebson, I.A.

Contingency management in methadone maintenance: Effects of

reinforcing and aversive consequences on illicit polydrug use. Drug

Alcohol Depend 22:1-7, 1988.

Karkus, H.D. Methadone vs. psychotherapy in the treatment of addiction.

Int J Addict 8:427-434, 1973.

Liebson, I.A.; Tommasello, A.; and Bigelow, G.E. A behavioral

treatment of alcoholic methadone patients. Ann Intern Med 89(3):342-

344, 1978.

Ling, E.; Weiss, D.G.; Charuvastra, C.V.; and O’Brien, C.P. The use of

disultiram for alcoholics on methadone maintenance. Arch Gen

Psychiatry 40:851-854, 1983.

Luborsky, L. Principles of Psychoanalytic Psychotherapy: A Manual for

Supportive-Expressive (SE) Treatment. New York: Basic Books, 1984.

Magura, S.; Casriel, C.; Goldsmith, D.S.; Strug, D.L.; and Lipton, D.S.

Contingency contracting with polydrug-abusing methadone patients.

Addict Behav 13(1):113-118, 1988.

McLellan, A.T.; Amdt, 1.0.; Metzger, D.S.; Woody, G.E.; and O’Brien,

C.P. The effects of psychosocial services in substance abuse treatment.

JAMA 269(15):1953-1959, 1993.

McLellan, A.T.; Childress, A.R.; Ehrman, R.; and O’Brien, C.P.

Extinguishing conditioned responses during opiate dependence

treatment turning laboratory findings into clinical procedures. J Subst

Abuse Treat 3:33-40, 1986.

McLellan, A.T.; Luborsky, L.; O’Brien, C.P.; and Woody, G.E.

Improved diagnostic instrument for substance abuse patients: The

Addiction Severity Index. J Nerv Ment Dis 168:26-33, 1980.

Metzger, D.S.; Woody, G.E.; McLellan, A.T.; O’Brien, C.P.; Druley, P.;

Navaline, H.; DePhilippis, D.; Stolley, P.; and Abrutyun: E. Human

immunodeficiency virus seroconversion among intravenous drug users

in and out of treatment: an 18 month prospective follow-up. J Acquir

Immune Defic Syndr 6:1049-1056, 1993.

Milby, J.B.; Garrett, C.; English, C.; Fritschi, 0.; and Clarke, C. Takehome methadone: Contingency effects on drug-seeking and

productivity of narcotic addicts. Addict Behav 3(3-4):215-220, 1978.

Nolimal, D., and Crowley, T.J. Difficulties in a clinical application of

methadone-dose contingency contracting. J Subst Abuse Treat

7(4):219-224, 1990.

16
Nyswander, M.; Winick, C.; Bernstein, A.; Brill, L.; and Kaufer, G. The

treatment of drug addicts as voluntary outpatients: A progress report.

Am J Orthopsychiatry 28:714-729, 1958.

O’Brien, C.P. Experimental analysis of conditioning factors in human

narcotic addition. Pharmacol Rev 27:535-543, 1975.

O’Brien, C.P.; Testa, T.; O’Brien, T.J.; Brady, J.P.; and Wells, B.

Conditioned narcotic withdrawal in humans. Science 195:1000-1002,

1977.

Rounsaville, B.J.; Glazer, W.; Silber, C.H.; Weissman, M.M.; and

Kleber, H.D. Short-term interpersonal psychotherapy in methadonemaintained opiate addicts. Arch Gen Psychiatry 40:629-636, 1983.

Saxon, A.J.; Calsyn, D.A.; Kivlahan, D.R.; and Roszell, D.K. Outcome

of contingency contracting for illicit drug use in a methadone

maintenance program. Alcohol Drug Depend 31(3):205-214, 1993.

Silverman, K.; Schuster, C.R.; Brooner, R.K.; Montoya, I.D.; and

Preston, K.L. ‘Contingency Management of Cocaine Use in a

Methadone Maintenance Program.” Paper presented at the annual

meeting of the College on Problems of Drug Dependence, Palm

Beach, June 21, 1994.

Stanton, M.D.; Todd, T.C.; Steier, F.; Van Dusen, J.M.; and Cook, L. The

Family Therapy of Drug Abuse and Addiction. New York: Guilford

Press, 1982.

Stitzer, M.L.; Bickel, W.K.; Bigelow, G.E.; and Liebson, I.A. Effect of

methadone dose contingencies on urinalysis test results of polydrugabusing methadone-maintenance patients. Alcohol Drug Depend

18(4):341-348, 1986.

Stitzer, M.L.; Bigelow, G.E.; Liebson, I.A.; and Hawthorne, J.W.

Contingent reinforcement for benzodiazepine-free urines: Evaluation

of a drug abuse treatment intervention. J App Behav Anal 15(4):494-

503, 1982.

Stitzer, M.L.; Iguchi, M.Y.; and Felch, L.J. Contingent take-home

incentive: Effects on drug use of methadone maintenance patients.

J Consult Clin Psychol 60(6):927-934, 1992.

Wikler, A. Dynamics of drug dependence: Implications of a conditioning

theory for research and treatment. Arch Gen Psychiatry 28:611-616,

1973.

Woody, G.E.; Luborsky, L.; McLellan, A.T.; O’Brien, C.P.; Beck, A.T.;

Blaine, J.; Herman, I.; and Hole, A. Psychotherapy for opiate addicts:

Does it help? Arch Gen Psychiatry 40:639-645, 1983.

17
Woody, G.E.; McLellan, A.T.; Luborsky, L.; and O’Brien, C.P.

“Psychotherapy in Community-Based Methadone Programs: A

Follow-Up Study.” Paper presented at annual meeting of North

American Society for Psychotherapy Research, Santa Fe, NM,

February 6, 1994.

Woody, G.E.; McLellan, A.T.; Luborsky, L.; O’Brien, C.P.; Blaine, J.;

Fox, S.; Herman, I.; and Beck, A.T. Severity of psychiatric symptoms

as a predictor of benefits from psychotherapy: The Veterans

Administration-Penn study. Am J Psychiatry 141(10):1172-1177,

1984.

ACKNOWLEDGMENTS

This review was prepared with support from National Institute on Drug

Abuse grants DA 006178, DA 003008, and from the DVA Medical

Research Service.

AUTHORS

Charles P. O’Brien, M.D., Ph.D.

Professor of Psychiatry

George E. Woody, M.D.

Clinical Professor of Psychiatry

A. Thomas McLellan, Ph.D.

Adjunct Professor of Psychology in Psychiatry

Treatment Research Center

University of Pennsylvania

3900 Chestnut Street

Philadelphia, PA 19104-6178

Philadelphia Veterans Affairs Medical Center

38th and Woodland Avenues

Philadelphia, PA 19 104

18
Integrating Psychotherapy and

Pharmacotherapy for Cocaine

Dependence: Results From a

Randomized Clinical Trial

Kathleen M. Carroll, Bruce J. Rounsaville, Charla Nich,

Lynn Gordon, and Frank Gawin

To date, research on treatment for cocaine dependence has focused on

either psychosocial or pharmacotherapeutic approaches, and neither the

relative effectiveness of both forms of treatment nor the potential benefits

of combined treatments have been the focus of a single trial. For

example, pharmacological trials have tended to evaluate the efficacy of

medications against a background of psychosocial treatments that are

intended to enhance treatment retention and medication compliance.

However, because the effectiveness of nonpharmacologic aspects of

treatments is not of primary interest in such studies, psychosocial

components of treatment are rarely specified or implemented according to

current standards of psychotherapy research. That is, little attention

usually is given to treatment manuals, training and selection of

appropriate therapists, monitoring therapists’ delivery of treatment, or

patient compliance with psychosocial aspects of treatment.

Lack of specification of nonpharmacologic aspects of treatment in

pharmacotherapy trials with cocaine abusers has several implications.

First, the role or effectiveness of psychosocial treatments in enhancing

treatment retention, medication compliance, or reduction of drug use

cannot be examined in such studies. Second, because variations in the

“psychosocial ground” against which pharmacologic agents are evaluated

may result in variations in their effectiveness (Klerman 1975, pp. 67-81)

across different studies, lack of specification of psychosocial treatments

in pharmacologic trials for cocaine dependence may impede meaningful

comparison of medication effects across studies (Carroll 1993).

Variations in level and type of psychosocial treatments, as well as sample

characteristics, may underlie much of the variation seen in drug effects

across studies (Levin and Lehman 1991). Third, the specification of

psychosocial treatments, which requires training of appropriate therapists

and monitoring their delivery of treatment, may enhance their

effectiveness (Rounsaville et al. 1988). Thus, studies that have not done

19
so may underestimate the potential effectiveness of psychosocial

treatments for cocaine dependence.

Similarly, studies of psychotherapeutic treatments for cocaine abusers

that have not utilized standard methods of psychotherapy research have

both failed to show psychotherapy effects and have produced findings

that are difficult to interpret (e.g., Kang et al. 1991). On the other hand,

studies that have used these features have suggested the efficacy of

behavioral over standard treatment (Higgins et al. 1993) and the specific

efficacy of cognitive behavioral treatment for high-severity cocaine users

(Carroll et al. 1991 a). Furthermore, no studies have evaluated how

psychotherapy outcomes might be enhanced by effects of specific

pharmacologic agents or even by placebo effects. For example, cocaine

abusers’ expectations for pharmacologic effects may enhance retention in

the early stages of psychotherapy, where attrition may be high or the

therapeutic relationship is still fragile.

STATE-TRAIT DISTINCTIONS

The variations in severity of cocaine abusers who present for treatment,

the multidimensionality of cocaine abusers’ problems, and the

heterogeneity of cocaine abusers presenting for treatment suggest the

potential value of evaluating and combining psychotherapy and

pharmacotherapy. For example, Extein and Bowers (1979) differentiate

between state disorders, described as time-limited, autonomous, and

unresponsive to psychotherapeutic intervention (such as acute psychosis

or delirium), and trait disorders, defined as “dysfunctional qualities which

individuals tend to develop and carry throughout life and which become

manifest as predictable patterns for interaction and response to stress”

(Extein and Bowers 1979, pp. 690-691), such as personality disorders.

Cocaine dependence (and other forms of substance dependence) can be

conceived as having attributes of both state and trait disorders, in varying

degrees among different abusers. Pharmacotherapy or other forms of

medical intervention are generally essential when “state” aspects are

present (such as withdrawal symptoms associated with physical

dependence, co-morbid Axis I disorders, or cocaine-induced organic

mental disorders), as these would not be expected to respond to

psychotherapy. Similarly, psychotherapy may be indicated for “trait”

aspects of cocaine dependence upon which pharmacotherapy would be

expected to have little impact (e.g., fostering motivation to reduce

20
substance use, restricting availability of cocaine, avoidance of situations

associated with use, development of noncocaine-using social supports).

With a state/trait model of substance use disorders, the unique action of

each particular approach can be investigated toward developing a more

comprehensive model of treatment that recognizes the importance of

heterogeneity among cocaine abusers. At lower severity levels and in the

absence of state disorders, psychotherapy alone may be adequate. At

higher levels of severity, the presence of state disorders may indicate the

need for a combination of psychotherapy and pharmacotherapy, although

in some cases the state disorder may be so dominant that it may be futile

to initiate psychotherapy until the patient is stabilized and becomes

available for psychotherapy (Carroll 1993).

ADVANTAGES OF COMBINING PSYCHOTHERAPY AND

PHARMACOTHERAPY

There are several potential advantages of combining psychotherapy and

pharmacotherapy for cocaine dependence. First, if psychotherapy is

conceived and implemented in an active rather than a supportive role

(that is, administered at full strength), it is more likely that maximal

effects of psychotherapy will emerge and be detected. Psychotherapy and

pharmacotherapy are assumed to work through different mechanisms

(e.g., desipramine to reverse cocaine-induced neuroadaptation and

psychotherapies such as relapse prevention skills training to improve an

abuser’s ability to cope with or avoid high-risk situations and relapse) and

to affect different symptom areas. Thus, a major potential advantage of

psychotherapy-pharmacotherapy combinations in which the integrity of

each treatment is protected is that integrative treatments may improve

outcome for more symptom areas than either treatment alone. Assuming

psychotherapy and pharmacotherapy affect different symptom areas, by

increasing the number of symptom areas potentially improved through

combination treatments, one may dramatically improve the “hit rate”

among cocaine abusers, who typically present with heterogeneity of

symptoms and problems. Such a model also allows for detection of

treatment specificity and so would guide future efforts toward

patient-treatment matching.

Another advantage of evaluating combination treatments is that potential

drawbacks associated with either treatment may be offset by the other.

For example, the provision of support through psychotherapy may reduce

21
the potential negative impact of side effects arising from most pharmacotherapies. Similarly, instillation of hope through administration of a

drug may support continuing participation in treatment during the early

stages of treatment where a developing therapeutic alliance may be fragile

or until coping skills are mastered and integrated (Carroll 1993).

In this chapter, data will be presented from a recently completed clinical

trial that evaluated psychotherapy and pharmacotherapy, alone and in

combination, as treatment for ambulatory cocaine abusers (Carroll et al.

1994a). In contrast to previous treatment efficacy studies with

ambulatory cocaine abusers, the authors sought to give both psychotherapy and pharmacotherapy a “fair trial,” that is, to: (1) protect the

integrity of both forms of treatment through specification of delivery of

psychotherapy and pharmacotherapy in manuals, (2) recruit and train

therapists who were experienced in and committed to the type of

treatment they performed in the trial, (3) closely monitor delivery of both

forms of treatment throughout the trial (e.g., through plasma levels for

medication and process assessment of session videotapes for psychotherapy), (4) allow adequate duration of treatment for emergence of

effects of both psychotherapy and pharmacotherapy, (5) include

assessments intended to tap specific effects of both forms of treatment,

(6) select appropriate control conditions for both forms of treatment, and

(7) use independent clinical evaluators who were blind to both forms of

treatment to make ratings of primary outcomes.

METHODS

Subjects

Subjects were recruited from individuals seeking treatment at the

Substance Abuse Treatment Unit of the Connecticut Mental Health

Center in New Haven, CT, and from respondents to newspaper

advertisements or public service announcements. Subjects were included

who met current Diagnostic and Statistical Manual-III-R (DSM-III-R)

criteria for cocaine dependence and who had used at least 12 g of cocaine

during the past 3 months. Individuals were excluded who (1) were

currently physically dependent on opiates, barbiturates, or alcohol, or

whose principal drug of dependence was not cocaine; (2) met current

DSM-III-R criteria for an Axis I disorder other than depressive or anxiety

disorders, met lifetime criteria for schizophrenia or mania, or expressed

significant current suicidal or homicidal ideation; (3) had a current

22
medical condition that would contraindicate ambulatory tricyclic

antidepressant therapy; (4) had been treated for substance use during the

previous 2 months or who were currently involved in psychotherapy or

pharmacotherapy for any other psychiatric disorder; or (5) had conditions

of probation or parole requiring reports of drug use to officers of the

court.

Therapists

Therapists were 11 doctoral-level therapists (7 psychiatrists and 4

psychologists) who saw an average of 11 patients (range 1 to 23).

Therapists selected were experienced in and committed to the type of

treatment they conducted in the trial. All therapists received extensive

training, which included successful completion of at least one closely

supervised training case. To assure adherence to manual guidelines and

to prevent drift through the main phase of the study, therapists in each

condition met weekly with study investigators to discuss case material

and review session videotapes.

Treatments

Each of the study treatments was manual-guided and delivered to patients

in weekly individual sessions offered over 12 weeks. All training and

main phase sessions were videotaped for supervision and process

assessment. Evaluation of session videotapes by raters blind to treatment

condition using an adaptation of the Collaborative Study Psychotherapy

Rating Scale (Hill et al. 1992) showed the treatments were discriminable

(Carroll et al. 1994b).

Desipramine. Subjects received an average of 200 mg/day of

desipramine (or four placebo pills) to a maximum dose of 300 mg/day.

Initial target plasma level ranges were 140 to 200 ng/mL. Dosage

adjustments were made by nonblind study psychiatrists in response to

serum blood levels and reported side effects, and these were yoked to

dose changes for subjects receiving placebo to maintain a medication

double blind.

Cognitive Behavioral Coping Skills Training. The cognitive

behavioral treatment was based on Marlatt’s Relapse Prevention (Marlatt

and Gordon 1985) and adapted for use with cocaine users (Carroll et al.

1991 b). The goal of this treatment was abstinence from cocaine and

other substances though identification of high-risk situations for relapse

23
and the implementation of effective coping strategies, which included

fostering resolution to stop cocaine use through exploring positive and

negative consequences of continued use, self-monitoring to identify highrisk situations for relapse, and the development of strategies for coping

with and avoiding cocaine craving and high-risk situations.

Clinical Management. Clinical management was adapted from the

guidelines developed for the National Institute of Mental Health (NIMH)

Collaborative Study on the Treatment of Depression by Fawcett and

colleagues (1987). The provision of clinical management was intended to

provide (1) nonspecific elements of a psychotherapeutic relationship,

including a supportive doctor-patient relationship, education, empathy,

and the instillation of hope, without providing active ingredients specific

to relapse prevention treatment, (2) medication management and

opportunity to monitor patients’ clinical status, and (3) a convincing

therapeutic rationale, greater retention in the protocol, and compliance

with medication.

Outcome Assessment

Patients were assessed before treatment, weekly during treatment, at

posttreatment, and at followup interviews conducted 1, 3, 6, and 12

months after termination by an independent clinical evaluator who was

blind to both the psychotherapy and pharmacotherapy condition. From

the perspective of the blind clinical evaluators, procedures intended to

protect the psychotherapy blind were only modestly effective but

comparable to standard procedures used to maintain pharmacotherapy

blinds (Carroll et al. 1994b).

Primary outcome measures were reduction in frequency of cocaine use

(percentage of days the subject reported using cocaine while in treatment)

and duration of longest period of consecutive abstinence. Patient

self-reports were verified through urine toxicology screens, which were

obtained at every visit. Of 622 urinalyses conducted, 7 1 percent were

consistent with patient self-report, 15 percent were negative for cocaine

although the patient reported recent cocaine use, and 14 percent were

positive for cocaine in cases where the patient had denied use. In cases of

discrepancy between self-report and toxicology reports, the source of data

that indicated cocaine use was used in outcome analyses.

Secondary Outcomes. The Addiction Severity Index (ASI) (McLellan

et al. 1980) was administered monthly during treatment to assess

24
multidimensional aspects of outcome and general functioning. The drug

abuse section of the ASI was supplemented in order to calculate separate

composite scores for cocaine versus other drugs, resulting in eight, rather

than seven, outcome domains.

RESULTS

Sample Description

There were 139 patients determined to be eligible and randomized to

treatment; of these, 121 (87 percent) began treatment and 110

(80 percent) completed two sessions or more. Of the 110 who were

exposed to two or more sessions and took medication at least one week,

30 (27 percent) were women, 59 (54 percent) were minority, 78

(7 1 percent) were single or divorced, and 58 (52 percent) were working

full- or part-time. Thirty-eight (34 percent) had some college education,

46 (42 percent) were high-school graduates, and 26 (24 percent) did not

complete high school. The mean age of the sample was 28.8 years

(SD 5.8). Subjects reported using an average of 4.4 g of cocaine per

week (SD 3.3) for an average of 4.2 years. Sixty-eight (62 percent)

reported predominantly freebase use of cocaine, 32 (29 percent) were

intranasal users, and 10 (9 percent) were intravenous users. Thirty-three

(30 percent) had some previous exposure to treatment. Forty-eight

percent met DSM-III-R criteria for a lifetime diagnosis of alcohol

dependence, 20 percent for a lifetime affective disorder, 13 percent for a

lifetime anxiety disorder, 49 percent for antisocial personality disorder,

and 65 percent for any other personality disorder. Analyses of variance

and chi-square tests revealed there were no statistically significant

differences by treatment group for any of these baseline variables.

Attrition

For subjects who initiated treatment (N = 121), the mean number of

sessions completed was 7.2 (SD 3.6), and 49 subjects (40 percent)

completed treatment (remained in treatment 12 weeks or completed

12 sessions). There were 4 subjects removed from the protocol due to

clinical deterioration, 3 because of failure to comply with medication, 3

because of medication side effects (of these 10, 3 were in clinical

management/desipramine, 4 in relapse prevention/desipramine, 2 in

clinical management/placebo, and 1 in relapse prevention/placebo).

There was one subject who became pregnant during treatment, one

25
subject who initiated AZT treatment, and four subjects who moved from

the area. The remainder of early terminators were due to dropouts

(N = 56).

The relapse prevention/desipramine group had the highest rate of subjects

completing the full 12 weeks of treatment (49 percent), followed by

comparable and lower rates in the clinical management/placebo, clinical

management/desipramine, and relapse prevention/placebo groups

(39 percent, 37 percent, and 36 percent, respectively, NS). By

psychotherapy and medication type, subjects receiving relapse prevention

were more likely to complete treatment than subjects receiving clinical

management (57 percent versus 43 percent, NS), as were subjects who

received desipramine as opposed to placebo (53 percent versus 47

percent, NS), although these differences were not statistically significant.

Outcome Analyses

Paired t-tests indicated that significant improvement occurred from preto posttreatment for all treatment groups. Significant effects for time

were found across all treatment groups in frequency and quantity of

cocaine use per week (p < 0.001), and for four of eight ASI domains

(cocaine, alcohol, family/social, and psychological). As shown in table 1,

no pre- to posttreatment changes were seen for medical, legal, and

noncocaine drug use ASI composite scores, as pretreatment scores in each

of these areas indicated low severity and were, therefore, unlikely to

improve during treatment.

Table 1 presents means, standard deviations, and results of ANOVAs for

primary (cocaine use) and secondary (ASI composite scores) outcome

measures for the 110 subjects who completed at least two treatment

sessions. There were no significant main effects for either psychotherapy

or medication type, nor were there significant interactions between

psychotherapy and medication.

To facilitate comparison with the authors’ previous studies of

desipramine with ambulatory cocaine abusers (Gawin et al. 1989), which

reported significant decreases in cocaine use over 6 rather than 12 weeks

of treatment as in the current study, the authors conducted repeated

measures MANOVAs evaluating frequency and quantity of cocaine use

per week during the first 6 weeks of treatment. There were significant

26
TABLE 1. Treatment outcome: Cocaine use during treatment and

pretreatment/ endpoint ASI composite scores by treatment

group-Results of analysis of variance (N = 110).

Cocaine use during treatment

Longest consecutive

days of abstinence’

Percent abstinent

days4

Percent cocainepositive urines

ASI Composite

Scores5, mean ±SD

Medical

Pretreatment

Endpoint

Employment

Pretreatment

Endpoint

Alcohol

Pretreatment

Endpoint

Cocaine’

Pretreatment

Endpoint

Other drug

Pretreatment

Endpoint

24.41±24.1 20.5±17.2 20.6±18.8 18.0±16.0 0.67

0.79±0.17 0.75±0.20 0.73±0.22 0.71±0.19 0.57

0.33 0.33 0.27 0.39 0.18

0.17±0.28 0.19±0.25 0.11±0.19 0.16±0.27

0.17±0.23 0.17±0.29 0.11±0.16 0.11±0.23 0.62

0.45±0.36 0.45±0.34 0.53±0.29 0.43±0.33

0.51±0.37 0.41±0.30 0.59±0.26 0.38±0.30 0.06

0.11±0.14 0.14±0.19 0.08±0.09 0.12±0.15

0.06±0.09 0.08±0.17 0.06±0.06 0.10±0.11 0.56**6

0.70±0.18 0.69±0.17 0.71±0.18 0.61±0.16

0.36±0.25 0.43±0.23 0.41±0.24 0.44±0.21 0.56**

0.02±0.03 0.04±0.04 0.02±0.03 0.02±0.02

0.01±0.02 0.03±0.04 0.02±0.03 0.02±0.02 0.07

27
TABLE 1. Treatment outcome: Cocaine use during treatment and

pretreatment/ endpoint ASI composite scores by treatment

group—Results of analysis of variance (N = 110)

(continued).

CM/DMI

N = 25

Treatment Group1

RP/DMI CM/PLA RP/PLA SIG2

N = 29 N = 27 N = 29 of

interaction

Legal

Pretreatment

Endpoint

0.04±0.08 0.09±0.16 0.08±0.14 0.09±0.14

0.09±0.17 0.06±0.12 0.05±0.13 0.06±0.11 0.68

Family/social

Pretreatment

Endpoint

0.28±0.18 0.29±0.20 0.29±0.23 0.24±0.19

0.16±0.17 0.27±0.23 0.20±0.21 0.15±0.15 0.12**

Psychological

Pretreatment

Endpoint

0.19±0.16 0.27±0.23 0.20±0.22 0.16±0.16

0.06±0.12 0.15±0.20 0.13±0.21 0.10±0.15 0.26**

1CM = clinical management; DMI = desipramine; RP = relapse

revention; PLA = placebo.

2Results of 2x2 ANOVA, significance of F value. For primary outcome

variables (consecutive days of abstinence during treatment, percent days

abstinent, percent urines positive for cocaine) unadjusted group mean

scores are presented. For ASI subscale composite scores, pretreatment

scores reflect unadjusted means. Posttreatment scores reflect endpoint

ratings for patients who were early terminators.

3

Indicates duration of longest period of consecutive abstinence during

treatment: Range 0 to 90.

4

Indicates days of cocaine use as a percentage of total days in treatment.

5Range is 0 to 1; higher scores indicate higher problem severity.

“**Indicates significant (p < 0.01) effect for time by paired t-test.

7

Indicates calculation of separate composite scores for cocaine versus

other drug use.

desipramine effects (F = 3.77, p c 0.05) for grams of cocaine used per

week, suggesting significant reduction in cocaine use for subjects treated

with desipramine over placebo between treatment weeks 2 and 6. This

28
effect, however, was not significant beyond 6 weeks, which may be

consistent with suggestions that desipramine treatment beyond 6 weeks

counter-therapeutically cues relapse due to late onset cocaine-like

stimulatory effects (Weiss 1988).

Severity by Treatment Interactions

Initial ANCOVAs indicated significant heterogeneity of regression for

baseline severity of cocaine use on several primary outcome variables,

suggesting the treatments worked differently at different levels of

severity. Furthermore, two previous studies (Carroll et al. 1991a; Carroll

et al. 1993a) suggested that severity was potentially an important

predictor of treatment response in cocaine abusers. Therefore, to evaluate

the relationship between baseline severity of cocaine use and treatment

outcome, the sample was stratified into three levels: low (1 to 2.5 g of

cocaine per week at baseline), moderate (2.6 to 4.4 g), and high severity

(more than 4.5 g per week) in order to sharpen contrasts between low and

high severity use. This classification of severity was associated with

other indicators of severity such as frequency and chronicity of cocaine

use and route of administration.

Exploratory 2x2x3 (medication by psychotherapy by severity) ANOVAs

are presented in table 2, and the pattern of results is illustrated in figure 1.

Significant severity by psychotherapy (relapse prevention versus clinical

management) interactions indicated that higher severity subjects who

received relapse prevention reported more consecutive days of

abstinence, and lower severity subjects reported briefer periods of

abstinence. The inverse was seen for clinical management; clinical

management was associated with longer periods of abstinence for lowseverity subjects and shorter periods of abstinence for high-severity

subjects.

Similarly, analyses for treatment retention suggested significant severity

by psychotherapy interactions. For relapse prevention, retention was

better for higher severity patients, as low severity patients completed

fewer total sessions (mean = 6.0), and higher severity patients completed

more sessions (mean = 8.6) (F = 3.6, p < 0.03). For clinical management,

there was better retention for low-severity patients (mean 8.0 sessions)

than high-severity subjects (mean 6.1 sessions).

29
TABLE 2. Interactions of treatment type with baseline level of severity

of cocaine use results of three-way analysis of variance

(N = 110).

Percent treatment

days abstinent

Low severity’

Moderate

High

Consecutive days

abstinent4

Low severity

Moderate

High

Percent urine

toxicology screens

positive for cocaine

Low severity

Moderate

High

No. of treatment

sessions completed5

TREATMENT

Psychotherapy Pharmacotherapy

RP CM DMI PLA1

N = 52 N = 58 N = 53 N = 57

Sig. of interaction’

0.78 0.82 0.79 0.80

0.83 0.77 0.82 0.79

0.78 0.81 0.82 0.78 ns

16.6

22.1

26.2

33.1

25.2

15.6

27.8

23.2

20.5

18.8

24.0

21.3

Psych/sev

p < 0.05

0.5 I

0.34

0.28

0.15

0.27

0.47

0.26

0.29

0.42

0.39

0.32 Psych/sev

0.30 p < 0.01

Low severity 6.0 8.0 6.4 7.2

Moderate 8.1 6.8 8.1 6.9

High 8.6 6.2 8.0 6.8

Psych/sev

p < 0.05

NOTE: 1RP = relapse prevention, CM = clinical management, DMI = desipramine,

PLA = placebo. *Results of 2x2x3 ANOVA, significance of F. ‘Indicates

severity of baseline cocaine use: Low = 1 to 2.5 g/week, Moderate = 2.6 to 4.4

g/week, High = 4.5+ g /week. 4Indicates duration of longest period of

consecutive abstinence during treatment: Range: 0 to 90. ‘Range: 1 to 12.

30
FIGURE 1. Severity by psychotherapy interaction: Abstinence

initiation in treatment (N = 110).

There were no significant pharmacotherapy by severity interactions for

treatment retention or reduction in cocaine use for the full sample.

However, among the subsample of subjects who remained in treatment at

least 5 weeks, greater efficacy of desipramine for low severity subjects

was found on several cocaine outcomes.

Depression and Treatment Response

Given that the sample size might have precluded detection of all but the

most robust psychotherapy-pharmacotherapy interactions, indications of

enhanced effectiveness of pharmacotherapy through adding

psychotherapy on an outcome where desipramine, a tricyclic

antidepressant, might be expected to have a more robust effect, that is, in

reduction of depressive symptoms, was then sought.

Thirty-seven percent of the sample was defined as having significant

depressive symptomatology at baseline, using a cutoff of 8 on the Beck

Depression Inventory (Beck and Beck 1972) and 6 or more on the

Hamilton Depression Rating Scale (Hamilton 1960). Preliminary results

indicate that desipramine appeared to be an effective antidepressant in

this sample, in that depressed subjects treated with desipramine

experienced a significant reduction in depressive symptoms compared to

placebo-treated depressed subjects (F = 4.0, p < 0.01). However,

31
desipramine was not associated with significant improvements in cocaine

use among either the depressed or euthymic subsamples. There were,

however, consistent significant interactions for depression and

psychotherapy, in that depressed subjects treated with relapse prevention

remained in treatment significantly longer than depressed subjects treated

with clinical management (9.7 versus 6.0 weeks, F = 10.3, p < 0.01) and

maintained longer periods of consecutive abstinence during treatment

(28.8 versus 20.2 days, F = 28.8, p = 0.01) (Carroll et al., in press).

CONCLUSIONS AND SUGGESTIONS FOR FUTURE

RESEARCH

1. These findings suggest that overall, cocaine abusers benefited from

treatment in significantly reducing their cocaine use from pretreatment

levels. Moreover, improvements were not confined to cocaine abuse,

but were seen for alcohol use, family and social interactions, and

psychological functioning as well.

2. Although immediate posttreatment outcomes failed to demonstrate

significant main effects for psychotherapy, pharmacotherapy, or their

interaction, several design features also precluded unambiguous

interpretation of the relative efficacy of psychotherapy versus

pharmacotherapy in this sample. For example, all subjects receiving

medication also received some form of psychotherapy; therefore, the

efficacy of pharmacotherapy alone, without nonspecific effects of

supportive clinical management or additional active ingredients of

relapse prevention, could not be determined. Similarly, all subjects

who received psychotherapy also received active or inert medication,

which may have influenced their expectations for treatment effects.

Several studies with depressed populations have failed to find

meaningful differences in outcomes for psychotherapy alone versus

psychotherapy plus placebo conditions (Frank and Kupfer 1992).

However, cocaine abusers, through having repeatedly sought effects of

psychoactive substances, may be more influenced by medication and

expectancy effects than other populations. Therefore, comparisons of

psychotherapy alone to psychotherapy/placebo combinations may be

warranted.

3. Exploratory analyses revealed several patient-treatment interactions

that might serve as guidelines for future patient-treatment matching

32
research, but which first require replication in other settings and

samples. These included: (a) better outcomes for high severity

cocaine users treated with cognitive-behavioral coping skills training

than supportive clinical management replication, and better outcomes

for low severity users treated with clinical management; (b)

significant reduction in depressive symptoms for depressed cocaine

abusers treated with desipramine over placebo; and (c) improved

reductions in cocaine use for depressed cocaine abusers treated with

relapse prevention over clinical management.

These findings are consistent with the state-trait model for cocaine

treatment mentioned previously. Moreover, they underline the

significance of heterogeneity among cocaine abusers, which will require

development of specialized treatments for clinically distinct subgroups of

cocaine abusers, rather than one simple pharmacologic or

psychotherapeutic approach for all patients, For example, state aspects of

cocaine dependence may indicate a need for specialized pharmacological

adjuncts, such as antidepressant treatments for depressed cocaine abusers,

disulfiram treatment for alcoholic cocaine abusers (Carroll et al. 1993b),

methylphenidate treatment for cocaine abusers with residual attention

deficit disorder (Khantzian et al. 1984), and so on. Similarly, while

low-intensity psychotherapies may be sufficient for less severe cocaine

abusers, specialized psychotherapies might be evaluated for cocaine

abusers with distinct characteristics who would not be amenable to

pharmacologic approaches. These might include motivational

approaches (Miller and Rollnick 1991) for patients who are ambivalent

around renouncing substance use, community reinforcement (Azrin 1976)

or twelve-step (Nowinski et al. 1992) approaches for patients low in

social supports and resources, cue extinction approaches (O’Brien et al.

1990) for those patients for whom continued conditioned craving for

cocaine is problematic, and more directive cognitive behavioral

approaches for higher severity and high psychopathology patients who

have greater need for structure and support.

REFERENCES

Azrin, N.H. Improvements in the community-reinforcement approach to

alcoholism. Behav Res Ther 14:39-48, 1976.

Beck, A.T., and Beck, R.W. Screening depressed patients in family

practice: A rapid technique. Postgrad Med 52:81-85, 1972.

33
Carroll, K.M. Psychotherapeutic treatment of cocaine abuse: Models for

its evaluation alone and in combination with pharmacotherapy. In:

Tims, F.M., and Leukefeld, C.G., eds. Cocaine Treatment: Research

and Clinical Perspectives. National Institute on Drug Abuse Research

Monograph 135. DHHS Pub. No. (ADM) 93-3639. Washington, DC:

Supt. of Docs., U.S. Govt. Print. Off., 1993.

Carroll, K.M.; Nich, C.; and Rounsaville, B.J. Differential symptom

reduction in depressed cocaine abusers treated with psychotherapy and

pharmacotherapy. J Nerv Ment Dis, in press.

Carroll, K.M.; Powers, M.D.; Bryant, K.J.; and Rounsaville, B.J.

One-year follow-up status of treatment-seeking cocaine abusers:

Psychopathology and dependence severity as predictors of outcome.

J Nerv Ment Dis 181:71-79, 1993a.

Carroll, K.M.; Rounsaville, B.J.; and Gawin, F.H. A comparative trial of

psychotherapies for ambulatory cocaine abusers: Relapse prevention

and interpersonal psychotherapy. Am J Drug Alcohol Abuse

17:229-247, 1991a.

Carroll, K.M.; Rounsaville, B.J.; Gordon, L.T.; Nich, C.; Jatlow, P.M.;

Bisighini, R.M.; and Gawin, F.H. Psychotherapy and

pharmacotherapy for ambulatory cocaine abusers. Arch Gen

Psychiatry 5 1: 177- 187, 1994a.

Carroll, K.M.; Rounsaville, B.J.; and Keller, D.S. Relapse prevention

strategies in the treatment of cocaine abuse. Am J Drug Alcohol Abuse

17:249-265, 1991b.

Carroll, K.M.; Rounsaville, B.J.; and Nich, C. Blind man’s bluff’? The

effectiveness and significance of psychotherapy and pharmacotherapy

blinding procedures in a randomized clinical trial. J Consult Clin

Psychol 62:276-280, 1994b.

Carroll, K.M.; Ziedonis, D.; O’Malley, S.S.; McCance-Katz, E.;

Gordon, L.; and Rounsaville, B.J. Pharmacologic interventions for

abusers of alcohol and cocaine: A pilot study of disulfiram versus

naltrexone. Am J Addict 2:77-79, 1993b.

Extein, I., and Bowers, M.B. State and trait in psychiatric practice Am J

Psychiatry 136:690-693, 1979.

Fawcett, J.; Epstein, P.; Fiester, S.J.; Elkin, I.; and Autry, J.H. Clinical

management-imipramine/placebo administration manual: NIMH

Treatment of Depression Collaborative Research Program.

Psychopharmacol Bull 23:309-324, 1987.

Frank, E., and Kupfer, D.J. Does a placebo tablet affect

psychotherapeutic treatment outcome? Results from the Pittsburgh

study of maintenance therapies in recurrent depression. Psychother

Res 2:102-111, 1992.

34
Gawin, F.H.; Kleber, H.D.; Byck, R.; Rounsaville, B.J.; Kosten, T.R.;

Jatlow, P.I.; and Morgan, C.B. Desipramine facilitation of initial

cocaine abstinence. Arch Gen Psychiatry 46: 117-121, 1989.

Hamilton, M. A rating scale for depression. J Neurol Neurosurg

Psychiatry 23:56-62, 1960.

Higgins, S.T.; Budney, A.J.; Bickel, W.K.; and Hughes, J.R. Achieving

cocaine abstinence with a behavioral approach. Am J Psychiatry

150:763-769, 1993.

Hill, C.E.; O’Grady, K.E.; and Elkin, I. Applying the Collaborative Study

Psychotherapy Rating Scale to rate therapist adherence in

cognitive-behavior therapy, interpersonal therapy, and clinical

management. J Consult Clin Psychol 60:73-79, 1992.

Kang, S.Y.; Kleinman, P.H.; Woody, G.E.; Millman, R.B.; Todd, T.C.;

Kemp, J.; and Lipton, D.S. Outcomes for cocaine abusers after

once-a-week psychosocial therapy. Am J Psychiatry 148:630-635,

1991.

Khantzian, E.J.; Gawin, F.I.; and Kleber, H.D. Methylphenidate treatment

of cocaine dependence: A preliminary report. J Subst Abuse Treat

1:107-112, 1984.

Klerman, G.L. Combining drugs and psychotherapy in the treatment of

depression. In: Greenblatt, M., ed. Drugs in Combination with Other

Therapies. New York: Grune and Stratton, 1975.

Levin, F.R., and Lehman, A.F. Meta-analysis of desipramine as an

adjunct in the treatment of cocaine addiction. J Clin Psychopharmacol

11:374-378, 1991.

Marlatt, G.A., and Gordon, J.R., eds. Relapse Prevention: Maintenance

Strategies in the Treatment of Addictive Behaviors. New York:

Guilford, 1985.

McLellan, A.T.; Luborsky, L.; Woody, G.E.; and O’Brien, C.P. An

improved diagnostic evaluation instrument for substance abuse

patients: The Addiction Severity Index. J Nerv Ment Dis 168:26-33,

1980.

Miller, W.R., and Rollnick, S. Motivational Interviewing: Preparing

People to Change Addictive Behavior. New York: Guilford, 1991.

Nowinski, J.; Baker, S.; and Carroll, K.M.. Twelve-step facilitation

therapy manual: A clinical research guide for therapists treating

individuals with alcohol abuse and dependence. NIAAA Project

MATCH Monograph Series Volume 1. DHHS Publication

No. (ADM)92-1893. Rockville, MD: National Institute on Alcohol

Abuse and Alcoholism, 1992.

35
O’Brien, C.P.; Childress, A.R.; McLellan, A.T.; and Ehrman, R.

Integrating systematic cue exposure with standard treatment in

recovering drug dependent patients. Addict Behav 15:355-365, 1990.

Rounsaville, B.J.; O’Malley, S.; Foley, S.; and Weissman, M.M. Role of

manual-guided training in the conduct and efficacy of interpersonal

psychotherapy for depression. J Consult Clin Psychol 56:681-688,

1988.

Weiss, R.D. Relapse to cocaine abuse after initiating desipramine

treatments. JAMA 260:2545-2546, 1988.

ACKNOWLEDGMENTS

Support was provided by the National Institute on Drug Abuse grants

R01-DA04299, R18-DA06963. and K05-DA00089. Drs. Michael

Barrios, Lisa Fenton, Andrew Grunebaum, Daniel Keller, Robert

Malison, Ismene Petrakis, Glen Pickett, Merrill Rotter, Marlene

Steinberg, and Robert Sbriglio made many contributions to the success of

this project through their work as therapists. Roseann Bisighini, Tami

Frankforter, and Glenna Kingn assisted in data collection and analyses.

AUTHORS

Kathleen M. Carroll, Ph.D.

Bruce J. Rounsaville, M.D.

Charla Nich, MS.

Lynn Gordon, R.N., M.P.A.

Division of Substance Abuse

Department of Psychiatry

Yale University School of Medicine

34 Park Street/SAC 208

New Haven, CT 065 19

and

The APT Foundation

New Haven, CT

Frank Gawin, M.D.

Laboratory for the Study of Addiction

University of California, Los Angeles

Los Angeles, CA 90024

36
Can Psychotherapy Rescue

Naltrexone Treatment of Opioid

Addiction?

Bruce J. Rounsaville

NALTREXONE’S PROMISE

Naltrexone pharmacotherapy for opioid addiction is, on paper, an almost

perfect treatment. To start with, it has a clear mechanism of action and a

compelling rationale. It selectively competes for opioid receptors and

prevents addicts from achieving reinforcement from continued opioid use

and from resuming physical dependence if they do use illicit opioids.

From a learning theory perspective, the conditioned linkage between use

of opioids and positive reinforcement should be extinguished over time as

the addict either refrains from further opioid use or obtains no

psychoactive effect from continued use. It is orally active, exquisitely

powerful (affinity for opioid receptors being 20 times that of morphine),

and can be dispensed on a three times/weekly schedule if monitored

dispensing is required. Alternatively, because it is not psychoactive,

diversion is not an issue, and patients or significant others can administer

the medication on an outpatient basis. The side-effect profile, at least on

the recommended dose of 50 mg per day, is generally benign, although

5 to 10 percent of detoxified opioid addicts experience immediate,

intolerable levels of withdrawal-like effects including agitation, anxiety,

insomnia, light-headedness, sweating, dysphoria, and nausea. Most

patients on naltrexone experience few or no symptoms after the first 1 to

2 weeks of treatment; for a substantial minority (20 to 30 percent)

protracted discomfort is experienced. The only really serious potential

side effect is hepatotoxicity (Maggio et al. 1985), but this has only been

shown to be a problem when daily dosage levels are six times the normal

dose. A serious inconvenience, although one that should only rarely be

an issue, is that patients on naltrexone are unresponsive to ordinary

dosages of opioid analgesics when these are legitimately administered for

control of pain.

To put naltrexone’s seeming excellence in perspective, one can evaluate

the pharmacotherapeutic agents available for treatment of other drugs of

abuse, such as alcohol, cocaine, stimulants, sedatives, or marijuana.

37
While alcohol can be treated with disulfiram, an aversive agent, selective

antagonists or aversive agents have not been developed for other classes

of drugs. In fact, searching for and testing of antagonist agents is a

prominent strategy in the process of developing pharmacotherapies for

cocaine and alcohol (Meyer 1989). This process is likely to be less

straightforward and less successful than in the case of opioids, as

psychoactive effects of alcohol and of cocaine do not appear to be

associated as clearly with a single type of central nervous system

receptor. Hence, development of an antagonist that is even nearly as

good as naltrexone for other substances would be a pharmacological

breakthrough. However, the optimism for the utility of alcohol or

cocaine antagonists should be reconsidered in light of the clinical

experience with naltrexone, a more specific and theoretically perfect

opioid antagonist.

NALTREXONE’S UNFULFILLED PROMISE

Despite naltrexone’s great promise, its impact on the practical

management of opioid addiction in the United States has been

vanishingly small since its introduction to the market in 1986. Data on

sales from naltrexone’s sole manufacturer have indicated that only around

9,000 to 12,000 prescriptions per year were filled for naltrexone between

1986 and 1992 (R. Croop, personal communication, July 1993). Given

that official estimates of the number of opioid addicts in the United States

are around 600,000, and that around 150,000 are in treatment at any

given time, it is clear that naltrexone has been used for only a small

percentage (i.e., 1 to 3 percent) of treated opioid addicts. Outside of

academic and research settings where original efficacy and safety studies

were conducted, naltrexone treatment is virtually unknown. Even at the

Substance Abuse Treatment Unit site in New Haven, which has utilized

naltrexone since the early 1970s the census for the Substance Abuse

Treatment Unit naltrexone maintenance program is 50 to 60 clients, while

the methadone maintenance programs treat around 600 patients.

Parallel to naltrexone’s limited impact in the treatment community,

research on naltrexone for opioid addicts has been at a virtual standstill

for the past decade. A literature review for a presentation on

psychosocial interventions and naltrexone showed that all of the

published reports are from the early 1980s and before. Only two recently

funded National Institute on Drug Abuse clinical trials have addressed

naltrexone: a study by McLellan and colleagues (McLellan et al.,

38
personal communication, June 1993) evaluating naltrexone treatment

linked to parole and one by Wesson and colleagues (Wesson et al.,

personal communication, May 1993) evaluating different naltrexone

induction strategies aimed at reducing initial dropout.

Even the initial phase of research on naltrexone for opioid addicts

generated only a handful of trials evaluating the impact of psychotherapy

or behavioral interventions, and, as shown below, many of these were

open or nonrandomized or both. The evaluations of naltrexone treatment

typically are focused on two phases: (1) initial stabilization, consisting of

the first 6 to 8 weeks of treatment, during which time prolonged

withdrawal symptoms and social supports are the key issues, and (2)

maintenance, when initial pharmacological issues are resolved and

treatment is aimed at rehabilitation.

STABILIZATION TRIALS

Several behavior modification approaches have been used during

stabilization. The project by Callahan (1980) and Martin and colleagues

(1973) reported that 21 percent completed 6 weeks on naltrexone alone,

while 49 percent completed 6 weeks with behavior therapy plus

naltrexone. The difference did not achieve significance because of the

small numbers. Their treatment included contingency contracting and

behavioral techniques such as thought stopping. Contingency payment is

another technique that has been employed with addicts. In a

nonrandomized study by Meyer and colleagues (1976, 1979, pp. 215-

230), addicts were paid $1.00 a day to consume naltrexone. The paid

addicts had a 72 percent success rate at 1 month compared to nonpaid

addicts, who had only a 25 percent success rate, a difference significant at

the .02 level. However, this followed a 2-month inpatient stay. Another

study of contingency payment by Grabowski (1979) showed an 89

percent success rate at both 1 and 2 months in the paid addicts, while

previous addicts who had received a similar amount of money (about $40

a month) without this contingency program had only a 60 percent success

rate at 1 month and a 40 percent success rate at 2 months. Judson and

Goldstein (1979) studied a group of 73 postlevomethadyl acetate

(LAAM) patients compared to 46 street addicts. The LAAM patients had

been extensively educated about naltrexone with handouts, discussion,

and even a quiz over a period of months. In spite of this, the group did

no better than the street group. Average retention initially was 6 to 7

weeks. By 1 month, approximately half of the patients had dropped out;

39
by 5 months only about 10 percent remained. Dose (60 mg versus 120

mg) did not have a significant effect on treatment duration.

Nonbehavioral therapies also have been tested. Resnick and colleagues

(1981) followed 37 addicts who had been randomly assigned to

individual counseling or no counseling. At 1 month, 77 percent (17/22)

were still in treatment in the counseling group, while only 33 percent

(5/15) were still in treatment in the noncounseling group. The difference

was significant at the .01 level. When the addicts were stratified by street

versus postmethadone, overall program retention was significantly better

for the street addicts with counseling, but not for the postmethadone

addicts. Thus, as during the induction phase, street addicts seem to

benefit from individual counseling and show improved program

retention. In a nonrandomized study of multiple family therapy at Yale

University, Anton and colleagues (1981) demonstrated that during the

first month of naltrexone therapy, addicts in family therapy had a very

low dropout-92 percent retention-significant at the .001 level. This

suggests that family therapy also may be of benefit to addicts during this

stabilization phase.

MAINTENANCE TRIALS

The project by Callahan (1980) and Martin and colleagues (1973) also

reported that behavior therapy lengthened time on naltrexone from an

average of 44 days up to 85 days, significant at the .02 level (Callahan

1976, pp. 150-157). A later paper from this program indicated that the

behavior therapy group had less drug use and better program retention

from 0 to 7 months, but no differences were evident at 8 to 14 months or

15 to 21 months (Callahan 1980). Together, these findings suggest that

contingency payment and behavior modification only delay the initial

dropout from a naltrexone program. Data from Resnick and colleagues

(1981) showed that the difference between the counseling groups was

smaller at 3-month and 6-month points than after the stabilization phase.

For addicts opiate-free at 3 months, the percentages were 54 percent

(counseling) versus 40 percent. Similar trends were evident for the

percentage of ex-addicts taking naltrexone; at 3 months the percentages

were 27 percent (6/22) (counseling) versus 0 percent (0/15), and at 6

months the percentages were 9 percent (2/22) versus 0 percent. In a

broader context, behavioral treatments improve compliance with

naltrexone, and naltrexone ingestion enables the counselor to establish a

40
therapeutic relationship within which lifestyle changes can be discussed

and made.

Figure 1 illustrates the pattern of dropout from naltrexone treatment for

behavior modification (BM) from Callahan’s program (1980) and

individual counseling (IC) from the program of Resnick and colleagues

(1981). By 3 to 4 months, these two treatments showed no difference in

the percentage of addicts remaining on naltrexone compared to the

control group of addicts. The control group curve is a composite of the

three studies illustrated with the standard error given for each month.

Figure 1 also compares the results for multiple family therapy (MFT) to

these other two treatments. For any month the percentage of addicts who

remained on naltrexone and drug-free was larger in the MFT group than

the percentage of addicts in the other two treatments or in the control

group.

FIGURE 1. Maintenance phase: Cumulative retention in three

programs ( ) compared to addicts maintained on

naltrexone alone ( ).

KEY: MFT = multiple family therapy (Anton et al. 1981)

BM = behavior modification (Callahan 1976)

IC = individual counseling (Resnick et al. 1981)

41
WHY IS NALTREXONE'S PROMISE UNFULFILLED?

While figure 1 illustrates the initial superiority of combined psychosocial

approaches to naltrexone alone and the more enduring promise of a

family therapy approach, it is hardly encouraging regarding the overall

6-month dropout rate of 70 percent or more for even the most successful

group of comparatively unselected addicts. Moreover, most of these

early dropouts return to illicit opioid use. These discouraging findings

are further compounded by survey results from treatment-seeking opioid

addicts showing that only 10 to 15 percent are willing to attempt

treatment with a drug that “keeps you from getting high” (Greenstein et

al. 1984).

A major factor in naltrexone’s limited role is that a powerful alternative

pharmacotherapy, methadone, already was available when naltrexone was

introduced. Compared with naltrexone, methadone has many key

advantages. First, there is no required detoxification phase. Hence, there

is no initial discomfort in taking methadone. Moreover, with methadone

there are no protracted withdrawal symptoms, which frequently endure

throughout the first 2 to 6 weeks on naltrexone. Second, methadone

provides a mild opioid “high” and does not preclude the use of illicit

opioids to boost this effect. Third, abrupt withdrawal of methadone

treatment results in a protracted and often severe opioid withdrawal

syndrome. Hence, addicts have powerful positive incentives to initiate

methadone treatment and negative consequences for premature dropout.

These advantages result in retention rates on methadone maintenance that

are the mirror image of those on naltrexone, with 50 to 90 percent of

patients remaining in treatment for 6 months or more (Lowinson et al.

1992, pp. 550-561).

In a free-choice situation, only a small minority of opioid addicts will

initially choose naltrexone, and most of these will drop out before

achieving a stable, opioid-free lifestyle. Thus, these factors explain the

very limited place of naltrexone maintenance treatment.

CAN PSYCHOTHERAPY SAVE NALTREXONE?

Before addressing this issue, it may be well to ask if naltrexone should be

saved or, rather, be more widely used in place of methadone or of drugfree approaches. This author would argue that naltrexone is

underutilized.

42
Compared with methadone, naltrexone has many potential advantages.

First, because it is nonaddicting, it can be used in a variety of

nonspecialized settings such as medical clinics, and it can be prescribed

without concerns about diversion. Second, the cost of naltrexone

treatment, in terms of demands on professional time and of patient time,

are much smaller than those associated with methadone maintenance

requiring daily or near-daily clinic visits. Third, the chances for success

after an adequate course of treatment are enhanced on naltrexone, as

protracted withdrawal already has been handled during the initial phase of

naltrexone treatment. In contrast, detoxification and postdetoxification

are periods of great vulnerability for relapse in methadone-maintained

patients because of the need for lengthy detoxification and of protracted

withdrawal symptoms. In fact, methadone maintenance may make

addicts more physically dependent on opioids than they were prior to

treatment, as the typical street addict can only obtain an intermittent

supply of opioids of varying strengths. Fourth, from a behavioral

perspective, the course of naltrexone treatment has allowed the patient to

decondition the connection between cues of everyday life and the

experience of opioid intoxication. This is likely to enhance an addict’s

ability to avoid cue-induced craving and relapse following medication

discontinuation. In contrast, the course of methadone maintenance is

characterized by continuing to go through the day in a medicated state.

Fifth, naltrexone is neither associated with continued potential

reinforcement from heroin use nor with potential synergistic effects from

cocaine use. Hence, addicts are less likely to continue intravenous drug

abuse while on naltrexone than on methadone, thereby reducing potential

spread of human immunodeficiency virus (HIV) and other needle-borne

diseases. Of course, none of these potential advantages of naltrexone can

be realized unless patients are inducted and retained in treatment.

The situation of naltrexone and psychotherapy for opioid addicts is one in

which neither treatment is likely to be effective alone, and a combined

approach is essential. As noted earlier, in the review of available trials,

naltrexone offered without a psychosocial intervention is largely

ineffective, and studies of ambulatory psychotherapy for opioid addicts

offered outside of methadone maintenance likewise were plagued by

unacceptably high dropout rates (O’Malley et al. 1972). This contrasts

with models for potential interaction between pharmacotherapy and

psychotherapy of other psychiatric disorders such as depression, in which

both treatments have been shown to be effective alone (Elkin et al.

1988a, 19886; Weissman 1979).

43
If psychotherapy or behavioral interventions are to enhance the efficacy

of naltrexone treatment, they must be tailored to address naltrexone’s

weaknesses, particularly its weaknesses in comparison to its strongest

competitor, methadone.

The first weakness to address is naltrexone’s lack of immediate positive

pharmacological reinforcement. To address this issue, provision of

positive incentives for initiation of and maintenance on naltrexone

treatment is needed. In fact, simple payment of a small fee improved

initial compliance in several early studies (Callahan 1980; Grabowski

1979; Martin et al. 1973; Meyer et al. 1976; Meyer et al. 1979, pp. 215-

230). Given that the major alternative to naltrexone treatment is

methadone, the provision of positive incentives could take the form of

more favorable conditions in contrast to methadone (e.g., shorter waiting

list, more privileges, lower fees). In addicted physicians (Tennant et al.

1984; Washton et al. 1984), a group for whom naltrexone has been

shown to have great promise, the relative lack of pharmacological

reinforcement of naltrexone is outweighed by the inconvenience and

public nature of methadone maintenance.

The second weakness for naltrexone is that there are no pharmacological

negative reinforcements for premature dropout. Whereas abrupt cessation

of methadone leads to serious withdrawal, naltrexone can be discontinued

easily. This weakness could be addressed with contingency contracting,

possibly involving family members as participants, in which negative

consequences are linked to premature dropout.

A third key weakness for naltrexone is the initial presence of aversive

naltrexone side effects and protracted withdrawal symptoms. While this

issue has been addressed by inpatient initiation and by pharmacological

strategies, psychosocial interventions such as provision of added support,

involvement of the addicts’ social network, and preparedness training

could be added. The presence of a major aversive consequence for

naltrexone discontinuation (i.e., return to incarceration) is the likely

reason for naltrexone’s success with parole and probation groups (Brahen

et al. 1984).

44
TECHNICAL CONSIDERATIONS IN NALTREXONE VERSUS

METHADONE RESEARCH DESIGNS

Because methadone maintenance is the major, more successful alternative

to naltrexone treatment, it is the optimal comparison condition for

systematic efficacy trials that combine psychosocial interventions with

naltrexone. It is noteworthy that this kind of systematic, randomized

comparison of naltrexone to methadone maintenance has not been

reported in the published literature. It is likely that problems with subject

recruitment in a noncoercive situation have made such direct comparisons

unfeasible. In the section below, a number of potential interventions that

may enhance naltrexone’s efficacy are described. For these to have an

impact on treatment approaches that are actually used, rigorous

demonstration of efficacy will be required. Such studies will need to

include design features that address special problems inherent in a

naltrexone versus methadone design.

First, the central problem in a naltrexone versus methadone study is

unfeasibility of noncoercive recruitment. Because methadone is the

standard treatment and is generally more initially acceptable, opioid

addicts seeking treatment have little incentive to enter a research protocol

in which they have a 50 percent chance of receiving naltrexone. To

manage this issue, one strategy would involve making naltrexone

treatment the standard initial approach for targeted subgroups of opioid

addicts such as those with no prior methadone experience, those under

legal pressure, or those with good prognostic features (e.g., employed,

good social supports). In a program with this approach, subjects might be

recruited more readily if they knew that they had a 50 percent chance of

receiving methadone instead of naltrexone. A drawback to this approach

is that clients may opt to enter alternative methadone programs in the

same geographical area rather than seeking treatment with naltrexone, a

problem that undermined the well-known therapeutic community versus

methadone trial attempted by Bale and colleagues (1980). Other

incentives for participation in such a trial might involve avoidance of a

waiting list for methadone, low-cost treatment or provision of other

desirable incentives such as those involved in a community reinforcement

approach (Higgins et al. 1993).

A second potential problem in research on naltrexone versus methadone

is a potentially high dropout rate and differential dropout. Naltrexone

and methadone are likely to appeal to different kinds of patients. Moreover, this author suggests that naltrexone would require some sort of

45
added psychosocial treatment (e.g., couple’s treatment) in order to

counter the early attrition problems seen in the past. Some of the

problems arising from high attrition or differential attrition can be dealt

with in the data-analysis phase. For example, endpoint analysis can be

used, including all subjects in the efficacy analysis by using their clinical

status at the time of attrition as the outcome rating (Fleiss 1986).

Alternatively, analysis can be performed on an “intention to treat” sample

at a standard time point regardless of the actual treatment the subject

received following dropout from initially assigned treatment (Lavori

1992). However, all of the data-analytic strategies for managing

differential attrition involve assumptions that may be incorrect and are

less satisfactory than those that prevent the problem in the first place.

This is best accomplished in the recruitment phase of the study by

ensuring that subjects entered are equally willing and able to become

engaged in the alternative approaches. For example, if a design involves

randomization to a spouse-assisted versus individual approach, it is

crucial that subjects randomized to both conditions have spouses who are

willing to participate in treatment. Demonstration of this potential for

spouse involvement could involve a requirement that the spouse

participate in pretreatment assessments.

A third consideration in designing naltrexone versus methadone studies is

the need to include outcome measures that are the most likely to tap the

likely strengths and weaknesses of the two treatments. Some of these

potential differences can be readily assessed in the course of a relatively

brief trial. For example, methadone is likely to be superior in terms of

attrition at 1 to 2 months, while naltrexone is likely to be superior in

terms of opioid-free urine specimens. However, the likely benefits of

naltrexone may not be noted with standard outcome measures or with

outcome measures evaluated in the long term. Naltrexone’s two major

areas of superiority are likely to be in cost-benefit and in long-term

abstinence from opioids. Because naltrexone does not involve daily

dosing, even in the initial phases of treatment, treatment may be less

expensive, both in terms of personnel costs and in terms of clients’ loss of

leisure or occupational time. Hence, detailed assessments and calculation

of total social and treatment costs and benefits of the two approaches

would be required to provide an optimal comparison. The greatest

potential area of superiority of naltrexone is at treatment termination, with

the lack of withdrawal symptoms easing the transition from treatment to a

drug-free state. Hence, a study comparing naltrexone to methadone

would necessitate a long-term, posttreatment followup. To be

practicable, such a study would require what many would see as

46
premature and arbitrary cessation of the comparison methadone treatment

(e.g., after 6 to 12 months of maintenance). Another potential difference

in outcome of naltrexone versus methadone is in long-term success of

early dropouts. An argument against initiating first-time treatment

seekers on naltrexone is that those who drop out early may become

discouraged about all treatment and fail to obtain alternative treatment

that might be more acceptable. Conversely, methadone’s high retention

is seen as a major strength, especially if early dropout is associated with

exposure to such dangers as needle-borne infections like HIV. To

evaluate such an issue, it is critical that investigators devote considerable

efforts to follow up not only treatment completers but also all early

dropouts.

PSYCHOTHERAPY AND NALTREXONE COMBINATIONSWHAT MIGHT WORK?

In this section, the general strategy of tailoring behavioral treatments to

naltrexone’s weaknesses will be elaborated and further explored in terms

of potential program designs.

Naltrexone as First-Line Treatment

One general strategy for enhancing acceptance and utilization of

naltrexone would require changes at the treatment organization level.

This would be a programmatic decision to require an initial course of

naltrexone treatment as a prerequisite for initiation of methadone

maintenance. This program revision would address naltrexone’s

weakness of having low initial attractiveness. Addicts with prior

methadone maintenance experience have been reported to have higher

dropout rates than those for whom naltrexone is the initial treatment

(Resnick et al. 1979). The main rationale for offering naltrexone as the

first-line treatment is that even if it is effective only with a minority, it

may save that group from the expense and disadvantages of methadone

maintenance mentioned earlier. More and more, methadone maintenance

is seen as a treatment of indefinite duration. Hence, before initiating a

treatment that may last for many years, use of an opioid-free treatment

may be highly desirable. However, this kind of programmatic

commitment to naltrexone has been the exception and not the rule. From

a research perspective, this kind of prior decision would be required to

deal with recruitment issues in a clinical trial contrasting naltrexone to

methadone maintenance as an initial treatment.

47
Negative Reinforcements for Discontinuation or Contingency

Contracting

To address the problem that naltrexone is comparatively easy to

discontinue (there are no withdrawal symptoms), it could be offered in

the context of a contract that would call for negative contingencies for

discontinuation. Such an approach has been reported as successful with

addicted physicians for whom the alternative to treatment is losing their

medical license (Tennant et al. 1984; Washton et al. 1984). While this

group constitutes only a small fraction of opioid addicts, contingency

contracting could be more broadly used with addicts under legal pressure,

where the alternative to treatment is violation of parole or probation.

While this approach has promise for the duration of the parole or

probation, experience with contingency contracting with cocaine abusers

suggests that continued avoidance of illicit drug use is likely to cease with

the expiration of the contract (Anker and Crowley 1982).

Increase Positive Incentives With Naltrexone

As noted above, early attrition from naltrexone has been substantially

reduced by providing basic positive incentives such as monetary

payments for taking the medication. This initial superiority in retention,

however, did not endure after several months. An approach that could

build on this finding would be to adapt the Community Reinforcement

Approach (CRA) to naltrexone maintenance. This is a multifaceted

program that combines cognitively oriented coping skills training,

provision of positive behavioral reinforcements for drug-free urine

specimens, and significant-other involvement in treatment (Azrin et al.

1973, pp. 952-959). Higgins and colleagues (1991, 1993) have reported

substantial benefits from this approach in ambulatory cocaine abusers,

demonstrating its superiority over standard treatment and the

effectiveness of individual program components including involvement

of the significant others and inclusion of a voucher system to reward

drug-free urine specimens. Adapting such a program to naltrexone could

deal with the early dropout issues by providing vouchers for taking

medication or for drug-free urine specimens. By using this early phase to

engage not only the addict but a significant other, the program is likely to

have an enhanced probability of long-term retention, such as that shown

by Anton and colleagues (1981) with naltrexone patients offered a family

therapy intervention. Provision of vouchers and of the social support

from a significant other also may counterbalance the discomfort

experienced by many opioid addicts during the initial naltrexone

48
induction phase. The willingness to endure mild withdrawal symptoms

during this time may be increased if other incentives are in effect.

CONCLUSIONS

Despite its many advantages over methadone maintenance, naltrexone

treatment is underutilized because of several key weaknesses relative to

methadone: it provides no opioid agonist effects, it is associated with

initial aversive side effects in a substantial number of clients, and it is

easy to discontinue because it lacks withdrawal effects, To maximize its

potential, naltrexone should be offered in the context of a program of

psychosocial interventions that address its key weaknesses. Potential

strategies could include offering of naltrexone as the first-line treatment,

contingency contracting to provide negative reinforcement for treatment

discontinuation, or use of a community reinforcement approach to

provide a range of positive incentives for recruitment and retention on

naltrexone. Such strategies are conducive to empirical testing, but

systematic efficacy studies would need to include design features that

have not been utilized in prior research on naltrexone treatment.

REFERENCES

Anker, A.A., and Crowley T.J. Use of contingency contracts in specialty

clinics for cocaine abuse. In: Harris, L.S., ed. Problems of Drug

Dependence 1981. National Institute on Drug Abuse Research

Monograph 41. DHHS Pub. No. (ADM)82-190760. Washington, DC:

Supt. of Docs., U.S. Govt. Print. Off., 1982.

Anton, R.F.; Hogan, I.; Jalai, B.; Riordan, C.E.; and Kleber, H.D.

Multiple family therapy and naltrexone in the treatment of opiate

dependence. Drug Alcohol Depend 8:157-168, 1981.

Azrin, N.H.; Naster, B.J.; and Jones, R. Reciprocity counseling: A rapid

learning based procedure for marital counseling. Behav Res Ther

11:364-382, 1973.

Bale, R.N.; Van Stone, W.W.; Kaldan, J.M.; Engelsing, T.M.J.; Elashiff,

R.M.; and Zarcone, V.P. Therapeutic communities vs. methadone

maintenance: A prospective controlled study of narcotic addiction

treatment: Design and one year follow-up results. Arch Gen

Psychiatry 37:179-193, 1980.

49
Brahen, L.S.; Henderson, R.K.; Capone, T.; and Kordal, N. Naltrexone

treatment in a jail work-release program. J Clin Psychiatry 45:49-52,

1984.

Callahan, E.J. Comparison of two naltrexone treatment programs:

Naltrexone alone versus naltrexone plus behavior therapy. In: Julius,

D., and Renault, P., eds. Narcotic Antagonists: Nultrexone. National

Institute on Drug Abuse Research Monograph 9. NTIS PB #255-

833/AS. Washington, DC: Supt. of Docs., U.S. Govt. Print. Off.,

1976.

Callahan, E.J. The treatment of heroin addiction: Naltrexone alone with

behavior therapy. Am J Drug Alcohol Abuse 7:795-807, 1980.

Elkin, I.; Pilkonis, P.A.; Docherty, J.P.; and Sotsky, S.M. Conceptual and

methodological issues in comparative studies of psychotherapy: I.

Active ingredients and mechanisms of change. Am J Psychiatry

145:909-917, 1988a.

Elkin, I.; Pilkonis, P.A.; Docherty, J.P.; and Sotsky, S.M. Conceptual and

methodological issues in comparative studies of psychotherapy: II.

Nature and timing of treatment effects. Am J Psychiatry

145:1070-1076, 19886.

Fleiss, J.L. The Design and Analysis of Clinical Experiments. New York:

John Wiley & Sons, Inc., 1986.

Grabowski, J. Effects of contingent payment on compliance with a

naltrexone regimen. Am J Drug Alcohol Abuse 6(3):355-365, 1979.

Greenstein, R.A.; Amdt, J.C.; McClellan, A.T.; O’Brien, C.P.; and

Evans, B. Naltrexone: A clinical perspective. J Clin Psychiatry

45:25-28, 1984.

Higgins, ST.; Budney, A.L.; Bickel, W.K.; Hughes, L.; Florian, F.; and

Gary, B. Achieving cocaine abstinence with a behavioral approach.

Am J Psychiatry 150:763-769, 1993.

Higgins, S.T.; Delaney, D.D.; Budney, A.J.; Bickel, W.K.; Hughes, J.R.;

Foerg, F.; and Fenwick, J.W. A behavioral approach to achieving

initial cocaine abstinence. Am J Psychiatry 148:1218-1224, 1991.

Judson, B.A., and Goldstein, A. Rapid induction to stable dosages of

levomethadyl acetate (LAAM). Drug Alcohol Depend 4:461, 1979.

Lavori, P.W. Clinical trials in psychiatry: Should protocol deviation

censor patient data? Neuropsychophurmucology 6:39-63, 1992.

Lowinson, J.H.; Marion, I.H.; Joseph, H.; and Dole, V.P. Methadone

maintenance. In: Lowinson, J.H.; Ruiz, P.; Millman, R.B.; and

Langrod, J.G. eds. Substance Abuse: A Comprehensive Textbook.

Baltimore: Williams and Wilkins. 1992.

50
Maggio, C.A.; Presta, E.; and Bracco, E.F. Naltrexone and human eating

behavior: A dose-ranging inpatient trial in moderately obese men.

Bruin Res Bull 14:657-661, 1985.

Martin, W.R.; Jasinski, D.; and Mansky, P. Naltrexone, an antagonist for

the treatment of heroin dependence. Arch Gen Psychiatry 23:784-789,

1973.

Meyer, R.E. Prospects for a rational pharmacotherapy of alcoholism.

J Clin Psychiatry 50:403-412, 1989.

Meyer, R.E.; Mirin, S.M.; Altman, J.L; and McNamer, B. A behavioral

paradigm for the evaluation of narcotic antagonists. Arch Gen

Psychiatry 33:371-377, 1976.

Meyer, R.E.; Mirin, S.M.; and Zackow, F. Community outcome on

narcotic antagonists. In: Meyer, R.E., and Mirin, S.M., eds. The

Heroin Stimulus. New York: Plenum Press, 1979.

O’Malley, J.E.; Anderson, W.H.; and Lazare, A. Failure of outpatient

treatment of drug abuse: I. Heroin. Am J Psychiatry 128:865-868,

1972.

Resnick, R.; Schuyten-Resnick, E.; and Washton, A.M. Narcotic

antagonists in the treatment of opioid dependence: Review and

commentary. Compr Psychiatry 20:116-125, 1979.

Resnick, R.B.; Washton, A.M.; Stone-Washington, N.; and Rawson, R.A.

“Psychotherapy and Naltrexone in Opioid Dependence.” Paper

presented at Committee on Problems of Drug Dependence, San

Francisco, CA, July 13, 1981.

Tennant, F.S.; Rawson, R.A.; Cohen, A.J.; and Mann, A. Clinical

experience with naltrexone in suburban opioid addicts. J Clin

Psychiatry 45:41-45, 1984.

Washton, A.M.; Pottash, A.C.; and Gold, M.S. Naltrexone in addicted

business executives and physicians. J Clin Psychiatry 45:39-41, 1984.

Weissman, M.M. The psychological treatment of depression: Evidence

for the efficacy alone, in comparison with and in combination with

pharmacotherapy. Arch Gen Psychiatry 36: 1261-1266, 1979.

ACKNOWLEDGMENTS

This work was supported in part by grants R18 and DA06963,

K05DA00089, K12DA00617, and R01 DA04299 from the National

Institute on Drug Abuse.

51
AUTHOR

Bruce J. Rounsaville, M.D.

Professor of Psychiatry

Substance Abuse Treatment Unit

Yale University School of Medicine

34 Park Street, Room S202

New Haven, CT 06519

52
Strategies To Maximize the

Efficacy of Naltrexone

for Alcohol Dependence

Stephanie S. O'Malley

Psychosocial treatments for alcoholism have been shown to increase

abstinence rates and improve the quality of life for many alcoholics

(Miller and Hester 1986, pp. 121-174). Nonetheless, a significant

proportion of alcoholics find it difficult to maintain initial treatment gains

and eventually relapse to problematic drinking. In an effort to reduce

relapse rates, there has been considerable interest in developing

pharmacological treatments that can be incorporated into psychosocial

treatment approaches (Litten and Allen 1991). One pharmacological

agent that currently is receiving increased attention is naltrexone, an

opioid antagonist. The potential value of naltrexone was initially

suggested by extensive research using animal models, which

demonstrated that opioid antagonists can reduce alcohol drinking under a

variety of conditions. (For a review, see Froelich and Li 1993.)

Subsequently, two controlled clinical trials have been conducted that

provide evidence for the efficacy of opioid antagonists in the treatment of

alcohol dependence (Volpicelli et al. 1992; O’Malley et al. 1992).

Volpicelli and his colleagues first evaluated the potential value of

naltrexone as adjunctive treatment to standard psychotherapy in a

placebo-controlled double-blind study of 70 recently detoxified alcohol

subjects (Volpicelli et al. 1988; Volpicelli et al. 1992). The results

showed that naltrexone-treated patients reported lower levels of alcohol

craving, fewer drinks consumed per occasion, fewer drinking days, and

lower rates of relapse than did placebo-treated patients. Differences in

relapse rates were most pronounced among subjects who “sampled”

alcohol and strongly favored naltrexone.

Volpicelli’s initial findings have been replicated and extended by this

author’s research group (O’Malley et al. 1992). Ninety-seven alcoholdependent subjects received 50 mg of naltrexone or placebo and either

coping skills/relapse prevention therapy or supportive therapy for 12

weeks. Consistent with Volpicelli’s findings, naltrexone-treated patients

relapsed at a lower rate than patients who received placebo (see figure 1)

irrespective of psychotherapy condition. Evidence was also found,

53
FIGURE 1. Rates of never relapsing by treatment group reported by

O‘Malley et al. 1992 (N = 97).

however, that naltrexone improved abstinence rates when combined with

a supportive therapy in which the goal of abstinence was unambiguous.

Taken together, these two studies suggest that naltrexone can support a

patient’s commitment to abstinence and reduce the likelihood that lossof-control drinking occurs if drinking is initiated. As such, naltrexone

appears to address defining features of alcohol dependence including the

primacy of alcohol consummatory behavior and impaired control over

drinking behavior (Meyer 1989; Meyer and Kranzler 1988).

Furthermore, many of the gains associated with naltrexone therapy appear

to be maintained for up to 6 months following cessation of treatment

(O’Malley et al. 1993). Preliminary analyses indicate that approximately

two-thirds of patients treated with placebo met Diagnostic and Statistical

Manual (DSM)-III-R criteria for alcohol abuse or dependence at

followup, whereas only one-third of naltrexone-treated patients received

an alcohol diagnosis. Additional analyses are underway to examine

measures of psychosocial functioning and rates of abstinence and relapse

over this followup period.

54
The consistent results across these two independent investigations suggest

that naltrexone is an effective pharmacological adjunct to psychosocial

treatments for alcohol dependence. Based on these studies, a number of

recommendations for using naltrexone in the treatment of alcohol

dependence can be made, although innumerable questions remain about

strategies to maximize the effective use of naltrexone. The goal of this

chapter will be to discuss issues that should be considered in the use of

naltrexone as a treatment for alcohol dependence, specifically focusing on

the integration of psychosocial interventions.

Dose and Duration of Treatment

In clinical practice, pharmacotherapists often are concerned about

providing the patient with an adequate medication dose. There is little

research, however, on the dose-response relationship for naltrexone

treatment of alcoholism. Consistent with the dose used for narcotic

addiction, 50 mg daily was shown to be efficacious in the two placebocontrolled trials of alcoholism (O’Malley et al. 1992; Volpicelli et al.

1992). In a study of heavy drinkers, Bohn (1993) found that subjects

significantly reduced their drinking with brief counseling and either 25

mg or 50 mg naltrexone daily, suggesting that low-dose naltrexone may

be effective in this population. Whether higher doses lead to greater

reductions in drinking behavior remains to be determined.

The potential benefits from higher doses must be weighed against the risk

of increased side effects. Higher doses of naltrexone (e.g., 1,400 to 2,100

mg per week) have been shown to be associated with greater risk of

hepatocellular toxicity. The occurrence of significant side effects can

also reduce medication compliance. Between 5 and 10 percent of

alcohol-dependent patients treated with naltrexone discontinued the

medication because of side effects, primarily nausea and vomiting

(O’Malley et al. 1992; Volpicelli et al. 1992). Consequently, a number of

investigators now are prescribing 25 mg of naltrexone for the initial dose

and then increasing the dose to 50 mg in an effort to reduce initial dropout due to side effects.

In addition to questions of dosage, the optimal duration of treatment with

naltrexone remains to be determined. The two extant clinical trials were

12 weeks (O’Malley et al. 1992; Volpicelli et al. 1992). Given that

alcohol dependence is a syndrome characterized by relapse, it will be

important to determine whether a long-term maintenance approach

enhances treatment outcome. Extended treatment, for example, may be

55
particularly crucial for individuals who have more severe alcohol

problems. As an alternative, short-term initial treatment with naltrexone

combined with the possibility of resuming naltrexone during high-risk

periods (e.g., the holidays) may be an effective maintenance strategy.

Annis and Peachy (Annis 1991; Peachey and Annis 1985, pp. 199-216)

have proposed and studied a similar two-phase treatment approach

integrating the use of calcium carbamide, an alcohol sensitizing agent,

and relapse prevention techniques. In this approach, continuous calcium

carbamide coverage is provided to initiate a stable period of abstinence.

As a maintenance strategy, calcium carbamide is utilized primarily in

high-risk situations that are identified by the patient, and this use is

gradually discontinued as the patient develops alternative coping

strategies for dealing with high-risk situations (Annis 1991).

MEDICATION COMPLIANCE

An important factor affecting dose response is medication compliance.

Although compliance with naltrexone by alcohol-dependent patients

appears to be substantially better than compliance reported in studies of

opiate addicts taking naltrexone or studies of alcoholics taking disulfiram

(Callahan et al. 1976; Fuller et al. 1986), subjects in early medication

trials are likely to be more compliant than patients treated outside of

research protocols (Bulpitt 1983). As a result, consideration should be

given to strategies intended to increase compliance and consequently

maximize treatment outcome. In this regard, much can be learned from

the disulfiram literature and the literature on the use of naltrexone in

opiate addiction. Better abstinence rates have been found when spouses

or treatment staff supervise disulfiram administration compared to when

the patient self-administers medication (Azrin et al. 1982; O’Farrell and

Bayog 1986). Among opiate addicts, family involvement with patients

receiving naltrexone therapy was shown to improve treatment retention

and outcome (Anton et al. 1981). Monitoring of medication compliance

by opiate addicts has been made more practical by having treatment staff

administer naltrexone 3 times per week with 100 mg given on Monday

and Wednesday and 150 mg given on Friday, rather than having the

patient take 50 mg daily.

Other strategies developed primarily to monitor compliance in medication

trials, such as riboflavin markers and microprocessor-based monitoring

systems, could be incorporated into behavioral strategies to enhance

compliance (Kruse and Weber 1990). Microprocessor-based monitoring

56
systems use microelectronics embedded in pill-bottle caps to record the

date and time that a patient opens his or her pill bottle. As a tool to

improve compliance, the data obtained with the cap could be used to give

the patient feedback about medication compliance, to help the patient

solve problems about situations in which he or she fails to take the

medication, and to illustrate to the patient the relationship between

compliance and treatment outcome.

INTENSITY OF PSYCHOSOCIAL TREATMENT

Paralleling the issue of medication dose, the “dose” of the psychosocial

treatment provided with naltrexone also can be varied in order to achieve

optimal treatment response. In treating a population of severely alcoholdependent subjects who initially required medical detoxification,

Volpicelli and colleagues (1992) used naltrexone in the context of an

intensive month-long day treatment program followed by twice-weekly

therapy. With a less dependent population, O’Malley and colleagues

(1992) provided naltrexone as an adjunct to less intensive once-weekly

outpatient individual psychotherapy. Although the majority of patients

treated with naltrexone in this author’s study did well, the group that

relapsed tended to be distinguished by having previous treatment failures.

One might speculate that this subset of patients would have benefited

from an increase in the frequency of sessions or transfer to a partial

hospital program while continuing on naltrexone.

Consequently, research is needed on the psychosocial interventions to

combine with naltrexone, specifically addressing the patient population to

be treated. While it seems likely that weekly contact with a treating

professional is important in the initiation of abstinence with naltrexone,

the frequency and type of psychosocial intervention needed beyond that

remains to be determined. As the data accrue on naltrexone’s efficacy,

for example, primary care physicians may prescribe naltrexone to

alcohol-dependent patients under their care, provide simple advice, and

conduct periodic monitoring of their liver functioning and clinical

response to the medication. Several studies (Chick et al. 1985;

Kristenson et al. 1982; Wallace et al. 1988) have shown that simple

advice offered by primary care providers has a beneficial effect on

drinking behavior compared to no intervention. The data do not exist

about whether or not primary care interventions provided together with

naltrexone treatment are effective and, if they are, for whom they work.

Given that 60 percent of alcohol abusers make at least one ambulatory

57
health care visit during a 6-month period and are unlikely to attend

specialized alcohol treatment clinics (Shapiro et al. 1984), the potential

significance of this minimal intervention cannot be underestimated.

At the same time, an argument can be made that a more intensive

intervention may be beneficial for individuals with significant alcohol

problems. Although some studies have failed to find an advantage on

drinking-related outcomes for extended clinic treatment over a single

session of advice (Chick et al. 1988; Edwards et al. 1976) these

treatments were not provided in conjunction with an effective

pharmacotherapy. Data from this author’s research, for example, indicate

that among patients pharmacologically supported by naltrexone, those

who were provided with concurrent coping skills training were less likely

to relapse if drinking was initiated than those who were given supportive

psychotherapy. The syndrome of alcohol dependence, while perhaps best

characterized by loss-of-control drinking, is often accompanied by a wide

range of psychosocial difficulties, including restricted leisure time

activities, impaired interpersonal functioning, and legal and vocational

difficulties. These problems are targeted by coping skills therapy, which

may lead to better long-term adjustment. Consistent with this hypothesis,

it was found that patients on naltrexone who received coping skills

therapy tended to have better adjustment in psychological functioning

and depressed mood than patients who received naltrexone and

supportive therapy.

As yet unexplored is the value of beginning naltrexone treatment in an

inpatient setting. While the opportunity to drink is minimized on an

inpatient unit, several advantages may derive from beginning naltrexone

at that time. Numerous studies have demonstrated that discharge from an

inpatient treatment program is an extremely high-risk period for

resumption of drinking, and that many patients fail to attend aftercare

sessions following discharge (Costello 1975). If patients were started on

naltrexone prior to leaving the hospital, the risk of a full-blown relapse

could be reduced should the patient sample alcohol following discharge.

Furthermore, participation in aftercare may be enhanced if the patient is

motivated to continue on naltrexone.

Inpatient naltrexone treatment also may provide an opportunity to

“inoculate” the patient against alcohol-related cues that elicit conditioned

craving (Siegel 1983, pp. 207-246; Wikler, 1965, pp. 85-100). In

addition to the finding that naltrexone prevented relapses following an

alcoholic drink, data from Volpicelli’s study and this author’s research

58
indicate that naltrexone may have an effect on craving that does not

depend on sampling of alcohol. It was found, for example, that patients

treated with naltrexone and supportive psychotherapy were less likely to

initiate drinking than patients treated with placebo. Anecdotally, patients

with high baseline levels of craving for alcohol report that they still

thought about alcohol once they began naltrexone, but that the urge to act

on the thought was diminished, and that, over time, the frequency of

thoughts about drinking also diminished.

Stewart, de Wit, and Eikelboom (1984) have argued that conditioned

stimuli associated with drug use can elicit neural states that are similar to

those produced by the drug itself and thereby increase the probability of

drug-related thoughts and behaviors. Extrapolating from this theory, cues

associated with drinking may act like a priming dose of alcohol and elicit

an appetitive motivational response, perhaps through conditioned

endogenous opioid release. If naltrexone blocks this response to

drinking-related stimuli, these alcohol-related cues may lose their ability

to elicit craving, alcohol-related thoughts, and alcohol-seeking behavior

with repeated exposures.

Based on this hypothesis, cue exposure techniques could be combined

with naltrexone in order to systematically extinguish the appetitive value

of these cues. Cue exposure techniques typically involve presenting an

alcoholic with repeated prolonged exposure to cues that elicit a desire to

drink, but with instructions not to drink (Cooney et al. 1987; Monti et al.

1987). A variety of alcohol-related cues are used including the sight and

smell of alcoholic beverages and induction through imagery of affective

states associated with drinking. The strongest alcohol-related cue is

actual alcohol consumption, which Sinclair (1990) argues is necessary for

an extinction program using opiate antagonists. Because exposure to

alcohol-related cues may trigger a relapse in an outpatient, cue exposure

is best implemented in an inpatient setting where the opportunity to drink

can be limited. Whether cue exposure techniques will enhance the

efficacy of naltrexone treatment remains to be determined by research on

the effect of naltrexone on reactivity to alcohol-related cues and research

examining whether or not naltrexone-induced changes in cue reactivity

translate to improvements in treatment outcome.

Ultimately, greater knowledge of the mechanisms underlying the effect of

naltrexone on alcohol consumption will help researchers to develop more

specific treatments. If naltrexone reduces the urge to drink and enhances

abstinence rates, then strategies to enhance the patient’s commitment to

59
abstinence could be developed. If the primary effect of naltrexone is on

loss-of-control drinking once alcohol is sampled, then greater focus

should be given to strategies to help the patient prevent a relapse.

PATIENT TREATMENT MATCHING

Efforts to maximize outcome will be informed by exploratory analyses of

patient-treatment-matching effects and future studies testing a priori

matching hypotheses. Preliminary analyses of this author’s data suggest,

for example, that baseline levels of alcohol craving interact with

medication condition (Jaffe et al. 1993). There was a strong positive

relationship between craving at baseline and drinking during treatment

for patients on placebo. In contrast, baseline craving did not predict

alcohol consumption during treatment for patients receiving naltrexone.

Instead, high cravers had outcomes comparable to patients with lower

levels of baseline craving, which suggests that naltrexone may be

particularly helpful to patients struggling with the urge to drink.

It also is conceivable that previously established patient predictors of

response to different forms of psychotherapy may be modified by

naltrexone treatment. For example, patients with poor cognitive abilities

have tended to fare less well in cognitive behavioral treatments compared

to supportive treatments presumably because the task demands of coping

skills therapy may be too difficult for these individuals (Kadden et al.

1989). If the patient’s cognitive abilities are impaired as a result of heavy

drinking, improvements in drinking behavior resulting from naltrexone

treatment are likely to result in parallel improvements in the patient’s

cognitive status. As a result of these improvements, the patient may now

be more available for learning and utilizing the techniques taught in

cognitive behavioral treatments.

Other potential patient characteristics that may interact with treatments

include demographic characteristics (Azrin et al. 1982; Fuller and Roth

1979), severity of alcohol dependence (Babor, unpublished data), and

presence and type of co-morbid psychopathology (Kadden et al. 1989;

McLellan et al. 1983). Finally, patient characteristics may influence the

ultimate goal of treatment. Bohn’s research (1993) suggests that

naltrexone may have benefit in reducing the level of alcohol consumption

for individuals who are drinking heavily but who do not meet criteria for

alcohol abuse or dependence. For this subset, education about

60
nonhazardous drinking levels and the development of drinking

moderation skills may be appropriate goals of treatment.

REFERENCES

Annis, H.M. A cognitive-social learning approach to relapse:

Pharmacotherapy and relapse prevention counseling. Alcohol Alcohol

Suppl 1:527-530, 1991.

Anton, R.F.; Hogan, I.; Jalali, B.; Riordan, C.E.; and Kleber, H.D.

Multiple family therapy and naltrexone in the treatment of opiate

dependence. Drug Alcohol Depend 8:157-168, 1981.

Azrin, N.H.; Sisson, R.W.; Meyers, R.; and Godley, M. Alcoholism

treatment by disulfiram and community reinforcement therapy.

J Behav Ther Exp Psychiatry 13:105-112, 1982.

Babor, T.F. “Experimental Design, in Project on Identification and

Management of Alcohol Related Problems.” Unpublished manuscript.

Bohn, M. “Randomized Trial of Safety and Efficacy of 25 versus 50 mg

Naltrexone and Brief Counseling to Reduce Heavy Drinking.” Paper

presented at the annual meeting of the Research Society on

Alcoholism, San Antonio, TX, June 22, 1993.

Bulpitt, C.J. Developments in Biostatistics and Epidemiology:

Randomised Controlled Clinical Trials. Boston, London: The Hague,

1983.

Callahan E.J. et al. Comparison of two naltrexone treatment programs:

Naltrexone alone versus naltrexone plus behavior therapy. In:

Julius, D., and Renault, P., eds. Narcotic Antagonists: Naltrexone.

National Institute on Drug Abuse Research Monograph 9. DHEW Pub

No, (ADM)76-387. Washington, DC: Supt. of Docs., U.S. Govt. Print.

Off., 1976. pp. 150-157.

Chick, J.; Lloyd, G.; and Crombie, E. Counseling problem drinkers in

medical wards: A controlled study. Br Med J 290:965-967, 1985.

Chick, J.; Ritson, G.; Connaughton, J.; and Stewart, A. Advice versus

extended treatment for alcoholism: A controlled study. Br J Addict

83:159-170, 1988.

Cooney, N.L.; Gillespie, R.A.; Baker, L.H.; and Kaplan, R.F. Cognitive

changes after alcohol cue exposure. J Consult Clin Psychol 55: 150-

155, 1987.

Costello, R.M. Alcoholism treatment and evaluation. In search of

methods. II. Collation of two-year follow-up studies. Int J Addict

10:857-867, 1975.

61
Edwards, G.; Gross, M.M.; Keller, M.; and Moser, J. Alcohol-related

problems in the disability perspective. J Stud Alcohol 37:1360-1382,

1976.

Froelich, J.C. and Li, T.K. Opioid peptides. In: Deitrich, R., and

Galanter, M., eds. Recent Developments in Alcoholism: Ten Years of

Progress. Vol. 11. New York: Plenum Press, 1993. pp. 187-205.

Fuller, R.K.; Branchey, L.; Brightwell, D.R.; et al. Disulfiram treatment

of alcoholism: A Veterans Administration cooperative study. JAMA

256:1449-1455, 1986.

Fuller, R.K., and Roth, H.P. Disulfiram for the treatment of alcoholism:

An evaluation in 128 men. Ann Intern Med 90:901-904, 1979.

Jaffe, A.; O’Malley, S.; Chang, G.; Schottenfeld, R.S.; Meyer, R.;

Rode, S.; and Rounsaville, B. “Matching Patients to Naltrexone,

Supportive Therapy, and Coping Skills Therapy: A Posttreatment

Analysis.” Paper presented at the annual meeting of the Research

Society on Alcoholism, San Diego, CA, June 15, 1993.

Kadden, R.M.; Cooney, N.L.; Getter, H.; and Litt, M.D. Matching

alcoholics to coping skills or interactional therapies: Posttreatment

results. J Consult Clin Psychol 57:698-704, 1989.

Kosten, T.R., and Kleber, H.D. Strategies to improve compliance with

narcotic antagonists. Am J Drug Alcohol Abuse 10(2):249-266, 1984.

Kristenson, H.; Trell, E.; and Hood, B. Serum of glutamyl-transferase in

screening and continuous control of heavy drinking in middle-aged

men. Am J Epidemiol 114:862-872, 1982.

Kruse, W., and Weber, E. Dynamics of drug regimen compliance - its

assessment by microprocessor-based monitoring. Eur J Clin

Pharmacol 38:561-565, 1990.

Litten, R.Z., and Allen, J.P. Pharmacotherapies for alcoholism:

Promising agents and clinical issues. Alcohol Clin Exp Res 15(4):620-

633, 1991.

McLellan, A.T.; Woody, G.E.; Luborsky, L.; O’Brien, C.P.; and Druley,

K.A. Increased effectiveness of substance abuse treatment:

A prospective study of patient-treatment “matching.” J New Ment Dis

171:597-605, 1983.

Meyer, R.E. Prospects for a rational pharmacotherapy of alcoholism.

J Clin Psychiatry 50:403-412, 1989.

Meyer, R.E., and Kranzler, H.R. Alcoholism: Clinical implications of

recent research. J Clin Psychiatry (Suppl) 49:8-12, 1988.

Miller, W.R., and Hester, R.K. The effectiveness of alcoholism treatment:

What research reveals. In: Miller, W.R., and Heather, N., eds. Treating

Addictive Behaviors: Processes of Change. New York: Plenum Press,

1986.

62
Monti, P.M.; Binkoff, J.A.; Zwick, W.R.; Abrams, D.B.; Nirenberg,

T.D.; and Liepman, M.R. Reactivity of alcoholics and nonalcoholics

to drinking cues. J Abnorm Psychol 96:122-126, 1987.

O’Farrell, T.J., and Bayog, R.D. Antabuse contracts for married

alcoholics and their spouses: A method to maintain Antabuse

ingestion and decrease conflict about drinking. J Subst Abuse Treat

3:1-8, 1986.

O’Malley, S.S.; Jaffe, A.; Chang, G.; Schottenfeld, R.S.; Meyer, R.; and

Rounsaville, B. Naltrexone and coping skills therapy for alcohol

dependence: A controlled study. Arch Gen Psychiatry 49:881-887,

1992.

O’Malley, S.S.; Jaffe, A.; Chang, G.; Rode, S.: and Rounsaville. R.

“Naltrexone and Coping Skills Therapy for Alcohol Dependence: 6

Month Follow-up Findings.” Paper presented at the annual meeting of

the Research Society for Alcoholism, San Antonio, TX, June 22,

1993.

Peachy, J.E., and Annis, H.M. New strategies for using the alcoholsensitizing drugs. In: Naranjo, C.A., and Sellers, E.M., eds. Research

Advances in New Psychopharmacological Treatments for Alcoholism.

Amsterdam: Elsevier, 1985.

Shapiro, S.; Skinner, E.A.; and Kessler, L.G. Utilization of health and

mental health services: Three epidemiologic catchment area sites.

Arch Gen Psychiatry 41:971-978, 1984.

Siegel, S. Classical conditioning, drug tolerance, and drug dependence.

In: Smart, R.; Glaser, F.; Israel, Y.; Kalant, H.; Popliam, R.; and

Schmidt, W., eds. Research Advances in Alcohol and Drug Problems.

Vol. 7. New York: Plenum Press, 1983.

Sinclair, J.D. Drugs to decrease alcohol drinking. Ann Med 22:357-362,

1990.

Stewart, J.; de Wit, H.; and Eikelboom, R. Role of unconditioned and

conditioned drug effects in the self-administration of opiates and

stimulants. Psychol Rev 91(2):251-268, 1984.

Volpicelli, J.R.; O’Brien, C.P.; Alterman, A.I.; and Hayashida, M.

“Naltrexone and the Treatment of Alcohol-dependence: Initial

Observations.” Paper presented at the satellite symposium of the 1988

meeting of the Society for Neuroscience, Toronto, Ontario, November

12, 1988.

Volpicelli, J.R.; Alterman, A.I.; Hayashida, M. Naltrexone in the

treatment of alcohol dependence. Arch Gen Psychiatry 49:876-880,

1992.

63
Wallace, P.; Cutler, S.; and Haines, A. Randomized controlled trial of

general practitioner intervention in patients with excessive alcohol

consumption. Br Med J 297:663-668, 1988.

Wikler, A. Conditioning factors in opiate addiction and relapse. In:

Wilner, D., and Kassenbaum, G., eds. Narcotics. New York: McGrawHill, 1965.

ACKNOWLEDGMENT

This chapter was prepared with support from NIAAA grant KZ002-

AA00171.

AUTHOR

Stephanie S. O’Malley, Ph.D.

Associate Professor of Psychiatry (Psychology)

Yale University School of Medicine

285 Orchard Street

New Haven, CT 06511

64
Disulfiram (Antabuse) Contracts

in Treatment of Alcoholism

Timothy J. O’Farrell, John P. Allen, and Raye Z. Litten

INTRODUCTION

Alcoholism is a major public health problem in the United States

(National Institute on Alcohol Abuse and Alcoholism 1990) and

throughout much of the world (World Health Organization 1977). It is

the most prevalent psychiatric disorder in the United States (Helzer et al.

1991, pp. 81-115). Development of effective treatments for alcoholism,

including the use of medications that reduce drinking, has been an

important public health goal for many years (National Academy of

Sciences 1990). Disulfiram (Antabuse) is a medication that inhibits

metabolism of acetaldehyde, a toxic breakdown product of alcohol, and

produces unpleasant symptoms (flushing, headache, nausea, vomiting,

dizziness, light-headedness, tachycardia) if a person consumes alcohol.

The patient who stops taking disulfiram can experience the disulfiramalcohol reaction for up to 14 days (and generally for at least 4 to 5 days)

after discontinuing ingestion of disulfiram. The rationale for disulfiram

in treating alcoholism is that most alcoholics taking disulfiram will not

drink for fear of getting sick. Disulfiram thus prevents impulsive

drinking in response to acute craving or stressors. Of course disulfiram

as a deterrent to drinking among alcoholics, like all medications, is only

effective for as long as the patient complies with taking the disulfiram.

Therefore, this chapter will review briefly the use of disulfiram in treating

alcoholism with a special emphasis on the use of behavioral contracts

between the alcoholic and a concerned significant other to maintain

compliance with disulfiram.

Classic Study of Disulfiram by Fuller and Colleagues 1986

In their classic large-scale clinical trial, Fuller and colleagues (1986)

randomly assigned male alcoholics to one of three treatment conditions:

(1) 250 mg of disulfiram (N = 202); (2) 1 mg of disulfiram (N = 204), a

control for the threat of the disulfiram-alcohol reaction; or (3) no

disulfiram (N = 199), a control for the counseling that all participants

received. All alcoholics in this study were scheduled to receive weekly

outpatient counseling for 6 months followed by biweekly counseling

65
sessions for the final 6 months. Followup interviews were scheduled to

occur bimonthly during the study year. Study participants on average

were middle aged (42 years mean age), ethnically diverse (54 percent

white), moderately socially stable (54 percent married, 70 percent

employed) chronic alcoholics (12 years of alcohol abuse).

The Fuller and colleagues (1986) study produced four major results.

First, a customary therapeutic dose (250 mg) of disulfiram was not

superior to placebo (1 mg) or no disulfiram in producing abstinence,

reducing time to first drink, or improving social or employment status

among male alcoholic patients. Second, failure of patients to take the

drug as prescribed may have rendered disulfiram ineffective. In fact,

only 20 percent of the subjects were judged “good compliers” as

evidenced by consistent urinalysis results positive for riboflavin, the

biochemical marker of disulfiram employed. Third, better compliance

was related to more abstinence. A higher percentage of compliant than

noncompliant patients was continuously abstinent for the 1 -year followup

period (43 percent for the compliant versus 8 percent for the

noncompliant, p < .001). Fourth, patient acceptance of disulfiram was

low. Only 38 percent of the 1,618 alcoholics who met study criteria and

were medically cleared to take disulfiram agreed to enter the study and

possibly take disulfiram. Most study refusals were due to patients’

reluctance to take disulfiram.

The Fuller and colleagues (1986) study showed that disulfiram was not

effective because of serious problems with patient acceptance and

compliance. However, abstinence was observed among patients who

took the medication consistently. Further, the low patient acceptance

may have been related to the fact that the disulfiram was not an integral

part of the alcoholism counseling used. Findings such as these

underscore the importance of techniques to increase compliance with

disulfiram. After an overview of such techniques, the use of behavioral

contracts to increase compliance and to make disulfiram an integral part

of psychosocial treatments for alcoholism will be considered in detail.

Overview of Techniques to Increase Compliance With

Disulfiram

Varied strategies to enhance disulfiram compliance have been devised.

This overview will examine implants, patient instructional sets, and

incentives, each of which are covered in depth elsewhere (Allen and

Litten 1992).

66
Disulfiram Implants. The most potent guarantee for disulfiram

compliance would seem to be physical implant to release disulfiram into

the bloodstream at a consistent rate and at a level sufficient to cause an

adverse physical reaction should the patient drink. Disulfiram implants

have been available for 30 years, and more recent investigations on

implants have been reasonably well controlled (e.g., Johnsen et al. 1990;

Wilson et al. 1984). Such studies have identified serious limitations,

however, to disulfiram implants. First, most such depots fail to release

adequate levels of disulfiram. Second, the bolus of the implant under the

skin has led to adverse effects of infections and rejection after the implant

surgical procedure. Third, controlled studies have not found superior

outcomes for alcoholics treated with currently available implants. These

results led Allen and Litten (1992) to conclude that disulfiram implants,

for biochemical reasons per se, have been largely ineffective.

Patient Instructions. An alternative strategy to enhance attractiveness

of taking disulfiram is modification of patient instructions and

expectations for the medication. Two different approaches have shown

promising results in initial investigations. Duckert and Johnsen (1987)

allowed patients a choice of methods for using disulfiram ranging from

the conventional long-term use to prevent drinking to infrequent, periodic

use for specific reasons chosen by the patient (e.g., to prevent drinking in

a high-risk situation). Kofoed (1987) significantly increased disulfiram

compliance among alcoholic outpatients by informing them and their case

managers of results of carbon disulfide breathalyzer tests taken at each

counseling session to corroborate extent of recent disulfiram use.

Tangible Incentives. Other studies have considered the effectiveness of

tangible incentives for taking disulfiram. Most of the incentives that have

been tried relate in some way to circumstances and conditions specific to

the patient group of interest. Among these have been (1) less restrictive

probation for individuals charged with alcohol-related offenses (Boume

et al. 1966; Brewer and Smith 1983); (2) methadone contingency for

methadone patients with alcohol problems (Liebson et al. 1973, 1978);

(3) money returned from a security deposit made by alcoholics initiating

outpatient counseling (Bigelow et al. 1976); (4) job security for industrial

workers referred by their employers for drinking-related job problems

(Robichaud et al. 1979); (5) continued affiliation with the treatment

program in which the patient is currently enrolled rather than discharge

from the program or referral to another clinic (Bickel et al. 1989; Sereny

et al. 1986); and (6) more frequent clinic visits as a form of psychological

67
incentive among socially isolated, inner-city alcoholics (Gerrein et al.

1973).

While each of these studies suffers from specific methodological

limitations, the findings uniformly suggest better disulfiram compliance

and more favorable clinical outcomes for those who received an incentive

for taking disulfiram. In such studies, direct observation of the patient

taking disulfiram by a court or clinic staff person, often referred to as

“supervised” disulfiram, was typically part of the procedure to assess

compliance so that the incentive could be provided. Observed or

supervised disulfiram without specified incentives is the basis for

disulfiram contracts and other compliance enhancement procedures-the

subject of the remainder of this chapter.

DISULFIRAM CONTRACTS AND SUPERVISED DISULFIRAM

Description and History of Disulfiram Contracts

“Behavioral contracting” is generally done with both the client and a

significant other, usually the spouse, in the client’s living environment.

Interestingly, behavioral agreements typically do not explicitly stipulate

tangible consequences for taking or refusing disulfiram, although they do

specify social reinforcers, e.g., expression of appreciation by the spouse

when the alcoholic takes disulfiram. These agreements also require that

both the patient and the significant other formally and publicly commit

themselves to observation of disulfiram use.

Figure 1 provides a sample disulfiram contract taken from O’Farrell and

Bayog (1986), who describe the clinical procedures involved in some

detail including methods for dealing with common resistances and

problems encountered. Two slightly different versions of the disulfiram

contract appeared in the literature at about the same time.

The Behavioral Marital Therapy (BMT) version, first described by Miller

and Hersen (1975) and Miller (1976) provides for observed disulfiram

with mutual thanking by alcoholic and spouse plus a commitment to

refrain from discussions (except during BMT sessions) about the

alcoholic’s drinking (see item 3 of the contract in figure 1).

68
DISULFIRAM (ANTABUSE) CONTRACT

FIGURE 1. Sample disulfiram contract used in behavioral marital

therapy with alcoholics.

Like all disulfiram contracts, the BMT version seeks to maintain

disulfiram ingestion and abstinence. The BMT version also seeks to

restructure the couple’s relationship to reduce their conflicts about past

drinking or the likelihood of future drinking and to decrease the spouse’s

anxiety, distrust, and need to control the alcoholic. The BMT version

tries to deal with these presumed relationship dynamics of the early

69
sobriety period in order to increase support for abstinence and reduce the

risk of relapse (O’Farrell 19933).

The Community Reinforcement Approach (CRA) version derives from

Azrin’s (I 976) attempt to augment the effectiveness of his CRA approach

to alcoholism treatment (Hunt and Azrin 1973) by adding a disulfiram

component to it. The CRA version of the disulfiram contract is identical

to the BMT version except that CRA does not include item 3 restricting

discussions about drinking. Studies of each of these two approaches are

considered next.

Behavioral Marital Therapy Studies of Disulfiram

Miller and Hersen (1975) reported a case in which a disulfiram contract

and BMT were used to promote abstinence and reduce marital conflict.

The 49-year-old factory worker husband, whose 10-year history of

alcoholism was characterized by many arrests, car accidents, and marital

problems, had been consuming a pint to a fifth of vodka daily prior to his

admission to a hospital for alcoholism treatment. The wife had decided

to divorce him if he did not stop drinking. Pretreatment assessment

revealed very little positive communication and extensive negative

comments by the wife about drinking (e.g., blaming for past drinking,

threats about future drinking). Treatment consisted of BMT sessions to

increase constructive communication and a contract specifying daily

disulfiram intake by the husband and cessation of discussion about

drinking by the wife. (The contract was quite similar to the model in

figure 1.) Treatment started with weekly sessions in the hospital with the

husband visiting home each weekend and continued on an outpatient

basis biweekly for 3 months and monthly thereafter for 3 months. Ninemonth followup revealed that the husband had remained abstinent and

was still taking disulfiram daily. In addition, the couple was

communicating more constructively and going out together regularly.

The wife had stopped mentioning the past and was generally more

pleasant. The couple had handled several problems quite well. The

positive BMT results from the Miller and Hersen (1975) case report,

along with similar affirming results from other early case reports and

uncontrolled studies of BMT, led to controlled studies of BMT. The

Counseling for Alcoholics’ Marriages (CALM) Project studies of BMT

included disulfiram contracts as part of the Project CALM BMT program

(O’Farrell 1993a, pp. 170-209).

70
In an initial Project CALM study (known as the CALM-l study),

O’Farrell and colleagues (O’Farrell et al. 1985, 1992) investigated the

effect of adding BMT couples group treatment with a disulfiram contract

to individually oriented outpatient treatment of married male alcohol

abusers. Thirty-six couples, in which the husband had recently begun

individual alcohol counseling that included a disulfiram prescription,

were randomly assigned to (1) 10 weekly sessions of a BMT (behavioral

rehearsal of communication skills and marital agreements) couples group

plus a disulfiram contract; (2) 10 weeks of an interactional (largely verbal

interaction and sharing of feelings) couples group without a disulfiram

contract; or (3) a no-marital-treatment control group. Results at the end

of treatment (O’Farrell et al. 1985) showed that adding BMT plus a

disulfiram contract to individual alcoholism counseling produced

significant improvements in marital and drinking adjustment that were

superior to outcomes of individual counseling alone and to individual

counseling plus interactional couples therapy. Results during the 2 years

after treatment (O’Farrell et al. 1992) showed that alcoholics and their

wives who received the additional BMT remained significantly improved

on marital and drinking adjustment throughout the 2 years. Although

BMT continued to appear superior to individual counseling alone on

marital adjustment throughout much of the 2-year followup, the strength

and the consistency of findings favoring BMT diminished as time after

treatment lengthened. In terms of drinking outcomes during the 2 years

after treatment, the addition of BMT no longer produced better results

than did interactional couples therapy or individual treatment alone.

The specific contribution of the disulfiram contract to the results observed

in the CALM-l study cannot be determined. The disulfiram contract was

part of the BMT program. The extent of patients’ use of disulfiram was

not measured. Still, it seems likely that during treatment the disulfiram

contract may have contributed importantly to the lower rate of drinking

and drinking-related problems observed in the BMT couples as compared

with the other couples who did not use the disulfiram contract. Perhaps

after treatment ended, use of the disulfiram contract decreased since BMT

no longer produced less drinking than the other treatments. The CALM-l

study results suggested the need for a study of treatment methods to

maintain the use of the disulfiram contract and the gains produced by

BMT, especially for drinking and related behaviors.

Results of CALM-l produced CALM-2, a study to evaluate the

usefulness of couples relapse prevention (RP) sessions for maintaining

changes in marital and drinking adjustment produced by short-term BMT.

71
Continued use of the disulfiram contract, especially for individuals

suffering more severe drinking problems, was one of the goals of the RP

sessions. In this study, after participating weekly for 5 months in a BMT

couples program, 59 couples with an alcohol-abusing husband were

assigned randomly to receive or not receive 15 additional couples RP

sessions over the next 12 months. Outcome measures were collected

before and after BMT and at quarterly intervals for the 2-1/2 years after

BMT.

The CALM-2 investigation produced three major findings (Cutter et al.

1993; O’Farrell et al. 1993). First, results for the entire sample showed

the additional RP sessions produced better outcomes during and for the

6 to 12 months after the end of RP. Specifically, alcohol abusers who

received RP after BMT had more days abstinent and used the disulfiram

contract more than those who received BMT alone. The superior RP

drinking outcomes continued through 18 months followup (i.e., 6 months

after the end of RP). Couples who received the additional RP also

maintained improved marriages longer (through 24 months followup)

than did their counterparts who received BMT only (through 12 months

followup). Second, for alcoholics with more severe marital and drinking

problems, RP produced better marital and drinking outcomes throughout

the 30-month followup period. Specifically, alcoholics with more severe

alcohol problems at study entry used the disulfiram contract more (see

figure 2) and showed a less steep decline in use of the disulfiram contract

(see figure 3) throughout the 30 months after BMT if they received the

additional RP than if they did not. Further, alcoholics with more severe

marital problems at study entry experienced better marital adjustment and

more days abstinent and maintained relatively stable levels of abstinence

if they received the additional RP, while their counterparts who did not

receive RP had poorer marital adjustment and fewer abstinent days and

showed a steep decline in abstinent days in the 30 months after BMT.

Third, greater use of the disulfiram contract was associated with more

days abstinent and more positive marital adjustment test scores after

BMT for all subjects irrespective of the amount of aftercare received.

To summarize, two Project CALM BMT studies of disulfiram contracts

have been completed. The CALM-l study showed that adding BMT plus

a disulfiram contract to individual alcoholism counseling led to better

short-term drinking and marital outcomes than a disulfiram prescription

alone accompanied by either an alternative form of couples counseling or

72
FIGURE 2. Two-way alcohol problem severity by treatment

interaction for use of disulfiram (Antabuse) contract

in Cutter and colleagues (1993) CALM-2 study of

BMT and disulfiram contract.

individual counseling alone. Superior BMT drinking results did not

persist through the 2-year followup period, possibly because many

couples discontinued their disulfiram contract after treatment ended. The

CALM-2 study indicated that adding couples RP sessions in the year after

BMT enhanced use of the disulfiram contract and yielded better marital

and drinking outcomes than BMT alone. These better RP outcomes

persisted for 18 to 24 months after BMT for the entire sample and

throughout the entire 30 months followup after BMT for those with more

severe marital and drinking problems. Thus the Project CALM studies

suggest that disulfiram contracts used with BMT are associated with less

drinking and greater disulfiram compliance. However, the specific

contribution of disulfiram contracts to the multifaceted BMT treatment

package remains to be investigated.

73
FIGURE 3. Three-way alcohol problem severity by treatment by time interaction for use of disulfram

(Antabuse) contract in Cutter and colleagues (1993) CALM-2 study of BMT and disulfiram

contract.
Community Reinforcement Approach Studies of Disulfiram

Contracts

Azrin developed a CRA to treating alcoholics that was based on operant

conditioning principles. CRA rearranged community reinforcers such as

the job, the family, and the social relations of the alcoholic such that

drinking produced a “time-out” from a high density of reinforcement.

The results from the initial CRA study convincingly demonstrated that

the eight alcoholics who received this CRA counseling drank less,

worked more, and spent more time with their families and out of

institutions than did a matched control group of eight alcoholics who did

not receive these procedures (Hunt and Azrin 1973).

Azrin (1976) attempted to augment the effectiveness of CRA by adding a

disulfiram component to it. Subjects were 18 inpatient alcoholic males

randomly assigned to CRA with a disulfiram contract or to a matched

control group receiving standard alcoholism treatment with general

advice to take disulfiram. Several procedures, all of which have become

standard in both CRA and BMT studies of the disulfiram contract, were

employed with the experimental group to heighten disulfiram

compliance. These included (1) instructing the client and significant

other on the rationale and benefits of disulfiram as a “chemical time-delay

device” to avoid impulsive drinking and its consequences, (2)

encouraging the alcoholic to personally request that the other person

monitor the use of disulfiram, (3) establishing specific links between

taking the medication and recurrent daily activities, (4) monitoring

disulfiram administration by the significant other or the counselor, and

(5) referring the client to a physician supportive of disulfiram. A formal

contract in which the client agreed to take disulfiram (similar to the one in

figure 1 except that item 3 was omitted) was signed with the counselor.

In the Azrin (1976) study, 6-month self-report followup measures

demonstrated that the CRA with the disulfiram contract was substantially

more effective in reducing the number of drinking days than standard

treatment with general advice to take disulfiram. Additional followup

for 2 years of CRA subjects (followup for the control-group subjects was

limited to 6 months) showed continued positive outcomes for CRA

subjects on number of days drinking, percent time employed, percent

time institutionalized posttreatment, and amount of time spent with the

family. The authors also concluded that the CRA with the disulfiram

contract was preferable to the previous version of CRA without

disulfiram in that the newer strategy reduced drinking and the amount of

75
CRA counseling time needed. While these results suggest benefits of

contracting for disulfiram and of employing a range of enhancement

techniques, unfortunately it is not possible to isolate the effects of the

disulfiram contract from the remaining elements of CRA itself.

A subsequent CRA study (Azrin et al. 1982) more explicitly evaluated

the benefits of disulfiram contracting and compliance aids. Outpatients in

a rural community alcoholism clinic who did not suffer co-morbid drug

dependence or psychosis were encouraged to take disulfiram and were

referred to the agency physician and a nearby pharmacy to obtain the

medication. Following the first session, 43 subjects were randomly

assigned to one of three treatment conditions:

1. Traditional treatment plus a prescription for disulfiram without

special disulfiram contract procedures;

2. Traditional treatment with disulfiram contract procedures similar to

those employed in the Azrin (1976) study cited above; or

3. CRA including disulfiram contracting.

Six-month followup in the Azrin and colleagues (1982) study

demonstrated that patients in the three conditions differed on number of

days on which disulfiram was taken, days drinking, days intoxicated, and

average amount of ethanol consumed per drinking episode. There were

two major findings: First, patients receiving CRA and a disulfiram

contract performed best; those in traditional therapy without disulfiram

contract fared worst; those in traditional therapy with a disulfiram

contract responded at a level intermediate between the other two groups.

Figure 4 suggests that, while the groups differed throughout the followup

period, disulfiram use declined appreciably by the second month for the

traditional therapy group without the disulfiram contract and decreased

quite rapidly thereafter with no disulfiram being taken after 3 months.

The clients in the two groups given the disulfiram contract were taking

disulfiram about 90 percent of the time initially and showed less of a

decrease over time remaining with two-thirds or more days taking

disulfiram on average through 6 months followup. Second, the authors

found that married or cohabiting clients assigned to the disulfiram

contract and traditional treatment performed about as well on the four

outcome measures as they did with CRA plus the disulfiram contract.

76
FIGURE 4. Mean number of days on which disulfiram (Antabuse)

was taken during each month (30 days) of the 6 months

of followup. Disulfiram was given in the usual manner

in the “traditional” group whereas adherence was

socially motivated for the “Disulfiram Assurance”

group. The “behavior therapy” group received

community-oriented reinforcement therapy in addition

to the disulfiram assurance program. (Reprinted from

Azrin et al. 1982, p. 109, by permission of Pergamon

Press.)

NOTE: Reprinted from Journal of Behavioral Therapy and

Experimental Psychiatry, Vol. 13, No. 2, Azrin, N.H.;

Sisson, R.W.; Meyers, R.; and Godley, M. Alcoholism

treatment by disulfiram and community reinforcement

therapy, pp. 105-112 (1982), with kind permission from

Elsevier Science Ltd., The Boulevard, Langford Lane,

Kidlington, 0X5 1GB, UK.

Single clients, however, achieved additional gain from CRA plus

disulfiram contract over traditional therapy and disulfiram contract.

Table 1 from the Azrin and colleagues (1982) study illustrates this

finding.

77
TABLE 1. Mean number of days abstinent during the 6th month

(30 days) of followup (N = 43).

Singles Couples

Traditional counseling

with disulfiram prescription 6.75 17.40

Traditional counseling

with disulfiram contract 8.00 30.00

CRA with disulfiram contract 28.30 30.00

Reprinted from Azrin et al. 1982, p. 110. Adapted by permission from

Pergamon Press.

NOTE: Reprinted from Journal of Behavioral Therapy and Experimental

Psychiatry, Vol. 13, No. 2, Azrin, N.H.; Sisson, R.W.; Meyers,

R.; and Godley, M. Alcoholism treatment by disulfiram and

community reinforcement therapy, Volume 13, pp. 105-112

(1982), with kind permission from Elsevier Science Ltd., The

Boulevard, Langford Lane, Kidlington 0X5 1GB, UK.

In summary, CRA studies of disulfiram contracts have produced two

major findings. First, the disulfiram contract with CRA produces better

disulfiram compliance and less drinking than traditional counseling with

a disulfiram prescription or simple advice to take disulfiram (Azrin 1976;

Azrin et al. 1982). Second, for married or cohabiting clients, a disulfiram

contract with either CRA or traditional counseling resulted in better

compliance and more abstinence than did traditional counseling with a

disulfiram prescription, while single clients required the CRA plus the

disulfiram contract to get beneficial outcomes (Azrin et al. 1982). The

CRA studies have attracted great interest because they show very good

treatment outcomes and clear superiority of CRA over comparison

treatments. However, the CRA studies have also been subjected to a

number of criticisms. The sample sizes have been small, the followup

periods have been limited to 6 months, and some of the followup period

has included time in treatment delivery. The intensity, credibility, and

content of the traditional counseling control group have been questioned

in that the same therapists delivered both CRA and the traditional

counseling, raising concerns that therapists may not have been equally

78
invested in the two treatments. The CRA groups received more sessions

than the other groups. The use of films and discussion on the disease of

alcoholism for the traditional counseling also has been questioned.

The interest in and criticisms of the disulfiram contract plus CRA studies

has led to larger scale, better controlled clinical trials, One of these

studies currently is in progress at the University of New Mexico under the

direction of William Miller. This study will randomly assign 160

alcoholics at a public alcoholism clinic to one of four treatments:

1. Traditional counseling with encouragement to take disulfiram but

without a disulfiram contract;

2. Traditional counseling with a disulfiram contract;

3. CRA with a disulfiram contract;

4. CRA without disulfiram.

Different counselors will deliver CRA and traditional treatments.

Counselors will be chosen and trained to be equally committed to each

treatment approach. Followup will be conducted periodically for 2 years

after the end of each treatment. Results from this study will provide

important information about the utility of disulfiram contracts in both

CRA and traditional counseling.

Other Studies of Disulfiram Contracts and Supervised

Disulfiram

Two other studies of disulfiram contracts or supervised disulfiram have

been reported. These studies were not done in the framework of BMT or

CRA. The specific disulfiram compliance procedure varied from the

versions used in BMT or CRA.

Further research on disulfiram contracting and monitoring with patients

and significant others was performed by Keane and colleagues (1984).

Male alcoholic inpatients (N = 25) being discharged from a 4-week

behaviorally oriented inpatient alcohol treatment program and a

significant other (usually the wife) living with them were subjects in the

study. All alcoholics agreed to take disulfiram. All significant others

also attended a discharge planning session with the alcoholic and

counselor, which included videotaped educational material about

79
disulfiram and the dangers of drinking while taking it. In addition, the

significant others were told that they would receive a monthly phone call

from a staff member to check on the use of disulfiram and to assist in

resolving any apparent difficulties surrounding it. Then subjects were

assigned randomly to one of three experimental conditions:

1. No contract/no recording group. While the patient was urged to take

the medication daily at 9 p.m., no contract was signed dealing with its

use or monitoring.

2. Contract/recording group. The couple agreed that disulfiram would

be taken daily in the presence of the monitor followed by signing the

date on the contract. Recording sheets were to be mailed back to the

clinic on a monthly basis.

3. Contract/recording plus instruction for positive reinforcement. In

addition to receiving the same instructions as group 2, participants

were encouraged to provide a weekly reinforcement contingent upon

taking disulfiram.

Compliance rates in the Keane and colleagues (1984) study appeared

quite high. All but one of the subjects in the latter two groups returned

their annotated charts to the clinic. Review of pharmacy records

demonstrated that a higher percentage of patients in these two groups had

their disulfiram prescriptions refilled than did those in group 1, a

marginally significant difference (p < .06). However, even in group 1,

56 percent of the patients had 3 months of disulfiram prescriptions filled.

Monthly interviews with significant others indicated that most patients,

regardless of group to which assigned, were continuing to take

disulfiram, and that only four subjects were drinking abusively at

3-month followup. There were no significant differences among

treatment groups in drinking. Thus the Keane and colleagues (1984)

study did not find better clinical results for those who employed the

disulfiram contract as compared to those who did not. The short duration

of followup and the small sample size may have precluded emergence of

convincing evidence of an advantage for the disulfiram contract. The

motivational and instructional aspects common to all subjects including

the comparison group also must be considered. All subjects started

disulfiram after at least 4 weeks of inpatient treatment, and the significant

others viewed a videotape on use of disulfiram and its effects with

instructions that they would be contacted regularly about the patient’s

compliance with disulfiram. The motivational and instructional sets

80
appear to have increased compliance in the noncontract group beyond

levels reported by others (Azrin et al. 1982; Fuller et al. 1986).

The final study by Chick and colleagues (1992) represents the largest

study of supervised disulfiram to date. Subjects were patients (N = 126)

attending seven alcoholism treatment centers in the UK. All subjects had

relapsed after previous therapy or other support. Pregnant women were

excluded, as were subjects with cardiac disease, co-morbid drug

dependence or psychosis, and those showing abnormally high levels of

serum bilirubin, aspartate aminotransferase (AST), or alanine

aminotransferase (ALT). Patients were already receiving or were offered

a range of outpatient counseling and support, which varied among

treatment centers. In addition to outpatient counseling, patients were

randomly assigned to one of the following:

1. Supervised 200 mg daily dose of disulfiram in which an informant

(usually the spouse) supervised daily ingestion of disulfiram by the

patient. The informant was encouraged to phone the clinic if the

patient refused the medication so that advice could be offered. No

written contract, however, was involved, and no formal sanctions

were invoked if the patient ceased taking the medication. The more

extensive compliance procedures used in BMT and CRA studies of

disulfiram contracts were not employed.

2. Supervised use of vitamin C to control for the effects of receiving

supervised medication and outpatient counseling. Patients were told

this rationale. If they asked further they were told that vitamin C was

chosen for the control medication because alcoholics may have

vitamin deficiencies, of which this is one.

An independent assessor, blind to the medication received, saw each

patient and informant at intake, again at weeks 2 and 4, and monthly

thereafter until the final interview at 6 months. Interview questions

concerned alcohol consumption, alcohol dependence, and alcohol-related

health and social problems. Blood tests to measure alcohol-related liver

dysfunction were taken at intake, and after 1, 3, and 6 months of

treatment. All data were used on an “intention-to-treat” basis irrespective

of patient compliance, and attempts were made to follow up all patients.

Fifty-seven patients (i.e., 45 percent of the sample, consisting of 28 on

disulfiram, 29 on vitamin C) did not adhere to their assigned treatment,

45 through failure to keep appointments or by withdrawing consent.

Followup interviews were not obtained in 20 percent (15 disulfiram

81
patients, 14 vitamin C patients). Both initial and final blood samples

were available in only 57 percent, because at followup some patients

were interviewed by telephone; also, at intake and followup some

samples were not analyzable because of delay or damage.

Results showed that alcoholics assigned to supervised disulfiram, when

contrasted with their counterparts receiving supervised vitamin C,

realized significantly greater improvement in the 6 months after as

compared with the 6 months before study entry on number of days

abstinent, typical weekly alcohol consumption, total alcohol consumption

for the 6-month period, and in serum gamma-GT levels-a biochemical

marker of recent heavy drinking and its negative acute effects on the

liver. Alcohol-related problems (e.g., violent episodes, time off work,

police involvement) showed a strong trend (p < .06) toward significantly

greater improvements in the supervised disulfiram group. At the end of

the study, two-thirds of the patients on disulfiram wanted to continue

treatment compared with only one-quarter of those on vitamin C

(p < .001). Furthermore, there were no medically serious adverse

reactions from disulfiram-alcohol reactions or from hepatic toxicity. A

few patients taking disulfiram developed skin rash, headaches, or

tiredness, but there was no disturbance of liver function.

Thus, Chick and colleagues (1992) found that supervised disulfiram plus

outpatient counseling produced better outcomes of more abstinence and

less drinking and fewer alcohol-related social and health problems than

counseling without supervised disulfiram. Importantly too, patients

receiving disulfiram did not experience liver problems in this sample

screened to be free of liver problems at study entry. In fact, those on

disulfiram actually showed decreases in serum GT levels while the

control group showed increases. The Chick and colleagues (1992) results

particularly merit credibility given the careful outcome evaluation

methods used, including blind assessors and inclusion of dropouts in the

analyses of the study sample. Certain considerations should, however, be

noted in considering these results. There was no control group that

received disulfiram without compliance enhancement. Disulfiram

compliance was not measured directly. Forty-five percent of patients

failed to continue with the assigned treatment, a higher dropout rate than

observed in BMT and CRA studies of disulfiram contracts. The BMT

and CRA studies used a more complex disulfiram contract that was an

integral part of the patients’ counseling. Finally, the role of the

counseling was difficult to determine since it varied considerably among

the treatment centers participating in the study.

82
SUMMARY AND CONCLUSIONS

Although studies repeatedly demonstrate that alcoholics who consistently

take disulfiram experience more favorable drinking outcomes, serious

problems with compliance among the majority of alcoholic patients have

reduced the effectiveness of disulfiram as a therapeutic adjunct. In

general, alcoholism counseling with disulfiram simply prescribed seems

no more effective than counseling without disulfiram (Fuller et al. 1986).

Problems with compliance as well as problems with acceptance by

patients and likely by clinical staff reduce the utility of disulfiram in the

treatment of alcoholism.

Implants, incentives, and various forms of observed or supervised

disulfiram have been studied as possible solutions to the problems with

compliance. Disulfiram implants appear largely ineffective due to failure

to release adequate levels of disulfiram and risks of surgical

complications and rejection. Newer techniques (see Allen and Litten

1992) may ultimately lead to a more effective implant.

Incentives with personally relevant and obvious reinforcement value such

as money, avoidance of incarceration, remaining employed, and

continuation of methadone for opiate addicts, have been used effectively.

Enhancement strategies with less tangible incentives also show promise.

Among these are feedback on results of biochemical measures of

disulfiram compliance and continuation in a familiar treatment program.

Although each of the studies of incentives suffers from specific

methodological limitations, the findings uniformly demonstrate better

disulfiram compliance, less drinking, and better clinical outcomes for

those who received a meaningful incentive for taking disulfiram.

External monitoring of the patient taking disulfiram to assure compliance

is typically used in studies evaluating incentives for taking the

medication. Observed or supervised disulfiram in its own right and

without tangible incentives also has received increasing attention as a

method for enhancing compliance. Incorporation of such a strategy

would seem to have potential for wide applicability in alcoholism

treatment programs. Three forms of supervised disulfiram have been

studied: (1) a written disulfiram contract, such as in BMT, with

instructions about the benefits of the disulfiram contract and methods to

establish disulfiram use as a daily habit and specifying that the alcoholic

will take disulfiram daily while the spouse observes, that the couple will

mutually thank each other, and that they will refrain from arguments or

83
discussions about the alcoholic’s drinking; (2) the disulfiram contract

used in CRA, which is identical in form to the BMT contract except that

talk about drinking is not prohibited; and (3) supervised disulfiram

without a written contract, special instructions, or explicit verbal

thanking. Studies of these three forms of observed disulfiram have been

among the better controlled studies. Each approach has produced very

promising results.

A disulfiram contract with BMT produced less short-term drinking than

disulfiram accompanied either by couples or individual counseling.

Unfortunately, the superior BMT drinking results eroded because many

couples discontinued their disulfiram contract after treatment ended

(O’Farrell et al. 1985, 1992). Adding couples RP sessions after BMT led

to better fulfillment of the disulfiram contract and better drinking and

marital outcomes than BMT alone. These better RP outcomes persisted

for 18 to 24 months after BMT for the entire sample and throughout the

entire 30-month followup after BMT for those with more severe drinking

and marital problems (O’Farrell et al. 1993). Thus, disulfiram contracts

used with BMT are associated with less drinking and greater disulfiram

compliance, while the specific contribution of disulfiram contracts to

BMT remains to be investigated.

A disulfiram contract with CRA produced better disulfiram compliance

and less drinking than traditional counseling with a disulfiram

prescription or advice to take disulfiram (Azrin 1976; Azrin et al. 1982).

For married or cohabiting clients, the disulfiram contract with either CRA

or traditional counseling produced better compliance and more abstinence

than did traditional counseling with a disulfiram prescription, while single

clients required the CRA plus disulfiram contract to enjoy favorable

outcomes (Azrin et al. 1982).

Supervised disulfiram (without special instructions or written contract)

plus outpatient counseling produced better outcomes of more abstinence,

less drinking, and fewer alcohol-related social and health problems than

counseling without supervised disulfiram (Chick et al. 1992). This was

the largest study to date of observed disulfiram or any other strategy to

enhance disulfiram compliance. The 4.5 percent dropout rate, however,

greatly exceeded that reported by studies of BMT and CRA disulfiram

contracts.

To summarize prior research, problems with patient compliance and

acceptance have seriously limited the utility of disulfiram as a therapeutic

84
adjunct in treating alcoholism. Implantation to increase compliance has

not been successful to date. Incentives tailored specifically to the

patient’s current situation (e.g., avoiding jail for alcohol-related offenses),

however, have shown significant promise. Observed or supervised

disulfiram with its potential for wide applicability also has demonstrated

very favorable outcomes in combination with BMT, CRA, and traditional

counseling. Results have included increased compliance, reduced

drinking, and fewer alcohol-related problems.

RECOMMENDATIONS FOR FUTURE RESEARCH

Much of the research on methods to increase disulfiram compliance has

suffered serious flaws in research design, such as failure to adequately

measure alcohol consumption and extent of compliance with disulfiram,

failure to include appropriate control groups, noncomparable followup

periods between experimental groups, failure to specify characteristics of

individuals who respond to the compliance strategy and those who do

not, and omission of reports on changes in drinking status following

discontinuation of disulfiram. Further, inadequate attention has generally

been given to the counseling or behavioral intervention received by

patients, including the degree to which disulfiram and the compliance

procedures were incorporated into the treatment. Resolution of these

methodological concerns should characterize future research.

The authors repeat here and expand upon recommendations for specific

research in disulfiram compliance that were offered in an earlier paper

(Allen and Litten 1992). First, at the most fundamental level it is

important to distinguish the contributions of medication compliance and

the pharmacological activity of disulfiram. A double-blind 2 x 2 repeated

measures design would be helpful in separating these two components.

Factors would be disulfiram level (clinical versus nominal dose) and

compliance enhancement (present versus absent). Analysis of variance

would then allow these two main effects to be contrasted and would

allow their interaction effects to be explained. Beyond issues of possible

pharmacological effects of disulfiram, questions of research interest

concern the relative effectiveness of supervised disulfiram versus

unsupervised disulfiram versus no disulfiram in combination with the

major forms of counseling (BMT, CRA, traditional 12-step disease

model) used with disulfiram in prior research. The type of counseling

received by subjects should be clearly specified and standardized.

Another important question concerns the relative effectiveness and

85
patient retention with the simpler supervised disulfiram (e.g., Chick et al.

1992) versus the more complex BMT and CRA disulfiram contracts.

In future studies, alcohol consumption should be measured during and

following the period of disulfiram administration. The postmeasures

performed at the end of the intervention and throughout followup points

also are quite important since the major benefit of disulfiram is believed

to be sustained long-term sobriety. A convergent validity approach to

measurement of compliance that includes biological measures (e.g.,

riboflavin as a urinary marker of compliance as in Fuller et al. 1986) and

patient and collateral report of compliance is recommended to yield more

accurate and complete data than reliance on a single indicator of

compliance.

Second, investigations are needed to distinguish disulfiram volunteers

who consistently take the drug from those who do not. Identification of

characteristics of the noncompliant might provide important clues on

more effective enhancement strategies. Third, while research on

differential effectiveness of alternative treatment interventions with

various subtypes of alcoholic patients has recently expanded (National

Academy of Sciences 1990; National Institute on Alcohol Abuse and

Alcoholism 1990), no patient-treatment matching studies with disulfiram

as the intervention appear to have been conducted. Since disulfiram has

been touted as a “chemical time-delay device” (Azrin 1976), it is possible

to predict that impulsive drinkers, for example, might respond

particularly well to it.

Fourth, minimal duration of disulfiram compliance to achieve long-term

alcoholism treatment benefits should be determined. To date, most

investigations on disulfiram compliance techniques have considered

relatively short periods (generally 6 months or less). Perhaps there is

some minimal time period needed for disulfiram assurance to establish a

“disulfiram habit” in the patient. Following formation of a disulfiram

habit, it is possible that patients would readily continue disulfiram even

without external prompts (e.g., monitoring or incentives). Beyond this,

there is the question of how long alcoholic patients should take disulfiram

to achieve long-term stable sobriety. Fifth, externally imposed

techniques to assure disulfiram compliance probably become quite

burdensome for patients and those who monitor disulfiram ingestion. It

would be helpful to develop and test “fading” procedures for disulfiram

compliance strategies. Fading procedures might include less frequent

monitoring and moving the patient to self-reinforce the use of disulfiram.

86
Lastly, a number of additional research questions focus on problems of

acceptance of disulfiram by both patients and clinical staff in alcoholism

treatment centers. In terms of patients, perhaps the most efficient way of

enhancing disulfiram compliance will ultimately prove to be more

convincing instructions on how disulfiram may benefit them and credibly

showing them the relationship of disulfiram to their overall treatment

plan. The disulfiram contracts used in BMT and CRA may be successful,

at least in part, because they are integral to the entire treatment regime.

Unfortunately, no research has as yet reported how varying instructional

sets relate to voluntary disulfiram compliance.

In terms of staff acceptance of disulfiram, other issues seem paramount.

Concerns about possible side effects and adverse reactions coupled with

lack of familiarity on the part of physicians and treatment providers likely

reduce utilization of disulfiram. Widely accepted guidelines for use of

disulfiram that include recommended dosage, contraindications, and

medical laboratory testing needed could facilitate its use by health care

professionals. Another concern among some providers is that patients

may see disulfiram as a panacea and refrain from seeking other treatments

to reinforce commitment to long-term sobriety. The fear is that drinking

will increase rapidly once disulfiram is stopped if patients have not

developed the skills and motivation necessary for continued abstinence.

The suggestion (Chick et al. 1992) that general practitioners might

arrange for the spouse or a practice nurse supervising treatment to

monitor disulfiram compliance would alarm many alcoholism treatment

providers in the United States. Although the need for additional

counseling beyond supervised disulfiram is ultimately an empirical

question, guidelines recommending the use of disulfiram with counseling

and instructions to providers on how to integrate disulfiram with ongoing

counseling could be very helpful. A final concern among some providers

is that supervised disulfiram might contribute to destructive patterns of

relating in alcoholics’ families. Implicit in this is an assumption that the

alcoholic may resent the spouse or other family member who observes

disulfiram ingestion and that the patient and/or spouse will assume that

the spouse is responsible for sobriety maintenance. Such coercive family

behavior coupled with tendencies by the alcoholic to avoid responsibility

are thought to exacerbate the family member’s emotional distress and

reduce the alcoholic’s chance of staying sober (O’Farrell 1993b). Both

the BMT and CRA forms of the disulfiram contract include elements that

address this concern, although simpler forms of supervised disulfiram do

not.

87
Disulfiram, even with compliance assured, is likely to prove simply one

helpful component to alcoholism treatment. Further, the authors strongly

agree with Heather (1989) that a “large, properly designed treatment trial

comparing supervised with unsupervised use of disulfiram” is needed.

Research studies to distinguish benefits deriving from disulfiram and

those deriving from the compliance strategy; determining the relative

effectiveness of supervised versus unsupervised versus no disulfiram in

combination with the major forms of counseling (BMT, CRA, traditional)

used with disulfiram in prior research; identifying patients who respond

most favorably to disulfiram; and discovering what types of compliance

procedures-for example, simple, observed disulfiram as opposed to

more comprehensive BMT and CRA disulfiram contracts-perform best

and most efficiently are strongly encouraged.

REFERENCES

Allen, J.P., and Litten, R.Z. Techniques to enhance compliance with

disulfiram. Alcohol Clin Exp Res 16:1035-1041, 1992.

Azrin, N.H. Improvements in the community-reinforcement approach to

alcoholism. Behav Res Ther 14:339-348, 1976.

Azrin, N.H.; Sisson, R.W.; Meyers, R.; and Godley, M. Alcoholism

treatment by disulfiram and community-reinforcement therapy.

J Behav Ther Exp Psychiatry 13:105-112, 1982.

Bickel, W.K.; Rizzuto, P.; Zielony, R.D.; Klobas, J.; Panglosonlis, P.;

Memiy, R.; and Knight, W.F. Combined behavioral and

pharmacological treatment of alcoholic methadone patients. J Subst

Abuse 1:161-171, 1989.

Bigelow, G.; Strickler, D.; Liebson, I.; and Griffiths, R. Maintaining

disulfiram ingestion among outpatient alcoholics: A security-deposit

contingency contracting procedure. Behav Res Ther 14:378-381, 1976.

Boume, P.G.; Alford, J.A.; and Bowcock, J.Z. Treatment of skid-row

alcoholics with disulfiram. J Stud Alcohol 27:42-48, 1966.

Brewer, C., and Smith, J. Probation linked supervised disulfiram in the

treatment of habitual drunken offenders: Results of a pilot study.

Br Med J 287: 1282-1283, 1983.

Chick, J.; Gough, K.; Falkowski, W.; Kershaw, P.; Hore, B.; Mehta, B.;

Ritson, B.; Ropner, R.; and Torley, D. Disulfiram treatment of

alcoholism. Br J Psychiatry 161:84-89, 1992.

88
Cutter, H.S.G.; O’Farrell, T.J.; Choquette, K.A.; Brown, E.D.; and

McCourt, W.F. “Couples Relapse Prevention Sessions after

Behavioral Marital Therapy for Alcoholics and Their Wives:

Outcomes During Three Years after Starting Treatment.” Paper

presented at the Annual Convention of the Association for the

Advancement of Behavior Therapy, Atlanta, November 21, 1993.

Duckert, F., and Johnsen, J. Behavioral use of disulfiram in the treatment

of problem drinking. Int J Addict 22:445-454, 1987.

Fuller, R.K.; Branchey, L.; Brightwell, D.R.; Derman, R.M.; Emrick,

C.D.; Iber, F.K.; James, K.E.; Lacoursiere, R.B.; Lee, K.K.;

Lowenstam, I.; Maany, I.; Neiderhiser, D.; Nocks, J.J.; and Shaw, S.

Disulfiram treatment of alcoholism: A Veterans Administration

Cooperative Study. JAMA 256:1449-1455, 1986.

Gerrein, J.R.; Rosenberg, CM.; and Manohar, V. Disulfiram

maintenance in outpatient treatment of alcoholism. Arch Gen

Psychiatry 28:798-802, 1973.

Heather, N. Disulfiram treatment for alcoholism. Br Med J 299:471-472,

1989.

Helzer, J.E.; Burnham, A.; and McEvoy, L.T. Alcohol abuse and

dependence. In: Robins, L.N., and Regier, D.A., eds. Psychiatric

Disorders in America: The Epidemiologic Catchrnent Area Study.

New York: Free Press, 1991.

Hunt, G.M., and Azrin, N.H. A community-reinforcement approach to

alcoholism. Behav Res Ther 11:91-104, 1973.

Johnsen, J.; Stowell, A.; Stensrud, T.; Ripel, A.; and Morland, J.

A double-blind placebo controlled study of healthy volunteers given a

subcutaneous disulfiram implantation. Pharmacol Toxicol 66:227-230,

1990.

Keane, T.M.; Foy, D.W.; Nunn, B.; and Rychtarik, R.G. Spouse

contracting to increase Antabuse compliance in alcoholic veterans.

J Clin Psychol 40:340-344, 1984.

Kofoed, L.L. Chemical monitoring of disulfiram compliance: A study of

alcoholic outpatients. Alcohol Clin Exp Res 11:481-485, 1987.

Liebson, I.; Bigelow, G.; and Flamer, R.C. Alcoholism among

methadone patients: A specific treatment method. Am J Psychiatry

130:483-485, 1973.

Liebson, I.A.; Tommasello, A.; and Bigelow, G.E. A behavioral

treatment of alcoholic methadone patients. Ann Intern Med

89:342-344, 1978.

Miller, P.M. Behavioral Treatment of Alcoholism. New York: Pergamon

Press, 1976.

89
Miller, P.M., and Hersen, M. “Modification of Marital Interaction

Patterns Between an Alcoholic and His Wife.” Jackson, MS:

University of Mississippi Medical Center, 1975.

National Academy of Sciences; Institute of Medicine. Broadening the

Base of Treatment for Alcohol Problems. Washington, DC: National

Academy Press, 1990.

National Institute on Alcohol Abuse and Alcoholism. Alcohol and

Health. Seventh Special Report to the U.S. Congress. DHHS

Publication No. (ADM)90-1656. Washington, DC: Supt. of Docs.,

U.S. Govt. Print Off., 1990.

O’Farrell, T.J. A behavioral marital therapy couples group program for

alcoholics and their spouses. In: O’Farrell, T.J., ed. Treating Alcohol

Problems: Marital and Family Interventions. New York: Guilford

Press, 1993a.

O’Farrell, T.J., ed. Treating Alcohol Problems: Marital and Family

Interventions. New York: Guilford, 1993b.

O’Farrell, T.J., and Bayog, R.D. Antabuse contracts for married

alcoholics and their spouses: A method to insure Antabuse taking and

decrease conflict about alcohol. J Subst Abuse Treat 3:1-8, 1986.

O’Farrell, T.J.; Choquette, K.A.; Cutter, H.S.G.; Brown, E.D.; and

McCourt, W.F. Behavioral marital therapy with and without additional

relapse prevention sessions for alcoholics and their wives. J Stud

Alcohol 54:652-666, 1993.

O’Farrell, T.J.; Cutter, H.S.G.; Choquette, K.A.; Floyd, F.J.; and Bayog,

R.D. Behavioral marital therapy for male alcoholics: Marital and

drinking adjustment during the two years after treatment. Behav Ther

23:529-549, 1992.

O’Farrell, T.J.; Cutter, H.S.G.; and Floyd, F.J. Evaluating behavioral

marital therapy for male alcoholics: Effects on marital adjustment and

communication from before to after therapy. Behav Ther 16:147-167,

1985.

Robichaud, C.; Strickler, D.; Bigelow, G.; and Liebson, I. Disulfiram

maintenance employee alcoholism treatment: A three-phase

evaluation. Behav Res Ther 17:618-621, 1979.

Sereny, G.; Sharma, V., Holt, J.; and Gordis, E. Mandatory supervised

Antabuse therapy in an outpatient alcoholism program: A pilot study.

Alcohol Clin Exp Res 10:290-292, 1986.

Wilson, A.; Blanchard, R.; Davidson, W.; McRae, L.; and Maini, K.

Disulfiram implantation: A dose response trial. J Clin Psychiatry

45:242-247, 1984.

World Health Organization: Alcohol-Related Disabilities. WHO Offset

Publication No. 32. Geneva: World Health Organization, 1977,

90
ACKNOWLEDGEMNTS

The National Institute on Alcohol Abuse and Alcoholism grant R01

AA08637 and the Department of Veterans Affairs provided support for

preparation of this chapter. Portions of this chapter are based upon

material in Allen, J.P., and Litten, R.Z. Techniques to enhance

compliance with disulfiram. Alcohol Clin Exp Res 16:1035-1041, 1992,

and are used with permission.

AUTHORS

Timothy J. O’Farrell, Ph.D.

Associate Professor of Psychology

Department of Psychiatry

Harvard Medical School

and

Associate Chief

Psychology Service

VA Medical Center (116B1)

Brockton, MA 02401

John P. Allen, Ph.D.

Chief

Raye Z. Litten, Ph.D.

Assistant Chief

Treatment Research Branch

Division of Clinical and Prevention Research

National Institute on Alcohol Abuse and Alcoholism

National Institutes of Health

6000 Executive Boulevard

Rockville, MD 20892-7003

91
Combining Behavioral Therapy

and Pharmacotherapy for

Smoking Cessation: An Update

John R. Hughes

INTRODUCTION

The purpose of this chapter is to update a prior review on the efficacy of

combining behavioral therapy and nicotine replacement for smoking

cessation (Hughes 1991). Specifically, this chapter will review five

areas: (1) how the current zeitgeist for smoking research and treatment

differs from that of traditional drug dependence, (2) major

methodological issues in assessing combined psychological and

pharmacological treatments, (3) efficacy of combined behavioral and

nicotine replacement for smoking cessation, (4) possible behavioral

mechanisms for the improved efficacy of combined treatments, and (5)

the importance of nonefficacy outcomes in assessing combined therapy.

(Note that the term behavioral treatments will be used in this chapter to

encompass true structured behavioral treatments and treatments that have

behavioral elements; e.g., most group therapies for smoking cessation

include both behavioral and supportive therapy elements. Also, the term

“drug abuse” will refer to nonnicotine, nonalcohol drug dependence or

abuse.)

RESEARCH AND TREATMENT TRADITIONS OF NICOTINE

VERSUS OTHER DRUG DEPENDENCIES

A brief history of research on and treatment of smoking can help

understand why its traditions differ so much from those of other drugs of

abuse (Lichtenstein and Glasgow 1992; Shiffman 1993). Early research

on smoking treatment was limited to a few studies of various medications

and studies of group education sessions. In the 1960s, psychologists

successfully developed behavioral treatments such as aversive

conditioning, contingency contracting, rapid smoking, self-monitoring,

stimulus control, and relapse prevention (Shiffman 1993). Many studies

showed these techniques increased abstinence rates from 20 to 40

percent. (All abstinence rates quoted in this chapter are for 1-year

followup unless otherwise noted.)

92
Despite this success, many became disenchanted with behavior therapy

because of the large financial and labor costs it would take to offer

behavior therapy to all 50 million smokers in the United States alone

(Chapman 1985). In addition, among smokers trying to stop, less than

7 percent have been willing to attend behavior therapy (Hughes 1993a).

Thus, research focused next on briefer interventions such as self-help

materials and physician advice. These showed modest effects; i.e.,

5 to 15 percent of those treated abstained (Lichtenstein and Glasgow

1992). The utility of these brief interventions was questioned because so

many smokers were stopping on their own due to the social and public

health pressure in the 1980s.

At this same time, a general recognition of smoking as a drug dependence

disorder became codified (American Psychiatric Association 1987; U.S.

Department of Health and Human Services 1988), and a belief arose that

those who were not quitting despite the intense social pressure were the

more nicotine-dependent smokers (Coambs et al. 1989, pp. 337-348;

Hughes 1993a). In 1984, nicotine polacrilex (nicotine gum) was

marketed in the United States as the first proven antismoking medication

followed soon after by transdermal nicotine (nicotine patch) (Hughes, in

press). Because of the huge pool of smokers, these products were

financial successes, and pharmaceutical companies became very

interested in antismoking medications.

In contrast, research in and treatment of alcohol and drug dependence in

the last 20 years has differed from smoking in several aspects (table 1).

For example, in the United States, alcoholism treatment has been

dominated by the disease model and 12-step traditions (Miller and Hester

1986, pp. 121-174). Interestingly, several behavioral interventions, brief

interventions (e.g., bibliotherapy and physician advice), and some

pharmacotherapies have been shown to improve outcomes, but these

validated treatments have not been integrated into mainstream alcoholism

therapy (Miller and Hester 1986, pp. 121-174). In summary, smoking

treatment has been dominated by the necessity of clinical research

demonstrating efficacy and by concern over cost-efficacy, whereas

alcohol treatment has been dominated by allegiance to certain models of

etiology and treatment.

One other comment about smoking versus alcohol and drug abuse

research bears mentioning. Those who do research in alcohol and drug

abuse rarely cite findings or methodologies of research in smoking and

93
TABLE 1. Differences in emphusis in research on and treatment of

nicotine, alcohol, and drug dependencies. *

Nicotine Alcohol Drug

Dependence Dependence Dependence

Most accepted

etiology

Typical subjects

Psychiatric

co-morbidity

Common

research

methods

Most common Group

psychological behavior

treatment therapy

Most common

pharmacological

treatment

Replacement

Brief

interventions

Much interest

Major mode of

treatment

delivery

Public

organizations,

primary care

Major outcome Biochemicalverified

continuous

abstinence

Behavioristic

Few social

problems,

compliant

Little interest

by researchers

Large trials,

long followup

Disease model

Interpersonal

problems,

noncompliant

Depression,

anxiety,

antisocial

Moderate-size

trials,

intermediate

followup

12-step

therapy

Disulfiram

Some interest

Private clinics

Obserververified

abstinence,

functional

improvement

Pharmacological

Multiple

problems,

noncompliant

Antisocial

personality

Small trials,

shorter followup

Counseling,

group therapy

Replacement

Little interest

Federal/State

funded clinics

Clean urines,

functional

improvement

NOTE: * These are the author’s subjective impressions of reading the

literature and of conducting research and clinical practice in these

areas.

94
vice versa. This suggests researchers in one area are either unaware of

findings in another or do not believe these findings are relevant. Those

who do research in alcohol and drug abuse can learn about relapse curves,

sophisticated data analyses, public health concerns, cost-efficacy, and so

forth by reading the smoking literature. Conversely, those who do

research in smoking can learn about assessing functional status,

psychiatric co-morbidity, improving treatment retention, and so forth, by

reading the alcohol and drug abuse literature.

EFFICACY OF NICOTINE REPLACEMENT IN THE ABSENCE

OF BEHAVIOR THERAPY

Traditionally, an adjunctive psychological treatment has been thought to

be essential for pharmacotherapy for drug abuse to be effective.

However, many have hypothesized that since most smokers do not have

as severe psychological problems as alcohol, cocaine, and heroin abusers,

that perhaps pharmacotherapy in the absence of a psychological therapy

would be effective in smokers (Hughes 1993a; Jarvis 1988, pp. 145-162).

Early conclusions by this author (Hughes 1986) and others (Lam et al.

1987) that nicotine polacrilex is only effective when given with behavior

therapy appear to have been incorrect. Several recent meta-analyses have

examined nicotine polacrilex and transdermal nicotine with and without

behavioral therapy (Baillie et al. 1994; Cepeda-Benito 1993; Fiore et al.

1994a; Gourlay and McNeil 1990; Lam et al. 1987; Silagy et al. 1994;

Tang et al. 1994) (table 2). Before discussing the results of these metaanalyses, two points need to be made. First, methodological procedures

such as subject selection and type of control group have a profound effect

on the absolute abstinence rates; thus, the fairest comparative measure in

these meta-analyses is the odds ratio; i.e., the relative increase in quitting

with nicotine polacrilex over a placebo or no-drug comparison group.

Second, most studies did not adequately describe the contents of either

the behavioral or pharmacological therapy; e.g., what behavioral

techniques were used or how much medication was given for how long

(Hughes 1991).

The four meta-analyses of nicotine polacrilex without behavior therapy

reported odds ratios favoring nicotine polacrilex of 1.4, 1.5, 1.8, and 2.1

(first column, table 2). However, the absolute difference in quit rates

with nicotine polacrilex is small; i.e., 0 percent to +7 percent (second

column, table 2). In contrast, the three meta-analyses of the efficacy of

95
TABLE 2. Meta-analysis of long-term quit rate with nicotine polacrilex

(NP) or transdermal nicotine (TN) versus placebo with and

without psychological therapy (PT).

NP TN

No PT PT No PT PT

OR OR OR OR

Baillie et al.

(1994)

Cepeda-Benito

(1993)

Fiore et al.

(1994a)

Gourlay and

McNeil (1990)

Hughes (1991)

Hughes (1993a)

Lam et al.

(1987)

Silagy et al.

(1994)

Tang et al.

(1994)

2.1

1.5

1.4

1.8

+7%

+2%

+4%

0

+5%

+3%

1.7

1.7

2.1

1.4

+10%

+15%

2.5 +12% 3.4 +13%

+7%

2.6 2.4

+9%

+8% 2.1 +10% 2 +10%

+11%

KEY: OR = odds ratio; A% = percent change.

transdermal nicotine without behavior therapy reported higher odds

ratios of 2.1, 2.5, and 2.1 (fifth column, table 2) and more substantial

increases in quit rates of +10 percent and +12 percent (sixth column,

table 2).

To summarize, in contrast to pharmacotherapies for alcohol and illicit

drug abuse, pharmacotherapy for smoking cessation (especially

transdermal nicotine) is effective even when given without a structured

psychological therapy.

96
EFFICACY OF ADDING NICOTINE REPLACEMENT TO

BEHAVIOR THERAPY

Four meta-analyses have presented data that can estimate the effect of

adding nicotine polacrilex to behavior therapy (third column, table 2). In

these four meta-analyses, the odds ratio for long-term abstinence with

adding nicotine polacrilex were 1.4, 1.7, 2.1, and 2.7, and absolute quit

rates increased from +7 percent to +15 percent. Three meta-analyses

have estimated the effect of adding transdermal nicotine to behavior

therapy (next-to-last column, table 2). The reported odds ratios were 2.0,

2.4, and 3.4, and the increase in absolute quit rates was +10 percent and

+ 13 percent.

Cross-study comparisons (as in table 2) are always risky. However, one

review examined several studies in which subjects were randomly

assigned to receive or not receive behavior therapy and/or nicotine

polacrilex (Hughes 1991). Thus, these were direct experimental tests of

the efficacy of adding nicotine polacrilex. In fact, these factorial studies

crossed the presence versus absence of pharmacotherapy with the

presence versus absence of behavior therapy all within the same pool of

subjects (figure 1).

The relative increase in cessation with adding nicotine polacrilex in these

direct tests was 1.0, 1.3, 1.6, 1.7, 1.7, 1.8, and 2.5, with increases in

cessation rates of 0 percent to +20 percent. Similar factorial studies with

transdermal nicotine have not been reported. To summarize, adding

Behavior Minimal/

Therapy No Therapy

Placebo/

No Drug

FIGURE 1. Experimental design forfactorial trial

of combining behavior therapy and

drug therapy.

97
nicotine gum or nicotine patch appears to double quit rates over those

obtained with behavior therapy alone.

EFFICACY OF ADDING BEHAVIOR THERAPY TO NICOTINE

REPLACEMENT

The converse question is how much quit rates would improve if behavior

therapy was added to nicotine replacement. In terms of cross-study

comparisons, none of the meta-analyses directly examined the efficacy of

adding behavior therapy. However, two meta-analyses reported pooled

quit rates with and without behavior therapy. Comparison of these rates

indicates a +13 percent increase with adding behavior therapy to nicotine

polacrilex (Silagy et al. 1994) and a +7 percent and +6 percent increase

with adding behavior therapy to transdermal nicotine (Fiore et al. 1994a).

In the previously mentioned review of direct tests (Hughes 1991), the

odds ratios for adding behavioral therapy to nicotine polacrilex were 0.8,

1.0, 1.6, 1.7, 1.7, 1.8, and 2.5, and absolute increases in quit rates were

0 percent to +27 percent. Since that review, one other study has reported

data that, when recalculated, produces an odds ratio of 2.7 (Goldstein et

al. 1989).

In terms of direct tests of adding psychological therapy to transdermal

nicotine, this author is aware of only one randomized study (Buchkremer

et al. 1991). That study examined adding training in relapse-coping

strategies with and without booster sessions and found no increased

efficacy with adding behavior therapy. One other article compared two

studies of transdermal nicotine in which subjects received group

behavioral therapy in one but little therapy in the other (Fiore et al.

1994b). Although subjects were not randomized to groups, they were

recruited in a similar manner, the drug treatment was similar, and the

outcomes were similarly defined. Comparison of the results of these two

studies indicates an odds ratio of 3.1 for adding behavior therapy to

transdermal nicotine. To summarize, the bulk of the evidence suggests

adding behavior therapy to nicotine replacement approximately doubles

quit rates over using nicotine replacement alone.

98
COMBINED THERAPY USING OTHER THERAPIES

The only other smoking cessation medication with a substantial database

is clonidine. One meta-analysis reported an odds ratio for adding

clonidine to behavior therapy of 4.2 (Covey and Glassman 1991). No

data were available for adding behavior therapy to clonidine. Although

this result suggests clonidine is a very effective drug at potentiating

behavior therapy, many of the studies reviewed in this meta-analysis had

only short-term outcomes and were published in abstract forms (Hughes,

in press). As importantly, more recent articles have not replicated these

effects (Glassman et al. 1993; Gourlay et al. 1994; Prochazka et al. 1992).

One other study done several years ago examined combining a nonnicotine pharmacological treatment and psychological treatments

(Schwartz and Dubitsky 1967, 1968). This study was essentially a 3x3

factorial contrasting tranquilizers, placebo, and no-drug conditions with

group therapy, individual therapy, and no-contact conditions. The

psychological therapies were effective but the tranquilizers were not;

thus, combined therapy was not any better than group or individual

therapy alone.

One other study examined adding different types of psychological

therapies (Hajek et al. 1985). Adding traditional group therapy to

nicotine polacrilex improved outcome with nicotine polacrilex more than

adding didactic, therapist-oriented group therapy (28 percent versus

17 percent). Replications of this finding have yet to be published.

BEHAVIORAL MECHANISMS TO EXPLAIN INTERACTIONS OF

BEHAVIOR AND PHARMACOLOGICAL TREATMENTS

Behavioral Mechanisms to Explain Negative Interactions

Attribution theory (Davison and Valin 1969) hypothesizes that if smokers

attribute their success to medications, then without medication they

should expect to relapse. State-dependent learning (Whitehead and

Blackwell 1979, pp. 157-189) hypothesizes that relapse-prevention skills

learned while on medication will not be remembered when smokers are

off medication and, thus, smokers will relapse after stopping medications.

In contrast to these theories, there is no evidence that relapse rates are

greater after recommended or forced cessation of nicotine gum than

99
during the comparable period for no-drug or placebo groups (Fiore et al.

1994a; Hughes 1993a; Sachs et al. 1994; Silagy et al. 1994).

COMPLEMENTARY EFFECTS ACROSS MEDIATING

VARIABLES

One description of why stopping smoking can be so difficult is that it

requires trying to make major behavioral and environmental changes

while at the same time suffering from withdrawal symptoms of difficulty

concentrating, irritability, insomnia, etc. Thus, the positive effect of

combined therapy could be because behavior therapy improves

behavioral skills and nicotine replacement improves withdrawal.

Interestingly, although nicotine replacement has been shown to decrease

withdrawal (Hughes et al. 1990, pp. 317-398), whether this is the

mechanism of its efficacy is suspect, because, surprisingly, the severity of

withdrawal is only minimally related to the ability to abstain (Hughes and

Hatsukami 1992; West, in press). Similarly, whether behavior treatments

actually change behaviors that are linked to the ability to abstain is

(surprisingly) unknown (Payne et al. 1990).

COMPLEMENTARY EFFECTS ACROSS TIME

A related explanation for the efficacy of combined therapy is that nicotine

replacement helps smokers stop in the first few weeks (when withdrawal

is at its worst), and then behavioral therapy kicks in to help smokers stay

stopped (since it may take a few weeks to learn the behavioral skills). If

this were true then in a factorial experiment one would expect the

behavior-therapy-only group to have higher relapse initially but lower

relapse later; the pharmacotherapy-only group to have lower relapse

initially and greater relapse later; the untreated control group to have high

relapse both early and late; and the combined treatment to have low

relapse both early and late (figure 2). One study did report less later

relapse with behavior therapy (Goldstein et al. 1989). However, the

expected pattern illustrated in figure 2 was not seen among the seven

factorial studies with nicotine polacrilex (Hughes 1991); e.g., the nicotine

polacrilex only group did not have high relapse rates after stopping

nicotine polacrilex and the behavior therapy groups did not have less

relapse between 3- and 12-month followup. Also, the pattern of relapse

in studies of nicotine patches without behavior therapy is similar to that

100
FIGURE 2. Expected outcome if behavior therapy and

pharmacotherapy worked at different times.

of studies of nicotine patches with behavior therapy (Fiore et al. 1994a;

Sachs et al. 1994; Silagy et al. 1994).

COMPLEMENTARY EFFECTS ACROSS SUBJECTS

Another related explanation for increased quit rates with combined

therapy is that behavior therapy and pharmacological therapy are helping

two different groups of smokers. The large majority of studies have

found that nicotine polacrilex is especially helpful to the more dependent

smoker (Fagerstrom and Schneider 1989); however, for unknown

reasons, it is not a robust predictor of benefit from transdermal nicotine

(Fiore et al. 1994a; Hughes 1993a). In addition, predictors of benefit

from behavior treatments for smoking have not been identified (Fiore et

al. 1994a; Hughes 1993a). Finally, the subgroups of responders to

behavior and to psychological therapy may not be orthogonal; e.g.,

101
dependent smokers may also especially need behavior therapy and

smokers who do not need pharmacotherapy may not need behavior

therapy as well.

ONE THERAPY INCREASES COMPLIANCE WITH THE OTHER

Pharmacotherapy may decrease distracting symptoms of irritability,

difficulty concentrating, and so forth, such that smokers are more able to

comply with behavioral skills training. Conversely, behavior therapy

may provide increased motivation, which translates to improved

compliance with the pharmacotherapy. Unfortunately, few studies

reported compliance across groups. Two studies did report greater

attendance at behavior therapy in groups that also received nicotine gum

versus groups that did not receive gum, but one study reported similar use

of gum in behavior therapy and no therapy groups (Hughes 1991). No

studies reported attendance at behavior therapy as a function of drug

group (Hughes 1991).

NONEFFICACY OUTCOMES

Efficacy (i.e., the increase in abstinence rates in a given study) is but one

measure of treatment utility (Hollon and Beck 1987, pp. 437-490). Other

measures are acceptability, availability, cost-efficacy, side-effect profile,

and universality. The acceptability of behavior therapy for smoking

cessation appears very poor, as less than 7 percent of smokers will attend

free psychological therapy (Hughes 1993a). This may be due to poor

availability (see below), nonreimbursement, or the general view that

although talking therapy is often needed to overcome alcohol problems,

this is not true for smoking. The acceptability of pharmacotherapy; e.g.,

how often smokers fill physician-initiated prescriptions for nicotine

replacement, is unknown. Psychiatrists often use pharmacotherapy

initially to engage a patient in treatment and then turn to psychotherapy

(Hughes and Pierattini 1992, pp. 97-126). Whether combining

pharmacological and behavior treatments for smoking would make either

treatment more acceptable is unknown.

The availability of psychological therapy for smoking cessation often is

very poor. The most widely available treatments are those by public

organizations such as the American Cancer Society, the American Heart

Association, the American Lung Association, the Seventh-Day

102
Adventists, or hospital/clinic programs. Often these are not available in

rural areas, and even in urban areas programs often occur only 2 or 3

times a year. Thus, to avail themselves of this treatment, many smokers

would have to wait for long periods and drive many miles to attend the

treatments. The availability of pharmacotherapy may appear high

considering the large number of prescriptions that are filled. However,

surprisingly few primary care physicians prescribe nicotine replacement

appropriately (Cummings et al. 1988; U.S. Department of Health and

Human Services 1988), and specialists in smoking cessation are not likely

to arise given the lack of reimbursement from health insurance. Thus, the

availability of adequate pharmacotherapy also appears limited. In terms

of combined therapy, many withdrawal clinics either ignore or discourage

use of pharmacological treatments (Hughes 1986, pp. 141-147), and

many physicians do not refer to behavioral treatments (Cummings et al.

1988; U.S. Department of Health and Human Services 1988); thus,

combined treatment is probably even less available to the large majority

of smokers.

The cost-efficacy of brief treatments for smoking cessation is so much

greater than that of all other medical interventions that it has been termed

the gold standard for comparison (Tsevat 1992). The cost-efficacy of a

course of nicotine replacement (Oster et al. 1986) and of intensive

psychological therapy (Altman et al. 1987) also are quite good. The real

question is whether adding a second treatment is cost-effective. To

examine this, some cost estimates from another article (Hughes et al.

1991) and the quit rates for the seven factorial studies of nicotine gum

(Hughes 1991) to estimate cost per quitter were used (tables 3 and 4).

Although adding a second therapy increases quit rates, it does not do so

to the extent that it prevents an escalation in cost per quitter. There are

two ways to interpret this result. The first interpretation points to the

increased cost per quitter with combined therapy and states that, until

there are ways to determine who needs combined therapy, there should

not be reimbursement for combined therapy for all comers. The second

interpretation points out the large economic benefits of smoking

cessation; e.g., the cost-benefit of a 40- to 45-year-old moderate smoker

stopping is $19,329 (Oster et al. 1984). Since these benefits greatly

exceed the cost of the combined treatment, then combined treatment

could be justified for all comers. Although the above two arguments are

overly simplistic (Warner 1987), they do illustrate the dilemma about

cost-efficacy that combined treatments face.

103
TABLE 3. Percent abstinent in meta-analysis of seven factorial studies

of nicotine gum. *

Psychological Treatment Control Treatment

Nicotine 30 22

Control 23 18

NOTE: * Reprinted with permission from Ablex Publishing

Corporation, J Subst Abuse 3:348, 1991.

The side effects of nicotine replacement are well known and are benign

(Hughes 1993b); e.g., less than 5 percent of those on transdermal nicotine

drop out due to side effects (Hughes and Glaser 1993). Side effects from

behavioral treatment have not been examined but are possible; e.g., a

decreased probability of future quit attempts among those who fail.

Universality refers to whether a treatment can help a large group of

persons with a disorder or only a small group; thus, this notion is closely

tied to the proposed behavioral mechanism of complementary effects

across subjects; i.e., more smokers are more likely to find something of

benefit in a combined therapy than in a single therapy. As stated above,

whether or not this is true for combined treatment of smoking is unclear.

TABLE 4. Median cost per quitter across seven factorial studies of

nicotine gum.

With Behavior Therapy Without Behavioral Therapy

Nicotine $1,060 $664

Control $850 $343

104
CONCLUDING COMMENTS

The available data suggest combined behavioral and pharmacological

therapy substantially increases smoking cessation over behavior therapy

alone and over pharmacological therapy alone. However, there are many

gaps in knowledge of the issue; e.g., how much does combined therapy

increase outcome with transdermal nicotine and how does combined

therapy increase quit rates? In this era of concern over health care costs,

perhaps the more important issues are the cost-efficacy of combined

therapy and the specification of which smokers need combined therapy

and which can do well with behavioral therapy alone or with

pharmacological therapy alone.

REFERENCES

Altman, D.G.; Flora, J.A.; Fortmann, S.P.; and Farquhar, J.W. The

cost-effectiveness of three smoking cessation programs. Am J Public

Health 77:162-165, 1987.

American Psychiatric Association. Diagnostic and Statistical Manual of

Mental Disorders. 3d ed. rev. Washington, DC: American Psychiatric

Association, 1987.

Baillie, A.; Mattick, R.P.; Hall, W.; and Webster, P. Meta-analytic review

of the efficacy of smoking cessation interventions. Drug Alcohol Rev

13:179-192, 1994.

Buchkremer, G.; Minneker, E.; and Block, M. Smoking-cessation

treatment combining transdermal nicotine substitution with behavioral

therapy. Pharmacopsychiatry 24:96-102, 1991.

Cepeda-Benito, A. Meta-analytical review of the efficacy of nicotine

chewing gum in smoking treatment programs. J Consult Clin Psychol

61:822-830, 1993.

Chapman, S. Stop-smoking clinics: A case for their abandonment. Lancet

1(8434):918-920, 1985.

Coambs, R.B.; Kozlowski, L.T.; and Ferrence, R.G. The future of

tobacco use and smoking research. In: Ney, T., and Gale, A., eds.

Smoking and Human Behavior. New York: John Wiley & Sons, Ltd.,

1989.

Covey, L.S., and Glassman, A.H. A meta-analysis of double-blind

placebo-controlled trials of clonidine for smoking cessation. Br J

Addict 86:991-998, 1991.

Cummings, S.R.; Hansen, B.; Richard, R.J.; Stein, M.J.; and Coates, T.J.

Internists and nicotine gum. JAMA 260: 1565-1569, 1988.

105
Davison, G.C., and Valin, S. Maintenance of self-attributed and

drug-attributed behavior change. J Pers Soc Psychol 11:25-33, 1969.

Fagerstrom, K.O., and Schneider, N.G. Measuring nicotine dependence:

A review of the Fagerstrom tolerance questionnaire. J Behav Med

12:159-182, 1989.

Fiore, M.C.; Kenford, S.L.; Jorenby, D.E.; Wetter, D.W.; Smith, S.S.;

and Baker, T.B. Two studies of the clinical effectiveness of the

nicotine patch with different counseling treatments. Chest

105:524-533, 19946.

Fiore, M.C.; Smith, S.S.; Jorenby, D.E.; and Baker, T.B. The

effectiveness of the nicotine patch for smoking cessation: A

meta-analysis. JAMA 271:1940-1946, 1994a.

Glassman, A.H.: Covey, L.S.; Dalack, G. W.; Stetner, F.; Rivelli, S.K.;

Fleiss, J., and Cooper, T.B. Smoking cessation, clonidine, and

vulnerability to nicotine among dependent smokers. Clin Pharmacol

Ther 54:670-679, 1993.

Goldstein, M.G.; Niaura, R.; Follick, M.J.; and Abrams, D.B. Effects of

behavioral skills training and schedule of nicotine gum administration

on smoking cessation. Am J Psychiatry 146:56-60, 1989.

Gourlay, S.; Forbes, A.; Marriner, T.; Kutin, J.; and McNeil, J. A

placebo-controlled study of three clonidine doses for smoking

cessation. Clin Pharmacol Ther 55:64-69, 1994.

Gourlay, S.G., and McNeil, J.J. Antismoking products. Med J Aust

153:699-707, 1990.

Hajek, P.; Belcher, M.; and Stapleton, J. Enhancing the impact of groups:

An evaluation of two group formats for smokers. Br J Clin Psychol

24:289-294, 1985.

Hollon, S.D., and Beck, A.T. Psychotherapy and drug therapy:

Comparisons and combinations. In: Garfield, S.L. and Bergin, A.E.,

eds. Handbook of Psychotherapy and Behavior Change. New York:

John Wiley and Sons, 1987.

Hughes, J.R. Problems of nicotine gum. In: Ockene, J.K., ed.

Pharmacologic Treatment of Tobacco Dependence: Proceedings of

the World Congress, November 3-5, 1985. Cambridge, MA: Institute

for the Study of Smoking Behavior and Policy, 1986.

Hughes, J.R. Combined psychological and nicotine gum treatment for

smoking: A critical review. J Subst Abuse 3:337-350, 1991.

Hughes, J.R. Pharmacotherapy for smoking cessation: Unvalidated

assumptions and anomalies, and suggestions for further research.

J Consult Clin Psychol 61:751-760, 1993a.

Hughes, J.R. Risk/benefit of nicotine replacement in smoking cessation.

Drug Saf 8:49-56, 1993b.

106
Hughes, J.R. Nicotine dependence. In: Schuster, C.R.; Gust, S.W.; and

Kuhar, M.J., eds. Pharmacological Aspects of Drug Dependence:

Toward an Integrative Neurobehavioral Approach: Handbook of

Experimental Psychology Series. New York: Springer-Verlag, in

press.

Hughes, J.R., and Glaser, M. Transdermal nicotine for smoking cessation.

Health Values 17:24-31, 1993.

Hughes, J.R., and Hatsukami, D.K. The nicotine withdrawal syndrome: A

brief review and update. Int J Smok Cessation 1:21-26, 1992.

Hughes, J.R.; Higgins, S.T.; and Hatsukami, D.K. Effects of abstinence

from tobacco: A critical review. In: Kozlowski, L.T.; Annis, H.;

Cappell, H.D.; Glaser, F.; Goodstadt, M.; Israel, Y.; Kalant, H.;

Sellers, E.M.; and Vingilis, J., eds. Research Advances in Alcohol and

Drug Problems. Vol. 10. New York: Plenum Press, 1990.

Hughes, J.R., and Pierattini, R. Principles of pharmacotherapy for mental

disorders. In: Grabowski, J., and Vandenbos, G.R., eds.

Psychopharmacology: Basic Mechanisms and Applied Interventions:

1991 Master Lectures in Psychology. Washington, DC: American

Psychological Association, 1992.

Hughes, J.R.; Wadland, W.C.; Fenwick, J. W.; Lewis, J.; and Bickel,

W.K. Effect of cost on the self-administration and efficacy of nicotine

gum: A preliminary study. Prev Med 20:486-496, 1991.

Jarvis, M. Nicotine replacement as sole therapy or as adjunct. In:

Pomerleau, O.F.; Pomerleau, C.S.; Fagerstrom, K.O.; Henningfield,

J.E.; and Hughes, J.R., eds. Nicotine Replacement: A Critical Review.

New York: Alan R. Liss, 1988.

Lam, W.L.; Sze, P.C.; Sacks, H.S.; and Chalmer, T.C. Meta-analysis of

randomized controlled trials of nicotine chewing gum. Lancet 2:27-29,

1987.

Lichtenstein, E., and Glasgow, R.E. Smoking cessation: What have we

learned over the past decade? J Consult Clin Psychol 60:518-527,

1992.

Miller, W.R., and Hester, R.K. The effectiveness of alcoholism treatment:

What research reveals. In: Miller, W.R., and Heather, N., eds. Treating

Addictive Behaviors: Processes of Change. New York: Plenum Press,

1986.

Oster, G.; Colditz, G.A.; and Kelly, N.L. The Economic Costs of Smoking

and Benefits of Quitting. Lexington, MA: D.C. Heath and Company,

1984.

Oster, G.; Huse, D.M.; Delea, T.E.; and Colditz, G.A. Cost-effectiveness

of nicotine gum as an adjunct to physicians’ advice against cigarette

smoking. JAMA 256:1315-1318, 1986.

107
Payne, T.J.; Etscheidt, M.; and Corrigan, S.A. Conditioning arbitrary

stimuli to cigarette smoke intake: A preliminary study. J Subst Abuse

2:113-119, 1990.

Prochazka, A.V.; Petty, T.L.; Nett, L.; Silvers, G.W.; Sachs, D.P.L.;

Rennard, S.I.; Daughton, D.M.; Grimm, R.H., Jr.; and Heim, C.

Transdermal clonidine reduced some withdrawal symptoms but did

not increase smoking cessation. Arch Int Med 152:2065-2069, 1992.

Sachs, D.P.L.; Bostrom, A.G.; and Hansen, M.D. “Relapse Hazard

Functions During and After Nicotine Patch Smoking Cessation

Treatment.” Abstract presented at the Society of Behavioral Medicine

Meeting, Boston, April 12, 1994.

Schwartz, J.L., and Dubitsky, M. The smoking control research project:

Purpose, design, and initial results. Psychol Rep 20:367-376, 1967.

Schwartz, J.L., and Dubitsky, M. One-year follow-up results of a

smoking cessation program. Can J Pub Health 59:161-165, 1968.

Shiffman, S. Smoking cessation treatment: Any progress? J Consult Clin

Psychol 61:718-722, 1993.

Silagy, C.; Mant, D.; Fowler, G.; and Lodge, M. The effectiveness of

nicotine replacement therapies in smoking cessation. Online J Curr

Clin Trials 113: [7,906 words; 110 paragraphs], 1994.

Tang, J.L.; Law, M.; and Wald, N. How effective is nicotine replacement

therapy in helping people to stop smoking? Br Med J 308:21-25,

1994.

Tsevat, J. Impact and cost-effectiveness of smoking interventions.

(Supplement 1 A). Am J Med 93:43S-47S, 1992.

U.S. Department of Health and Human Services. The Health

Consequences of Smoking: Nicotine Addiction: A Report of the U.S.

Surgeon General. Washington, DC: Supt. of Docs., U.S. Govt. Print.

Off., 1988.

Warner, K.E. Health and economic implications of a tobacco-free society.

JAMA 258:2080-2086, 1987.

West, R.J. The “nicotine replacement paradox” in smoking cessation:

How does nicotine gum really work? Br J Addict 87:165-167, 1992.

Whitehead, W.E., and Blackwell, B. Interactions between drugs and

behavior therapy. In: McNamara, J.R., ed. Behavioral Approaches to

Medicine. New York: Plenum Press, 1979.

108
AUTHOR

John R. Hughes

Human Behavioral Pharmacology Laboratory

Department of Psychiatry

University of Vermont

38 Fletcher Place

Burlington, VT 05401-1419

109
Integrating Psychological and

Pharmacological Treatment of

Dually Diagnosed Patients

Roger D. Weiss, Shelly F. Greenfield, and Lisa M. Najavits

INTRODUCTION

In the past decade, there has been substantially increased interest in

patients with coexisting psychiatric illness and substance use disorders

(Meyer 1986a; Minkoff and Drake 1991; Mirin 1984). Two main factors

have contributed to the interest in this subject. First, studies of both

primary substance abusers (Mirin et al. 1991; Ross et al. 1988;

Rounsaville et al. 1991) and patients with primary psychiatric disorders

(Caton et al. 1989; Drake and Wallach 1989; McLellan and Druley 1977)

in clinical settings have revealed substantial rates of co-morbidity with

the other disorder. Moreover, results of the National Institute of Mental

Health Epidemiological Catchment Area study (Regier et al. 1990)

confirmed that the frequent association between substance use disorders

and psychiatric illness is not due to the bias inherent in studying clinical

populations, but occurs in the general population at a significantly higher

rate than would be expected by chance alone.

A second reason for the interest in these so-called “dually diagnosed”

patients is the fact that research conducted in the early 1980s (McLellan

et al. 1983) revealed that substance abusers with high levels of psychiatric

severity (regardless of the exact nature of the specific coexisting

psychiatric disorder) had poor treatment outcomes. In a series of studies

by McLellan (1986, pp. 97-139), the level of psychiatric severity was the

most robust predictor of treatment outcome in their population of alcohol

and drug-dependent patients. Moreover, certain forms of traditional drug

abuse treatment, such as the confrontational approach utilized in

residential therapeutic communities (TCs), were found to be particularly

ill-suited for patients with coexisting psychiatric illness, as demonstrated

by the finding that such patients who were treated in TCs had worse

outcomes with longer treatment.

The combined findings of high rates of co-morbidity and a growing

recognition of the ineffectiveness of traditional forms of substance abuse

110
treatment for dually diagnosed patients has led clinicians and researchers

in recent years to (a) characterize more clearly the relationship between

substance abuse and psychiatric disorders, and (b) search for effective

approaches to the treatment of this patient population.

THE RELATIONSHIP BETWEEN SUBSTANCE ABUSE AND

PSYCHOPATHOLOGY

In treating a patient with a substance use disorder and coexisting

psychiatric illness, it is important to understand the potential relationship

between the patient’s two disorders. Meyer (1986b) has described six

different ways in which substance abuse and psychopathology may

interrelate: (a) Axis I or Axis II disorders may act as risk factors for

substance use disorders, (b) psychopathology may affect the course of a

substance use disorder, (c) psychiatric symptoms may develop in the

course of chronic intoxication, (d) chronic substance use may lead to the

development of psychiatric disorders that do not remit despite cessation

of substance use, (e) substance use and psychiatric symptoms may

become meaningfully linked over time, and (f) the two disorders may

coexist without being related to each other.

In addition to the multiple potential relationships between substance use

disorders and psychiatric illness, it is important to recognize the

multiplicity of clinical presentations that can be subsumed by the term

“dually diagnosed” patient (Weiss et al. 1992a). For example, the nature,

length, and severity of psychopathology and of the substance use disorder

may vary widely. Dually diagnosed patients thus include a broad range

of individuals, including patients with chronic severe mental illness and

relatively mild substance use disorders, as well as patients with severe

substance dependence and mild psychopathology, e.g., a simple phobia

that is unrelated to the substance use. Moreover, even patients with the

same two disorders, e.g., alcohol dependence and depression, may have

different severity patterns based on a number of factors, including which

disorder occurred initially (i.e., which disorder was “primary”). For

example, Weissman and colleagues (1977) noted that patients with

secondary depression and primary substance use disorder had less severe

depressive symptoms than patients with primary mood disorder and

secondary substance use disorder. This heterogeneity in patients who are

dually diagnosed underscores the need to develop a variety of treatment

approaches when working with this population.

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GENERAL PRINCIPLES IN TREATING DUALLY DIAGNOSED

PATIENTS

A number of studies (Kosten et al. 1987; McLellan et al. 1981) have

shown that although patients with substance use disorders may have a

wide range of problems associated with their addiction, these problems

(including psychiatric problems) are not necessarily caused by their

addictive disorder, and therefore do not necessarily improve merely as a

result of achieving abstinence. Therefore, there has been increasing

recognition that patients with coexisting substance use disorders and

psychiatric illness need to receive treatment for both disorders, as well as

for associated problems such as vocational, legal, medical, and

interpersonal difficulties (McLellan et al. 1992, pp. 231-252). Although

there are differences of opinion regarding which specific techniques to

utilize in dual diagnosis treatment, several stages have commonly been

described in the treatment of these patients: crisis intervention, medical

and psychiatric stabilization, engagement, motivation or “persuasion” of

the patient to seek substance abuse treatment, asking the patient to make a

commitment to pursue active treatment, and relapse prevention (Fariello

and Scheidt 1989; Kofoed and Keys 1988; Minkoff 1989; Ridgely 1991,

pp. 29-42). Since both psychiatric illnesses (particularly those of greater

severity) and addictive disorders are frequently accompanied by

minimization or denial of symptoms, overcoming this resistance to

treatment (which is frequently related to feelings of shame, stigma, and

hopelessness) is an important early step in the treatment process.

There has been some controversy over whether the treatment of dually

diagnosed patients should occur in an “integrated” or a “sequential”

program (Minkoff 1989). Integrated treatment programs, which provide

simultaneous substance abuse and psychiatric treatment, have recently

gained favor (Minkoff 1989; Ries and Ellingson 1990), although the

authors are aware of no studies that have clearly demonstrated the

superiority of this approach over sequential treatment, in which dually

diagnosed patients receive episodes of substance abuse treatment and

psychiatric treatment in sequence (in either order, depending on the

patient, program, or response to treatment).

Despite some fundamental differences in the integrated versus sequential

models, one similarity between the approaches is the general use of

pharmacotherapy to primarily treat the patient’s psychiatric disorder (Siris

1990), with the implicit hope that improvement in psychiatric symptoms

112
will (a) help make a patient more accessible to psychosocial treatment for

substance abuse, and (b) reduce the patient’s vulnerability to relapse to

substance use by diminishing symptoms such as psychosis, depression, or

anxiety. Indeed, one of the problems with some of the early studies of

antidepressant treatment of alcoholic patients was related to this implicit

assumption. Indeed, some such studies failed to measure changes in both

depression and drinking behavior as outcome measures (Ciraulo and Jaffe

1981). One of the advances in more recent clinical and research

approaches to this topic has been the clear understanding that the

treatment of dually diagnosed patients requires specific attention to both

disorders, and measurement of outcome in both domains.

POTENTIAL EFFECTS OF COMBINING PSYCHOTHERAPY

WITH PHARMACOTHERAPY

The integration of psychotherapeutic and pharmacologic approaches to

psychiatric illnesses other than substance abuse has been the subject of a

great deal of research (Beitman and Klerman 1991; Karasu 1982;

Sarwer-Foner 1983, pp. 165-180). Klerman (1991, pp. 3-19) has outlined

a number of potential interactional effects between pharmacologic

treatment and psychotherapy. He has divided these into both positive and

negative effects; the potential effects of pharmacotherapy on psychotherapy are listed in table 1.

Klerman (1991, pp. 3-19) also has described the potential beneficial and

detrimental effects of psychotherapy on psychopharmacologic treatment.

First, some individuals may hold the belief that since psychotropic drug

treatment is designed to correct an underlying metabolic or biochemical

imbalance or dysfunction, then adding psychotherapy (while not

necessarily harmful) would represent an unnecessary investment in time,

energy, and expense. Moreover, it is possible that exploratory

psychotherapy, particularly when undertaken early in the treatment

process, may disrupt early defenses and undo some of the healing and

“sealing over” that is facilitated by the use of medications. It is important

to note that these potential objections to psychotherapy are theoretical and

not based on empirical studies that demonstrate the worsening of patients

when psychotherapy is added to their pharmacotherapeutic regimen.

Theoretical benefits to the addition of psychotherapy to medication

treatment include (a) the facilitation of medication compliance by helping

the patient to further understand the nature of his or her illness and

113
TABLE 1. Potential positive and negative effects of pharmacologic

treatment on psychotherapy.

Positive Effects

1. Medications facilitate accessibility to psychotherapy.

2. Medications influence the ego-psychological functions

(cognitive functioning, attention, verbal skills, concentration)

required for participation in psychotherapy.

3. Medications may promote abreaction.

Negative Effects

1. Reduction of symptoms may lead patients to stop

psychotherapy.

2. Medications may undercut defenses.

3. For patients who value psychotherapy, the use of

medications may be seen as a failure on their part.

enhancing motivation for positive change; and (b) the correction of

associated difficulties such as interpersonal problems and poor

self-esteem, which may occur as a result of having a psychiatric illness.

Patients with substance use disorders, even in the absence of associated

psychopathology, are frequently noncompliant with medication regimens

and suffer from poor self-esteem, shame, interpersonal difficulties, and a

variety of other associated problems. It therefore could be posited that

psychotherapeutic interventions with dually diagnosed patients, who

experience these difficulties in a more profound way as the result of

having more than one illness, would serve to both help improve

compliance and to assist in the rehabilitative process. Since ensuring

medication compliance is one of the primary treatment goals in working

with psychiatric patients, and since dually diagnosed patients tend to have

poorer medication compliance than either patients with substance use

disorders alone or psychiatric illness alone (Drake et al. 1989), addressing

this issue is critical.

TREATMENT OUTCOME STUDIES WITH DUALLY

DIAGNOSED PATIENTS

Despite evidence from studies of both substance abusers and other

psychiatric patients that a combination of psychotherapy and

114
pharmacotherapy is more effective than either alone, there have been

virtually no studies of this subject in dually disordered patients. Rather,

most treatment studies of patients with substance use disorders and

coexisting mood or anxiety disorders have thus far involved trials of

medications that are primarily designed to treat the coexisting psychiatric

illness, with the hope that by carefully identifying and treating coexisting

psychiatric disorders in substance abusers, the outcome of their substance

use disorders can be improved as well. Studies of patients with psychotic

and substance use disorders have, on the other hand, primarily focused on

psychosocial strategies that integrate the treatment of the two disorders;

the medications used are generally held constant and are typically those

medications ordinarily prescribed for the treatment of psychosis.

DEPRESSION

A number of studies have examined the treatment of depressed substance

abusers with antidepressants (Weiss and Mirin 1989). Despite the

aforementioned methodological flaws of early antidepressant studies,

more recent research has suggested the potential benefit of this treatment

approach, at least for improving mood. Nunes and colleagues (1993)

studied the efficacy of imipramine in patients with primary depression

and alcoholism. They treated 60 such patients in a 12-week open-label

trial; the 35 patients (58 percent) who were judged to be responders

during this initial period (i.e., they had substantial improvement in both

mood and drinking behavior), were then offered the opportunity to enter

a double-blind, placebo-controlled, 6-month discontinuation trial.

Twenty-six patients entered this phase of the study, 23 of whom

completed the trial. Four of 13 patients (31 percent) relapsed on

imipramine, as compared with 7 of 10 (70 percent) who relapsed on

placebo (p = 0.09). The authors noted that in a subgroup of patients,

imipramine had a more powerful effect on mood than on drinking.

Moreover, patients with coexisting panic disorder appeared to have a

more robust response to imipramine than did patients with depression

alone.

A small study of desipramine for patients with depression secondary to

alcoholism also suggested its potential utility. Mason and colleagues

(1992) compared 11 patients on desipramine with 10 patients on placebo

in a 6-month random assignment trial and found that patients treated with

desipramine had significantly more sober days and significantly fewer

depressive symptoms than patients who were given placebo.

115
Thus, recent studies of antidepressant treatment of coexisting depression

and alcoholism suggest the possibility of a positive response, although the

major benefit of this treatment approach may be the reduction of

depressive symptoms. Although this is intrinsically helpful, mood

improvement is not necessarily associated with a corresponding reduction

in drinking. These studies have generally been hampered by small

sample sizes and a number of confounding variables (e.g., the mixture of

patients with major depression and dysthymia, primary alcoholism and

primary depression, and patients with and without coexisting panic

disorder), all of which render clear interpretation of these data difficult.

Studies of antidepressants in depressed opioid addicts receiving

methadone maintenance treatment have been plagued by analogous

methodological problems, and have thus yielded similarly modest results.

In most such studies, depression was diagnosed on the basis of a current

assessment of depressive symptoms rather than a lifetime clinical

historical assessment. Moreover, virtually all of these studies have had

small sample sizes, thus increasing the possibility of a type II error (i.e.,

accepting a false-negative result as true) in the interpretation of results.

As with the studies of depressed alcoholics, the effect of antidepressants

on mood has been more robust than the effect on drug use (Weiss and

Mirin 1989). In a recent study of imipramine in 17 methadone

maintenance patients with either primary or chronic depression, 9 (53

percent) improved on measures of both mood and drug use after being

treated with imipramine for a period of time ranging from 6 weeks to 11

months (Nunes et al. 1991). However, patients with dysthymia and major

depression were both included, and the potential confounding effect of

coexisting panic disorder in some patients may have affected these

results. Moreover, this was an open-label study, and previous work with

this population has shown the potential importance of a response to either

a placebo or the extra attention and psychosocial treatment given to

research subjects (Kleber et al. 1983).

Ziedonis and Kosten (1992, p. 365) conducted a comparative study of

amantadine, desipramine, and placebo in 20 depressed and 74

nondepressed cocaine-abusing methadone maintenance patients; all

patients also received relapse prevention treatment. The depressed

patients who were treated with placebo had a significantly worse

treatment outcome than the nondepressed group. However, the depressed

patients who were treated with medication reported significantly less

cocaine use than the depressed patients who were given placebo. Thus,

these data suggest that relapse prevention treatment alone is not

116
particularly effective for depressed, cocaine-abusing methadone

maintenance patients. However, a combination of relapse prevention

treatment and medication may be beneficial for this population.

In sum, while there are some encouraging findings regarding the potential

efficacy of antidepressants in substance abusers with coexisting

depression, methodological difficulties involved in performing these

studies have limited the generalizability of their results. Moreover, the

most powerful effect of antidepressants in these patients appears (not

surprisingly) to be a reduction in depressive symptoms. Unfortunately,

while this may be associated with a corresponding reduction in substance

use in some patients, this is not universally true. This appears to be an

area in which the interaction between psychotherapeutic interventions and

pharmacotherapies could be very important and should be studied. For

example, it would be important to know which patients exhibit

improvement in their mood symptoms and are thus able to reduce or stop

their substance use, and which patients are not. It is possible, for

instance, that factors that influence the likelihood of improvement in

substance use are independent of the nature and/or severity of the

patient’s coexisting mood disorder. Conversely, it would be important to

study patients who do not respond to an antidepressant with mood

improvement, but who are able to stop their drug use anyway; such

patients may be responding more powerfully to a psychosocial

intervention.

BIPOLAR DISORDER

Studies of pharmacologic treatment of patients with substance abuse and

bipolar disorder have yielded mixed results. Although an early small

study by Gawin and Kleber (1984) found that lithium helped cocaine

abusers with cyclothymic or bipolar disorder, a subsequent study by

Nunes and colleagues (1990) showed that lithium did not help to reduce

cocaine use in patients with cocaine dependence and bipolar spectrum

disorder. These studies involved only 5 and 10 patients respectively, and

are thus limited by their increased likelihood of generating a type II error.

The authors are aware of no research on the effect of integrating

psychological and pharmacologic approaches to the treatment of patients

with bipolar disorder and substance abuse.

Although Goodwin and Jamison (1990) report that there are no specific

guidelines for the treatment of patients with coexisting drug dependence

117
and bipolar disorder, they postulate that clinical care for these patients

should follow the same general guidelines for bipolar patients with

alcohol dependence. They specify that bipolar patients with or without

alcohol use disorders need to be informed about their increased morbidity

risk if they drink alcohol. Specifically, such patients need to be told that

(1) alcohol has additive and sometimes synergistic effects with lithium,

which may affect judgment and driving; (2) lithium can alter the nature of

alcohol intoxication; (3) alcohol can affect an individual’s ability to

comply with a prescribed medication regimen; (4) alcohol can alter sleep

patterns, which can exacerbate or precipitate mania or mixed states;

(5) alcohol can induce mood changes in susceptible individuals; and

(6) patients with mixed states are especially vulnerable to decreased

treatment response if they drink alcohol.

Himmelhoch and colleagues (1983) have written that patients with

co-occurring bipolar disorder and alcohol dependence are likely to need

more frequent outpatient visits, an increased number of brief

hospitalizations, family and group therapy, and other strategies to

mobilize a social network. They posit that inpatient treatment programs

that are organized to treat both disorders concurrently are also useful for

these patients. Although patients with bipolar and substance use

disorders sometimes benefit from attending self-help groups such as

Alcoholics Anonymous and Narcotics Anonymous, such patients may

need to be forewarned that certain self-help group members may not

understand their need for prescribed medications such as lithium. Thus,

their need for the medication must be particularly emphasized by the

physician.

ANXIETY DISORDERS

Several studies (Kleinman et al. 1990; Nunes et al. 1989; Rounsaville et

al. 1991) have revealed that a substantial minority of patients with

substance use disorders also suffer from coexisting anxiety disorders.

Quitkin and colleagues (1972) published an early report on successful

imipramine treatment of a small group of patients with coexisting

substance abuse and panic disorder; both their drinking behavior and their

panic attacks improved. Since then, however, the treatment of patients

with these coexisting disorders has received relatively little attention.

Two studies of patients with substance use disorders and generalized

anxiety disorder revealed that treatment with buspirone improved

patients’ levels of anxiety. However, drinking behavior was not

118
significantly improved in the study by Tollefson and colleagues (1992),

in which 51 outpatients were randomly assigned to a 24-week trial of

either buspirone or placebo; substance use was not measured as an

outcome variable in a study of 60 patients with coexisting anxiety and

substance abuse, reported by Olivera and colleagues (1990). The

interaction between psychosocial treatment and pharmacologic treatment

was not discussed in either of these reports.

The use of benzodiazepines in the treatment of patients with coexisting

substance use disorders and anxiety disorders has long been the subject of

controversy. Although some authors (Annitto and Dackis 1990) argue

that the ongoing use of benzodiazepines in this population is

contraindicated, others (Adinoff 1992; Ciraulo et al. 1988; Lydiard 1990)

have argued that a subgroup of patients who do not respond to other

psychosocial or pharmacologic treatments may be treated successfully

with benzodiazepines without abusing them. Indeed, Adinoff (1992)

recently described a series of seven alcohol-dependent patients who had

been prescribed benzodiazepines for several years while maintaining

substantial periods of abstinence from alcohol and not developing

evidence of benzodiazepine abuse. Adinoff (1992) cautioned that these

patients are unusual, and that developing double-blind studies to further

delineate the characteristics of benzodiazepine responders may be

impractical. However, such reports point out the critical importance of

developing specific psychosocial treatment strategies that may help

patients in a high-risk group (e.g., patients with substance use disorders)

to be able to tolerate treatment with a pharmacologic agent, e.g., a

benzodiazepine, that might otherwise not be prescribed.

PSYCHOTIC DISORDERS

Much of the literature on the treatment of dually diagnosed patients has

focused on patients with substance use disorders and chronic psychotic

illness (Minkoff and Drake 1991; Pepper et al. 1981; Rosenthal et al.

1992a). However, unlike studies of patients with mood disorders,

research on this population has focused primarily on psychosocial

approaches (Hellerstein and Meehan 1987; Kofoed et al. 1986; Rosenthal

et al. 1992b). Indeed, the authors are aware of only one study of this

population that specifically investigated the effects of a medication on

substance use in a population of patients with schizophrenia. Ziedonis

and colleagues (1992) conducted a 12-week, open-label study of 27

outpatients with schizophrenia who were abusing cocaine. Twelve

119
patients received desipramine plus antipsychotic agents, whereas 15

patients received antipsychotic medications alone. All patients

participated in a Dual Diagnosis Relapse Prevention program, which

integrates psychiatric social skills training with relapse prevention

techniques traditionally used in substance abuse programs. Patients

receiving desipramine in this context had a rate of cocaine-positive urine

screens that was similar to that of the patients not receiving desipramine

during the first 2 months of treatment. However, in the third and final

month of the study, patients given desipramine and antipsychotics had

significantly fewer cocaine-positive urines than did the patients receiving

antipsychotics alone (10 percent versus 56 percent, p < .001). Moreover,

the researchers pointed out that 70 percent of the patients in this study

completed the 12-week treatment program, as compared to a 27 percent

completion rate among their patients without coexisting chronic mental

illness. Although treatment retention was somewhat greater in the group

receiving desipramine (83 percent versus 60 percent), this difference was

not statistically significant. These data therefore suggest that the Dual

Diagnosis Relapse Prevention program may have been largely

responsible for this high completion rate.

Other psychosocial treatment strategies with chronically psychotic

substance abusers have also shown some promise. Most of these

approaches emphasize the importance of integrating aspects of substance

abuse and psychiatric treatment both theoretically (Minkoff 1989) and

geographically (Rosenthal et al. 19926). Integrated treatment for these

patients may include psychotropic medications, supportive

psychotherapy, peer group support of sobriety, psychoeducation, drug

abuse counseling, self-help groups, case management, family support,

and occupational therapy (Rosenthal et al. 1992b). Drake and colleagues

(1993) have emphasized the importance of training mental health

professionals regarding substance use issues as a means of providing

integrated treatment. It is important to adapt standard mental health and

substance abuse treatment approaches to fit the specific needs of dually

diagnosed psychotic patients. For example, integrated treatment may

differ from traditional substance abuse treatment insofar as it views

abstinence as a long-term treatment goal rather than as a short-term

treatment requirement, since patients with psychotic illnesses may have

more frequent relapses and may be initially difficult to engage (Carey

1989; Rosenthal et al. 19926). Adaptation of treatment techniques for

dually diagnosed psychotic patients also includes prescription and

monitoring of psychotropic medications that are mindful of the patients’

substance dependence (Carey 1989); a realization that while some

120
patients may benefit from self-help group attendance, the increased

frequency of paranoid ideation in this population may make self-help

groups counterproductive for some; and decreased use of confrontation in

group and individual treatment, because of the difficulty that chronically

psychotic patients generally experience with this approach (Kofoed and

Keys 1988; Rosenthal 1992b).

Integrated treatment models have been described for both inpatient,

outpatient, and day hospital settings. For example, Minkoff (1989) has

described an integrated treatment program for hospitalized substanceabusing psychotic patients that utilizes the principles of combined

treatment described above. This dual diagnosis inpatient unit is designed

to simultaneously stabilize both psychiatric and substance use disorders,

engage the patient in both forms of treatment, and provide education and

referrals for prolonged stabilization and rehabilitation. However,

outcome data from such studies are limited. Ries and Ellingson (1990)

have described an integrated model of dual diagnosis treatment in an

inpatient setting, but have published pilot (albeit encouraging) data on

only 17 patients at 1 -month followup. Kofoed and Keys (1988) reported

on a group therapy intervention for dually diagnosed patients admitted to

a general psychiatric unit; the group was co-led by a staff member from

the substance abuse program and a staff member from the psychiatric

unit. The authors compared 109 patients on the unit that had the dual

diagnosis group with 109 patients from a similar inpatient unit in the

same hospital that had no dual diagnosis group. They found that the unit

with the group more frequently developed discharge plans that included

substance abuse treatment. However, the patients were not followed up

beyond discharge.

Although a number of outpatient programs for this population also have

been described, these, too, have presented relatively little outcome data.

Drake and colleagues (1993) recently reported 4-year outcome data from

an integrated outpatient program for patients diagnosed with both

schizophrenia and alcohol dependence. Of 18 patients followed at 4

years, 61 percent had achieved stable remission from alcohol dependence.

Alfs and McClellan (1992) designed an 8-week day hospital program for

dually diagnosed patients and found that fewer patients completed this

program (66 percent) than completed the regular day hospital program

(77 percent), although the relapse rate among those in the dual diagnosis

program (33 percent) was lower than anticipated. Fariello and Scheidt

(1989) reported on a citywide case management program that was

implemented in San Francisco for substance abusing chronically

121
psychotic patients, but outcome results for those patients are not

available. Rosenthal and colleagues (1992a, 19926) have implemented a

4-year pilot program of weekly outpatient group treatment for substanceabusing psychotic patients. Patients from a dual diagnosis inpatient unit

are randomly assigned either to the dual diagnosis outpatient group at

discharge or to traditional separate mental health and substance abuse

treatment modalities. Although descriptive data for the 30 enrolled

patients have been published (Rosenthal et al. 1992a, 1992b), outcome

data are not yet available. However, the authors reported an earlier pilot

study of 10 patients with schizophrenia and substance dependence who

attended a weekly outpatient dual diagnosis group, and they found a

decreased rate of rehospitalization for these patients during the year

following enrollment in the group (Hellerstein and Meehan 1987).

Kofoed and colleagues (1986) have described a pilot program with 32

patients enrolled in a dual diagnosis outpatient group and have reported

that although treatment retention was only 34 percent at 3 months, it

remained stable at this rate at 24 months followup.

Despite the promising early reports on the treatment of chronically

mentally ill substance abusers, the authors are aware of no published

studies that have reported data comparing different models of treatment

and their relative efficacy in these patients; specifically, no studies that

have compared the effect of two different psychosocial interventions on

the effectiveness of a psychopharmacologic treatment approach in this

population. Clearly, one reason for this is the lack of research on the

effect of medications alone for these patients. The early positive findings

from the study of cocaine-abusing schizophrenics by Ziedonis and

colleagues (1992) suggest that the investigation of the effect of

psychosocial treatment on this process is worthy of further study.

SUMMARY AND RECOMMENDATIONS

Despite the high rate of co-morbidity of substance use disorders and other

psychiatric disorders, the research literature on the treatment of these

dually diagnosed patients remains relatively sparse. Much of what is

written about the treatment of these patients is anecdotal, theoretical,

descriptive, or uncontrolled; most empirical studies with these patients

have involved small numbers of patients, whose heterogeneity has often

made interpretation of data very difficult. Controversies in the field over

diagnostic methodology, e.g., how to diagnose coexisting psychiatric

122
disorders in substance abusers (Weiss et al. 1992b), has only served to

further hamper the advance of knowledge in this field.

Among the treatment studies in dually diagnosed patients that have been

performed, virtually none have examined the interaction between

psychological and pharmacological treatment approaches. The use of

medications with these patients has generally focused on treatment of the

psychiatric disorder, fueled by the hope that this will improve outcome in

the coexisting substance use disorder. For the most part, this hope has

been incompletely fulfilled, as most such studies demonstrate more

improvement in psychiatric symptomatology than in substance use.

Although comprehensive psychosocial approaches to patients with

coexisting substance use disorders and psychotic illness have proved

promising, these findings can only be regarded as preliminary at this

time.

The discrepancy between the improvement in psychiatric symptoms and

substance use highlights the potential importance of the development of

specific behavioral or psychotherapeutic treatment modalities to treat

these dually diagnosed patients.

It is known, for example, that the treatment of carefully diagnosed

anxiety, mood, and psychotic disorders with appropriate medications

helps those disorders. It also is becoming clearer that the pharmacologic

treatment of patients with these disorders plus a substance use disorder in

the absence of a specific psychosocial treatment program designed for

this population is not optimally effective in treating the coexisting

substance use disorder. Rather, some combination treatment, similar to

the promising data of Ziedonis and colleagues (1992), who integrated

Dual Diagnosis Relapse Prevention treatment with desipramine for

cocaine-abusing schizophrenic patients, is needed in the treatment of

other dually diagnosed patients. In developing such psychological

therapies, it is important to recognize the heterogeneity of dually

diagnosed patients (Weiss et al. 1992a), and to not necessarily assume

that a dual diagnosis psychosocial treatment that is successful for

chronically psychotic patients also will be useful for patients with panic

disorder, dysthymia, personality disorders, or other psychiatric illnesses.

Rather, research is needed in the development of specific psychosocial

treatment techniques for specific subgroups of dually diagnosed patients

in order to enhance the known benefits of pharmacotherapy and improve

overall treatment outcome in this population.

123
REFERENCES

Adinoff, B. Long-term therapy with benzodiazepines despite alcohol

dependence disorder. Am J Addict 1(4):288-293, 1992.

Alfs, D.S., and McClellan, T.A. A day hospital program for dual

diagnosis patients in a VA medical center. Hosp Community

Psychiatry 43:241-244, 1992.

Annitto, W.J., and Dackis, CA. Use of benzodiazepines by alcoholics.

Reply. Am J Psychiatry 147: 129, 1990.

Beitman, B.D., and Klerman, G.L. Integrating Pharmacotherapy and

Psychotherapy. Washington, DC: American Psychiatric Press, Inc.,

1991.

Carey, K.B. Emerging treatment guidelines for mentally ill chemical

abusers. Hosp Community Psychiatry 40:341-343, 1989.

Caton, C.L.M.; Gralnick, A.; Bender, S.; and Simon, R. Young chronic

patients and substance abuse. Hosp Community Psychiatry

40:1037-1040, 1989.

Ciraulo, D.A., and Jaffe, J.H. Tricyclic antidepressants in the treatment of

depression associated with alcoholism. J Clin Psychopharmacol

1:146-150, 1981.

Ciraulo, D.A.; Sands, B.F.; and Shader, R.I. Critical review of liability

for benzodiazepine abuse among alcoholics. Am J Psychiatry

145:1501-1506, 1988.

Drake, R.E.; McHugo, G.J.; and Noordsy, D.L. Treatment of alcoholism

among schizophrenic outpatients: 4-year outcomes. Am J Psychiatry

150:328-329, 1993.

Drake, R.E.; Osher, F.C.; and Wallach, M.A. Alcohol use and abuse in

schizophrenia: A prospective community study. J New Ment Dis

177:408-414, 1989.

Drake, R.E., and Wallach, M.A. Substance abuse among the chronic

mentally ill. Hosp Community Psychiatry 40:1041-1046, 1989.

Fariello, D., and Scheidt, S. Clinical case management of the dually

diagnosed patient. Hosp Community Psychiatry 40:1065-1067, 1989.

Gawin, F.H., and Kleber, H.D. Cocaine abuse treatment: Open pilot trial

with desipramine and lithium carbonate. Arch Gen Psychiatry

41:903-909, 1984.

Goodwin, F.K., and Jamison, K.R. Manic Depressive Illness. New York:

Oxford University Press, 1990.

Hellerstein, D.H., and Meehan, B. Outpatient group therapy for

schizophrenic substance abusers. Am J Psychiatry 144:1337-1339,

1987.

124
Himmelhoch, J.M.; Hill, J.S.; and Steinberg, B. Lithium, alcohol, and

psychiatric diagnosis. J Psychiatr Treat Eval 5:83-88, 1983.

Karasu, T.B. Psychotherapy and pharmacotherapy: Toward an integrative

model. Am J Psychiatry 139:1102-1114, 1982.

Kleber, H.D.; Weissman, M.M.; Rounsaville, B.J.; Wilber, C.H.; Prusoff,

B.A.; and Riordan, C.E. Imipramine as treatment for depression in

addicts. Arch Gen Psychiatry 40:649-653, 1983.

Kleinman, P.H.; Miller, A.B.; Millman, R.B.; Woody, G.E.; Todd, T.;

Kemp, J.; and Lipton, D.S. Psychopathology among cocaine abusers

entering treatment. J New Ment Dis 178:442-447, 1990.

Klerman, G.L. Ideological conflicts in integrating pharmacotherapy and

psychotherapy. In: Beitman, B.D., and Klerman, G.L., eds. Integrating

Pharmacotherapy and Psychotherapy. Washington, DC: American

Psychiatric Press, Inc., 1991.

Kofoed, L.; Kania, J.; Walsh, T.; and Atkinson, R.M. Outpatient

treatment of patients with substance abuse and coexisting psychiatric

disorders. Am J Psychiatry 143:867-872, 1986.

Kofoed, L., and Keys, A. Using group therapy to persuade dual-diagnosis

patients to seek substance abuse treatment. Hosp Community

Psychiatry 39:1209-1211, 1988.

Kosten, T.R.; Rounsaville, B.J.; and Kleber, H.D. Multidimensionality

and prediction of treatment outcome in opioid addicts: 2.5-year

follow-up. Compr Psychiatry 28:3-13, 1987.

Lydiard, R.B. Use of benzodiazepines by alcoholics. Letter to the editor.

Am J Psychiatry 147:128-129, 1990.

Mason, B.J.; Kocsis, M.D.; and Ritvo, E.C. “Desipramine for Secondary

Depression in Alcoholism.” Presented at the 145th Annual Meeting of

the American Psychiatric Association, Washington, DC, May 2-7,

1992.

McLellan, A.T. “Psychiatric severity” as a predictor of outcome from

substance abuse treatments. In: Meyer, R.E., ed. Psychopathology and

Addictive Disorders. New York: Guilford Press, 1986.

McLellan, A.T., and Druley, H.A. Non-random relation between drugs of

abuse and psychiatric diagnosis. J Psychiatr Res 13:179-184, 1977.

McLellan, A.T.; Luborsky, L.; Woody, G.E.; and O’Brien, C.P. Are the

“addiction-related” problems of substance abusers really related?

J New Ment Dis 169:68-74, 1981.

McLellan, A.T.; Luborsky L.; Woody, G.E.; O’Brien, C.P.; and Druley,

K.A. Predicting response to drug and alcohol treatments: Role of

psychiatric severity. Arch Gen Psychiatry 40:620-625, 1983.

125
McLellan, A.T.; O’Brien, C.P.; Metzger, D.; Alterman, A.I.; Comish, J.;

and Urschel, H. Is substance abuse treatment effective-compared to

what? In: O’Brien, C.P., and Jaffe, J., eds. Addictive States. New

York: Raven Press, 1992.

Meyer, R.E. How to understand the relationship between

psychopathology and addictive disorders: Another example of the

chicken and the egg. In: Meyer, R.E., ed. Psychopathology and

Addictive Disorders. New York: Guilford Press, 1986b.

Meyer, R.E. Psychopathology and Addictive Disorders. New York:

Guilford Press, 1986a.

Minkoff, K. An integrated treatment model for dual diagnosis of

psychosis and addiction. Hosp Community Psychiatry 40:1031-1036,

1989.

Minkoff, K., and Drake, R.E. Dual Diagnosis of Major Mental Illness

and Substance Disorder. San Francisco: Jossey-Bass, Inc., 1991.

Mirin, S.M. Substance Abuse and Psychopathology. Washington, DC:

American Psychiatric Press, Inc., 1984.

Mirin, S.M.; Weiss, R.D.; Griffin, M.L.; and Michael, J.L.

Psychopathology in drug abusers and their families. Compr Psychiatry

32:36-51, 1991.

Nunes, E.V.; McGrath, P.J.; Quitkin, F.M.; Stewart, J.P.; Harrison, W.;

Tricamo, E.; and Ocepek-Welikson, K. Imipramine treatment of

alcoholism with comorbid depression. Am J Psychiatry 150:963-965,

1993.

Nunes, E.V.; McGrath, P.J.; Wager, S.; and Quitkin, F.M. Lithium

treatment for cocaine abusers with bipolar spectrum disorders. Am J

Psychiatry 147:655-657, 1990.

Nunes, E.V.; Quitkin, F.M.; Brady, R.; and Stewart, J.W. Imipramine

treatment of methadone maintenance patients with affective disorder

and illicit drug use. Am J Psychiatry 148:667-669, 1991.

Nunes, E.; Quitkin, F.; and Klein, D. Psychiatric diagnosis in cocaine

abuse. Psychiatry Res 28:105-114, 1989.

Olivera, A.A.; Sarvis, S.; and Heard, C. Anxiety disorders coexisting

with substance dependence: Treatment with buspirone. Curr Ther Res

47:52-61, 1990.

Pepper, B.; Kirshner, M.C.; and Ryglewicz, H. The young adult chronic

patient: Overview of a population. Hosp Community Psychiatry

32:463-469, 1981.

Quitkin, F.M.; Rifkin, A.; Kaplan, J.; and Klein, D.F. Phobic anxiety

syndrome complicated by drug dependence and addiction. Arch Gen

Psychiatry 27:159-162, 1972.

126
Regier, D.A.; Farmer, M.E.; Rae, D.S.; Locke, B.Z.; Keith, S.J.; Judd,

L.L.; and Goodwin, F.K. Comorbidity of mental disorders with

alcohol and other drug abuse: Results from the Epidemiological

Catchment Area (ECA) study. JAMA 264:2511-2518, 1990.

Ridgely, M.S. Creating integrated programs for severely mentally ill

persons with substance disorders. In: Minkoff, K., and Drake, R.E.,

eds. Dual Diagnosis of Major Mental Illness and Substance Disorder.

San Francisco: Jossey-Bass, Inc., 1991.

Ries, R.K., and Ellingson, T. A pilot assessment at one month of 17 dual

diagnosis patients. Hosp Community Psychiatry 41:1230-1233, 1990.

Rosenthal, R.N.; Hellerstein, D.J.; and Miner, C.R. Integrated services for

treatment of schizophrenic substance abusers: Demographics,

symptoms, and substance abuse patterns. Psychiatr Q 63:3-26, 1992a.

Rosenthal, R.N.; Hellerstein, D.J.; and Miner, C.R. A model of integrated

services for outpatient treatment of patients with comorbid

schizophrenia and addictive disorders. Am J Addict 1(4):339-348,

1992b.

Ross, H.E.; Glaser, F.B.; and Germanson, T. The prevalence of

psychiatric disorders in patients with alcohol and other drug problems.

Arch Gen Psychiatry 45:1023-1032, 1988.

Rounsaville, B.J.; Foley Anton, S.; Carroll, K.; Budde, D.; Prusoff, B.A.;

and Gawin, F. Psychiatric diagnoses of treatment-seeking cocaine

abusers. Arch Gen Psychiatry 48:43-51, 1991.

Sarwer-Foner, G.J. An overview of combined psychopharmacology and

psychotherapy. In: Greenhill, M.H., and Gralnick, A., eds.

Psychopharmacology and Psychotherapy. New York: Free Press,

1983.

Siris, S.G. Pharmacological treatment of substance-abusing schizophrenic

patients. Schizophr Bull 16:111-122, 1990.

Tollefson, G.D.; Montague-Clouse, J.; and Tollefson, S.L. Treatment of

comorbid generalized anxiety in a recently detoxified alcoholic

population. J Clin Pharmacol 12:19-26, 1992.

Weiss, R.D., and Mirin, S.M. Tricyclic antidepressants in the treatment of

alcoholism and drug abuse. J Clin Psychiatry 50(Suppl 7):4-9, 1989.

Weiss, R.D.; Mirin, S.M.; and Frances, R.J. The myth of the typical dual

diagnosis patient. Hosp Community Psychiatry 43:107-108, 1992a.

Weiss, R.D.; Mirin, S.M.; and Griffin, M.L. Methodological

considerations in the diagnosis of coexisting psychiatric disorders in

substance abusers. Br J Addict 87: 179-187, 1992b.

127
Weissman, M.M.; Pottenger, M.; Kleber, H.; Ruben, H.L.; Williams, D.;

and Thompson, W.D. Symptom patterns in primary and secondary

depression: A comparison of primary depressives with depressed

opiate addicts, alcoholics, and schizophrenics. Arch Gen Psychiatry

34:854-862, 1977.

Ziedonis, D., and Kosten, T. Depression as a treatment matching factor in

cocaine dependence treatment. In: Harris, L., ed. Problems of Drug

Dependence 1991: Proceeding of the 53rd Annual Scientific Meeting.

National Institute on Drug Abuse Research Monograph No. 119.

DHHS Pub. No. (ADM)92-1888. Washington, DC: Supt. of Docs.,

U.S. Govt. Print. Off., 1992.

Ziedonis, D.; Richardson, T.; Lee, E.; Petrakis, I.; and Kosten, T.

Adjunctive desipramine in the treatment of cocaine abusing

schizophrenics. Psychopharmacol Bull 28(3):309-314, 1992.

ACKNOWLEDGMENTS

This research was supported by grants DA-05944, DA-07693, DA07252, and DA-08631 from the National Institute on Drug Abuse and by

a grant from the Dr. Ralph and Marian C. Falk Medical Research Trust.

AUTHORS

Roger D. Weiss, M.D.

Shelly F. Greenfield, M.D.

Lisa M. Najavits, Ph.D.

Alcohol and Drug Abuse Program

McLean Hospital

115 Mill Street

Belmont, MA 02 178

128
Combining Pharmacotherapy

With Psychotherapy for

Substance Abusers With

Borderline Personality Disorder:

Strategies for Enhancing

Compliance

Marsha M. Linehan

INTRODUCTION

Treatment programs integrating both psychosocial and pharrnacotherapy

interventions are commonly recommended across the entire spectrum of

mental disorders. As this volume indicates, such integrated treatments

increasingly are recommended for the treatment of some substance abuse

problems. Combined treatments also may be recommended when the

client has a dual diagnosis of substance abuse concurrent with another

disorder. In these cases the psychotropic medications often are prescribed

for the disorder co-occurring with the substance abuse. The effectiveness

of these combined treatment programs depends on the treated individual’s

ability and willingness to comply with the requirements of both treatment

components. In psychosocial interventions, this includes attending

treatment sessions and, in the case of cognitive and behavioral therapies,

performing requisite homework assignments. In pharmacotherapy, the

individual has to take the required medications in the correct doses and,

in some cases, refrain from taking other medications or other substances

that would counteract or reduce the effectiveness of the prescribed

medication.

Compliance with treatment regimes is a continuing cause of concern

when treating substance abuse. Noncompliance with psychosocial

interventions, particularly premature treatment dropout, is common

(Allison and Hubbard 1985). Furthermore, in general psychiatric

populations, substance abuse is one of the best predictors of

noncompliance with therapy appointments (Matas et al. 1992; Sparr et al.

1993). Medication compliance, in particular, poses several problems.

Effective treatment of drug abusers with pharmacotherapy may require a

129
behavioral capability (i.e., managing drug use responsibly) that the drug

abuser simply does not have. Depending on the individual’s particular

drug use history, prescribed drugs may increase the danger of relapse to

the primary drug abuse. Finally, drug abusers in pharmacotherapy also

may participate in other treatment programs where use of any medication

is proscribed or strongly disapproved of.

While substance abusers are among the most noncompliant Axis I clients,

the addition of an Axis II disorder can further exacerbate the problems.

Matas and colleagues (1992) found that, in addition to substance abusers,

those diagnosed with a personality disorder were less likely than others to

follow through on a referral to an outpatient psychiatry program. Among

individuals diagnosed with borderline personality disorder (BPD),

dropout rates from psychotherapy in most studies average around 50

percent at the 6-month point (Koenigsberg et al., in press). In studies

investigating pharmacotherapy in this population, dropout rates also are

very high (Cowdry and Gardner 1988). Waldinger and Frank (1989)

reported interviews with 36 psychiatrists who prescribed medications for

borderline clients. By their report, on average 47 percent of those who

received medications in each therapist’s practice abused the medication at

some point. Eighty-seven percent of the therapists cited medication

misuse, including taking other than prescribed dosages or taking an

overdose, as a common problem. In a pilot study conducted in this

author’s research clinic, six of nine (67 percent) suicidal women meeting

criteria for BPD abused prescribed medications.

As reviewed elsewhere (Linehan 1993c) the overlap between substance

abuse and BPD is substantial. Among individuals meeting criteria for

substance abuse, a concomitant diagnosis of BPD is common, ranging

from 13 percent in a study of consecutive admissions to an alcohol

treatment program (Nace et al. 1983) to 66 percent among psychiatric

outpatients (Vaglum and Vaglum 1985). Up to one-third of all substance

abusers may show a high number of BPD traits (Tousignant and Kovess

1989). Looking at the overlap from the other direction, individuals

meeting criteria for BPD commonly report a history of substance abuse

(Akiskal et al. 1985) and score high on substance abuse scales (McCann

et al. 1992; Pitts et al. 1985). Estimates suggest that from 57 percent to

84 percent of BPD individuals currently or previously have met criteria

for substance abuse or dependence (Dulit et al. 1990; Zanarini et al.

1989), although the estimated number with a primary Axis I diagnosis of

substance abuse is much lower at 21 percent (Koenigsberg et al. 1985).

BPD substance abusers are uniformly more disturbed than those abusers

130
who do not meet criteria for BPD. They are more commonly co-morbid

for depressive disorders, have more frequent suicide attempts and

accidents, and score higher on impulse dyscontrol and antisocial

tendencies and lower on reality testing (Inman et al. 1985; Kosten et al.

1989).

Borderline clients, like substance abusers, are notoriously difficult to

treat. Although their frequent suicidal threats and parasuicidal behaviors

coupled with frequent displays of hostility and anger are important causes

of this difficulty, problems in obtaining compliance with therapy regimes

also are a frequent source of conflict in the treatment of these individuals.

Over the last several years, Linehan and colleagues (1991; in press-u)

have developed and evaluated an outpatient psychosocial behavioral

intervention for chronically impaired individuals meeting criteria for

BPD. The treatment, Dialectical Behavior Therapy (DBT), is

multimodal, flexible, and manualized (Linehan 1993a, 19936; Linehan et

al., in press-b). Aspects of the treatment were designed specifically to

address the multiple compliance problems encountered in treating BPD.

It is these specific treatment strategies that will be discussed in this

chapter. The general application of DBT to substance abuse problems

has previously been outlined and, thus, will only be summarized briefly

here.

DBT OVERVIEW

DBT is based on a biosocial model that synthesizes motivational and

capability deficit models of behavioral dysfunction (including substance

abuse and borderline behavioral patterns) theorizing that (1) individuals

with behavioral dysfunctions lack important interpersonal, self-regulation

(including emotion regulation), and distress tolerance skills, and

(2) personal and environmental factors both inhibit the use of behavioral

coping skills the individual does have and often reinforce dysfunctional

behavioral patterns. The tension between these two models, capability

deficit versus faulty motivation, is reflected in the frequent conflict

between etiological formulations that focus on commitment and client

responsibility as crucial to change (motivational models) and those that

focus on acceptance (surrender in Alcoholics Anonymous [AA] terms)

and development of new capabilities (relapse prevention models) as

crucial to change. In DBT, treatment requires commitment and client

responsibility, on the one hand, and, on the other, focuses considerable

therapeutic energy on accepting and validating the patient’s current

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condition. Therapeutic contingencies that reinforce functional behaviors

and extinguish or punish dysfunctional behaviors are balanced by efforts

aimed at increasing the client’s capacity to emit the requisite functional

behaviors. Confrontation is balanced by support. It was the tension and

ultimate resolution of this essential conflict between demanding that the

client change this very moment versus acceptance of the client as is that

led to the use of dialectics in the title of the treatment. As a world view,

furthermore, dialectics anchor the treatment within other perspectives that

emphasize (1) the holistic, systemic, and interrelated nature of human

functioning and reality as a whole, asking always “what is being left out

of our understanding here”; (2) searching for synthesis and balance to

replace the rigid, often extreme, and dichotomous responses characteristic

of severely dysfunctional individuals; and (3) enhancing comfort with

ambiguity and change, which are viewed as inevitable aspects of life.

With severely dysfunctional clients, including serious substance abusers,

DBT assumes that, on the one hand, necessary skill training is

extraordinarily difficult (if not impossible) within the context of a therapy

oriented to reducing motivation to engage in dysfunctional behaviors

(including drug abuse), and, on the other hand, sufficient attention to

motivational issues cannot be given in a treatment with the rigorous

control of therapy agenda needed for skill training. To resolve this

dilemma, the treatment is divided into two components: one that focuses

primarily on skill acquisition and one that focuses primarily on

motivational issues and skill strengthening. A third component is added

to foster generalization of skills to the individual’s everyday life. In

outpatient DBT, these modes are psychosocial groups (for skills training),

individual psychotherapy (addressing motivational issues and skills

strengthening), and telephone contact with the individual therapist

(addressing generalization). This mixture of many different modes of

treatment for the individual is similar to the highly complex treatment

programs often used with substance abusers (Hubbard 1992, pp. 596-

611).

In DBT as a whole, the hierarchy of treatment targets, from most to least

important, is very specific and clear as follows: (1) reducing suicidal and

other life-threatening behaviors; (2) reducing therapy-interfering

behaviors (including noncompliance); (3) reducing severe quality-of-life

interfering behaviors (including serious substance abuse); (4) increasing

skillful coping behaviors, including distress tolerance, emotion

regulation, interpersonal effectiveness, and mindfulness; (5) reducing

posttraumatic stress responses; (6) enhancing self-respect; and (7) other

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goals of the client. The hierarchy for individual psychotherapy is the

same as for the treatment as a whole, and the agenda of each individual

psychotherapy session is set weekly depending on the client’s behavior

since the last session. Target behaviors are focused on according to the

hierarchy and recursively as higher priority behaviors reappear. Highpriority behaviors are never ignored in DBT. Information about the

client’s behaviors since the last session can come from a number of

sources, including direct contact with the client, collateral reports or

phone calls, urinalyses or blood tests, verbal report by the client at the

beginning of the session, and weekly diary cards that the client brings to

each session. Besides information about suicidal ideation and deliberate

self-injurious behaviors during the week, the diary cards also elicit

information about daily use of prescribed, over-the-counter, and illicit

drugs. Failure to complete or bring the cards to the session and, if

necessary, dishonesty are targeted directly as therapy-interfering

behaviors.

PROTOCOL FOR COMBINING PHARMACOTHERAPY WITH

DBT

There is nothing in DBT that proscribes ancillary mental health care not

offered in DBT as long as these programs of treatment are clearly

ancillary to DBT and are not the primary treatment. Outpatients may be

admitted for brief psychiatric inpatient visits or residential substance

abuse programs; take psychotropic medications and see a physician,

nurse, or other pharmacotherapist for monitoring; participate in

behavioral skills classes offered in the community; attend group meetings

and meet with their counselor in residential treatment communities; see a

case manager associated with ancillary treatment; go to marriage

counseling, vocational counseling, or movement therapy; participate in

day treatment; and attend AA, Narcotics Anonymous, or similar

meetings. Clients also are likely to make occasional contact with other

mental health care professionals in crisis clinics and emergency rooms,

for example.

There are specific case management strategies that guide DBT therapists

in their interactions with ancillary treatment programs, including with

pharmacotherapists. The spirit of these strategies is that the primary role

of the DBT therapist is as consultant to the client rather than to the

client’s network. The overriding implication of this is that, in general,

DBT therapists do not intervene to adjust environments for the sake of

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the client, nor do they consult with other ancillary professionals about

how to treat the client unless the client is present. The client, not the

therapist, is the intermediary between the treatment program and other

professionals, including pharmacotherapists. The therapist’s job is to

consult with the client on how to interact effectively with the

environment, rather than consult with the environment on how to interact

effectively with the client.

The consultation-to-the-client strategies are guided by three objectives.

First, the aim of treatment is to teach clients how to manage their own

lives and care for themselves. The consultant strategy both assumes and

targets enhancement of clients’ abilities to take care of themselves, to

interact effectively with medical professionals, and to obtain whatever

services they may need. Second, the consultant strategy was designed to

decrease instances of “splitting” between DBT therapists and other

professionals treating the client. Splitting occurs when different

professionals in the person’s network hold differing opinions on how to

treat the client. By remaining in the role of a consultant to the client, the

therapist stays out of such arguments. Third, the consultant strategy

promotes respect for clients by imparting the message that they are

credible, believable, reliable, and capable of performing interventions on

their own behalf. Because health care professionals routinely exchange

information, routine use of the consultant strategy ordinarily requires

orienting ancillary professionals to the strategy. Although consultation

between professionals actually is encouraged, not discouraged, the

requirement that clients be present (and, preferably, arrange the

consultation) is somewhat different than usual consultation in the

community. In consulting with an ancillary pharmacotherapist, therefore,

the DBT therapist attends joint meetings with the client or arranges to

speak via speakerphone to the pharmacotherapist while the client is

actually present. For every rule, of course, there are exceptions and, in

medical emergencies or when the immediate safety of the client is an

issue, the DBT therapist does whatever is necessary to protect the client.

But, similar to the rehabilitation medicine model, in DBT the capabilities

of the client rather than the disabilities are the most immediate focus of

attention.

In standard DBT, the primary therapist (usually the psychotherapist) does

not supervise, manage, or prescribe psychotropic medications. Instead,

the role of the psychotherapist is to consult with the client about how to

interact effectively with physicians and nurse practitioners who do

prescribe and manage psychotropic medications. The goal is to teach the

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client to be a responsible and competent medical consumer. This policy

of separating psychosocial from pharmacotherapy interventions came

directly from the findings cited above that BPD clients often abuse

prescribed medications. In this author’s pilot work, it became

increasingly clear that when the primary therapist had the role of drug

prescriber, the client had an incentive to lie about drug abuse as a means

of obtaining more drugs from the therapist. From a behavioral point of

view, this rendered the therapist almost totally ineffective in the role of

teacher of proper drug use. Essentially, the therapist was in the position

of power with the ability to dispense the potent reinforcers that drugs

constitute, and such a role interfered with the ability of the therapist to

work collaboratively with the client regarding the proper use of

medications.

Misuse or abuse of prescribed drugs, according to the target hierarchy

described above, would be addressed in DBT as a first priority when it is

immediately life threatening or done as a way of intentionally harming

the self (e.g., parasuicidal behavior, including suicide attempts). Misuse

or abuse of prescribed drugs would be targeted as a second priority (i.e.,

as therapy-interfering behavior) when the drugs misused were prescribed

as part of DBT or as ancillary treatment for either substance abuse or

other mental health problems. All other substance abuse would be

targeted as a third priority, at least when it is clear that a life of quality is

not possible unless the substance abuse is stopped. Drug misuse is

treated using the same strategies as in treating any other problematic

targeted behavior. Briefly, these strategies require the therapist to balance

validation strategies with problem-solving strategies. Problem solving in

DBT consists of behavioral analyses of the dysfunctional behavior,

analyses of alternative functional responses, implementation of necessary

procedures to develop the requisite behavioral capabilities (skills training)

or improve motivation (application of contingency management,

exposure techniques, and cognitive modification), and application of

commitment strategies designed to enhance compliance and change.

COMPLIANCE-ENHANCING DBT STRATEGIES

A number of treatment strategies and protocols were developed

specifically to enhance both the capability and the motivation of clients to

comply with the DBT treatment regime. Although data suggest that DBT

is quite successful at enhancing treatment retention (Linehan et al. 1991),

it is not clear which components of the treatment actually are conducive

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to high compliance rates. What follows is a description of DBT strategies

that either were designed specifically to enhance compliance or are likely

related to compliance on theoretical grounds. While these strategies are a

small part of the treatment overall, they may nonetheless be important in

this context.

Orienting and Commitment Strategies

Clearly specified orienting and commitment strategies are used during the

first several meetings with clients to orient them to what DBT is about,

what is expected of them, what they can expect of the therapist, and, in

general, how and why the treatment is expected to work. The orientation,

or pretreatment meetings, are held at the very beginning between the

client and the intake person, and the goal is to forge a commitment

between the individual and the treatment program as a whole to work

together as a therapy team. Separate meetings then are held with the

individual therapist and with the group leaders to organize mutual

commitments between the individual therapist and client and between the

group leaders and the client. The first meeting of the group therapy itself

is a repeat of this process, and the goal is to obtain the commitment of the

group as a whole (including the group leaders) to work together.

Thereafter, the orienting and commitment strategies are used for

reorientation and recommitment whenever the client (1) is violating the

therapy contract or is threatening to (e.g., says he or she is quitting the

skills training); (2) is threatening suicide or other dysfunctional

behaviors, such as substance abuse; (3) appears to be making unrealistic

demands or have unrealistic expectations of the therapists or therapy; or

(4) is having difficulty using therapy appropriately (e.g., doesn’t call the

therapist when appropriate because of fear of imposing). In short, the

treatment contract is made over and over again.

Orienting. Orienting involves giving clients task information about the

process and requirements of treatment as a whole, about a specific

treatment procedure, and about what is required to implement a specific

course of action decided upon during problem solving. The rationale

here is that many apparent treatment failures to learn or change stem from

failures to understand what must be learned or changed or from

misunderstandings of the conceptual model underlying the treatment

procedure being used. Role induction has been shown to enhance

treatment retention in psychotherapy in general (LaTorre 1977) and may

enhance retention in substance abuse programs. In DBT, role induction is

used to clarify expectations about treatment, to enhance positive outcome

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expectancies, and to communicate and agree on the time limits of the

treatment. Problems that may arise in establishing and maintaining a

therapeutic alliance are discussed, and problem-solving is begun right

from the start. In addition, very similar procedures are used at every

point in therapy where some positive behavioral change or effort is

expected, for example when giving behavioral homework assignments or

when resolving conflicts about treatment or personal limits of the

therapist.

Clarity of Dropout Rules. In DBT, the initial treatment contract is for a

specified period of time, usually either 6 months or 1 year. Renewal of

the contract is contingent on the client improving during the initial period

of treatment. For clients who wish to maintain the therapeutic

relationship, this contingency counteracts their fear that improvement will

result in loss of therapy. In addition, rules for number of allowed missed

sessions are clearly specified. In standard DBT, clients are out of the

program if they miss 4 scheduled weeks of therapy in a row-either

individual or group treatment. If they “drop out” in this manner, they

cannot be readmitted to the program until the end of the contracted

period. The rule is rigidly enforced and does not depend on whether the

reason for missing is deemed “good” or “bad.” The premise is that there

is never a good reason for missing so many weeks of therapy. The

4-week rule, however, does allow a client to attend a 30-day inpatient

substance abuse program without being dropped. In general, however,

clients are told that no matter what happens, including inpatient

hospitalization, it is their responsibility to get to enough sessions to stay

in the program. The clarity and nonnegotiability of this rule is likely

effective for several reasons. First, it makes drifting out of therapy more

difficult. Many clients miss therapy thinking “I’ll go next week.” They

keep putting off returning until they are actually out. In this system, it is

clear how many weeks they can put off coming. Other clients drop out of

therapy due to shame or fear about returning after missing only one or

two sessions. This system makes it perfectly clear that if three sessions

are missed, returning is acceptable.

Commitment Strategies. Commitment to therapy and the therapeutic

goals is essential in any psychosocial intervention. With borderline and

substance abuse clients, obtaining and keeping behavioral commitments

can be especially difficult. DBT relies on a series of strategies that are

applied during the first meetings with the client and are reapplied at every

point thereafter whenever commitment appears to be slipping. They also

are applied whenever new procedures requiring the client’s cooperation

137
are to be implemented and to develop commitment to whatever

behavioral solutions the client and therapist arrive at in problem solving.

The main commitment strategies in DBT are as follows.

Marketing the treatment program to the community, especially the

community of clients, is a critical part of DBT. Marketing is based on the

idea that people keep commitments they believe in better than those they

do not believe in. Thus, once one or more action plans have been

proposed, the therapist engages the client in a discussion of the pros and

cons of actually making the proposed commitment to a specific plan or

solution. The aim is twofold: (1) to rehearse the good points of the

treatment, procedure, or action plan already evaluated and chosen, and

(2) to develop counterarguments to reservations that will almost certainly

come up later, usually when the client is alone and without help in

combating doubts.

Once a tentative commitment is made, the therapist tries to increase the

commitment if at all possible by playing the devil’s advocate. The idea

here is for the therapist to pose arguments against making a commitment.

That is, the therapist takes the place of the devil, making sure that the

counterarguments to commitment are slightly weaker than the client’s

arguments for commitment. This tactic also is helpful in enhancing the

client’s sense of choice and “illusion” of control.

The foot-in-the-door (Freedman and Fraser 1966) and the door-in-the

face techniques (Ciadini 1975) are well-known social psychology

procedures for enhancing compliance with requests and previously made

commitments. (The terms come from the initial research on door-to-door

canvassing for donations to charities.) The foot-in-the-door technique

increases compliance by making an easier first request followed by a

more difficult request (for example, first getting an agreement to set

reducing substance abuse as a goal, then asking for a commitment to stay

off drugs this week). In the door-in-the-face technique, the procedure is

reversed. One first requests something much larger than is actually

wanted and then requests something easier (for example, requesting the

client first to agree not to use any illicit drugs during the upcoming week,

then a request to call the therapist or sponsor before using drugs). A

combined procedure, asking first for something very hard, then moving

to something very easy, progressing to a more difficult request may at

times be the most effective strategy (Goldman 1986). For example,

during the initial orientation the therapist may present treatment goals

vaguely and favorably, omitting discussing the difficulty of reaching the

138
goals. After a commitment to these general goals is obtained, the

therapist then ups the ante, presenting more fully the difficulties of

achieving the goals, and subsequent commitments are obtained. After

escalating the difficulties for a few exchanges (each time getting a

commitment) the therapist may jump to a very difficult commitment, then

reduce somewhat the scope or difficulty of the request and obtain a final

commitment.

A variation on the foot-in-the-door tactic is to remind the client of

previous commitments. This always is done when the strength of a

commitment seems to be fading or when the client’s behavior is

incongruent with previous commitments. It can be particularly useful in

a crisis situation, especially when the client is threatening suicide or some

other destructive response. In reminding the client of previous

commitments, the therapist also discusses whether the client still has a

commitment made previously. If the commitment or goal is essential to

DBT (such as committing to working on reducing suicidal behavior) or to

the therapist’s own limits for conducting therapy, the therapist next

moves to establishing a recommitment. If changes do not conflict with

DBT or the therapist’s limits, then renegotiation of commitments is done.

A number of other commitment strategies also are employed such as

highlighting the freedom to choose goals and behaviors and the

simultaneous absence of reasonable alternatives, using principles of

shaping to gradually increase the level of commitment to change, and

generating hope via encouragement and appropriate praise.

Focus on Therapy-Interfering Behaviors

As noted above, reducing therapy-interfering behaviors of both client and

therapist is the second target in DBT. The focus here is on keeping

clients and therapists working together collaboratively. Although this is

likely an implicit second priority in most psychotherapies, it is rarely

discussed as explicitly as in DBT. However, the chronic nature of most

borderline clients’ problems, their high tendency to end therapy

prematurely, and the likelihood of therapist burnout and iatrogenic

behaviors when treating BPD require explicit attention with this

population. Both client and therapist behaviors that threaten the

relationship or therapeutic progress are addressed in a direct manner

immediately, consistently, and constantly, and, most importantly, before

either the therapist or the client no longer wants to continue. Interfering

behaviors of the client, such as those that interfere with actually receiving

the therapy or with other clients benefiting from therapy (in group or

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milieu settings) and that bum out or cross the personal limits of the

therapist, are treated within therapy sessions. Those of the therapist,

including any that are iatrogenic as well as behaviors that unnecessarily

cause the client distress or make progress difficult, are dealt with within

therapy sessions if brought up by the client but also are dealt with within

the consultation/supervision meeting.

SUMMARY

DBT is a comprehensive, behaviorally oriented treatment designed for

highly dysfunctional individuals meeting criteria for BPD. Many of these

criteria are characteristic of drug abusers, and some of the problems

encountered in treatment of drug abusers, especially when various

treatments are combined, are similar. The basic armamentarium of the

DBT therapist is the balancing of validation and acceptance treatment

strategies with problem-solving procedures, including contingency

management, exposure-based procedures, cognitive modification, and

skills training. In addition, a number of specific strategies have been

woven together to enhance compliance and to reduce the staff splitting

that is so frequent with this population. Those described in this chapter

include orienting and commitment strategies and the focus in DBT on

reducing therapy-interfering behavior and on consultation with the client

rather than with the client’s network.

REFERENCES

Akiskal, H.S.; Chen, SE.; Davis, G.C.; Pusantian, V.R.; Kashgariam, M.;

and Bolinger, J.M. Borderline. An adjective in search of a noun. J Clin

Psychiatry 46:1-48, 1985.

Allison, M., and Hubbard, R.L. Drug abuse treatment process: A review

of the literature. Int J Addict Behav 20:1321-1345, 1985.

Ciadini, R.B. Reciprocal concessions procedure for inducing compliance:

The door-in-the-face technique. J Pers Soc Psychol 31:206-215, 1975.

Cowdry, R.W., and Gardner, D.L. Pharmacotherapy of borderline

personality disorder: Alprazolam, carbamazepine, trifluoperazine, and

tranylcypromine. Arch Gen Psychiatry 45:111-119, 1988.

Dulit, R.A.; Fyer, M.R.; Haas, G.L.; Sullivan, T.; and Frances, A.J.

Substance use in borderline personality disorder. Am J Psychiatry

147:1002-1007. 1990.

140
Freedman, J.L., and Fraser, S.C. Compliance without pressure: The footin-the-door technique. J Pers Soc Psychol 4:195-202, 1966.

Goldman, M. Compliance employing a combined foot-in-the-door and

door-in-the-face procedure. J Soc Psychol 126: 111-116, 1986.

Hubbard, R.L. Evaluation and treatment outcome. In: Substance Abuse: A

Comprehensive Textbook. Lownson, J.H.; Ruiz, P.; Millman, R.B.;

and Langrod, J.G., eds. Baltimore: Williams and Wilkins, 1992.

Inman, D.J.; Bascue, L.O.; and Skoloda, T. Identification of borderline

personality disorders among substance abuse inpatients. J Subst Abuse

Treat 2:229-232, 1985.

Koenigsberg, H.W.; Clarkin, J.; Kernberg, O.F.; Yeomans, F.; and

Gutfreund, J. Some measures of process and outcome in the

psychodynamic psychotherapy of borderline patients. The integration

of research and psychoanalytic practice. In: Proceedings of the IPA‘s

First International Conference on Research, in press.

Koenigsberg, H.; Kaplan, R.; Gilmore, M.; and Cooper, A.M. The

relationship between syndrome and personality disorder in DSM-III:

Experience with 2,462 patients. Am J Psychiatry 142:207-212, 1985.

Kosten, T.A.; Kosten, T.R.; and Rounsaville, B.J. Personality disorders in

opiate addicts show prognostic specificity. J Subst Abuse Treat 6:163-

168, 1989.

LaTorre, R.A. Pretherapy role induction procedures. Can Psychol Rev

8:308-320, 1977.

Linehan, M.M. Cognitive Behavioral Therapy of Borderline Personality

Disorder. New York: Guilford Press, 1993a.

Linehan, M.M. The Skills Training Manual for Treating Borderline

Personality Disorder. New York: Guilford Press, 1993b.

Linehan, M.M. Dialectical behavior therapy for treatment of borderline

personality disorder: Implications for the treatment of substance abuse.

In: Onken, L.S.; Blaine, J.D.; and Boren, J.J., eds. Behavioral

Treatments for Drug Abuse and Dependence. National Institute on

Drug Abuse Research Monograph 137. NIH Pub. No. 93-3684.

Washington, DC: Supt. of Docs., U.S. Govt. Print. Off., 1993c.

Linehan, M.M.; Armstrong, H.E.; Suarez, A.; Allmon, D.; and Heard,

H.L. Cognitive-behavioral treatment of chronically parasuicidal

borderline patients. Arch Gen Psych 48:1660-1064, 1991.

Linehan, M.M.; Heard, H.E.; and Armstrong, H.E. Naturalistic follow-up

of a behavioral treatment for chronically suicidal borderline patients.

Arch Gen Psych, in press-a.

Linehan, M.M.; Tutek, D.A.; Heard, H.L.; and Armstrong, H.E.

Cognitive behavioral treatment of chronically parasuicidal borderline

patients: Interpersonal outcomes. Am J Psychiatry, in press-b.

141
Matas, M.; Staley, D.; and Griffin, W. A profile of the noncompliant

patient: A thirty month review of outpatient psychiatry referrals. Gen

Hosp Psychiatry 14:124-130, 1992.

McCann, J.T.; Flynn, P.M.; and Gersh, D.M. MCMI-II diagnosis of

borderline personality disorder: Base rates versus prototypic items.

J Pers Assess 58:105-114, 1992.

Nace, E.P.; Saxon, J.J.; and Shore, N. A comparison of borderline and

nonborderline alcoholic patients. Arch Gen Psych 40:54-60, 1983.

Pitts, W.M.; Gustin, Q.L.; Mitchell, C.; and Snyder, S. MMPI critical

item characteristics of the DSM-III borderline personality disorder.

J Nerv Ment Dis 173:628-631, 1985.

Sparr, L.F.; Moffitt, M.C.; and Ward, M.F. Missed psychiatric

appointments: Who returned and who stays away. Am J Psychiatry

150:801-805, 1993.

Tousignant, M., and Kovess, V. Borderline traits among community

alcoholics and problem-drinkers: Rural-urban differences. Can

J Psychiatry 34:796-799, 1989.

Vaglum, S., and Vaglum, P. Borderline and other mental disorders in

alcoholic female psychiatric patients: A case control study.

Psychopharmacology 18:50-60, 1985.

Waldinger, R.J., and Frank, A.F. Clinicians’ experiences in combining

medication and psychotherapy in medication and psychotherapy in the

treatment of borderline patients. Hosp Community Psychiatry 40:712-

718, 1989.

Zanarini, M.C.; Gunderson, J.G.; Frankenburg, F.R.; and Chancey, D.L.

The revised diagnostic interview for borderlines: Discriminating BPD

from other axis II disorders. J Pers Disord 3: 10-18, 1989.

AUTHOR

Marsha M. Linehan, Ph.D.

Professor of Psychology

Department of Psychology, NI-25

University of Washington

Seattle, WA 98195

142
Integration of Behavioral and

Pharmacological Treatments for

Panic Disorder: Implications for

the Treatment of Substance

Dependence

Michael W. Otto, Mark H. Pollack, Susan G. Ball, and

Jerrold F. Rosenbaum

INTRODUCTION

To illustrate possible strategies for integrating behavioral and

pharmacological interventions for the treatment of substance abuse, this

chapter considers similar issues in the conceptualization and treatment of

panic disorder. Significant advances in the treatment of panic disorder

have been achieved through basic research, analog studies, and treatment

outcome investigations. The recent National Institutes of Health (NIH)

Consensus Development Conference (National Institutes of Health 1991)

on the treatment of panic disorder identified both pharmacologic and

cognitive behavioral interventions as effective treatment strategies.

Difficulties with side effects and treatment discontinuation were cited as

limitations of pharmacologic interventions. In contrast, brief cognitive

behavioral treatments were identified as offering promising outcome in

the short and long term without side effects.

Of possible pharmacotherapies for panic disorder, high-potency

benzodiazepines and antidepressants have been well studied. In

controlled treatment trials of the short-term efficacy of high-potency

benzodiazepines, mainly alprazolam and clonazepam, panic-free rates at

treatment endpoint range from 48 percent to 70 percent (Ballenger et al.

1988; Cross-National Collaborative Panic Study 1992; Tesar et al. 1991).

Placebo response rates have ranged from 14 percent to 50 percent in these

studies. Patients treated with imipramine, the most commonly studied

tricyclic antidepressant, achieved comparable panic-free rates as patients

treated with benzodiazepines (Cross-National Collaborative Panic Study

1992), although in treatment trials problems with tolerability of

imipramine have led to large dropout rates, often in the range of 30

percent to 35 percent (Aronson 1987; Cross-National Collaborative Panic

143
Study 1992; National Institutes of Health 1991). In clinical practice,

however, gradual dosage titration has been associated with greater

tolerance of treatment (Pollack and Rosenbaum 1988). Monoamine

oxidase inhibitors (MAOIs) are considered among the most

comprehensively effective pharmacologic agents for the treatment of

panic disorder and its complications, although their use is associated with

a number of treatment-emergent side effects (Sheehan et al. 1980).

Further, patients may be daunted by the dietary proscriptions and fears of

hypertensive crises.

In comparison to pharmacotherapy, studies of short-term treatment

efficacy for behavior therapy report response rates often above 80 percent

(Barlow et al. 1989; Beck et al. 1992; Clark 1986; Michelson et al. 1990).

In one study directly comparing alprazolam treatment to behavior

therapy, a 50 percent panic-free rate was found for alprazolam compared

to an 86 percent panic-free rate for behavior therapy (Klosko et al. 1990).

Long-term followup studies of cognitive-behavioral therapy also indicate

maintenance of treatment gains. In a recent trial of panic disorder

patients treated with cognitive behavioral therapy, 81 percent remained

panic-free at a 2-year followup (Craske et al. 1991). These rates compare

favorably to long-term followup studies of medication-treated patients

that have found 50 percent to 80 percent of patients remain symptomatic

and 40 percent of patients continued to have panic attacks at followup

periods ranging from 1.5 to 6 years (Nagy et al. 1989; Noyes et al. 1989;

Pollack et al. 1994).

In summary, outcome studies of cognitive behavioral and pharmacologic

treatments indicate that these treatments are superior to wait-list control

groups or placebo treatment, and results to date indicate that cognitive

behavioral treatments may provide a higher panic-free rate and longer

maintenance of treatment gains in some groups of patients. To

understand how cognitive behavioral treatments differ from

pharmacologic treatment, and how these treatment strategies may be

combined, it is important to understand the model of panic disorder on

which these treatments are based. Cognitive behavioral interventions

follow naturally from this model. The model also highlights elements of

panic disorder that may be untreated by medication interventions and

may be especially amenable to cognitive behavioral strategies.

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A COGNITIVE BEHAVIORAL MODEL OF PANIC DISORDER

Cognitive behavioral models of panic disorder have benefited from an

extensive research base that includes both clinical and analog studies.

Cognitive behavioral accounts of panic disorder (Barlow 1988; Beck et

al. 1985; Clark 1986; Goldstein and Chambless 1978; McNally 1990)

propose that panic disorder is maintained by a “fear of fear” cycle in

which patients learn to fear the bodily sensations of anxiety itself, In

these accounts, panic episodes are viewed in the context of the

organism’s emergency response to danger. Biological differences in

emotional reactivity may facilitate this response, where some individuals

may have a lower threshold for autonomic arousal and/or the full firing of

the alarm reaction. However, it is the overattention to and catastrophic

misinterpretations of somatic sensations of anxiety that is thought to

maintain the disorder.

Under conditions of actual danger cueing the alarm reaction, attention is

typically focused on the source of the danger (e.g., focus on the physical

danger from a near car accident) rather than the sensations themselves. In

contrast, initial panic attacks often occur at a time of stress, but when no

physical danger is apparent. When the alarm reaction fires in the absence

of external danger, individuals often devote attention to the bodily

reaction itself. For patients with panic disorder, the interpretations of

these bodily sensations include some of the most fearsome events

imaginable, typically fears of death or disability triggered by the panic

sensations (“I’m about to have a stroke”; “I am having a nervous

breakdown”) or the perceived consequences of these sensations (“I am

about to lose control and everyone will notice”). These catastrophic

thoughts become cues for reactivation of the alarm response. With each

subsequent panic episode, the alarm response becomes more firmly

linked with these catastrophic cognitions and the intensification of the

anxiety reaction. Over time, patients may respond automatically with

panic to feared sensations without attention to mediating cognitions.

The fear-of-fear cycle can be intensified by anticipatory anxiety, which

increases arousal and primes the body for another emergency response.

Vigilance to feared somatic sensations ensures that subtle sensations are

noticed, essentially providing more phobic stimuli that may be interpreted

catastrophically. Together, vigilance to and catastrophic

misinterpretation of somatic sensation help feed the disorder, such that

once-innocuous stimuli become cues for panic episodes. For example,

patients frequently report fear or panic in response to subtle body

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sensations such as the increased heart rate that may occur after climbing

stairs or drinking coffee. Avoidance of physical activity or caffeine may

result. This same process accounts for the development of agoraphobic

avoidance, where the avoidance is of situations where panic attacks may

occur. Typically the strongest avoidance is of those situations where

perceived coping responses (including escape) are blocked. The

complete fear-of-fear cycle is represented in figure 1.

For the cognitive behavioral therapist, the treatment of panic disorder

becomes a task of eliminating the fear-of-fear cycle. For this task, the

clinician is faced with a number of complementary problems including:

(1) the patient’s vigilance to bodily sensations, (2) the catastrophic

interpretations of these sensations, (3) conditioned fear reactions to these

sensations, (4) the development of chronic arousal, and (5) the emergence

of agoraphobic avoidance and other maladaptive coping techniques. The

challenge of treating panic disorder thus becomes a case of eliminating

these five problems.

Current cognitive behavioral treatments commonly utilize five

components of treatment. The first is an informational component that

provides an overview of the fear-of-fear cycle and offers a basis for

understanding the patterns inherent to the disorder and a rationale for

treatment interventions. The second component is the cognitive

interventions that address the role of catastrophic thoughts and help

patients eliminate these thoughts by providing cognitive restructuring and

self-coaching strategies (Barlow and Craske 1989; Beck et al. 1985). The

third component is exposure to the somatic sensations of anxiety

associated with panic. This exposure (interoceptive exposure) is achieved

through a variety of activities such as hyperventilation, running in place,

and spinning in a chair (Barlow and Craske 1989). Interoceptive

exposure provides an opportunity both to elicit catastrophic cognitions

and rehearse coping strategies, but the primary aim is to promote

habituation to the somatic sensations themselves. The fourth component

is the somatic management skills designed to eliminate bodily reactions

that may increase panic sensations. In particular, these strategies are

aimed at providing breathing retraining using diaphragmatic and slow

breathing skills, and decreasing muscle tension using progressive muscle

relaxation procedures. A final component is exposure to avoided

situations. This in vivo exposure is associated with effective treatment of

agoraphobia by helping patients eliminate their feared reactions to

avoided situations. As noted above, short-term treatments using these

interventions, typically 10 to 15 sessions, are associated with panic-free

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FIGURE 1. Cognitive behavioral model of panic disorder (Reprinted

from Otto et al. 1992, p. 12.5).

rates above 80 percent, and maintenance of these gains at 2-year followup

(Craske et al. 1991).

FEAR-OF-FEAR AND PHARMACOLOGIC TREATMENT

To understand the interaction between pharmacologic and behavioral

treatment, it is helpful to examine the elements of the fear-of-fear cycle

that are affected by medications. From a cognitive behavioral

perspective, several actions of pharmacotherapy are likely. First,

pharmacotherapy may block generalized anxiety. A decrease in

generalized anxiety is important because, according to the fear-of-fear

model, anticipatory anxiety is a cue for vigilance to somatic sensations

and catastrophic cognitions and is the source of somatic sensations of

anxiety to be noticed. Second, pharmacotherapy raises the threshold for

the alarm reaction itself, making it more difficult for patients to have a

panic attack. Finally, pharmacotherapy may operate by providing a

conditioned safety cue. That is, patients know that they are on their

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medication and that the likelihood of panic is reduced. This knowledge

may have direct effects on the vigilance to bodily sensations and the

likelihood of catastrophic cognitions, thereby further decreasing the

likelihood of panic. The sometimes dramatic effects of safety cues on

panic may be reflected in the high placebo response rates (30 to 50

percent) found in controlled studies (Ballenger et al. 1988; CrossNational Collaborative Panic Study 1992).

Conditioned safety cue effects may be somewhat greater with

benzodiazepines relative to other medications because patients experience

a rapid anxiolytic effect after medication ingestion. This conditioned

safety cue effect may be further emphasized by difficulties with interdose

rebound anxiety, as patients experience the return of anxiety a few hours

after their last benzodiazepine dose, particularly with shorter acting

agents (Pollack and Rosenbaum 1988). High-potency benzodiazepines

may provide the strongest learning of safety cues for medication, but

patients also report a sense of safety on antidepressant treatments.

Although these hypothesized actions of pharmacotherapy are enough to

provide panic cessation in approximately 50 percent to 70 percent of

treated patients, these actions do not focus directly on elimination of

fearful reactions to somatic sensations. Hence, patients may continue a

pattern of vigilance and fear of these sensations, making it difficult for

pharmacological treatment to fully eliminate the disorder. One clear area

for the interaction between cognitive behavioral therapy and

pharmacotherapy, then, is the use of cognitive behavioral techniques,

particularly interoceptive exposure and cognitive restructuring, to

eliminate untreated “fear of fear” in patients undergoing

pharmacotherapy. In the next several sections, this type of treatment is

detailed as it is applied to medication treatment-resistant patients, patients

undergoing discontinuation of pharmacotherapy, and finally to programs

combining pharmacotherapy and behavior therapy from the initiation of

treatment.

COGNITIVE BEHAVIOR THERAPY FOR TREATMENTREFRACTORY PANIC DISORDER PATIENTS

As noted above, followup studies of patients with panic disorder who are

treated with tricyclic antidepressants and high-potency benzodiazepines

indicate that many patients remain symptomatic over the long term.

Studies utilizing assessments ranging from 1.5 years to 6 years after the

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initiation of medication treatment indicate that the majority of patients

remain on medication and 50 percent to 86 percent continue to be

symptomatic (Nagy et al. 1989; Noyes et al. 1989; Pollack et al. 1993).

As such, many patients undergoing pharmacotherapy may require

additional interventions to achieve full remission of their disorder.

In a recent study of patients with panic disorder who were treatment

refractory or relatively treatment refractory, the authors found that

cognitive behavioral strategies were effective in improving treatment

outcome (Pollack et al. 1994). Subjects for the study were 15

consecutive patients with panic disorder and agoraphobia who were

referred because of incomplete response to pharmacotherapy; eight of

these patients were defined as relatively refractory. Reasons for

inadequate treatment included: (1) the patient’s desire to control

symptoms without medication, (2) physician or patient concern about

withdrawal or addiction, (3) physician opinion that the patient had

received an adequate trial, or (4) medication side effects. The remaining

patients had received a fully adequate trial but failed to respond

satisfactorily. The panic disorder was the primary disorder under

treatment, but patients in the study had a wide range of co-morbid anxiety

and affective disorders, including one patient with a past history of

mania.

All patients were treated in a 12-week cognitive behavioral therapy group

modeled on the treatment program described by Barlow and Craske

(1989). Interventions in the group included the interoceptive exposure,

cognitive restructuring, somatic management skills, and in vivo exposure

interventions described above. Results at the endpoint of treatment and at

several months posttreatment indicated substantial improvement, with

significant decreases in both global severity of the disorder and panic

frequency. Three patients (20 percent) also discontinued part or all of

their medication treatment during the course of behavioral treatment.

The results of this open trial of behavior therapy for medication-resistant

and relatively resistant patients are consistent with previous studies

demonstrating an additive effect when pharmacotherapy and behavioral

therapy are combined. For example, Mavissakalian (1990) found that the

addition of exposure-based behavior therapy after an initial 8-week trial

of imipramine resulted in continued improvement in anxiety, depression,

and phobic avoidance. Other studies indicate that the combination of

imipramine treatment and exposure is superior to imipramine treatment

alone (Mavissakalian et al. 1983; Telch et al. 1985). When combined

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treatment is compared to in vivo exposure alone, imipramine treatment

appears to enhance the effects of exposure acutely, but not at followup

evaluations (Mavissakalian and Michelson 1986a, 1986b; Telch et al.

1985). However, a recent study by Marks and colleagues (1993a)

examining the combination of exposure treatment and benzodiazepine

treatment found no incremental benefit when alprazolam was combined

with exposure treatment for patients with panic disorder and significant

agoraphobic avoidance. In addition, alprazolam treatment appeared to

hinder the maintenance of gains resulting from exposure treatment when

the alprazolam was discontinued. Notably, the Marks and colleagues

(1993a) protocol did not include a specialized program for the

discontinuation of alprazolam treatment, nor did it include interoceptive

exposure and cognitive restructuring treatment elements.

COGNITIVE BEHAVIORAL THERAPY FOR BENZODIAZEPINE

DISCONTINUATION IN PATIENTS WITH PANIC DISORDER

Difficulties with discontinuing benzodiazepine treatment have been welldocumented. Discontinuation distress occurs with both short and long

half-life benzodiazepines, even when slowly tapered (Fyer et al. 1987;

Mellman and Uhde 1986; Rickels et al. 1990; Roy-Byrne and Hommer

1988). Patients with panic disorder often have marked difficulties

discontinuing benzodiazepines. For example, Noyes and associates

(1991) found that panic attacks recurred in 74 percent of patients

undergoing discontinuation of their alprazolam treatment. Of these

patients, 64 percent were not successful in the discontinuation attempt,

and 60 percent experienced symptoms during discontinuation that were

equal to or more severe than experienced prior to treatment. Similar

difficulties have been found for the discontinuation of long half-life

agents in patients with panic disorder (Noyes et al. 1991; Rickels et al.

1990).

A cognitive behavioral account of discontinuation difficulties in patients

with panic disorder has been reported (Otto et al. 1992). The authors

hypothesize that difficulties during benzodiazepine discontinuation occur

because patients are exposed to anxiety sensations at a time when they

fear a return of the disorder and are especially vigilant to symptoms due

to removal of the conditioned safety cue of medication. Benzodiazepine

withdrawal symptoms mimic many of the symptoms of panic disorder

(Roy-Byrne and Hommer 1988), and hence the medication taper ensures

an exacerbation of somatic sensations of anxiety at a time when patients

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are fearing this increase. Because of untreated fears of these sensations

and worries that these sensations represent a return of panic disorder,

patients frequently respond to these sensations with catastrophic

interpretations and fear, contributing to an increase in anxiety and panic

episodes.

Given the model of discontinuation difficulties, it has been hypothesized

that an effective behavioral treatment for benzodiazepine withdrawal

must:

1. Decrease conditioned fears of somatic sensations and

the tendency to catastrophically misinterpret these

sensations.

2. Provide patients with coping skills for managing the

severity of panic sensations.

3. Provide patients with skills for minimizing

withdrawal symptoms (Otto et al. 1992, p. 127).

In a test of the authors’ hypotheses, a treatment for benzodiazepine

discontinuation that incorporated the informational, cognitive

restructuring, interoceptive exposure, and somatic management skills

were designed, as discussed above. The authors studied 33 outpatients

treated for panic disorder who had been treated with either alprazolam or

clonazepam for a minimum of 6 months (Otto et al. 1993). These

patients were seeking help in discontinuing their benzodiazepine

treatment and were randomly assigned to one of two taper conditions: a

slow-taper condition with physician support, or a slow-taper condition

with support plus 10 sessions of group cognitive behavioral therapy.

Consistent with previous studies high rates of discontinuation failure in

patients undergoing the slow-taper-alone program were found. Seventyfive percent of these patients were unable to discontinue their medication

on schedule. In contrast, 76 percent of patients receiving the adjunctive

cognitive behavioral treatment were successful in achieving medication

discontinuation. In addition, patients successfully discontinuing their

medication had lower levels of distress than they had at pretreatment.

Three months postdiscontinuation followup indicated that most patients

in the cognitive behavioral program (77 percent) remained

benzodiazepine-free. Also, two of three patients who crossed over to the

cognitive behavioral program from the slow-taper-alone program

achieved successful benzodiazepine discontinuation on schedule. In

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summary, it appears that a brief focused trial of cognitive behavioral

treatment is effective in aiding benzodiazepine discontinuation.

The authors believe that the most important elements of this program

were the interoceptive and cognitive restructuring components.

Interoceptive exposure was designed to treat the fear-of-fear reaction to

somatic sensations associated with panic and to help treat anxiogenic

reactions to somatic sensations that may arise due to medication

discontinuation. In addition to trying to eliminate catastrophic

interpretations of symptoms, cognitive restructuring interventions were

used to help patients reconceptualize their withdrawal symptoms and

mobilize preexisting coping efforts. One particular strategy was to have

patients identify their reactions to the symptoms experienced when

having the flu. Patients reported responding to flu sensations without

anxiety or fear; they accepted that uncomfortable sensations were part of

the flu and went about their daily activities as best they could. Patients

were then asked to apply this familiar skill to the bodily discomfort they

were experiencing during the benzodiazepine taper process. In short,

they were asked to use existing skills to be more comfortable with their

taper-induced “benzodiazepine flu.” These procedures are illustrated in

greater detail in the authors’ treatment manuals (Otto et al., in press; Otto

et al. 1994), but this example is illustrative of the use of cognitive

interventions to mobilize preexisting coping skills to aid in medication

discontinuation. The combination of these cognitive interventions with

interoceptive exposure procedures ensures that patients have in-session

training in reacting differently to somatic sensations associated with

anxiety, panic, and withdrawal symptoms.

Similar to the program for treatment-refractory patients, these

interventions were preceded by a significant informational component.

Discontinuation difficulties were explained in terms of the fear-of-fear

model, and compensatory interventions also were outlined in ten-ns of this

model. Hence, prior to initiation of medication taper, patients had a

model of the action of their medications, the alternative interventions

offered by cognitive behavioral therapy, the symptoms that may be

encountered during medication taper, and the types of skills that will be

developed for coping with these sensations and the underlying disorder.

The authors believe this informational component increased comfort and

compliance with cognitive behavioral treatment and the discontinuation

procedures. Findings of marked efficacy for the discontinuation program

encourage application of these interventions to other drug discontinuation

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programs where taper-associated symptoms result in significant

discontinuation difficulties.

COMBINED BENZODIAZEPINE AND COGNITIVE

BEHAVIORAL TREATMENTS

At present there are few studies of combined treatments using

benzodiazepine and cognitive behavioral therapy. Benzodiazepine

treatment has the advantage of quick onset of action (Pollack and

Rosenbaum 1988), and hence one strategy for combined treatment is to

use benzodiazepine treatment to help block panic attacks and anticipatory

anxiety while patients are introduced to the initial skills of cognitive

behavioral therapy. Cognitive behavioral therapy can then be used to

help patients successfully discontinue their benzodiazepine treatment and

continue to develop skills for eliminating panic disorder over the long

term.

In the authors’ clinic program, successful treatment of several patients

using this method have been observed. To offer an understanding of the

treatment process, patients were provided a behavioral model of the

disorder and treatment at an early stage, and the rationale for short-term

benzodiazepine treatment was presented in this context. Recently, Hegel

and associates (1994) reported on a small open trial combining cognitive

behavioral treatment and alprazolam treatment. In this study, 25 patients

were initially treated with or switched to a panic suppression dose of

alprazolam. Following a 2-week panic-free stabilization period, patients

began a 12-session individual cognitive behavioral treatment program

modeled after Barlow and Craske (1989). After 4 weeks of treatment,

patients began a gradual tapering of alprazolam medication. Three

patients were lost to followup. Of the original sample, 80 percent were

panic-free at the end of the treatment period, with further improvements

evident at 12 months followup, where 85 percent of patients were panicfree.

Spiegel and associates (1994) investigated combined treatment in 2 1

patients with panic disorder. Patients were first treated with a panicsuppressing dose of alprazolam and then were discontinued in a slowtaper program or in an identical-taper program plus 12 weeks of cognitive

behavioral therapy. Eighty percent of taper only and 90 percent of the

taper-plus-cognitive behavioral therapy patients were able to discontinue

their acute alprazolam treatment, but whereas all patients in the cognitive

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behavioral therapy program maintained their gains, half the subjects in

the taper-only group relapsed and went back on drugs during a 6-month

followup period. This study again supports the effectiveness of shortterm alprazolam treatment combined with a cognitive behavioral therapy

program.

These data indicate that treatments combining very short-term treatment

with high-potency benzodiazepines followed by brief cognitive

behavioral treatment may offer patients the best of both treatments. This

brief benzodiazepine treatment offers rapid blockade of anxiety and

panic, whereas the cognitive behavioral treatment is used to treat the

cognitive behavioral patterns associated with the fear-of-fear cycle to aid

benzodiazepine discontinuation and the maintenance of a panic-free

status over the long term.

The combination of other pharmacologic interventions, (e.g., tricyclic or

MAOI antidepressants) and behavior therapy may offer similar

advantages, but additional research is necessary to determine whether

chronic treatment with these agents is superior to behavior therapy alone

for the average patient. As argued by Marks and colleagues (1993b), the

success of behavior therapy for the majority of patients in treatment

studies may support the initial application of behavioral treatment for

most patients. Nonetheless, combined treatment may be the treatment of

choice for the patients with panic disorder who do not respond to brief

cognitive behavioral therapy trials or for patients who insist upon

immediate medication treatment. The relative advantages of cognitive

behavioral, pharmacological, or combined treatments also may change

depending on the intensity of co-morbid conditions, as most treatment

studies exclude patients with significant co-morbidity.

POTENTIAL PROBLEMS FOR THE COMBINATION OF

COGNITIVE BEHAVIORAL THERAPY AND PHARMACOLOGIC

TREATMENTS

In the above discussions of combined cognitive behavioral and

pharmacological interventions, efforts have been emphasized in

providing patients with a model of the disorder and treatment. Whereas

this model includes assumptions of potential biological diatheses for the

disorder, it implicates nonbiological factors as primary in sustaining the

disorder. A potential problem for the combined treatments is conflict

between models provided to patients by caregivers. Many patients

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receiving medication treatment accept the implicit biological formulation

that panic disorder is a manifestation of a chemical dysregulation.

Correspondingly, medications are viewed as a means to correct this

dysregulation. If a patient is told, for example, that panic disorder is

analogous to diabetes, that both are chronic diseases, and that like the

diabetic who controls the condition with insulin, the panic disorder

patient must control his or her condition with medication, this

conceptualization would be counterproductive to having the patient fully

engage in cognitive behavioral therapy.

To address this issue in the authors’ behavior therapy clinic, where

inadequate responders to medication treatment are commonly referred,

attention was devoted in the first treatment session to providing a broader

model of the disorder. In particular, biological provocation studies have

been used to support a purely biological conceptualization of panic

disorder. In these studies a number of biological agents, ranging from

yohimbine and lactate to carbon dioxide inhalation and caffeine, were

used to provoke panic in patients with panic disorder but not in control

subjects (Clark 1986). In the authors’ treatment program, patients learn

about these and additional studies that support psychological

interpretations of this finding. These studies indicate that individuals

who fear somatic sensations of anxiety respond to these procedures with

anxiety and panic, regardless of a history of panic disorder or panic

attacks (McNally and Lorenz 1987; Telch and Harrington 1992). Instead

of sharing a common biological pathway, the most important shared

characteristic of these agents may be the ability to unexpectedly induce

bothersome somatic sensations (Clark 1986). Hence, findings from

provocation studies that also could support a biological model of panic

disorder now support a fear-of-fear model. This information is used to

help patients understand some of the evidence for each model of the

disorder and to prepare them for a new conceptualization of the disorder

that precedes cognitive behavioral therapy. In the discontinuation

program the fear-of-fear model is used to explain potential mechanisms

for drug action (i.e., blocking baseline anxiety, raising the threshold for

the alarm response, and providing a conditioned safety cue) and the

alternative interventions to be addressed in behavior therapy (i.e.,

cognitive restructuring, interoceptive exposure, somatic management

skills, and in vivo exposure). Patients thus have a unified model for the

disorder and their past and current treatment.

To review, the goal of the presentation of these empirical findings and the

model of the disorder is to help patients fully engage in cognitive

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behavioral treatment. This is especially important because behavioral

clinicians are offering interventions that require more effortful

assimilation than taking a pill. This informational presentation also

serves to educate patients about their disorder and the purpose of each

intervention so that they can be better prepared to guide their own

interventions during and after the treatment period. It is important to

underscore the significance of information interventions at the outset of

treatment and clear communication between behaviorally and

pharmacologically oriented caregivers throughout the treatment process

to ensure that patients receive consistent messages about the treatments

they are receiving.

A second concern for the combination of behavioral and pharmacologic

treatments is the use of a dosing schedule that avoids pill taking as an

immediate coping response to panic attacks. Patients in behavioral

treatment must learn alternative responses to anticipatory anxiety and

panic attacks if treatment is to be effective. “As needed” (PRN) use of

benzodiazepine medications could potentially interfere with this process.

Thus, the use of fixed dosing schedules and the substitution of behavioral

strategies for PRN dosages is important for the transition to behavioral

treatment of panic disorder.

More traditional concerns about the combination of pharmacologic and

behavioral treatments focus on state-dependent learning and the

attribution of therapeutic gains to medications rather than skill acquisition

(Barlow 1988; Marks et al. 1993a). Concerns about state-dependent

learning focus on whether skills learned while on medication will

disappear when medications are withdrawn (Bouton et al. 1990). The

authors’ experience with benzodiazepine discontinuation suggests that

state-dependent learning is not a problem when behavioral skills are

rehearsed over the course of discontinuation. This rehearsal requires that

patients have experience with behavioral skills in the absence of drug

treatment.

As noted by Barlow (1988), the attribution of treatment efficacy to other

sources is not limited to medications; patients may also attribute early

treatment effects to the presence of their therapist, to luck, or to any of a

number of safety cues in addition to medications. The attribution of

treatment effects to other sources can be eliminated by selection of

appropriate homework assignments where patients are placed in

situations where success with their new skills occurs independently of the

therapist or other perceived aid. In relation to medication treatment, the

1.56
use of an organized discontinuation program or close monitoring of the

effects of behavior therapy (while medication treatment is held constant)

can be used to help patients identify the source of their progress. Selfmonitoring diaries are especially useful for this purpose.

Finally, concerns have been raised whether pharmacological treatments

interfere with the actions of behavioral treatment. One proposed action,

termed biological “toughening up,” is the desensitization of the central

nervous system resulting from repeated exposure to anxiogenic stimuli;

benzodiazepines are hypothesized to interfere with this process (Barlow

1988). Tricyclic antidepressants have drawn less concern, especially as

there is some evidence that they may provide short-term potentiation of

exposure treatment (Mavissakalian and Michelson 1986a, 1986b; Telch

et al. 1985). Although individual doses of benzodiazepines may have a

beneficial effect on exposure therapy under select conditions (Marks et al.

1972), Marks and associates (1993a) have provided recent evidence that

brief benzodiazepine treatment may hinder rather than help exposurebased treatment, at least in patients with severe agoraphobia who did not

have the benefit of a behavioral discontinuation program or interoceptive

exposure procedures. In addition, research needs to address whether the

authors’ pilot program combining cognitive behavioral therapy with brief

benzodiazepine treatment for patients seeking immediate relief really

offers the “best of both worlds” as has been proposed. It is clear that

adding behavior therapy to medication treatment offers significant

benefit. Research must now address which patients benefit from each

treatment individually and which patients may require combined

treatment for maximal improvement.

APPLICATION OF FINDINGS TO ISSUES OF DRUG

DEPENDENCY

The combination of pharmacotherapy and behavior therapy has been

described as it is applied to treatment-resistant patients with panic

disorder, patients requiring medication discontinuation, and as a

combined intervention with short-term benzodiazepine treatment.

Although research investigating combined pharmacologic and cognitivebehavioral treatment is still in its infancy, several lessons can be learned

from the research on panic disorder conducted thus far. These lessons

include the use of (1) a clear model to guide treatment and combinations

of treatments, (2) a clear rationale for treatment interventions, (3) a focus

on skill acquisition with specific practice of skills in relevant circum157
stances, and (4) exposure procedures for interoceptive cues. Each of

these lessons has potential application to the treatment of drug

dependency, with particular application to the design of combined

treatments, the addition of behavior therapy to aid in minimizing drug

withdrawal effects, and in maintaining effective outcome when tapering

pharmacotherapy.

Use of an Empirically Supported Model to Guide Treatment

An advantage of a comprehensive model is that it suggests treatment

interventions for elements of the disorder not addressed by medication.

By identifying what is and is not addressed by each intervention,

clinicians can choose the best from each treatment. In the area of panic

disorder, this strategy was exemplified by programs targeting patients

with panic disorder who were not fully responsive to medication, were

undergoing medication discontinuation, or who were starting treatment.

In each case, untreated fears of somatic sensations were a primary target

of treatment, following the notion that this fear and associated behavior

patterns remained untreated for many patients undergoing

pharmacotherapy. In the area of drug dependence, the application of

combined treatments may be aided by a similar conceptual model: a

model that identifies the nature of the disorder and the type of change that

results from pharmacologic and cognitive behavioral interventions. With

specification of the elements of the disorder altered by one set of

interventions, combined interventions can be structured to best “cover”

the range of factors maintaining the substance abuse.

Improving Motivation and Compliance: The Value of

Informational Interventions

These authors repeatedly identified the value of informational

interventions for patients. By specifying the elements of the disorder that

may be treated by each form of intervention and the purpose of each

intervention, active participation in combined treatment may be

maximized. This intervention has been identified as important when

cognitive behavioral therapy was being added to existing

pharmacotherapy, when pharmacotherapy was being replaced by a shortterm cognitive behavioral therapy program, and when pharmacotherapy

and behavior therapy were combined at treatment onset. This

informational component of treatment may be especially important for

the treatment of drug dependence. Attrition and compliance is a major

issue for the treatment of drug dependence (e.g., Rounsaville et al. 1983;

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Sanchez-Craig et al. 1987, pp. 287-331), and like patients in the authors’

discontinuation program, patients treated for substance abuse must learn

to develop and substitute behavioral skills for previous drug-taking

behavior. A clear rationale for the exact benefits to be received by this

substitution of behavior therapy for drug-taking behavior may aid this

process.

A Focus on Skill Acquisition in Realistic Circumstances

The focus on skill acquisition represents a third component of the

cognitive behavioral approach toward panic disorder that may offer

benefit to the treatment of substance abuse. In the cognitive behavioral

treatment of panic disorder, patients are provided with an abundance of

training in developing skills to eliminate aspects of the panic cycle. For

example, they are provided with breathing retraining and muscle

relaxation skills to help ameliorate the intensity of their symptoms and to

help stop anxiogenic reactions to initial anxiety or withdrawal sensations.

When possible, patients are helped to draw upon existing skills for

maximizing cognitive interventions. For example, in the benzodiazepine

discontinuation program the concept of “benzodiazepine flu” is

introduced to help patients cope with withdrawal symptoms. Finally,

newer cognitive behavioral programs ensure that patients have direct

practice with eliminating panic cycles by exposing them to feared bodily

sensations in interoceptive exposure procedures. In all cases, these

strategies were practiced independently from the use of medications and,

where relevant, during the process of medication discontinuation. This

practice in both medicated and nonmedicated states, as well as under

conditions of induced anxiety, help circumvent issues of state-dependent

learning. The treatment of drug dependence may benefit from similar

strategies (Niaura et al. 1988), where component skills are identified and

rehearsed before and during discontinuation and maintenance phases as

part of preparation for high-risk situations.

Treatment Interventions for lnteroceptive Cues

The final lesson from the cognitive behavioral treatment of panic disorder

is the usefulness of interoceptive exposure techniques. In the authors’

treatment for benzodiazepine discontinuation, interoceptive exposure

techniques were used to help patients reduce their fear of somatic

sensations of both anxiety and withdrawal and to develop skills for

coping with these sensations. Patients were exposed to interoceptive

sensations during the treatment session, providing them with the

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opportunity for habituation and an opportunity to rehearse cognitive and

behavioral skills. Patients thus had existing skills and experiences when

similar interoceptive cues were experienced during the course of

benzodiazepine withdrawal or when anxiety sensations were encountered

thereafter.

Treatments of drug dependency have recognized various contextual cues

for drug-seeking or drug-taking behaviors (Niaura et al., 1988; Rohsenow

et al. 1990-1991). Although there has been clear identification that some

important cues are interoceptive rather than external contextual cues

(Marlatt and Gordon 1978, pp. 410-452; O’Connell and Martin 1987),

cue exposure treatments have focused primarily on the external

contextual cues surrounding drug use (O’Brien et al. 1990; Powell et al.

1990; Rohsenow et al. 1990-1991). This focus on environmental cues is

similar to older treatments of panic disorder and agoraphobia that targeted

in vivo exposure rather than exposure to the somatic sensations of

anxiety. In parallel to advances in the treatment of panic disorder, the

treatment of substance abuse also may benefit from interoceptive

exposure techniques.

Extending these procedures to the treatment of substance abuse,

interoceptive exposure procedures could be used to help patients achieve

initial drug discontinuation and to resist cues for relapse. Novel

interoceptive exposure procedures (e.g., mood induction) may be needed

for select affective cues, but in many cases similar procedures to those

described by Barlow and Craske (1989) may be appropriate. For

example, George and colleagues (1988) found that alcohol withdrawal is

not discriminated from panic sensations in individuals who have both

alcohol dependence and panic disorder. Furthermore, fears of somatic

sensations occur at moderate to high levels in substance-abusing

populations. In particular, scores on one measure of fear of anxiety

symptoms, the Anxiety Sensitivity Index, have been found to be elevated

in samples of alcoholics (McNally et al. 1987) and in opiate-dependent

patients (Pollack et al., unpublished data). If one component of ongoing

substance abuse is the “self-medication” of disturbing interoceptive cues

resulting from withdrawal, anxiety, or stress, then interoceptive exposure

techniques may offer an additional means to intervene with substanceabusing populations. The authors’ clinical research group is now

investigating the application of these interventions to patients undergoing

opiate withdrawal. Similar interventions may be of use for nicotine and

alcohol withdrawal.

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CONCLUSION

Overall, the cognitive behavioral treatment of panic disorder offers a

number of important insights that may be applied to issues of combined

treatment of substance abuse. These lessons include the development of a

clear model of the disorder to guide treatments and help patients

understand and comply with the interventions, ongoing practice of skills

to improve coping with manifestations of the disorder, and the use of

interoceptive techniques to help substance-dependent patients cope with

withdrawal sensations they may experience as they try to taper and

discontinue their substance use. Application of these methods may lead

to further advances in the treatment of substance abuse. More generally,

the opportunity for professionals in two distinct areas of study to review

one another’s work and findings is encouraged as a method to increase

the effectiveness of research in both areas of study. The organizers of the

NIDA Technical Update Conferences should be commended for their

efforts in encouraging this process.

REFERENCES

Aronson, T.A. A naturalistic study of imipramine in panic disorder and

agoraphobia. Am J Psychiatry 144(8):1014-1019, 1987.

Ballenger, J.; Burrows, G.; DuPont, R.; and Lesser, I.M. Alprazolam in

panic disorder and agoraphobia: Results from a multicenter trial: I.

Efficacy in short-term treatment. Arch Gen Psychiatry 45(5):413-422,

1988.

Barlow, D.H. Anxiety and Its Disorders: The Nature and Treatment of

Anxiety and Panic. New York: Guilford Press, 1988.

Barlow, D.H., and Craske, M.G. Mastery of Your Anxiety and Panic.

Albany, NY: Graywind Publications, 1989.

Barlow, D.H.; Craske, M.G.; Cemy, J.A.; and Klosko, J.S. Behavioral

treatment of panic disorder. Behav Ther 20(2):261-282, 1989.

Beck, A.T.; Emery, G.; and Greenberg, R.L. Anxiety Disorders and

Phobias: A Cognitive Perspective. New York: Basic Books, 1985.

Beck, A.T.; Sokol, L.; Clark, D.A.; Berchick, R.; and Wright, F.

A crossover study of focused cognitive therapy for panic disorder. Am

J Psychiatry 149(6):778-783, 1992.

Bouton, M.E.; Kenney, F.A.; and Rosenbard, C. State dependent fear

extinction with two benzodiazepine tranquilizers. Behav Neurosci

104(1):44-55, 1990.

161
Clark, D.M. A cognitive approach to panic. Behav Res Ther 24(4):461-

470, 1986.

Craske, M.G.; Brown, T.A.; and Barlow, D.H. Behavioral treatment of

panic: A two year follow-up. Behav Ther 22(3):289-304, 1991.

Cross-National Collaborative Panic Study, Second Phase Investigators.

Drug treatment of panic disorder: Comparative efficacy of alprazolam,

imipramine, and placebo. Br J Psychiatry 160:191-202, 1992.

Fyer, A.J.; Liebowitz, M.R.; Gorman, J.M.; Campeas, R.; Levin, A.;

Davies, SO.; Goetz, D.; and Klein, D.F. Discontinuation of

alprazolam treatment in panic patients. Am J Psychiatry 144:303-308,

1987.

George, D.T.; Zerby, A.; Noble, S.; and Nutt, D.J. Panic attacks and

alcohol withdrawal: Can subjects differentiate the symptoms? Biol

Psychiatry 24:240-243, 1988.

Goldstein, A.J., and Chambless, D.L. A reanalysis of agoraphobia. Behav

Ther 9(1):47-59, 1978.

Hegel, M.T.; Ravaris, C.L.; Ahles, T.A. Combined cognitive-behavioral

and time-limited Alprazolam treatment of panic disorder. Behav Ther

25:183-195, 1994.

Klosko, J.S.; Barlow, D.H.; Tassinari, R.B.; and Cemy, J.A. Comparison

of alprazolam and behavior therapy in the treatment of panic disorder.

J Consult Clin Psychol 58(1):77-84, 1990.

Marks, I.M.; Swinson, R.P.; Basoglu, M.; Kuch, K.; Noshirvani, H.;

O’Sullivan, G.; Lelliott, P.T.; Kirby, M.; McNamee, G.; Sengun, S.;

and Wickwire, K. Alprazolam and exposure alone and combined in

panic disorder with agoraphobia: A controlled study in London and

Toronto. Br J Psychiatry 162:776-787, 1993a.

Marks, I.M.; Swinson, R.P.; Basoglu, M.; Noshirvani, H.; Kuch, K.;

O’Sullivan, G.; Lelliott, P.T.; and Wickwire, K. Reply to comment on

the London/Toronto study. Br J Psychiatry 162:790-794, 1993b.

Marks, I.M.; Viswanathan, R.; Lipsedge, M.D.; and Gardner, R.

Enhanced relief of phobias by flooding during waning diazepam

effect. Br J Psychiatry 121:493-505, 1972.

Marlatt, G.A., and Gordon, J.R. Determinants of relapse: Implications for

the maintenance of behavior change. In: Davidson, P.O., and

Davidson, S.M., eds. Behavioral Medicine: Changing Health

Lifestyles. New York: Brunner/Mazel, 1978. pp. 410-452.

Mavissakalian, M. Sequential combination of imipramine and selfdirected exposure in the treatment of panic disorder with agoraphobia.

J Clin Psychiatry 51(5):184-188, 1990.

162
Mavissakalian, M.; Michelson, L.; and Dealy, R.S. Pharmacological

treatment of agoraphobia: Imipramine versus imipramine with

programmed practice. Br J Psychiatry 143:348-355, 1983.

Mavissakalian, M., and Michelson, L. Agoraphobia: Relative and

combined effectiveness of therapist-assisted in vivo exposure and

imipramine. J Clin Psychiatry 47(3):117-122, 1986a.

Mavissakalian, M., and Michelson, L. Two year follow up of exposure in

imipramine treatment of agoraphobia. Am J Psychiatry 143(9):1106-

1112, 1986b.

McNally, R.J. Psychological approaches to panic disorder: A review.

Psychol Bull 108(3):403-419, 1990.

McNally, R.J., and Lorenz, M. Anxiety sensitivity in agoraphobics.

J Behav Ther Exp Psychiatry 18(1):3-11, 1987.

McNally, R.J.; Luedke, D.L.; Besyner, J.K.; Peterson, R.A.; Bohn, K.;

and Lips, O.J. Sensitivity to stress-relevant stimuli in posttraumatic

stress disorder. J Anx Disord 1(2):105-116, 1987.

Mellman, T.A., and Uhde, T.W. Withdrawal syndrome with gradual

tapering of alprazolam. Am J Psychiatry 11(143):1464-1466, 1986.

Michelson, L.; Marchione, K.; Greenwald, M.; Glanz, L.; Testa, S.; and

Marchione, N. Panic disorder: Cognitive-behavioral treatment. Behav

Res Ther 28(2):141-151, 1990.

Nagy, L.M.; Krystal, J.H.; Woods, S.W.; and Chamey, D.S. Clinical and

medication outcome after short-term alprazolam and behavioral group

treatment of panic disorder. Arch Gen Psychiatry 46(11):993-999,

1989.

National Institutes of Health. Treatment of panic disorder. NZH Consens

Dev Conf Consens Statement 9(2):September 25-27, 1991.

Niaura, R.S.; Rohsenow, D.J.; Binkoff, J.A.; Monti, P.M.; Pedraza, M.;

and Abrams, D.B. Relevance of cue reactivity to understanding

alcohol and smoking relapse. J Abnorm Psychol 97(2):133-152, 1988.

Noyes, R.; Garvey, M.; and Cook, B. Follow up study of patients with

panic attacks treated with tricyclic antidepressants. J Affec Disord

16(1-2):249-257, 1989.

Noyes, R.; Garvey, M.J.; Cook, B.; and Suelzer, M. Controlled

discontinuation of benzodiazepine treatment for patients with panic

disorder. Am J Psychiatry 148(4):517-523, 1991.

O’Brien, C.P.; Childress, A.R.; McLellan, T.; and Ehrman, R. Integrating

systematic cue exposure with standard treatment in recovering drug

dependent patients. Addict Behav 15:355-365, 1990.

163
O’Connell, K.A., and Martin, E.J. Highly tempting situations associated

with abstinence, temporary lapse, and relapse among participants in

smoking cessation programs. J Consult Clin Psychol 55:367-371,

1987.

Otto, M.W.; Jones, J.C.; Craske, M.G.; and Barlow, D.H. “Therapist’s

Manual for Panic Control Therapy for Benzodiazepine

Discontinuation (PCT-BD).” Under agreement for publication.

Albany, NY: Greywind Publications, 1994.

Otto, M.W.; Pollack, M.H.; and Barlow, D.H. “Stopping Anti-Anxiety

Medications: A Workbook for Patients Wanting to Discontinue

Benzodiazepine Treatment for Panic Disorder.” Albany, NY:

Greywind Publications, in press.

Otto, M.W.; Pollack, M.H.; Meltzer-Brody, S.; and Rosenbaum, J.F.

Cognitive-behavioral therapy for benzodiazepine discontinuation in

panic disorder patients. Psychopharmacol Bull 28(2):123-130, 1992.

Otto, M.W.; Pollack, M.H.; Sachs, G.S.; Reiter, S.R.; Meltzer-Brody, S.;

and Rosenbaum, J.F. Discontinuation of benzodiazepine treatment:

Efficacy of cognitive-behavior therapy for patients with panic

disorder. Am J Psychiatry 150:1485-1490, 1993.

Pollack, M.H.; Otto, M.W.; Kaspi, S.P.; Hammemess, P.G.; and

Rosenbaum, J.F. “Cognitive-Behavior Therapy for Treatment

Refractory Panic Disorder.” J Clin Psychiatry 55:200-205, 1994.

Pollack, M.H.; Otto, M. W.; Tesar, G.E.; Cohen, L.S.; Meltzer-Brody, S.;

and Rosenbaum, J.F. Long-term outcome after acute treatment with

clonazepam and alprazolam for panic disorder. J Clin

Psychopharmacol 13:257-263, 1993.

Pollack, M.H., and Rosenbaum, J.F. Benzodiazepines in panic-related

disorders. J Anx Disord 2:95-107, 1988.

Powell, J.; Gray, J.A.; Bradley, B.P.; Kasvikis, Y.; Strang, J.; Barratt, L.;

and Marks, I. The effects of exposure to drug-related cues in

detoxified opiate addicts: A theoretical review and some new data.

Addict Behav 15:339-354, 1990.

Rickels, K.; Case, W.G.; Schweizer, E.; Garcia-Espana, F.; and Fridman,

R. Benzodiazepine dependence: Management of discontinuation.

Psychopharmacol Bull 26(1):63-68. 1990.

Rohsenow, D.J.; Childress, A.R.; Monti, P.M.; Niaura, R.S.; and Abrams,

D.B. Cue reactivity in addictive behaviors: Theoretical and treatment

implications. Int J Addict 25A:957-993, 1990-1991.

Rounsaville, B.J.; Glazer, W.; Wilber, C.H.; Weissman, M.M.; and

Keber, H.D. Short-term interpersonal psychotherapy in methadonemaintained opiate addicts. Arch Gen Psychiatry 40:629-636, 1983.

164
Roy-Byrne, P.P., and Hommer, D. Benzodiazepine withdrawal:

Overview and implications for the treatment of anxiety. Am J Med

84:1041-1052, 1988.

Sanchez-Craig, M.; Wilkinson, D.A.; and Walker, K. Theory and

methods for secondary prevention of alcohol problems: A cognitive

approach. In: Cox, W.M., ed. Treatment and Prevention of Alcohol

Problems: A Resource Manual. Orlando, FL: Academic Press, 1987.

Sheehan, D.V.; Ballenger, J.; and Jacobsen, G. Treatment of endogenous

anxiety with phobic, hysterical and hypochondriacal symptoms. Arch

Gen Psychiatry 39:51-59, 1980.

Spiegel, D.A.; Bruce, T.J.; Falkin-Gregg, S.M.; and Nuzzarello, A. “Does

Cognitive Behavior Therapy Assist Slow-Taper Alprazolam

Discontinuation in Panic Disorder.” Am J Psychiatry 151:876-881,

1994.

Telch, M.J.; Agras, W.S.; Taylor, C.B.; Rothe, W.T.; and Gallen, C.

Combined pharmacological and behavioral treatment for agoraphobia.

Behav Res Ther 23(3):325-335, 1985.

Telch, M.J., and Harrington, P.J. “Anxiety Sensitivity and Expectedness

of Arousal in Mediating Affective Response to 35% Carbon Dioxide

Inhalation.” Paper presented at the 26th Annual Association for

Advancement of Behavior Therapy Convention, Boston, MA,

November 19-22, 1992.

Tesar, G.E.; Rosenbaum, J.F.; Pollack, M.H.; Otto, M.W.; Sachs, G.S.;

Herman, J.B.; Cohen, L.S.; and Spier, S.A. Double-blind placebocontrolled comparison of clonazepam and alprazolam for panic

disorder. J Clin Psychiatry 52(2):69-76, 1991.

AUTHORS

Michael W. Otto, Ph.D.

Director of Research, Behavior Therapy Unit

Assistant Professor, Department of Psychiatry

Mark H. Pollack, M.D.

Director of Anxiety Disorders Program

Clinical Psychopharmacology Unit

Assistant Professor, Department of Psychiatry

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Susan B. Ball, Ph.D.

Psychology Fellow, Behavior Therapy Unit

Jerrold R. Rosenbaum, M.D.

Director of Outpatient Psychiatry

Chief, Clinical Psychopharmacology and Behavior Therapy Units

Associate Professor, Department of Psychiatry

Harvard Medical School

Massachusetts General Hospital

15 Parkman Street

WACC-815

Boston, MA 02114

166
Some Methodological Comments

Kenneth I. Howard

At the first meeting of the Society for the Exploration of Psychotherapy

Integration (SEPI), this author was talking to a senior psychotherapist

about his experiences in trying to integrate different theoretical constructs

in the actual conduct of psychotherapy. He ended the conversation by

saying “I tried to be an integrationist for a year, but it gave me such a

headache that I went back to being eclectic.”

The contrast suggested by this poignant statement is between integration

and combination. Integration requires a clear statement of theory that

brings together constructs from two or more theoretical perspectives.

This dependence on theory leads to hypothesis testing and an emphasis

on the internal validity of research findings, usually requiring the

methodology of randomized experiments. Treatment combination, on the

other hand, entails optimum seeking-finding the best treatment for a

specific type of patient. This task requires exploratory, applied research,

and an emphasis on external validity. Each methodology requires

replication of findings, but replication is even more important in

exploratory studies (and in secondary or post hoc analyses).

In either case, types of patients and treatment goals must be specified in

order to evaluate treatment efficacy. As Linehan has emphasized in this

volume, these goals should be sequential (process goals-e.g.,

establishing a therapeutic alliance); specific interventions should be

tailored for each goal, and there must be an operational method for

assessing the integrity of the intervention and the attainment of goals.

THE CONDUCT OF EMPIRICAL INQUIRY

Each presenter has shown that the doing of science is an art-an

investigator must interact with his or her data in order to find meaning.

For example, each presenter took recourse to secondary, post hoc

analyses, driven there by within-group heterogeneity, attrition, and other

exigencies of actually executing a study. Some of these exigencies

follow.

With the use of relatively small samples, randomization virtually never

equates groups with regard to all potential confounding variables. For

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example, what if researchers knew (on the basis of previous research) that

there were four causally efficacious variables that were not controlled in a

study? What are the odds that random assignment of 20 subjects to each

of two groups would orthogonalize the two groups with regard to these

four variables? Very slim indeed. This leaves researchers with the

problem of determining whether the comparison groups are comparable.

One approach to establishing comparability is to test statistically the

differences between the groups on some potentially confounding

variables; if the differences are not statistically significant, accept the null

hypothesis. Elementary statistics say, however, that the null hypothesis

can only be rejected; it can never be accepted on the basis of failure to

find a significant difference. The fact that two groups are not

significantly different does not imply that they are the same.

In any case, main effects are unlikely and are usually not very

informative-i.e., there is always real within-group variance (i.e.,

variance not attributable to measurement error) to be explored.

Moreover, the mean is an imaginary number that often does not represent

any specific patient. In nearly every presentation of research findings,

secondary (post hoc) data analyses were performed to examine what else

was causally efficacious in the study. Post hoc analyses should be

planned for and relevant data gathered on all patients regarding potential

causal variables (e.g., severity). Researchers need to include these in

research designs and give up the illusion that a study will go as

proposed-it rarely does. It is in this sense that a randomized experiment

often is a poorly designed quasi-experiment; poorly designed in the sense

of not assessing a sufficiently broad range of variables.

Attrition is the tallest hurdle. Few patients completely comply with a

treatment protocol; most are dropouts to some extent in the sense of

missing data as well as missing treatment units (e.g., sessions). There is

no way to correct for this without assuming some form of random

attrition (i.e., estimating what the missing data would have been), and this

is a logical counter-to-fact conditional.

REPORTING RESULTS

Statistical significance is rarely adequate for the communication of

results. Effect sizes are better, but they are still difficult to translate into

practical language. [Based on the Smith, Glass, and Miller (1980)

meta-analyses, a colleague once asked me if I thought that I really made a

.8 s.d. difference in my patients’ lives!] The notion of statistical clinical

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significance has gained-some adherents, but this, too, often is based on

only psychometric considerations (i.e., the standard error of

measurement) to determine reliable improvement. Obviously, clinical

criteria (e.g., percent abstinent for a year) are the most meaningful.

In clinical research, special attention must be paid to the practical value of

results. Researchers have to take a stand on a meaningful magnitude of

improvement and report the percent of patients who meet this criterion.

This provides the most clinically informative comparison of treatments

and is easily understood by clinical practitioners-the researcher’s most

important research goals.

REFERENCE

Smith, M.L.; Glass, G.V.; and Miller, T.I. The Benefits of Psychotherapy.

Baltimore, MD: Johns Hopkins Press, 1980.

AUTHOR

Kenneth I. Howard, Ph.D.

Department of Psychology

Northwestern University

2029 Sheridan Road

Evanston, IL 60208-27 10

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Comments

Stephen T. Higgins

Following are brief comments on the series of excellent presentations at

the National Institute on Drug Abuse Technical Review Meeting on

“Integrating Behavioral Therapies With Medications in the Treatment of

Drug Dependence.”

Dr. Carroll’s presentation was consistent with this author’s reading of the

extant literature on treatments for cocaine dependence. The pharmacotherapies are not yet producing reliable positive results, but several

psychosocial interventions look promising. Interventions with behavioral

and cognitive behavioral orientations appear to be particularly promising.

The relapse prevention approach that Dr. Carroll has been investigating

(Carroll et al. 1991, 1994), the Community Reinforcement Approach

(CRA) under investigation in this author’s clinic (Higgins and Budney

1993, pp. 97-122; Higgins et al. 1991, 1993, 1994), the contingency

management procedures under investigation in Dr. Stitzer’s clinic (Stitzer

et al. 1992), and the enhanced therapy reported by McLellan and

colleagues (McLellan et al. 1993), which involved contingency

management procedures, have all been efficacious in decreasing cocaine

abuse in randomized, controlled trials. The consistently positive

outcomes observed with the behavioral and cognitive behavioral

interventions is not unique to cocaine dependence. A similar picture has

emerged in treatments for problem drinking (Miller and Hester 1986, pp.

121-174) and smoking (U.S. Department of Health and Human Services

1988), and is consistent with the extensive basic science literature

demonstrating a fundamental role of reinforcement and other learning

factors in the genesis and maintenance of substance abuse (Goldberg and

Stolerman 1986). The efficacy of behavioral interventions is great news

and underscores the importance of placing comparable priority on

behavioral and pharmacological initiatives in the development of

treatments for drug dependence. Until recently, efforts in treatment

development for cocaine dependence appeared to be disproportionately

slanted in the direction of pharmacotherapies.

Dr. Hughes’ presentation illustrated an important basic tenet of

behavioral pharmacology: the behavioral effects of drugs are not inherent

properties of the molecular structure of the compound but, instead,

depend on the behavioral/environmental context in which the drugs are

170
administered (McKearney and Barrett 1978, pp. 1-68). Dr. Hughes’ data

showed in a compelling manner that behavior therapies can potentiate the

efficacy of nicotine replacement therapy. Understanding the mechanisms

controlling that potentiation should enhance the efficacy of smoking

cessation interventions and could extend the researcher’s understanding

of the basic behavioral pharmacology of nicotine.

Dr. Hughes’ point regarding the need to carefully specify what is meant

by the term behavior therapy is an important one-one that is likely to

become more important as researchers attempt to treat those who

continue smoking despite the widespread social pressures to quit. By

definition, such individuals have illustrated that their smoking is resistant

to a variety of different behavioral interventions that are occurring in their

environment. The clinical challenge is one of carefully specifying the

therapeutic conditions under which their smoking will remit.

Dr. O’Farrell’s work with monitored disulfiram therapy also illustrates

the need to specify the conditions under which pharmacotherapies are

effective. Like naltrexone, disulfiram therapy appears to be

underutilized. The research of Dr. O’Farrell and colleagues (O’Farrell et

al. 1992) and Azrin and colleagues (Azrin et al. 1982) illustrate that

through the use of behavioral contracts and other medication compliance

procedures, disulfiram can be an effective intervention in alcoholics.

More research is needed on methods to effectively introduce disulfiram to

patients, which is an essential but not well understood step in the

successful use of this medication. It is very likely that Dr. O’Farrell’s

experience is like this author’s. With experience, clinicians become

progressively more effective in getting patients to initiate monitored

disulfiram therapy. These skills could be operationalized, researched, and

possibly have the potential to improve the use of disulfiram as well as

other pharmacotherapies like naltrexone (Miller 1993, pp. 303-321).

Such a technology is especially important to the optimal use of any

pharmacotherapy in substance abusers in which the medication does not

function as a positive reinforcer or eliminate adverse withdrawal signs or

symptoms.

Dr. O’Malley’s chapter on treating alcoholism with naltrexone is

encouraging in that it offers promise of a broader array of efficacious

medications for use in problem drinkers. The clinical findings parallel

new and interesting basic science observations regarding possible

mechanisms by which opioid systems may be involved in the

neuropharmacology of ethanol (Benjamin et al. 1993). It is significant to

171
note the apparently high levels of compliance with naltrexone therapy in

alcoholics. Certainly that differs from the experience of naltrexone

therapy in opioid-dependent patients or disulfiram therapy in alcoholics.

Those differences are very interesting and may offer an opportunity to

improve the researchers’ understanding of the factors that control

medication compliance in substance abusers. Possibly part of the reason

alcoholics comply with naltrexone therapy is that they can continue to

drink without complete blockade of the reinforcing effects or any notable

adverse effects.

With regard to the efficacy of naltrexone in decreasing drinking in

alcoholics, controlled trials comparing naltrexone to disulfiram could

soon be underway. Such trials would seem to provide an important

context for understanding the potential contribution of naltrexone to the

treatment of problem drinking. To this author’s knowledge, the only

study reported on that topic was a preliminary trial conducted by the Yale

group examining naltrexone and disulfiram therapies in alcoholics who

were also cocaine dependent (Carroll et al. 1993). In that report,

naltrexone appeared much less efficacious than disulfiram in decreasing

alcohol or cocaine use, both of which were decreased significantly by

disulfiram therapy. Of course, any greater efficacy of disulfiram therapy

in decreasing drinking in the short term might be offset by greater patient

compliance with naltrexone therapy in the long term. Thus, it will be

important that such trials examine the short- and long-term efficacy of

these compounds and also whether or not naltrexone therapy might be

acceptable to a larger proportion of alcoholics than disulfiram therapy.

With regard to Dr. Rounsaville’s presentation, already mentioned was

the importance of researching various methods for introducing patients to

disulfiram and naltrexone and, of course, maintaining compliance with

these medication regimens. The incentive studies by Meyer and

colleagues (Meyer et al. 1976) and Grabowski and colleagues

(Grabowski et al. 1979), in this author’s opinion, merit followup studies.

There are many ways to reinforce behavior. If paying a couple of dollars

effectively maintains naltrexone compliance, it is likely that other

reinforcers could work as well. Researchers must be careful not to hastily

dismiss studies on incentives of the sort that Meyer and colleagues and

Grabowski and colleagues investigated. They represent important initial

steps toward addressing the important reinforcement issues involved in

naltrexone therapy.

172
Dr. O’Brien’s presentation provided a compelling demonstration of the

benefits of integrating pharmacological and psychosocial therapies in the

treatment of drug dependence. The important advances those studies

represent really need no additional comment here. However, one

observation reported by Dr. O’Brien to encourage additional research

should be mentioned. Dr. O’Brien outlined the clinical improvements

gained by providing supportive expressive and cognitive behavioral

psychotherapy to depressed methadone-maintenance patients (Woody et

al. 1991, pp. 152-166). Improvements were evident even in those

depressed patients who also had Antisocial Personality Disorder (APD),

but not those who had APD without depression. This latter group did not

derive any discernible benefits from these psychotherapeutic

interventions. Whether such APD methadone-maintenance patients

might have benefited from an alternative intervention, to this author’s

knowledge, was not investigated, but it illustrates an important direction

for future drug abuse research. In alcoholics, for example, patients

scoring high on measures of sociopathy and global psychopathology have

significantly better outcomes across a 2-year followup period if they

received coping skills training rather than interactional therapy (Cooney

et al. 1991). More research is needed examining specific psychosocial

and pharmacological interventions for specific co-morbid psychiatric

disorders in specific types of drug abusers. By carefully specifying their

interventions, the other psychiatric disorders targeted, and the particular

drug abuse disorders involved, researchers will be in a position to discern

basic functional relationships among these complicated co-morbid

disorders. Such efforts would likely facilitate both more effective clinical

practices, including patient-treatment matching, and improve researchers’

basic understanding of how these co-morbid disorders are related, which

at this time still seems somewhat muddled.

One area not specifically touched on in Dr. O’Brien’s presentation that

merits more research is how to make greater therapeutic use of the

reinforcing effects of methadone. Methadone can be a potent reinforcer

in the opioid-dependent population (Bickel et al. 1986). Unfortunately,

little explicit therapeutic use is made of that function. Granted,

researchers inadvertently reinforce clinic attendance by requiring that

patients ingest their medication under staff observation. Typically, staff

does so well on that front that loitering becomes a problem. What is

needed is more research directed at using methadone to reinforce other

types of behavior important to treatment process (e.g., abstinence from

illicit drugs and involvement in educational and other prosocial

behaviors).

173
A trial this author conducted with Dr. Stitzer and colleagues illustrates

how methadone’s reinforcing effects can support abstinence from illicit

opiates (Higgins et al. 1986). Opiate-dependent patients were

randomized to three treatment groups during a 90-day outpatient

detoxification. In one treatment group, patients could receive methadone

dose supplements contingent on submitting urine specimens that were

opiate-negative in urinalysis testing (contingent group); in a second

group, they could obtain the same dose supplements independent of

urinalysis results (noncontingent group); in a third group, they were

ineligible for dose supplements (control group). The contingent and

noncontingent groups had significantly lower percentages of opiatepositive urinalysis results than the control group, demonstrating the

efficacy of the extra medication in suppressing illicit opiate use, probably

through cross-tolerance and satiation (figure 1). Importantly, the

contingent group had significantly lower percentages of opiate-positive

urinalysis results than the noncontingent group, demonstrating the

additional efficacy gained by utilizing methadone’s reinforcing effects to

directly strengthen abstinence from illicit drug use. As was noted above,

methadone can be a powerful reinforcer in the opiate-dependent

population, and researchers should carefully consider how that feature

might be more effectively incorporated into the treatment process.

Regarding Dr. Linehan’s presentation, this author would like to expound

on a point she made regarding extra efforts to retain patients in treatment.

This author is a proponent of what amounts to an outreach approach to

treatment of ambulatory substance abuse patients. In this author’s CRA

treatment for cocaine dependence, for example, staff members telephone

patients, mail them letters, and have street workers attempt to locate

patients if they fail to show up for a scheduled therapy session. (CRA

does not permit patients to easily discontinue treatment.) Considering the

well-known associations between treatment retention and outcome, this

approach makes sense. However, experimental data are needed to

appropriately assess whether such outreach procedures are effective in

decreasing drug use or improving other outcomes. Considering the evergrowing relationships between substance abuse and many of society’s

health and social problems, identifying effective strategies to promote

treatment retention should be an important research priority.

Dr. Otto’s presentation underscores the function that behavioral therapies

can serve even with disorders for which effective pharmacotherapies

exist; an observation that is consistent with the recent study by McLellan

and colleagues (1993) demonstrating the benefits of combining enhanced

174
FIGURE 1. Percent opiate-positive urinalysis results as a function

of consecutive treatment weeks. Results obtained

during a dose-stabilization period (weeks 2-3) are

presented as a 2-week block and results during the

intervention period (weeks 4-12) are presented in two

I-week blocks. The contingent group is represented by

closed circles, the noncontingent group by open circles,

and the control group by triangles; brackets represent

+/- 1 SEM.

SOURCE: Higgins et al. (1986).

psychosocial services with methadone therapy. Effective

pharmacotherapies do not obviate the need for effective behavioral

interventions.

Two other points illustrated in Dr. Otto’s presentation are the importance

of a theoretically cohesive model of the target disorder and the

175
appropriate utilization of laboratory studies in efforts to understand and

treat the problem. In this author’s opinion, substance abuse research

often is conducted outside of any obvious theoretical model, and often it

is difficult to discern much, if any, interaction between laboratory and

treatment research efforts. This is probably more the case regarding

behavioral than pharmacological factors, but improvements could be

made in both areas. Behavioral pharmacology has much to offer

substance abuse researchers in terms of a cohesive theoretical model and

rich basic science literature on behavioral and pharmacological factors

involved in the genesis and maintenance of substance abuse (Schuster

1986, pp. 357-385).

Regarding Dr. Weiss’s presentation, it was noted earlier how important it

is that researchers experimentally assess for functional relationships

between specific types of co-morbid psychiatric disorders and substance

abuse. Doing so is likely to advance researchers’ basic understanding of

the disorders involved as well as their ability to treat them. When

considering the high prevalence of substance abuse in populations with

other psychiatric disorders, it seems that researchers may be too apt to

hypothesize self-medication and other accounts that are unique to these

populations. A reasonable alternative approach is to examine whether

some of the more generic factors that contribute to substance abuse in the

general population might also be present in psychiatric patients. The high

levels of unemployment, economic deprivation, familial dysfunction, and

social isolation common in psychiatrically disturbed individuals, for

example, might increase risk both for drug abuse and other psychiatric

problems. Said another way, these populations may be deprived of

access to alternative, prosocial reinforcers that can effectively compete

with the reinforcing effects of abused drugs (Schuster 1986, pp. 357-

385). Examining how such factors influence this apparent greater

vulnerability to substance abuse in psychiatric populations might result in

a more parsimonious account of their drug-using behavior.

REFERENCES

Azrin, N.H.; Sisson, R.W.; Meyers, R.; and Godley, M. Alcoholism

treatment by disulfiram and community reinforcement therapy.

J Behav Ther Exp Psychiatry 13:105-112, 1982.

Benjamin, D.; Grant, E.R.; and Pohorecky, L.A. Naltrexone reverses

ethanol-induced dopamine release in the nucleus accumbens in awake,

freely moving rats. Brain Res 621:137-140, 1993.

176
Bickel, WK.; Higgins, S.T.; and Stitzer, M.L. Choice of blind methadone

dose increases by methadone maintenance patients. Drug Alcohol

Depend 18:165-171, 1986.

Carroll, K.M.; Rounsaville, B.J.; and Gawin, F.H. A comparative trial of

psychotherapies for ambulatory cocaine abusers: Relapse prevention

and interpersonal psychotherapy. Am J Drug Alcohol Abuse 17:229-

247, 1991.

Carroll, K.M.; Rounsaville, B.J.; Gordon, L.T.; Nich, C.; Jatlow, P.;

Bisighini, R.M.; and Gawin, F.H. Psychotherapy and

pharmacotherapy for ambulatory cocaine abusers. Arch Psychiatry

51:177-187, 1994.

Carroll, K.; Ziedonis, D.; O’Malley, S.; McCance-Katz, E.; Gordon, L.;

and Rounsaville, B. Pharmacologic interventions for alcohol- and

cocaine-abusing individuals. Am J Addict 2:77-79, 1993.

Cooney, N.L.; Kadden, R.M.; Litt, M.D.; and Getter, H. Matching

alcoholics to coping skills or interactional therapies: Two-year followup results. J Consult Clin Psychol 59:598-601, 1991.

Goldberg, S.R., and Stolerman, I.P. Behavioral Analysis of Drug

Dependence. Orlando, FL: Academic Press, Inc., 1986.

Grabowski, J.; O’Brien, C.P.; Greenstein, R.; and Temes, J. Effects of

contingent payment on compliance with a naltrexone regimen. Am J

Drug Alcohol Abuse 6:355-365, 1979.

Higgins, S.T., and Budney, A.J. Treatment of cocaine dependence

through the principles of behavior analysis and behavioral

pharmacology. In: Onken, L.S.; Blaine, J.D.; and Boren, J.J., eds.

National Institute on Drug Abuse Research Monograph 137.

Behavioral Treatments for Drug Abuse and Dependence. NIH Pub.

No. (ADM)93-3684. Washington, DC: Supt. of Docs., U.S. Govt.

Print. Off., 1993.

Higgins, S.T.; Budney, A.J.; Bickel, W.K.; Foerg, F.E.; Donham, R.; and

Badger, G.J. Incentives improve outcome in outpatient behavioral

treatment of cocaine dependence. Arch Gen Psychiatry 51:568-576,

1994.

Higgins, S.T.; Budney, A.J.; Bickel, W.K.; Hughes, J.R.; Foerg, F.; and

Badger, G. Achieving cocaine abstinence with a behavioral approach.

Am J Psychiatry 150:763-769, 1993.

Higgins, ST.; Delaney, D.D.; Budney, A.J.; Bickel, W.K.; Hughes, J.R.;

Foerg, F.; and Fenwick, J.W. A behavioral approach to achieving

initial cocaine abstinence. Am J Psychiatry 148:1218-1224, 1991.

Higgins, S.T.; Stitzer, M.L.; Bigelow, G.E.; and Liebson, I.A. Contingent

methadone delivery: Effects on illicit opiate use. Drug Alcohol Abuse

17:311-322, 1986.

177
McKearney, J.W., and Barrett, J.E. Schedule-controlled behavior and the

effects of drugs. In: Blackman, D.E., and Sanger, D.J., eds.

Contemporary Research in Behavioral Pharmacology. New York:

Plenum Press, 1978.

McLellan, A.T.; Amdt, 1.0.; Metzger, D.S.; Woody, G.E.; and O’Brien,

C.P. The effects of psychosocial services in substance abuse treatment.

JAMA 269:1953-1959, 1993.

Meyer, R.; Randall, M.; Barrington, B.A.; Mirin, S.; and Greenberg, I.

Limitations of an extinction approach to narcotic antagonist treatment.

In: Julius, D., and Renault, P., eds. National Institute on Drug Abuse

Research Monograph 9. Narcotic Antagonists: Naltrexone. DHEW

Pub. No. (ADM)76-0000. Washington, DC: Supt. of Docs., U.S.

Govt. Print. Off., 1976.

Miller, W.R. Behavioral treatments for drug problems: Where do we go

from here? In: Onken, L.S.; Blaine, J.D.; and Boren, J.J., eds.

Behavioral Treatments for Drug Abuse and Dependence. National

Institute on Drug Abuse Research Monograph 137. NIH Pub. No.

(ADM)93-3684. Supt. of Docs., U.S. Govt. Print. Off., 1993.

Miller, W.R., and Hester, R.K. The effectiveness of alcoholism treatment

methods: What research reveals. In: Miller, W.R., and Heather, N.,

eds. Treating Addictive Behaviors: Processes of Change. New York:

Plenum Press, 1986.

O’Farrell, T.J.; Cutter, H.S.G.; Choquette, K.A.; Floyd, F.J.; and Baylog,

R.D. Behavioral marital therapy for male alcoholics: Marital and

drinking adjustment during the two years after treatment. Behav Ther

23:529-549, 1992.

Schuster, C.R. Implications of laboratory research for the treatment of

drug dependence. In: Goldberg, S.R., and Stolerman, I.P., eds.

Behavioral Analysis of Drug Dependence. Orlando, FL: Academic

Press, Inc., 1986.

Stitzer, M.L.; Iguchi, M.Y.; and Felch, L.J. Contingent take-home

incentive: Effects on drug use of methadone maintenance patients.

J Consult Clin Psychol 60:927-934, 1992.

U.S. Department of Health and Human Services. The Health

Consequences of Smoking: Nicotine Addiction, A Report of the

Surgeon General. DHHS Pub. No. (CDC)88-8406. Washington, DC:

Supt. of DOCS., U.S. Govt. Print. Off., 1988.

178
Woody, G.E.; McLellan, A.T.; O’Brien, C.P.; and Luborsky, L.

Addressing psychiatric comorbidity. In: Pickens, R.W.; Leukefeld,

C.G.; and Schuster, C.R., eds. Improving Drug Abuse Treatment.

National Institute on Drug Abuse Research Monograph 106. DHHS

Pub. No. (ADM)91-1754. Supt. of Docs., U.S. Govt. Print. Off., 1991.

ACKNOWLEDGMENT

This work was supported by grant DA06113 from the National Institute

on Drug Abuse.

AUTHOR

Stephen T. Higgins, Ph.D.

Department of Psychiatry

University of Vermont

328 Fletcher Place

Burlington, VT 05401-1419

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133 SIGMA, PCP, AND NMDA RECEPTORS. Errol B. De Souza,

Ph.D.; Doris Clouet, Ph.D., and Edythe D. London, Ph.D., eds.

NCADI #Ml 33 NTIS PB #94-169539 (A12) $36.50

134 MEDICATIONS DEVELOPMENT: DRUG DISCOVERY,

DATABASES, AND COMPUTER-AIDED DRUG DESIGN. Rao

S. Rapaka, Ph.D., and Richard L. Hawks, Ph.D., eds.

GPO Stock #017-024-01511-3 $11.00

NCADI #M134 NTIS PB #94-169547 (A14) $44.50

135 COCAINE TREATMENT: RESEARCH AND CLINICAL

PERSPECTIVES. Frank M. Tims, Ph.D., and Carl G. Leukefeld,

D.S.W., eds.

NCADI #M135

GPO Stock #017-024-01520-2 $11.00

NTIS PB #94-169554 (A13) $36.50

136 ASSESSING NEUROTOXICITY OF DRUGS OF ABUSE.

Lynda Erinoff, Ph.D., ed.

NCADI #M136

GPO Stock #017-024-01518-1 $11.00

NTIS PB #94-169562 (A13) $36.50

137 BEHAVIORAL TREATMENTS FOR DRUG ABUSE AND

DEPENDENCE. Lisa Simon Onken, Ph.D.; Jack D. Blaine, M.D.,

and John J. Boren, Ph.D., eds.

NCADI #M137

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NTIS PB #94-169570 (A 15) $44.50

188
138 IMAGING TECHNIQUES IN MEDICATIONS

DEVELOPMENT: CLINICAL AND PRECLINICAL ASPECTS.

Heinz Sorer, Ph.D., and Rao S. Rapaka, Ph.D., eds.

NCADI #M138

139 SCIENTIFIC METHODS FOR PREVENTION INTERVENTION

RESEARCH. Arturo Cazares, M.D., M.P.H., and Lula A. Beatty,

Ph.D., eds.

NCADI #Ml 39

140 PROBLEMS OF DRUG DEPENDENCE, 1993: PROCEEDINGS

OF THE 55TH ANNUAL SCIENTIFIC MEETING, THE

COLLEGE ON PROBLEMS OF DRUG DEPENDENCE, INC.

VOLUME I: PLENARY SESSION SYMPOSIA AND ANNUAL

REPORTS. Louis S. Harris, Ph.D., ed.

NCADI #M140

141 PROBLEMS OF DRUG DEPENDENCE, 1993: PROCEEDINGS

OF THE 55TH ANNUAL SCIENTIFIC MEETING, THE

COLLEGE ON PROBLEMS OF DRUG DEPENDENCE, INC.

VOLUME II: ABSTRACTS. Louis S. Harris, Ph.D., ed.

NCADI #M141

142 ADVANCES IN DATA ANALYSIS FOR PREVENTION

INTERVENTION RESEARCH. Linda M. Collins, Ph.D., and

Larry A. Seitz, Ph.D., eds.

NCADI #M142

143 THE CONTEXT OF HIV RISK AMONG DRUG USERS AND

THEIR SEXUAL PARTNERS. Robert J. Battjes, D.S.W.; Zili

Sloboda, Sc.D.; and William C. Grace, Ph.D., eds.

NCADI #M143

189
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145

146

147

148

149

THERAPEUTIC COMMUNITY: ADVANCES IN RESEARCH

AND APPLICATION. Frank M. Tims, Ph.D.; George De Leon,

Ph. D.; and Nancy Jainchill, Ph.D., eds.

NCADI #M144

NEUROBIOLOGICAL MODELS FOR EVALUATING

MECHANISMS UNDERLYING COCAINE ADDICTION.

Lynda Erinoff, Ph.D., and Roger M. Brown, Ph.D., eds.

NCADI #M145

HALLUCINOGENS: AN UPDATE. Geraldine C. Lin, Ph.D.,

and Richard A. Glennon, Ph.D., eds.

NCADI #M146

DISCOVERY OF NOVEL OPIOID MEDICATIONS.

Rao S. Rapaka, Ph.D., and Heinz Sorer, Ph.D., eds.

NCADI #M147

EPIDEMIOLOGY OF INHALANT ABUSE: AN

INTERNATIONAL PERSPECTIVE.

Nicholas J. Kozel, M.S.; Zili Sloboda, Sc.D.;

and Mario R. De La Rosa, Ph.D., eds.

NCADI #M148

MEDICATIONS DEVELOPMENT FOR THE TREATMENT OF

PREGNANT ADDICTS AND THEIR INFANTS.

C. Nora Chiang, Ph.D., and Loretta P. Finnegan, M.D., eds.

NCADI #M149

*U.S. GOVERNMENT PRINTING OFFICE: 1995 386-912/00013

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NIH Publication No. 95-3899

Printed 1995