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Overview of COMBINE

Clinical Trial Combining Medication and Behavioral Therapies for the Treatment of Alcoholism



This treatment manual and a companion manual in this series are provided to the public to permit replication of the behavioral therapies employed in COMBINE, a multisite clinical trial started in 1997 and funded as a cooperative agreement by the National Institute on Alcohol Abuse and Alcoholism (NIAAA).

The goal of COMBINE is to determine if improvements in treatment outcome for alcohol dependence can be achieved by combining pharmacotherapy and behavioral interventions. COMBINE seeks to evaluate the efficacy of the two most promising medications (naltrexone and acamprosate), both singly and together, when used in conjunction with two behavioral treatments of differing intensities.

One behavioral intervention, Medical Management (MM), employs a series of brief counseling sessions to enhance medication adherence and abstinence from alcohol. The other, Combined Behavioral Intervention (CBI), is a more intensive treatment that combines several successful features from previously evaluated interventions. The brief session therapy (MM) is a type of treatment that might be suitable for delivery in primary care settings. The more intensive therapy (CBI) is suitable for delivery by trained psychotherapists working in specialized alcoholism treatment facilities.

The following sections summarize the nature of the treatments tested in COMBINE, the study design, and considerations for those contemplating use of the manuals. This information has been previously published in greater detail by the COMBINE Research Group. For further information, consult the publications on the study’s methods and rationale (COMBINE Research Group 2003a); the safety and tolerability of the combined medications (Johnson et al. 2003); and the results of a protocol feasibility study (COMBINE Research Group 2003b). The first page of the COMBINE Web site ( lists topics on the Web site that are accessible to the public.

The COMBINE Interventions

Medication Treatments


Each of the COMBINE medications, naltrexone and acamprosate, has shown efficacy in the treatment of alcohol dependence in placebo-controlled clinical trials conducted in the United States and Europe (Kranzler and Van Kirk 2001; Streeton and Whelan 2001; Mann et al. 2004). In most of these studies, patients received a behavioral treatment to which the active medication or placebo was added. Outcomes typically reported included the amount of drinking or the proportions of patients remaining abstinent. Naltrexone has been approved as a treatment for alcohol dependence by the U.S. Food and Drug Administration (FDA) since 1994 and is approved in over 30 countries around the world (Litten and Allen 1998). Acamprosate currently is approved for treating alcohol dependence throughout most of Europe and South America, Australia, and parts of Asia and Africa and is now under FDA review in the United States (Mason and Ownby 2000).


A body of laboratory and clinical data suggests that naltrexone and acamprosate act on different neurochemical systems involved in the addictive response and presumably target different aspects of the alcohol dependence syndrome.


Naltrexone acts to block the opioid receptors, causing a reduction in the dopamine levels in the nucleus accumbens and leading to an attenuation in the positive reinforcement effects of alcohol (O’Malley and Froehlich 2003). Naltrexone appears to decrease craving for alcohol as well as decrease the rate of alcohol consumption (O’Malley et al. 2002). Most studies have also observed a decrease in the number of days of heavy drinking (Anton and Swift 2003). Acamprosate interacts with the glutamate receptor in a manner that is still unclear (Harris et al. 2002; Koob et al. 2002). This interaction appears to diminish the negative reinforcement of conditioned craving that follows cessation of drinking by reducing the protracted alcohol withdrawal symptoms (Spanagel and Zieglgansberger 1997; Koob et al. 2002). It is therefore reasonable to hypothesize that the combination of naltrexone and acamprosate might make it easier both to abstain from alcohol and to prevent a slip from turning into a relapse to drinking. Acamprosate may be particularly useful in avoiding initial alcohol consumption and enhancing treatment retention by attenuating symptoms of protracted alcohol withdrawal. Naltrexone may be particularly efficacious in reducing the likelihood of heavy drinking following a slip.

Behavioral Treatments


Modern pharmacotherapy efficacy studies in alcohol dependence generally have employed intensive psychotherapies delivered by trained therapists. However, treatment has increasingly moved toward treating alcoholics within a managed care setting in which the number of sessions is limited, and the sessions usually are provided by staff without specialized training in addiction treatment. It is therefore important to determine if the effects of pharmacotherapy depend on the type of counseling or psychotherapy with which it is combined. The two behavioral approaches tested in COMBINE contrast a treatment feasible for the primary care environment (MM) and one more suitable for use in an alcohol dependence specialty treatment facility (CBI).

Pharmacological and behavioral treatments are not mutually exclusive and indeed may enhance each other. Thus, pharmacotherapies may reduce craving for alcohol and/or the reinforcement experienced from drinking alcohol. Behavioral therapies can teach skills needed to maintain sobriety for extended periods. Several studies have demonstrated that the type of psychosocial intervention can influence the outcome with naltrexone (Anton and Swift 2003).

Medical Management (MM) is a manualized treatment (Pettinati et al. 2000) designed to approximate a primary care approach to alcohol dependence. The treatment, delivered by a medical professional (e.g., nurse or physician), provides strategies to increase medication adherence and supports abstinence through education and referral to support groups (Emrick et al. 1993; Barrett and Morse 1998; Carty et al. 1998). The initial session (40–60 minutes) involves discussion of the alcohol dependence diagnosis and negative consequences from drinking, a recommendation to abstain, medication information, strategies to enhance medication adherence, and referral to support groups such as Alcoholics Anonymous. In the eight subsequent 15- to 25-minute visits, the clinician assesses the client’s drinking, overall functioning, medication adherence, and any medication side effects.

Session structure varies according to the client’s drinking status and treatment compliance. When the client does not adhere to the medication regime, the clinician evaluates the reasons and helps the client devise plans to address the problem(s). Clinicians urge clients who drink to attend support groups and offer commonsense recommendations, such as avoiding bars. If the client suffers from medical side effects, the clinician specifies procedures for using concomitant medication to ameliorate them or reduces the dosage of either one or both study agents, resuming the study agents if side effects remit. If a client discontinues medication because he or she cannot tolerate it, the clinician schedules a monthly 15- to 25-minute “medical attention” meeting, during which the clinician employs a similar approach that focuses on the client’s drinking and overall health, omitting the medication adherence component.

Combined Behavioral Intervention (CBI) was designed to be a state-of-the-art individual outpatient psychotherapy for alcohol dependence. It merges a variety of well-supported treatment methods into an integrated approach. A manual-guided therapy, CBI nevertheless allows for normal clinical flexibility and individualization of treatment. CBI builds upon features in the manualized therapies of Project MATCH (Kadden et al. 1995; Miller et al. 1992; Nowinski et al. 1995; Project MATCH Research Group 1993) and provides skills training and support-system involvement modeled on a community reinforcement approach to treatment (Azrin et al. 1982; Meyers and Smith 1995). A maximum of 20 sessions is permitted, with the treatment course organized in four phases:

Phase 1 emphasizes building motivation for change. It begins with a single session of motivational interviewing (Miller and Rollnick 1991), which is the general clinical style used throughout CBI. This is followed by client assessment feedback in the style of motivational enhancement therapy (Miller et al. 1992).

Phase 2 includes a functional analysis of the client’s drinking, a review of the client’s psychosocial functioning, and a survey of the client’s strengths and resources, the results of which will be used in developing an individual plan for treatment and change. The therapist emphasizes the merits of an abstinence goal, and each client is encouraged to become involved in a 12-step or other mutual-help group. Whenever possible, a supportive significant other is identified to participate in the client’s treatment sessions as frequently as seems appropriate, ranging from a few to all sessions. The supportive significant other’s role is to facilitate the client’s compliance and abstinence and to reinforce as many of the CBI modules as the nature of the relationship appears to warrant.

Phase 3 draws upon a menu of nine cognitive-behavioral skill-training modules chosen on the basis of the client’s needs identified during Phase 2 (cf. Kadden et al. 1995). The modules include (1) assertiveness skills, (2) communication skills, (3) coping with craving and urges, (4) drink refusal and social pressure, (5) job finding, (6) mood management, (7) mutual-help group facilitation, (8) social and recreational counseling, and (9) social support for sobriety. All modules involve specific behavioral coaching and skill practice.

Phase 4 involves maintenance checkups in which the therapist and client review progress to date, renew motivation for change, and reaffirm commitment to an original or revised change plan.

CBI also includes a set of eight optional “pull-out” procedures that can be used at any appropriate point during treatment: (1) sobriety sampling, (2) raising therapist’s concerns, (3) implementing case management, (4) handling resumed drinking, (5) supporting medication adherence, (6) responding to a missed appointment, (7) telephone consultation, and (8) crisis intervention.

The number, frequency, and duration of CBI treatment sessions are negotiated between the therapist and client within the bounds of 20 sessions and 16 weeks. Weekly 50-minute outpatient visits are typical but not absolute. All therapy sessions are audiotaped, and random samples are reviewed and rated for quality control purposes.

Study Design

Study Population


The goal recruitment for the trial was 1,375 subjects drawn from 11 clinical research units. Patients met the criteria for alcohol dependence specified in the American Psychiatric Association’s Diagnostic and Statistical Manual, Fourth Edition (DSM–IV) (American Psychiatric Association 1994).

To be eligible, subjects had to acknowledge a desire to stop drinking and a history of alcohol consumption at or above a certain threshold. Prior to randomization and initiation of study pharmacotherapy, all subjects were required to complete any needed detoxification and abstain from alcohol for 4 days. Subjects had to have been drinking a minimum of 14 drinks (females) or 21 drinks (males) on average per week over a consecutive 30-day period in the 90-day period prior to initiation of abstinence. They also had to have had 2 or more days of heavy drinking (defined as four drinks for females and five drinks for males) in the previous 90 days, with the last drink being within 21 days of randomization to treatment.

Subjects were excluded if they reported recent opiate use, past 6-month opiate abuse or dependence disorder, or active dependence disorder with any substance other than cannabis or nicotine; serious psychiatric disorders requiring specific pharmacological intervention; unstable medical conditions for which either of the study medications was contraindicated (including liver function tests that were more than three times normal); and having received either study medication within the past 30 days.

Participants were recruited from in- and outpatient referrals within the study sites and from community and media sources. Subjects had to have had a breath alcohol level of zero to complete the informed consent and baseline measures. A certificate of confidentiality was obtained by all clinical sites.

Treatment Conditions


After assessment, subjects were randomly assigned to one of nine treatment conditions, as shown in Figure 1, using a permuted block randomization procedure with varying block sizes, which resulted in approximately 153 subjects per cell. Subjects in one cell (termed “cell 9”) were to receive no study medication (active or placebo) or MM intervention but only CBI therapy. This cell was included to contrast the effects of pill-taking (Barlow et al. 2000) on the outcome achievable with CBI alone and was considered a control condition for placebo effects that might result from the pill-taking regimen of 8 pills per day for 16 weeks.

Figure 1: COMBINE Treatment Combinations

Medical Management


Medical Management + Psychotherapy
 PlaceboAcamprosateNo Pills
No Pills   9

The medications were dispensed to subjects in blister packs with sections divided into morning, noon, and evening doses. Naltrexone was supplied in two tablets to be taken each morning, as 25 milligrams (mg) for the first 3 days, 50 mg for the next 4 days, and 100 mg per day thereafter. Acamprosate was provided in 500-mg pills, as two pills to be taken three times per day, for a total of 3 grams. The two drugs look different, and each has a matched (i.e., identical) placebo. Subjects were given no information about the identity of the medications they received.

All participants randomized into the eight cells, involving either active or placebo medication, were assigned to nine Medical Management appointments at weeks 0, 1, 2, 4, 6, 8, 10, 12, and 16. The subset of participants who also received CBI had a maximum of 20 sessions over a total of 16 weeks of study participation. They also were evaluated for drinking history and craving by research assistants on the days they attended their MM sessions, with longer assessments at weeks 8 and 16. After week 16, all treatments were stopped, but subjects were followed for the next 52 weeks and seen in person on weeks 26, 52, and 68 (following randomization) for drinking history and other assessments.

If necessary, subjects were terminated from the treatment portion of the protocol, primarily for adverse events, serious clinical deterioration, or lack of interest. All subjects who left prematurely underwent an end-of-treatment evaluation and were encouraged to attend research followups.


The assessment battery measured the following broad domains: (1) screening and inclusion/exclusion criteria; (2) history/physical, physiological, and laboratory assessments; (3) treatment-related expectancies; (4) drinking-related, psychological, and behavioral outcomes, predictors, mediators, and generalizability measures; and (5) therapy and medication adherence and therapy process measures. Subject compliance was tracked by several methods: attendance records to monitor behavioral intervention participation, counting pills from returned medication cards, and a timeline followback procedure to assess self-reported medication compliance.

Most measures were administered at baseline and again at one or more followup points. Measures considered to be particularly sensitive to subject reactivity (e.g., drinking self-report measures) were placed earlier in the battery. The primary followup assessments occurred at postrandomization weeks 8, 16, 26, 52, and 68. Within-treatment measures of drinking and craving were administered at weekly intervals or at each of the MM visits.

Caveats and Considerations

It is important to understand the conditions under which Medical Management and Combined Behavioral Intervention were delivered in the COMBINE trial. Therapy was conducted in the context of a structured research situation. Both of the manual-guided COMBINE treatments were administered by experienced therapists who had received specialized training in one of the two project interventions. Therapists closely followed the procedures outlined in the manuals. With few exceptions, all sessions were audiotaped to allow both local and project-wide clinical supervisors to observe therapists in action and provide session quality control. Therapists who deviated from protocol or demonstrated weakness in generic counseling skills were “redlined” for further training and monitoring. This manual was written for therapists who had similar training and supervision and may not affect participants the same way if it is given under different quality-control conditions.

Likewise, the manual was designed to standardize the delivery of the therapy within the particular context of the COMBINE project design. For example, all clients received their behavioral treatment(s) after undergoing an extensive baseline assessment battery. Before each therapy session, the client had a breath alcohol test to ensure sobriety. If the client tested positive for alcohol, the session was rescheduled, and arrangements were made to help the client get home safely. Therapists were prohibited from mixing other treatment approaches with the experimental intervention. All therapy was completed within 16 weeks of randomization.

Other standardized features of clinical trials that may also influence the effect of the therapy include inclusion/exclusion criteria, randomized assignment to treatment, and guidelines for dealing with clients who are late for treatment, fail to attend, or deteriorate clinically during the 16-week treatment period. Guidelines regulated and documented the type and amount of therapy the client could receive from sources other than COMBINE. The research and therapy components were kept separate, and all data collection was performed by trained research assistants who did not deliver treatment (although there is anecdotal evidence that some clients may not have grasped the distinctions among the different types of personnel with whom they came into contact).

Although the procedures and principles of the intervention are the result of careful development and are based on models validated in other studies, the COMBINE study and NIAAA staff make no claims or guarantees regarding the effectiveness of the treatments described herein. All manuals of this kind should be regarded as being under development and subject to ongoing improvement based on subsequent research and clinical experience. Information on the efficacy of this approach relative to other approaches and on the types of clients for whom it may be most useful will be available when study results are published, a process expected to begin in 2005. In the interim, it is our hope that the COMBINE treatment manuals will be useful tools for the community, as the Project MATCH therapy manuals have been. (The Project MATCH manuals, previously published by NIAAA, continue to be widely requested by researchers and clinicians from all sectors of the community.) The authors of the COMBINE manuals and NIAAA welcome feedback from users on their experiences with these newest treatment manuals.

Margaret E. Mattson, Ph.D., COMBINE Staff Collaborator

Raye Z. Litten, Ph.D., COMBINE Project Officer, Division of Treatment and Recovery Research

National Institute on Alcohol Abuse and Alcoholism


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