Chapter  3:  Pharmacotherapy for Alcohol Dependence: Evidence Report/Technology Assessment Number 3

Inclusion and Exclusion Criteria for the Literature Search

The inclusion criteria were related to the population being studied, the treatment setting for patients with alcohol dependence, the countries where these studies typically are done, and the publication languages. The inclusion criteria were:

• Publication from 1966 through November 1997 in English, French, or German.

• Adult subjects, 18 years of age or older, with alcohol dependence.

• Sample sizes of 10 or more subjects.

• Use of a control group for comparison.

Reviews, letters to the editor, and studies that did not address the efficacy of the key therapies were excluded.

The MeSH terms used for the search included the key therapies (disulfiram, the opiate antagonists [naltrexone and nalmefene], acamprosate, serotonergic agents such as ondansetron, buspirone, and the selective serotonin reuptake inhibitors [SSRIs], and lithium), alcoholism, alcohol drinking, study characteristics, and study design. The project librarian defined study characteristics and study design before using them in the search. An extensive gray literature search also was conducted to identify symposia proceedings, industry reports, and unpublished documents that contained efficacy data.

The search used the "explode" function, which includes all the individual brand and generic drug names without the need to list all the names separately. Because "alcohol dependence" does not have its own MeSH entry, the terms alcoholism and alcohol drinking were used.

In this search, "study characteristics" included: analytic studies, case-control studies, retrospective studies, cohort studies, longitudinal studies, followup studies, prospective studies, cross-sectional studies, clinical protocols, clinical trials (phases I-IV), controlled clinical trials, RCTs, intervention studies, and sampling studies. "Study design" included: cross-over studies, double-blind method, matched pair analysis, meta-analysis, random allocation, reproducibility of results, and sample size.

The searches were conducted in MEDLINE®, HealthSTAR, the American Society of Health-System Pharmacists' International Pharmaceutical Abstracts database, EMBASE, Alcohol and Alcohol Problems Database, and PsycINFO®. Materials available from the Cochrane Collaboration and the National Health Service Centre for Reviews and Dissemination were also reviewed.

An extensive search of the gray literature was conducted to identify literature from nontraditional sources including:

• Government documents and monographs.

• Industry reports and publications.

• Unpublished studies and works in progress.

• Review of tables of contents from symposia proceedings.

• FDA Medical Officer Reviews of efficacy data.

Data Abstraction Process

Four detailed data extraction forms were developed for entry of relevant information from the efficacy publications: the primary Data Extraction Form, Followup Results Form, Comorbid Study Results Form, and the Adverse Events Form.

These forms were pretested several times before use. An Extraction Guide was developed for use during the formal training session and as a reference guide during the extraction process. A dual abstraction method was employed using a content reviewer and a method reviewer. The content reviewers had been trained in the basic sciences, understanding the effects of alcohol on animals. The method reviewers had been more generally trained in qualitative and quantitative methods such as epidemiology, economics, and statistics. The abstraction process was monitored by the project's task leader and scientific director, reviewing the forms for consistency and providing feedback as necessary. Because of the complexities in the topic area being reviewed, the task leader and scientific director chose to conduct a third conflict-resolution review of each article. The review of harms data was limited; thus a formal and extensive harms review was not conducted.

Assessment of Article Quality and Grading of the Evidence

To assess the quality of the articles from the design, analysis, and reporting perspectives, a quality rating form was developed and included as the last two pages of the Data Extraction Form. It was used to evaluate, among other factors, the study design, diagnostic and outcome measurements, statistical analyses, and the discussion of the reviewed articles. The form was based on questions that summed to 40 points and were then scaled to 100 points.

Besides evaluating the quality of the articles, grades were assigned for the evidence. Two grades were provided, one for efficacy and another for harms. The grades for efficacy were based on the adequacy of the data (i.e., consistency, quality, sample size, and magnitude of effects). For harms, the seriousness of the side effect, whether it was a known or an unexpected side effect of the therapy, and its frequency compared with placebo were considered. The grades were defined as follows:
Efficacy data grades:

• Good (A): Data are sufficient for evaluating efficacy. The sample size is adequate. The data are consistent and indicate that the key drug is clearly superior to placebo for treating alcohol dependence.

• Fair (B): Data are sufficient for evaluating efficacy. The sample size is adequate. The data indicate that inconsistencies in the findings for the alcohol outcomes between the key therapy and placebo are such that the efficacy of the key therapy for treating alcohol dependence is not clearly established.

• Poor (C): Data are sufficient for evaluating efficacy. The sample size is adequate. The data show that the key therapy is no more efficacious for treating alcohol dependance than placebo.

• Incomplete evidence (I): Data are insufficient for assessing the efficacy of the key therapy for treating alcohol dependence based on limited sample size or poor methodology.

• Low: The side effects are not life threatening; those reported are known side effects of the therapy.

• High: A life-threatening side effect; it is serious and its frequency of occurrence is greater in the key therapy group than in the placebo group.

Evidence Table Development and Supplemental Analyses

Two separate evidence tables (study design and study outcomes) were developed for each key therapy evaluated. Several different variables are used in the alcohol literature to assess return to drinking. Although a meta-analysis comparing each of the key therapies for one or more outcome variables would have been useful for treatment providers, the data were not available for this type of analysis at this time.

Disulfiram

• A substantial literature has been generated on the use of disulfiram in alcoholism, but the number of controlled clinical trials is limited.

• Controlled clinical trials of disulfiram reveal mixed findings. There is little evidence that disulfiram enhances abstinence, but there is evidence that disulfiram reduces drinking days. When measured, compliance is a strong predictor of outcome.

• Studies of disulfiram implants are methodologically weak and generally without good evidence of bioavailability.

• Studies of supervised disulfiram administration are provocative but limited.

Naltrexone

• Trials of naltrexone in the treatment of alcoholism are recent and of generally good quality.

• There is good evidence that naltrexone reduces relapse and number of drinking days in alcohol-dependent subjects.

• There is some evidence that naltrexone reduces craving and enhances abstinence in alcohol-dependent subjects.

• There is good evidence that naltrexone has a favorable harms profile.

Acamprosate

• Trials of acamprosate in alcohol dependence are large but limited to European populations.

• There is good evidence that acamprosate enhances abstinence and reduces drinking days in alcohol-dependent subjects.

• There is minimal evidence on the effects of acamprosate on craving or rates of severe relapse in alcohol-dependent subjects.

• There is good evidence that acamprosate is reasonably well tolerated and without serious harms.

Serotonergic Agents

• There are several controlled clinical trials of serotonergic agents in primary alcoholics without comorbid mood or anxiety disorders.

• There is minimal evidence on the efficacy of serotonergic agents for treatment of the core symptoms of alcohol dependence.

• There is some evidence on the efficacy of serotonergic agents for the treatment of alcohol-dependent symptoms in patients with comorbid mood or anxiety disorders, although the data are limited.

Lithium

• There are limited studies on the effects of lithium in primary alcoholics without comorbid mood disorders.

• There is evidence that lithium is not efficacious in the treatment of the core symptoms of alcohol dependence.

• There is minimal evidence for efficacy of lithium for the treatment of alcohol-dependent symptoms in patients with comorbid depression.

Disease Biology

Two aspects of the biology of alcoholism warrant brief review in this report, because they drive a good deal of the theory behind the use of current pharmacotherapies and the development of new medications. An overview of the possible means by which certain classes of drugs may act, for instance on the brain, to control craving or intake of alcohol is presented first. This is followed by a brief discussion of the genetic aspects of this disorder. More explicit causal pathways for the key therapies that were reviewed for this report are presented in Chapter 2 on methodology.

Epidemiology and Disease Burden

Disease Incidence and Prevalence

To determine the public health significance of alcohol dependence, policymakers and researchers typically rely on estimates of disease incidence or prevalence. Although the preferred measure of disease burden is incidence, which is the risk of developing the disease in a given period of time, studies of alcohol dependence typically report disease prevalence, which is the proportion of a population that is affected by a disease at a specific point in time (Rothman, 1986).

Prevalence rates of alcoholism in the U.S. population have been estimated through a variety of sampling techniques, but the definitions for alcoholism often vary. One of the more extensive studies that estimated prevalence based on direct interview is the Epidemiologic Catchment Area Survey sponsored by the National Institute of Mental Health (Regier, Farmer, Rae, et al., 1990). This survey involved interviews of a total of 20,291 adults aged 18 and older based on household surveys conducted between 1980 and 1984 in Baltimore, MD; St. Louis, MO; Durham, NC; New Haven, CT; and Los Angeles, CA. Residents of long-term mental hospitals, nursing homes, and penal institutions were sampled at higher probability rates than the community. The diagnosis of alcoholism was based on the DSM-IIIR (APA, 1987). The overall 6-month and lifetime prevalence rates of alcohol dependence were, respectively, 2.8 and 7.9 per 100 persons aged 18 and older.

Table 2. One-year prevalence of alcohol dependence (more...)

Table 2. One-year prevalence of alcohol dependence (DEP) reported by all national studies, in percentages, by sex

	Men	Women	Total
	DEP	DEP	DEP
National Health Interview Survey (1988)
DSM-III-R	9.6	3.2	6.3
DSM-IV	9.2	3.0	5.9
National Alcohol Survey (1990)
DSM-III-R	5.3	1.7	3.2
DSM-IV	5.7	2.2	3.9
ICD-10	7.8	3.4	5.4
National Comorbidity Survey (1992)
DSM-III-R	?	?	7.2
National Longitudinal Alcohol Epidemiologic Survey (1992)
DSM-IV	6.3	2.6	4.4

?= Data not published. Source: Ninth Special Report, 1997.

Four national surveys that measured the 1-year prevalence of alcohol abuse and dependence were summarized in the 1997 Ninth Special Report to the U.S. Congress on Alcohol and Health (hereafter the Ninth Special Report), the 1988 National Health Interview Survey (NHIS), the 1990 National Alcohol Survey (NAS), the 1992 National Comorbidity Survey, and the 1992 National Longitudinal Alcohol Epidemiologic Survey (NLAES) (Ninth Special Report, 1997). As a result of the changing diagnostic criteria over time and differences in terminology between studies, the estimates of alcohol dependence are relatively inconsistent (Table 2). For example, using DSM-IV criteria, the NHIS and the NAS reported greatly divergent prevalence rates for alcohol dependence in males despite a 2-year time span between studies.

More than 8 million Americans suffered from alcohol dependence in 1992 according to the NLAES (Grant, Harford, Dawson, et al., 1994). Alcohol dependence is more frequent in males and races other than black. The age range at highest risk are men and women of all races who are 18 to 29 years of age. The overall lifetime risk of alcohol dependence is estimated to be 9.6 percent for men and 3.2 percent for women (Grant, Harford, Hasin, et al., 1992).

Treatment

Final Key Questions

Our evidence synthesis addresses five questions relevant to the pharmacotherapy for treatment of alcohol-dependent patients. The first three questions relate to three agents used to reduce craving, reduce drinking days and relapse rates, and enhance abstinence. Two of these therapies have Food and Drug Administration (FDA) approval for use in alcohol dependence; the third is still under review. These agents have been in use for different periods of time and, as will be seen, the amount of evidence available for them differed considerably. The last two questions involve pharmacotherapies that, although used principally to treat other conditions, have been found useful by some clinicians for treating alcohol dependence; and/or there is some evidence of their efficacy in reducing alcohol intake.

• 1

  What is the efficacy of disulfiram relative to placebo in treating alcohol dependence?

• 2

  What is the efficacy of opiate antagonists (naltrexone and nalmefene) relative to placebo in treating alcohol dependence?

• 3

  What is the efficacy of acamprosate relative to placebo in treating alcohol dependence?

• 4

  What is the efficacy of serotonergic agents relative to placebo in the treatment of alcohol dependence?

• 5

  What is the efficacy of lithium relative to placebo in the treatment of alcohol dependence?

In the context of alcohol dependence pharmacotherapies, efficacy refers to the medication's ability to reduce (or eliminate) alcohol intake and the desire to seek alcohol under the ideal setting and circumstances of a clinical trial. The efficacy of each of the drugs specified in our key questions was determined by assessing the following factors: reduction in the average number of standard drinks of alcohol; number or percentage of drinking/nondrinking days; number of episodes of heavy drinking (>5 drinks per day for men, >4 drinks per day for women); time to return to drinking; overall resumption of drinking over the course of the study (the definition of which may differ among studies); reduction in relapse rates where the definition of relapse uses one or more of the aforementioned outcomes; and craving or urge for alcohol.

Examination of treatment efficacy must be balanced with assessment of treatment harm. Evidence on treatment side effects - i.e., harm - is sometimes found within randomized controlled trials (RCTs), but it may also be identified through prospective cohort studies or secondary data sources. We used all types of controlled studies to evaluate the side effects of these medications. However, data on harms were not systematically sought outside the controlled clinical trials identified by our literature review. Therefore, by definition, harms as reported in this evidence report are limited in scope. (As with the efficacy studies, the information on harms will be presented in the form of summary tables at the conclusion of this report.)

Disulfiram

Figure 1. Hypothesized causal pathway for the use of (more...)

   Figure 1. Hypothesized causal pathway for the use of disulfiram for alcohol dependence

Disulfiram is classified as an alcohol-sensitizing agent or deterrent drug. This class of drugs works by deterring the problem drinker from drinking by producing a very unpleasant physiological reaction when the person consumes alcohol. Additional information on disulfiram's mechanism of action for the treatment of alcohol dependence is provided in Chapter 1. The hypothesized causal pathway for the use of disulfiram in the treatment of alcohol dependence is provided in Figure 1.

Opiate Antagonists (Naltrexone and Nalmefene)

Figure 2. Hypothesized causal pathway for the use of (more...)

   Figure 2. Hypothesized causal pathway for the use of opiate antagonists (naltrexone and nalmefene) for alcohol dependence

Naltrexone, an opioid antagonist, was originally developed for the treatment of heroin addiction. The FDA first approved its use for treating alcohol-dependent patients in the United States in 1994. Naltrexone binds to opioid receptors in the central nervous system (CNS) and competitively inhibits the actions of opioid drugs (both pure agonists and agonists/antagonists) and endogenous opioids (see Chapter 1 for a more thorough discussion of the opiate antagonists' mechanism of action for the treatment of alcohol dependence). In the work that follows, we occasionally refer also to nalmefene, which is another opiate antagonist. Thus, opiate antagonists should be understood to include naltrexone and nalmefene. The hypothesized causal pathway for the use of opiate antagonists for the treatment of alcohol dependence is provided in Figure 2.

Acamprosate

Figure 3. Hypothesized causal pathway for the use of (more...)

   Figure 3. Hypothesized causal pathway for the use of acamprosate for alcohol dependence

Acamprosate, also known as calcium acetyl homotaurinate, has been approved for treating alcoholism in Europe for several years and is now in wide use there; it has demonstrated promising results in regard to abstinence and dropout rates (see Chapter 1 for a more thorough discussion of acamprosate's mechanism of action for the treatment of alcohol dependence). The hypothesized causal pathway for the use of acamprosate in alcohol dependence is provided in Figure 3.

Serotonergic Agents

Figure 4. Hypothesized causal pathway for the use of (more...)

   Figure 4. Hypothesized causal pathway for the use of serotonergic agents for alcohol dependence

An extensive literature exists on abnormalities of serotonergic function in alcohol-dependent humans and alcohol-preferring rats. Serotonergic agents represent a group of medications that modulate serotonin neurotransmission. For this review, some are individual drugs, and others belong to the subclass known as selective serotonin (5-HT) reuptake inhibitors (SSRIs). Chapter 1 provides a more thorough discussion of the serotonergic agent's mechanism of action for the treatment of alcohol dependence. The hypothesized causal pathway for the use of serotonergic agents in treating alcohol dependence is provided in Figure 4.

Serotonergic agents that have appeared in the literature for the treatment of alcohol dependence include buspirone, ondansetron, and several of the SSRIs (fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram, and viqualine). Other serotonergic agents, such as ritanserin, initially had been reported to reduce alcohol intake. Communications with the representatives of the pharmaceutical manufacturer (August 1997) indicate that ritanserin is no longer being evaluated for use in alcohol dependence, presumably because of lack of efficacy. Thus, ritanserin is not included in the summary tables.

Lithium

Figure 5. Hypothesized causal pathway for lithium use (more...)

   Figure 5. Hypothesized causal pathway for lithium use in alcohol dependence

Because the literature contains several evaluations of lithium as a potential pharmacotherapy for alcohol dependence, the American Society of Addiction Medicine (ASAM) suggested that lithium be included in our review. Lithium has been a mainstay of therapy in the treatment of bipolar affective disorder, although the literature in the area of alcohol dependence is somewhat limited. The mechanism of action has not been established, but lithium may be helpful in treating alcoholism owing to its antidepressant or mood-stabilizing effects. The exact mechanism of action of lithium is unknown though lithium enhances serotonergic activity and affects a variety of second messenger systems (see Chapter 1 for a more thorough discussion of lithium's mechanism of action for the treatment of alcohol dependence). The hypothesized causal pathway for use of lithium in treating alcohol dependence is provided in Figure 5.

Comparisons Across Drugs

Apart from understanding the efficacy (and harms) of these agents taken one at a time, an important related issue is whether one of these agents appears to be more efficacious than one or more of the others. Few data are available from controlled trials that directly compare these agents. However, one very small study (Gerra, Caccavari, Delsignore, et al., 1992) did address the issue of comparisons across drugs (acamprosate vs. fluoxetine vs. placebo).

Inclusion and Exclusion Criteria for the Literature Search

Table 3. Pharmacotherapy for alcohol dependence: Inclusion/exclusion (more...)

Table 3. Pharmacotherapy for alcohol dependence: Inclusion/exclusion criteria

Category area	Criteria
Study population	Humans Adults (ages 18 and older) Males and females Alcohol-dependent subjects Exclude: children and infants; pregnant women
Study setting	Inpatient and outpatient settings All study settings should reflect current practice
Time period	1966 and later Depends on date of approval for pharmaceutical products
Geographic site of study	United States, Canada, Europe, Latin America, Asia, Australia/New Zealand Exclude: locations based on language of publication
Publication languages	English, French, and German
Admissible evidence	Study design (RCT - double, single-blinded; non-RCT - prospective and retrospective cohort studies, case control) Other designs (meta-analysis, meta-regression, cross-design synthesis, review article for reference list searches, cost-effectiveness, quality of life [QOL]) Sample size (>10 subjects)

Table 4. Systematic search strategy and results

Table 4. Systematic search strategy and results

Search strategy	Results
Explode disulfiram	2,005
Explode naltrexone	2,837
Acamprosate	33
Calcium acetyl homotaurinate	5
Explode serotonin uptake inhibitors	8,923
Explode ritanserin	234
Explode alcohol deterrents	2,171
Explode buspirone	819
Explode lithium or lithium carbonate or lithium chloride or lithium compounds	15,290
Explode alcoholism	47,989
Explode alcohol drinking	19,257
Explode "study characteristics"	512,366
Explode "study design"	160,932

In this search, "study characteristics" included: analytic studies, case-control studies, retrospective studies, cohort studies, longitudinal studies, follow-up studies, prospective studies, cross-sectional studies, clinical protocols, clinical trials (phases I-IV), controlled clinical trials, RCTs, intervention studies, and sampling studies. "Study design" included: cross-over studies, double-blind method, matched pair analysis, meta-analysis, random allocation, reproducibility of results, and sample size.

Main Databases Searched

Searches initially were conducted of the U.S. National Library of Medicine (NLM) databases MEDLINE and HealthSTAR.

Other Databases Searched

The same search strategy was used in several other databases as well. Because the MeSH controlled vocabulary is not standard across other databases, analogous terminology was used to retrieve the widest range of articles from these sources.

Compilation into ProCite®

The results from all searches were compiled into a ProCite® bibliographic database, removing all duplicate records. The bibliographic software was used to tag eligible articles and, for articles determined to be ineligible, the reason for their exclusion from the evidence report.

Table 5. Search results by type or name of pharmaceutical (more...)

Table 5. Search results by type or name of pharmaceutical agent

Drug	Number of articles retrieved
Disulfiram	135
Naltrexone	73
Acamprosate	37
Serotonergic agents Buspirone Ondansetron Ritanserin Serotonin reuptake inhibitors (SSRIs) Fluoxetine Fluvoxamine Paroxetine Sertraline Citalopram Viqualine	28 9 12 62 34 13 2 5 27 4
Lithium	46
Total	487

The final database contained 375 publications. This number is lower than would be produced by summing over the number of articles retrieved (n=487) for each drug type, because some articles addressed more than one drug.

Exclusion of Articles

Table 6. Principal reasons for excluding articles after (more...)

Table 6. Principal reasons for excluding articles after title/abstract review and numbers of articles excluded

Reason for exclusion	Number of articles
Opinion/editorial	37
Review article	112
Drug investigated was not one of our key therapies	27
Methodological work relevant to alcohol research	20
Studies in health volunteers	5
Studies with fewer than 10 subjects	6
Other alcohol/clinical problem, not alcohol dependence	30
Studies of key therapies but subjects were not alcohol-dependent, e.g., some were heavy or social drinkers	28
Studies of side effects only	13
Biomarker studies, not evaluating efficacy	4
Studies that did not address alcohol outcomes, e.g., abstinence, relapse	11
Studies without a control group	10
Studies of counseling or other therapies that did not include any of our key therapies	13
Animal studies	2
Unavailable*	4
Reviewed for efficacy	53
Total	375

*

Unavailable: a dissertation, a German article requested several times, subset of original study published but main study was not published, and a very new publication.

Gray Literature

Useful data for an evidence report often can be found in symposium proceedings, government monographs, industry reports, articles submitted for publication, and other nontraditional sources. Collectively, this is considered the "gray literature." For the purposes of this report, gray literature was defined as information that has not appeared in peer-reviewed journals but is available as follows:

• Government documents and monographs (aside from FDA documents).

• Industry reports and studies.

• Unpublished studies and works in progress.

• Conference proceedings and symposia.

• FDA Medical Officers Review (MOR).

Individuals were contacted in industry, government, and professional societies (including ASAM) to elicit information or reports that are not retrievable through literature database searches (i.e., specifically through MEDLINE or EMBASE). This was done for the following medications: disulfiram; the opiate antagonists naltrexone and nalmefene; acamprosate; and the serotonergic agents.

Data Extraction Form

The task leader and scientific director worked with the core project staff to develop a data extraction form to use for entry of relevant information from the eligible publications that addressed efficacy. The data extraction form was developed in an iterative fashion with extensive communication between the methodologists and alcohol researchers. The process was begun by outlining the relevant study designs and outcomes and identifying the variables most important to address for studies involving the efficacy of medications for alcohol dependence. These included:

• Study designs.

• Practice setting.

• Description of patient populations, e.g., severity of dependence, instrument for diagnosing alcohol dependence, inclusion/exclusion parameters, and prior alcohol treatments.

• Interventions, e.g., dose titration and maximum dosing, compliance with medication, length of study.

• Co-interventions.

• Data collection techniques for assessing outcome.

• Statistical analysis.

• Outcome measures, e.g., drinks per day or per week, relapse, craving, compliance with treatment.

• Side effects of treatment.

• Limitations noted by authors.

• Limitations noted by reviewers.

• Conclusions noted in article and whether the reviewer concurred with the stated conclusions.

These variables were incorporated into the data extraction form, whose basic structure was taken from one developed for spinal cord clinical guidelines work. The draft form underwent an extensive review process that included pretesting on several randomly selected alcohol articles. After each pretest, the form was revised to increase its utility and efficiency. After extensive pretesting, the form was also sent to the TEAG for comment. Several TEAG members suggested inclusion of pretreatment variables such as detoxification, length of abstinence, and pre-randomization psychosocial therapies; the extraction form was revised accordingly. The final data extraction form can be found in Appendix C.

The RTI-UNC EPC used two types of abstractors for the data extraction process, content reviewers and methods abstractors. The content abstractors are basic science researchers who specialize in understanding alcohol effects on the brain and other physiologic aspects of this disease. The methods abstractors are more generally trained in qualitative and quantitative methods such as epidemiology, economics, and statistics. In addition, reviewers included an epidemiologist with special expertise in pharmacotherapy (task leader), a psychiatrist with special expertise in treating patients with alcoholism (scientific director), and an internist with broad clinical responsibilities and a substantial research background (senior advisor to the project).

To collect high-quality data, an extraction guide was developed for use during training and as an ongoing reference for each of the items in the data extraction form. In addition to providing guidance on specific items, the guide also delineated general rules for this process that were intended, insofar as possible, to guarantee consistency across abstractors. For example, abstractors were instructed that the outcomes data for the results section of the data extraction form could come only from text or tables, not from graphic data presentations. Furthermore, when inconsistencies occurred between results stated in the text of an article and the results presented in tabular form, the abstractors were instructed to use the data from the text. Abstractors also were instructed to extract the alcohol outcomes data from the intent-to-treat analyses whenever possible. Subgroup analyses (e.g., compliant patients) were extracted onto a separate section of the abstraction form.

Each of the abstractors had used drafts of the data extraction form (e.g., during pretesting). Nonetheless, a formal training session was held to discuss the extraction guide and various changes to the data extraction form, provide final guidance on the abstracting procedures, and answer questions with regard to the final instruments.

At the completion of abstractor training, the data abstraction process began. The task leader, scientific director, and both the RTI and UNC research coordinators monitored progress. To this end, the task leader and scientific director conducted extensive reviews of the first three data extraction forms completed by each abstractor and provided both individual and group feedback for particularly problematic items. This was done to enhance consistency between abstractors.

Two especially difficult problems in the abstraction process were (1) accounting for comorbidities and (2) capturing information on followup of initial interventions. Addressing these issues ultimately required the development of two separate supplemental forms. These additional forms are also provided in Appendix C.

Side-Effect Profile Form

The harms literature was abstracted onto a side effect profile form (Appendix C) that elicited data on the following:

• Type of side effects.

• Total sample size of the study.

• Frequency of the side effect in the key therapy and placebo groups.

• Whether there was a statistically significant difference between the key therapy and placebo groups.

• Methodology for collecting side effect data.

This information was sought for all of the eligible efficacy articles reviewed (n=53) as well as from articles on side effects and all others that included a control group for comparison purposes. Because the main emphasis of this report was efficacy and not harms, these data were not collected by dual abstraction. A registered pharmacist (who is also a Ph.D. candidate) collected the side effect and withdrawal data for the evidence tables on harms. However, it should again be emphasized that an extensive search for harms data was not completed as part of this evidence report; the listing of harms reflects those that have been detected in clinical trials and not in general clinical practice.

Quality Control and Adjudication

Quality control to determine eligibility for abstraction has been described (see "Title and Abstract Review"). In short, all titles and abstracts were subject to dual review, and the scientific director adjudicated discrepancies. Each article was abstracted by two independent abstractors - one an expert in alcohol research (content reviewer) and the other a methodologist. Abstractors were blinded to the authors' names and the institution that produced the work. Owing to the time-consuming nature of deleting all reference to the journal title and the distinct formatting of certain journals (such as the Archives of General Psychiatry), the abstractors were not blinded to the journal title.

In concordance with an article by Morley, Finney, Monahan, et al. (1996), the RTI-UNC EPC noted that the quality of the literature and the heterogeneity of outcomes caused considerable difficulties in the data abstraction process as discussed in Chapter 4. As can be seen by reviewing the data extraction form (Appendix C), a great deal of information was abstracted from each article. In reviewing the completed abstracts, it was noted that agreement was good for the core variables (sample size, study design, outcomes, etc.), but agreement was lower for the more peripheral variables. With such a large number of variables abstracted, many disagreements were found that required adjudication. Because the adjudication process is time-consuming, the RTI-UNC EPC staff decided to have an additional reviewer, the task leader or scientific director, complete a third form for all articles. In reporting on this whole process and our final results, the primary study design and results are based on this third review, which took into account the reporting of the content and methods abstractors, whereas the quality rating, study limitations, and conclusions are those provided by the method and content reviewers.

Reliability

An important aspect of the dual abstraction process is to determine the reliability of data collection between the two reviewers. To this end, the task leader, scientific director, and the clinical methodologist selected the following eight key variables for reliability assessment:

• Study design (categorical variable).

• Diagnostic criteria for alcohol dependence (categorical variable).

• Total number of controls entered into the trial (continuous variable).

• Maximum dose per day for intervention group 1 (continuous variable).

• Whether compliance with treatment was measured (continuous variable).

• Average number of standard drinks for intervention group 1 (continuous variable).

• Average number of episodes of heavy drinking for intervention group 1 (continuous variable).

• Average time to first drink for intervention group 1 (continuous variable).

From the reviewed articles (n=53), nine articles were randomly sampled to assess the reliability of abstraction between the content and method abstractors. The kappa statistic, which corrects for chance agreement, was used. Kappa was not evaluated for four of the eight variables because there was near perfect agreement between the reviewers but no variation among the nine articles for these variables (study design, average number of standard drinks for intervention group 1, average number of episodes of heavy drinking for intervention group 1, and average time to first drink for intervention group 1). For example, for study design, all the abstractors said the articles were RCTs with only one disagreement. Thus, the observed agreement was 87.5 percent, with a chance agreement of 87.5 percent as well. Since kappa takes the chance agreement into account, its computation in these circumstances produces a low kappa statistic that does not actually reflect the excellent agreement observed. For this reason, the kappas for the variables with no variation among the nine articles have been omitted.

For the variables with variation among the articles, substantial agreement was noted, as follows:

• Criteria for alcohol dependence (kappa 0.84).

• Total controls initially entered in the trial (kappa 0.74).

• Maximum dose per day for intervention group 1 (kappa 0.66).

• Compliance with treatment not measured (kappa 0.77).

A kappa value greater than 0.60 is considered very good; a kappa greater than 0.80 is considered almost perfect.

Quality Rating Development and Analysis

Quality of the evidence can be judged on two levels: at the level of the individual article and in summary over the spectrum of articles addressing each of the key therapies. This section of the report describes our approaches to the development of quality ratings on both levels.

Quality of Individual Articles

Figure 6. Quality rating scale for alcohol dependence (more...)

Figure 6. Quality rating scale for alcohol dependence pharmacotherapy review

Category 1: Problem or question studied (5 points)
	Not at All	Somewhat	Okay
Alcohol dependence problem clearly stated?	0	1	1	2	1
	Little or No	Yes
Significance of alcohol dependence problem discussed?	0	1
	No	Yes
Is research question capable of being answered with the methods proposed?	0	1
	No	Yes
Is the question placed in the broader context of alcohol research?	0	1
	No	Yes
Random allocation of treatment?	0	2
	Unknown or >40%	<40%
Dropout rate of patients invited into the study.	0	1
	No	Yes
Diagnostic criteria clearly specified.	0	1
	No	Yes
Is the sample clearly described?	0	1
	No	Yes
Reliability/validity of the diagnostic measurement tool specified or referenced?	0	1
	No	Yes
Reliability/validity of the outcome measurement tool specified or referenced?	0	2
	No	Yes
Compliance with regimen assess (pill count, biologic marker, etc)	0	1
	No	Yes
Are the outcome measurements clinically relevant?	0	1
	No	Yes	N/A
Are potential confounding effects addressed (differences between two groups such as age, sex, type of alcohol dependence, other substance abuse)?	0	1
	No	Yes
Was the co-intervention (e.g., psychotherapy) similar between two study groups?	0	1
	No	Yes
Was the co-intervention (e.g., psychotherapy) compliance monitored?	0	1
	No	Yes
Was a concurrent control group present?	0	2
	No	Yes
Do the study conclusions apply to U.S. alcohol-dependent patients?	0	3
	No	Yes
Is the clinical setting specified clearly?	0	2
	No	Yes
Appropriate alcohol dependence diagnostic criteria used?	0	2
	No	Yes
Do the measured outcomes relate to the construct of alcohol dependence?	0	2
	No	Yes
Are other variables clearly described in terms of their relationship to alcohol dependence?	0	1
	No	Yes	N/A
If multiple univariate tests performed, multiple comparisons taken into account?	0	1
	No	Yes
Power analysis performed?	0	1
	No	Yes
In regression analysis, is number of variables in model less than 1/10th of the sample size?	0	1
	No	Yes
Are statistically significant findings clinically significant?	0	1
	No	Yes
Are statistical tests used appropriate to the data?	0	1
	No	Yes
Are the conclusions warranted from the data?	0	5

The RTI-UNC approach to assessing the quality of the individual articles (see Figure 6) takes into account the internal and external validity of each study. It encompasses, among other issues, study design, measurement issues, statistical analyses, and the appropriateness of the conclusions drawn.

To assess the internal validity of a study - i.e., the likelihood that the design and conduct of the study minimize systematic error (bias) - the following factors were evaluated from each study:

• Sample size and statistical power.

• Selection bias and inclusion criteria.

• Selection of comparison groups.

• Randomization and comparability of the groups.

• Definition of the intervention and exposures with an assessment of patient compliance with therapy.

• Definition of outcome measures, attrition rates, confounding variables, data collection methods, and observation bias.

• Methods of statistical analysis.

Statistical considerations included assessing the adequacy of the sample size for drawing conclusions and identifying whether the authors did a power calculation for small studies. When the authors of a given article presented numerous descriptive analyses in a single publication, our rating addressed whether they had taken these multiple comparisons into account in their analyses. For studies that used regression techniques, the rating assessed whether the number of variables for the model exceeded the limitations imposed by the size of the population studied. The rating scale also addressed the clinical relevancy of the statistical findings.

With regard to diagnostic and outcome measures, the quality rating instrument assessed whether the study design incorporated validated measurement instruments or relied on unstructured and/or unvalidated instruments. In addition, the abstractors evaluated whether the diagnostic criteria and outcomes were clearly specified and appropriately measured.

External validity - i.e., whether the findings of the study can be generalized to populations other than those in the study - was also considered for the quality rating. Especially important for this evidence report was whether the results from studies that took place outside of North America are relevant to U.S. population groups.

The quality rating instrument was based on a 40-point scale with higher scores denoting better studies. Each abstractor completed the quality rating for each article reviewed. The individual scores provided in the evidence table for each article were derived by calculating the following ratio: the points from the responses circled by the abstractor (numerator) divided by the total number of points that could have been awarded, typically 40 points (denominator). When the items were determined to be not applicable, "NA," then we removed total number of points for that item from both the numerator and the denominator. Quality rating scores (Figure 6) for each article were not averaged across the two abstractor types, i.e., content and methods abstractors, because of the large discrepancies noted. Generally, content abstractors tended to give higher (better) scores than did the methods experts. Because averaging the two abstractors' scores would mask these patterns, both scores are presented for comparison.

Main Efficacy Results

Subgroup and Followup Studies

The two Fuller studies evaluated rates of abstinence in compliant patients on oral disulfiram as a subgroup analysis (Fuller and Roth, 1979; Fuller, Branchey, Brightwell, et al., 1986). The 1979 study found that those who abstained were significantly more likely to have been compliant (70 percent) than those who returned to drinking (32 percent), regardless of treatment group. Similarly, in the 1986 study, men who were compliant experienced 1-year abstinence rates between 38 and 50 percent, whereas men who were noncompliant had abstinence rates between 6 and 10 percent, regardless of treatment group.

Limitations

The main limitation of the disulfiram implant literature is the very small sample sizes for each of the studies, ranging from a low of 20 patients randomized to two groups to a high of 100 patients randomized to four groups. In addition, only two of the six implant studies assessed the bioavailability of disulfiram by measuring drug blood levels. As with many alcohol studies, alcohol consumption was unverified.

Of the four efficacy studies of oral disulfiram, the total number of patients who may have benefited from therapy was unclear. Two studies did not provide the number of patients who completed therapy (Fuller and Roth, 1979; Fuller, Branchey, Brightwell, et al., 1986) and a third study (Chick, Gough, Falkowski, et al., 1992) had a 46-percent dropout rate. Other limitations included nonrandom allocation to therapy (Schuckit, 1985) and unblinding of patients post-randomization (Chick, Gough, Falkowski, et al., 1992).

Harms

Disulfiram has been in use in treatment settings for more than 40 years. Over that time a number of side effects have been reported, including some that are considered to be serious (such as liver toxicity, peripheral neuropathy, and psychosis). In addition, the disulfiram-ethanol reaction can be serious and require medical intervention, especially in patients with other conditions such as esophageal varices. In the reviewed efficacy trials (Evidence Tables 3a and 3b), disulfiram appeared to be reasonably well tolerated. Side effects reported to occur significantly more often with the drug than with placebo included stiffness of neck, drowsiness, and sexual dysfunction. Chick, Gough, Falkowski, et al. (1992) reported a 3.1 percent dropout rate because of dizziness and nausea, 1.6 percent secondary to possible neuropathy, and 3.1 percent because of skin rash. Overall, the harms profile was low, although clinicians should be aware of the potential for rare, serious side effects.

Evidence Grades

Efficacy grade: B; Harms grade: Low.

Main Efficacy Results

Only the study by O'Malley, Jaffe, Chang, et al. (1992) evaluated the standard number of drinks per drinking day among four treatment groups: naltrexone and coping therapy, naltrexone and supportive therapy, placebo and coping therapy, and placebo and supportive therapy. The authors reported that the naltrexone and coping therapy group consumed fewer drinks per drinking day (3.7 drinks) compared with the placebo groups (coping: 7.1 drinks; supportive: 6.5 drinks) or the naltrexone and supportive therapy group (6.4 drinks), a result that was not statistically significant for the entire study population but was for the treatment completers (p<0.05).

Of the three naltrexone studies that evaluated the alcohol outcome "abstinence" or "return to drinking" (O'Malley, Jaffe, Chang, et al., 1992; Volpicelli, Alterman, Hayashida, et al., 1992; Volpicelli, Rhines, Rhines, et al., 1997), only one showed a statistically significant benefit of naltrexone versus placebo (O'Malley, Jaffe, Chang, et al., 1992). In the O'Malley, Jaffe, Chang, et al. (1992) study, the patients who received naltrexone plus supportive therapy showed lower rates of return to drinking (39 percent) than those who received either naltrexone plus coping therapy (72 percent) or placebo plus either supportive (81 percent) or coping therapy (79 percent).

Reduction in drinking days during treatment also was evaluated in the three naltrexone studies (O'Malley, Jaffe, Chang, et al., 1992; Volpicelli, Alterman, Hayashida, et al., 1992; Volpicelli, Rhines, Rhines, et al., 1997). In Volpicelli and colleagues' 1992 study, compared with baseline, drinking days per week increased by a mean of 0.51 day in the placebo group but only by 0.09 day in the naltrexone group (p<0.03); at the end of the study, drinking days were 0.11 per week in the naltrexone group and 0.57 per week in the placebo group. A similar result was reported for the later Volpicelli, et al. (1997) study; percentage drinking days were 10.76 percent for the placebo group and 6.2 percent for the naltrexone group. This difference was statistically significant for the treatment completers (p=0.01) but not for the entire study sample. For the O'Malley, Jaffe, Chang, et al. (1992) study, regardless of the type of counseling, both naltrexone groups drank on fewer days during the trial than did either of the placebo groups (p<0.01).

All three naltrexone studies also examined craving, although they used different visual analog scales (VAS) to do so. In the O'Malley, Jaffe, Chang, et al. (1992) study, which used a 20-point VAS, the naltrexone and coping therapy groups exhibited the lowest rates of craving among the four intervention groups: 3.1 (naltrexone and coping), 5.3 (placebo and coping therapy), 4.7 (placebo and supportive therapy), and 4.4 (naltrexone and supportive therapy). Only the earlier of the two Volpicelli et al. studies (1992) demonstrated a statistically significant decrease in craving among subjects receiving naltrexone compared with those receiving placebo.

Both Volpicelli et al. studies (1992 and 1997) also examined GGT levels over the course of treatment. In both studies, the naltrexone group had lower GGT values at the conclusion of the trial than did the placebo group, but only in the 1997 study did the difference reach statistical significance (p=0.03).

Various methods were used to measure compliance in these studies; one study used pill counts (Volpicelli, Rhines, Rhines, et al., 1997), and the other used riboflavin levels as a marker of use (O'Malley, Jaffe, Chang, et al., 1992). The O'Malley (1992) work found that 78 percent of the urine samples collected from subjects on placebo were positive for riboflavin, compared with 92 percent of those collected from subjects taking naltrexone. Although compliance was not specifically measured in the first Volpicelli et al. (1992) study, it was a major aspect of the 1997 study. In that study, the investigators used pill counts and patient self-report to determine the proportion of patients who were compliant for 90 percent or more of their visits - 47 percent of placebo patients and 58 percent of naltrexone patients were compliant (Volpicelli, Rhines, Rhines, et al., 1997).

Subgroup and Followup Studies

Three studies looked at subgroups and followup (O'Malley, Jaffe, Chang, et al., 1996; O'Malley, Jaffe, Rode, et al., 1996; Volpicelli, Watson, King, et al., 1995). O'Malley, Jaffe, Chang, et al., (1996) followed a subgroup of patients for 6 months after completion of a double-blind trial, while they were not taking medication. In examining the drinking outcomes of these patients over the entire 6-month followup period, they found that the naltrexone and coping therapy group had the lowest rates of heavy drinking in the followup period (43 percent) compared with the other three treatment groups (naltrexone and supportive [68 percent], placebo and coping [80 percent], and placebo and supportive [75 percent]) (p<0.05). Both the O'Malley and Volpicelli teams also studied a subgroup of their populations who had experienced relapse to examine their emotional response to having done so (O'Malley, Jaffe, Rode, et al., 1996; Volpicelli, Watson, King, et al., 1995). In both studies, patients receiving naltrexone reported statistically significant reduced craving or "highs" following alcohol consumption compared with patients in the placebo groups.

Limitations

These studies were conducted with modest sample sizes - a total of 271 subjects across the three trials. In addition, patients were further allocated to placebo and drug groups, and the O'Malley, Jaffe, Chang, et al., 1992 study further subdivided patients into two types of psychosocial therapy. In addition, dropout rates in all three studies were high, resulting in small numbers of subjects completing the trials. Finally, compliance with drug therapy was assessed in only two of the three naltrexone studies (O'Malley, Jaffe, Chang, et al., 1992; Volpicelli, Rhines, Rhines, et al., 1997), a factor that appears to be important for understanding the benefits of therapy.

Harms

All three efficacy studies just discussed evaluated potential side effects of naltrexone therapy (Evidence Tables 6a and 6b). In the controlled trials, side effects that were more prevalent with naltrexone than placebo included nausea, dizziness, and weight loss. O'Malley, Jaffe, Chang, et al. (1992) reported that 9.6 percent of subjects receiving naltrexone dropped out of the study because of nausea or dizziness. The large safety and tolerability study (Croop, Faulkner, Labriola, et al., 1997) compared 570 subjects who were receiving naltrexone with 295 subjects in a nonmedicated reference group. New-onset nausea was reported in 9.8 percent of the naltrexone subjects compared with 0 percent of the reference subjects and headache in 6.6 percent of naltrexone subjects compared with 1.7 percent of reference subjects. In addition, 15.0 percent of subjects on naltrexone discontinued the study because of side effects. In short, no serious side effects were reported in any of the trials. Despite this, clinicians might evaluate patient comorbidities such as acute hepatitis, liver failure, or opiate abuse when prescribing naltrexone.

Evidence Grades

Efficacy grade: A; Harms grade: Low.

Main Efficacy Results

This pilot study evaluated several different measures of return to drinking: mean number of standard drinks per drinking day, number of nondrinking days, and relapse where relapse was defined similarly to that for the naltrexone studies - five or more drinks on one occasion or drinking more than 5 days per week (Evidence Tables 4 and 5). Fewer of the patients in the higher-dose nalmefene treatment group met the criteria for relapse at the end of the 12-week study (two of seven) compared with the placebo (four of six) and lower-dose nalmefene groups (six of six) (p< 0.05). These investigators also evaluated craving but found no differences between the nalmefene and placebo groups.

Of the four opiate antagonist efficacy studies, this study had the most stringent criteria for compliance. Subjects who did not take at least 75 percent of their prescribed medications (based on pill count) for two consecutive visits were considered noncompliant and dropped from the study.

Limitations

The most obvious limitation is the very small sample size, with only nine treatment completers. Compared with the other opiate antagonist studies that provided a structured counseling program, this pilot study only encouraged subjects to attend Alcoholics Anonymous.

Harms

The side effects of nalmefene therapy are derived from this study as well (Evidence Tables 6a and 6b). Headache, nausea, rash, and sleep disturbance were reported as side effects, with dizziness and rash as problems that caused study withdrawal. There were no statistically significant differences between treatment groups for any reported side effect.

Evidence Grades

Efficacy grade: Insufficient evidence; Harms grade: Insufficient evidence.

Main Efficacy Results

Of the nine studies, seven evaluated the number of nondrinking days over the course of the trial. In all seven, acamprosate showed a statistically significant improvement over placebo (Ladewig, Knecht, Leher, et al., 1993; Paille, Guelfi, Perkins, et al., 1995; Sass, Soyka, Mann, et al., 1996; Whitworth, Fischer, Lesch, et al., 1996; Geerlings, Ansoms, and Van den Brink, 1997; Pelc, Verbanck, Le Bon, et al., 1997; Poldrugo, 1997).

Abstinence rates during the trials were evaluated in eight of the studies; the results are less consistent than those for nondrinking days. For example, four of seven trials (Sass, Soyka, Mann, et al., 1996; Whitworth, Fischer, Lesch, et al., 1996; Pelc, Verbanck, Le Bon, et al., 1997; Poldrugo, 1997) showed that significantly fewer patients taking acamprosate resumed drinking during the trial compared with those receiving placebo. Two additional trials (Ladewig, Knecht, Leher, et al., 1993; Paille, Guelfi, Perkins, et al., 1995) show advantage for acamprosate at selected time points within the trial but not for the overall study. The remaining two studies (Roussaux, Hers, and Ferauge, 1996; Geerlings, Ansoms, and Van den Brink, 1997) did not show statistically significant differences between acamprosate and placebo although in the Geerlings, et al. (1997) trial, the patients receiving acamprosate had higher abstinence rates compared with those on placebo (25 vs. 13 percent, p=0.06).

Five acamprosate studies examined average time to first drink. Four of the studies showed a statistically significant improvement for the acamprosate group; compared with patients on placebo, those taking acamprosate took longer to sample alcohol (Paille, Guelfi, Perkins, et al., 1995; Sass, Soyka, Mann, et al., 1996; Pelc, Verbanck, Le Bon, et al., 1997; Poldrugo, 1997). The Geerlings team noted no significant difference between placebo and acamprosate for time to first drink, although the trend was in the same direction as the other four studies.

Craving was evaluated in six of the nine acamprosate trials (Gerra, Caccavari, Delsignore, et al., 1992; Paille, Guelfi, Perkins, et al., 1995; Roussaux, Hers, and Ferauge, 1996; Sass, Soyka, Mann, et al., 1996; Geerlings, Ansoms, and Van den Brink, 1997; Pelc, Verbanck, Le Bon, et al., 1997). In only two of those trials are sufficient data available to examine the effects of acamprosate compared with placebo. Using a categorical craving scale, significantly more patients receiving acamprosate reported no desire for alcohol compared with those on placebo (Pelc, Verbanck, Le Bon, et al., 1997). The Sass team (1996) reported no statistically significant difference between placebo and acamprosate subjects based on a visual analog scale for craving. Reports from the Gerra (1992), Paille (1995), Roussaux (1996), and Poldrugo (1997) teams did not provide sufficient information to evaluate craving for alcohol.

Compliance with treatment was assessed by pill count in four trials (Paille, Guelfi, Perkins, et al., 1995; Roussaux, Hers, and Ferauge, 1996; Geerlings, Ansoms, and Van den Brink, 1997; Pelc, Verbanck, Le Bon, et al., 1997) and by pill count and a urine marker in one other trial (Sass, Soyka, Mann, et al., 1996). The Geerlings team (1997) found similar rates of treatment compliance in the acamprosate and placebo groups (86 and 88 percent, respectively). Compliance appeared to be high in the Sass (1996) study, but data were not reported by treatment group; however, the authors did indicate that pill counts did not differ between the acamprosate and placebo groups. Also, compliance rates in the acamprosate-treated patients differed between subjects who abstained and those who relapsed, with positive urines in 82 percent of those who abstained and in 67 percent of those who relapsed.

Mean corpuscular volume (MCV), carbohydrate-deficient transferrin (CDT), and GGT were measured in several of the acamprosate clinical trials (Paille, Guelfi, Perkins, et al., 1995; Roussaux, Hers, and Ferauge, 1996; Sass, Soyka, Mann, et al., 1996; Poldrugo, 1997). The Sass (1996) and Roussaux (1996) teams found no significant differences between the acamprosate and placebo groups for GGT, MCV, or CDT. The Paille group (1995) reported that the percentage of patients with GGT levels within the normal range was significantly higher for the acamprosate than the placebo group, at both 6 and 12 months followup. They also reported a statistically significant improvement in MCV for the acamprosate group over placebo at 6 months but not at 12 months. Poldrugo (1997) also reported a greater percentage of acamprosate patients with GGT within 1.3 times the upper limit of normal at 6 months compared with controls (p=0.0017).

Subgroup and Followup Studies

Four acamprosate studies reported on followup analyses to assess return to drinking after the trial concluded. The most promising showed a greater number of cumulative nondrinking days at both 12 and 24 months, where the 24-month result is the sum of the nondrinking days over the entire 24-month period (Sass, Soyka, Mann, et al., 1996). Patients taking acamprosate averaged 387 nondrinking days and those on placebo averaged 250 nondrinking days, a statistically significant difference (p<0.001). This study also examined the number of patients who resumed drinking at 24 months. Again, significant differences were noted in favor of acamprosate over placebo for a resumption of drinking, with rates of 60.0 and 82.7 percent, respectively (p<0.003). Similarly, Poldrugo (1997) reported significant findings for both nondrinking days and for abstinence at the 52-week followup. Patients on acamprosate reported a mean of 167.7 nondrinking days compared with 120.5 for those on placebo (p=0.014). Similarly, 56 percent of the acamprosate group and 70 percent of those on placebo had resumed drinking at 52 weeks (p=0.05). In a 12-month followup, Whitworth, Fischer, Lesch, et al. (1996) did not find a significant difference between the acamprosate and placebo groups for the number of nondrinking days. Although these investigators found that more patients remained abstinent in the acamprosate group (11.9 percent) than in the placebo group (4.9 percent) (p<0.05), the analysis conducted by Ladewig, Knecht, Leher, et al. (1993) failed to find an advantage for acamprosate vs. placebo at 90 or 180 days post-trial followup with respect to the number of subjects who remained abstinent.

Limitations

The acamprosate studies have several limitations, most of which are generic to alcohol studies. They include high or unreported dropout rates, with some studies losing approximately 60 percent of their subjects. Although most of the studies did assess compliance with therapy based on pill counts, the extent of individual patient compliance often was not reported. In addition, most of the acamprosate studies either did not specify the type of psychosocial co-intervention or did not provide group and/or individual counseling. Lastly, alcohol consumption was typically measured by self-report, a technique where underreporting is a major concern.

Harms

Information on the side effects of acamprosate therapy is derived from the efficacy studies that included more than 2,000 patients (Evidence Tables 9a and 9b). The side effect profile of acamprosate appears to be acceptable from a clinical standpoint, with the most frequently reported problem being diarrhea (approximately 10 to 40 percent of patients). Additional side effects reported more often in acamprosate patients than in placebo patients included dizziness, itching, and increased sexual desire. Dropouts due to any single side effect were less than 1 percent. No life-threatening side effects were reported in the trials.

Evidence Grades

Efficacy grade: A; Harms grade: Low.

Main Efficacy Results

Trials of medications that affect serotonergic neurotransmission also have been conducted for the treatment of primary alcohol dependence. These studies have evaluated the selective serotonin reuptake inhibitors (SSRIs) fluoxetine, citalopram, and fluvoxamine, along with the anxiolytic 5-hydroxytryptamine-1A (5-HT_1A) receptor agonist buspirone, and the 5-hydroxytryptamine-3 (5-HT₃) receptor antagonist ondansetron. Additional serotonergic agents have been studied but not with well-conducted controlled trials (Evidence Tables 10 and 11).

Subgroup and Followup Studies

Only one subgroup analysis was conducted (Janiri, Gobbi, Mannelli, et al., 1996). Of 10 depressed patients, all of the six patients on fluoxetine remained abstinent whereas only two of the four patients on placebo remained abstinent. Although encouraging, these results should be viewed with caution in light of the very small sample size.

Harms

Numerous, nonserious side effects were noted more frequently for those using serotonergic agents than for those on placebo (Evidence Tables 14a and 14b). Most of the reported side effects are typical for each class of drugs. For the SSRIs, the most frequently reported side effects were symptoms related to fatigue, nausea or vomiting, and sexual dysfunctions. The side effects for buspirone were those already known about this drug including dizziness, drowsiness, and nausea. None of the side effects or reasons for withdrawal appeared to be serious or clinically significant.

Evidence Grades

Efficacy grade: Insufficient data; Harms grade: Low.

Main Efficacy Results

One study of the efficacy of fluoxetine has been conducted in alcoholic patients who were also depressed (Cornelius, Salloum, Ehler, et al., 1997). That trial was a randomized, controlled, double-blind study over a 12-week treatment period in 51 patients, 46 of whom completed the study. During the 12-week period, the fluoxetine group had fewer standard drinks (p<0.03), drinking days (p<0.05), and days of heavy drinking (p=0.04) than did the placebo group, with a trend toward longer time to first drink for those on fluoxetine (p=0.08).

Two studies examined the effects of buspirone on symptoms in alcohol-dependent patients who also had anxiety disorder (Malcolm, Anton, Randall, et al., 1992; Kranzler, Burleson, Del Boca, et al., 1994). Compared with patients on placebo, the buspirone patients had fewer standard drinks per day and fewer drinking days during the trial, but neither of these differences in alcohol outcomes was statistically significant; however, time to first heavy drinking was longer in the buspirone group compared with placebo (p=0.03) (Kranzler, Burleson, Del Boca, et al., 1994). The Malcolm team (1992) conducted a 26-week study and reported no significant differences between placebo and buspirone subjects in drinks consumed over a given 28-day period, the percentage of patients who resumed drinking, time to first drink, or craving for alcohol.

Both these buspirone trials assessed compliance with therapy using urine riboflavin, and both reported very good compliance for the buspirone and placebo groups, with rates that did not differ between the two groups. The Cornelius group (1997) assessed compliance by pill count and serum drug levels, reporting that more than 99 percent of those on fluoxetine indicated compliance with drug therapy.

Subgroup and Followup Studies

One set of followup analyses at 6 months indicated that individuals who had received buspirone had significantly fewer drinking days than those who received placebo (p<0.01) (Kranzler, Burleson, Del Boca, et al., 1994).

Limitations

In the fluoxetine study (Cornelius, Salloum, Ehler, et al., 1997), compliance by pill count was not reported for either the fluoxetine or placebo group, yet it appeared to be high for the fluoxetine patients based on serum drug levels. In addition, the sample was rather small (n=51) and composed of patients with severe depression based on their suicidal tendencies. This group may not be generalizable to the universe of alcohol-dependent patients who also suffer from depression, most of which is not as severe.

The buspirone studies also had a limited sample size (in total) of 128 subjects. Also, nearly half of the placebo patients in one study did not complete the trial (Kranzler, Burleson, Del Boca, et al., 1994). The dropout rate was even higher in another trial, in which nearly two-thirds of each treatment group left the study (Malcolm, Anton, Randall, et al., 1992).

Harms

The fluoxetine and buspirone side effect data were reviewed in the previous section on serotonergic agents (Evidence Tables 14a and 14b).

Evidence Grades

Efficacy grade: Insufficient data; Harms grade: Low.

Main Efficacy Results

The total sample size across these six studies was 750 subjects. The largest study assessed 286 nondepressed alcoholics and 171 depressed alcoholics (Dorus, Ostrow, Anton, et al., 1989). Trial lengths ranged from 12 to 96 weeks; the two largest studies lasted 52 and 72 weeks (Dorus, Ostrow, Anton, et al., 1989; Clark and Fawcett, 1989, respectively). Three trials administered lithium to achieve serum levels between 0.6 and 1.2 milliequivalents per liter (Kline, Wren, Cooper, et al., 1974; Merry, Reynolds, Bailey, et al., 1976; Pond, Becker, Vandervoort, et al., 1981); three other trials gave oral doses of lithium in the range of 600 to 1200 milligrams per day (Clark and Fawcett, 1989; de la Fuente, Morse, Niven, et al., 1989; Dorus, Ostrow, Anton, et al., 1989).

These lithium trials examined three alcohol outcome variables: drinking days, episodes of heavy drinking, and return to drinking. Of the three studies that evaluated drinking days, two showed no effect for lithium compared with placebo (de la Fuente, Morse, Niven, et al., 1989; Dorus, Ostrow, Anton, et al., 1989); the third study (Merry, Reynolds, Bailey, et al., 1976) reported fewer incapacitating days for depressed patients on lithium (0.7 days) than for depressed patients on placebo (5.1 days) (p<0.05), with no information available for those without depression.

Kline, Wren, Cooper, et al. (1974) and Merry, Reynolds, Bailey, et al. (1976) examined the effect of lithium on heavy drinking. Heavy drinking was defined as "percent of time incapacitated by drink" by the Merry (1976) team. They reported that depressed alcoholics on lithium had a lower percentage of time incapacitated (0.4 percent) than did depressed patients on placebo (1.5 percent), a result that was statistically significant (p< 0.05). The Kline group (1974) defined heavy drinking as "disabling" episodes of drinking. Although the treatment and placebo groups in their trial did not differ on levels of disabling drinking at baseline, patients on lithium had a lower percentage of disabling episodes (25 percent) than did those on placebo (64 percent) at the end of lithium treatment (p<0.05).

Two studies (de la Fuente, Morse, Niven, et al., 1989; Dorus, Ostrow, Anton, et al., 1989) examined the effects of lithium on return to drinking. One 6-month trial found that 56 percent of alcohol-dependent patients on placebo and 21 percent of patients in the lithium treatment group returned to drinking (p<0.01) (de la Fuente, Morse, Niven, et al., 1989). The other trial did not report statistically significant differences for return to drinking between the placebo and lithium treatment groups in either depressed or nondepressed subgroups (Dorus, Ostrow, Anton, et al., 1989).

Compliance with active (lithium) treatment was assessed in all studies, either by blood level measures or pill counts. When lithium blood levels were used for compliance, there was no corresponding measure of compliance for the placebo subjects. To maintain the blinding of the patients and study personnel, study investigators changed a placebo patient's treatment regimen when they changed a lithium patient's dosage. The Dorus team (1989) provided rigorous definitions for medication compliance but reported compliance only by depression status, not by treatment group, which diminishes the usefulness of their compliance data. Pond, Becker, Vandervoort, et al. (1981) used pill count to monitor compliance, reporting high compliance with therapy.

Subgroup and Followup Studies

Three trials conducted subgroup analyses (Pond, Becker, Vandervoort, et al., 1981; Clark and Fawcett, 1989; de la Fuente, Morse, Niven, et al., 1989). In the Clark and Fawcett (1989) subgroup analysis, subjects were divided by treatment (lithium vs. placebo), blood level (high vs. low), and compliance. Lithium-compliant patients with high blood levels had the lowest rates of rehospitalization (7 percent); all other groups had admission rates in the range of 23 to 29 percent (p=.006). When abstinence was examined, those with high blood lithium levels had the highest abstinence rate (57 percent).

Limitations

The limitations of the lithium trials are similar to those of other drug trials of alcoholism: small sample sizes, high dropout rates, and unconfirmed reports of alcohol consumption. The lithium data also are complicated by the fact that four of the six trials did not analyze results separately for depressed and nondepressed subjects (Kline, Wren, Cooper, et al., 1974; Pond, Becker, Vandervoort, et al., 1981; Clark and Fawcett, 1989; de la Fuente, Morse, Niven, et al., 1989). In addition, of the six lithium studies we evaluated, two (Kline, Wren, Cooper, et al., 1974; Pond, Becker, Vandervoort, et al., 1981) were cross-over designs, a study design that may not be appropriate for evaluating drug efficacy in alcohol-dependent populations (Peck, Pond, Becker, et al., 1981).

As noted, all the studies were of alcohol-dependent patients who also had depression or bipolar disorder, but only two (Merry, Reynolds, Bailey, et al., 1976; Dorus, Ostrow, Anton, et al., 1989) stratified their patient populations by the presence or absence of coexisting mental disorder (depression). Thus, in the studies that did not stratify by mood disorder, it is difficult to determine whether the results could be attributable to lithium's effects on the core symptoms of alcoholism or to its effects on mood disorder symptoms.

Harms

Evidence Grades

Efficacy grade: C; Harms grade: Low.

Naltrexone and Acamprosate

Overall, the evidence-based review demonstrated that two pharmacologic agents - naltrexone and acamprosate - have moderate and strong evidence of efficacy in treating patients with alcohol dependence. Specifically, we found evidence that: naltrexone and acamprosate lead to reductions in drinking frequency; naltrexone leads to a reduction in drinking quantity, an outcome not measured in the acamprosate trials; acamprosate and (to a lesser extent) naltrexone help maintain abstinence from alcohol in some studies; naltrexone helps prevent relapse to heavy drinking, another measure not ascertained in the acamprosate trials; and naltrexone may be effective in reducing the "high" in response to drinking in alcohol-dependent patients. We considered the evidence for efficacy to be at an "A level" for both these agents because each has been demonstrated to be more efficacious than placebo in more than one RCT with adequate sample sizes and without evidence of substantial harm. Currently, naltrexone is approved for the treatment of alcohol dependence in the United States and at least 18 other countries. Eighteen trials targeting about 3,000 subjects are being conducted under the sponsorship of the National Institute on Alcohol Abuse and Alcoholism (NIAAA), and 600 subjects will be studied in a cooperative trial funded by the Department of Veterans Affairs. Acamprosate, currently approved in many European countries, is undergoing a large-scale clinical trial in this country seeking FDA approval. The trial is being sponsored by Lipha Pharmaceuticals and involves about 450 subjects.

The evidence for efficacy of these agents in the treatment of alcohol dependence is strong, but the magnitude of the benefit is variable. For example, as documented in the evidence tables, acamprosate consistently reduced drinking frequency by 40 to 60 percent over 6 to 12 months, although its effects on maintaining abstinence ranged from no effect to a doubling of abstinence rates. However, a majority of patients receiving acamprosate did return to some degree of drinking during these trials. With naltrexone, drinking frequencies and relapse rates were reduced by about 50 percent over the 3 months of the trials; compliance being a significant predictive factor of drug effect in one study (Volpicelli, Rhines, Rhines, et al., 1997). In the naltrexone trials, a majority of subjects also returned to some degree of drinking regardless of medication status so that only marginal evidence was found that naltrexone enhanced abstinence.

Therefore, although the studies consistently demonstrate that both acamprosate and naltrexone are more effective than placebo in treating patients with alcohol dependence, the magnitude of the benefit is open to interpretation. If the goal of treatment is to ensure continuous abstinence, a goal of most programs, then the effects of the medications appear modest at best. If, however, the goal of treatment is to diminish the intensity and frequency of alcohol consumption, then the outcomes are more impressive. Finally, clinicians will recognize that these results are averages across study populations; if a medication is beneficial to an individual, then the effect for that one patient can be substantial.

The benefits observed with naltrexone and acamprosate also must be considered in the context of study settings that probably maximize the benefit of the therapy. Many of the trials were performed either at or in conjunction with academic centers. Patients were willing to commit to a controlled study, with all of the attendant effort of having an extensive introductory physical and psychological evaluation, completing forms, and returning for followup visits more frequently than might be the case in a practice situation. Thus, the patients enrolled in these trials probably had a somewhat greater commitment to abstinence and an overall better prognosis than would the average alcohol-dependent patient. The quality of care provided within controlled studies is generally excellent, so the trials are representative of "best case" clinical care.

These two issues (volunteer effect and excellent clinical care in the controlled study context) do not affect the above statements regarding the efficacy of naltrexone and acamprosate, but they may affect the generalizability of the results. The reported efficacy probably represents the greatest benefit that might be expected given committed patients, first-rate care settings, and skilled caregivers. Average patients in typical care settings will likely show less benefit than reported in these trials. Thus, an important next step would be to conduct effectiveness studies of these medications.

Patients in these controlled studies were almost always receiving either individualized or group therapy for their alcohol dependence, typically provided in a substance abuse treatment setting. The nature of the co-intervention varied, including cognitive-behavioral and supportive treatment, but multiple models were used. Many of the co-interventions, particularly in the acamprosate trials, were not described in sufficient detail to allow detailed assessment of the co-intervention or replication studies. Future research should describe these co-interventions better.

The available data do not allow a determination of the efficacy of these medications if used with minimal psychosocial co-intervention in a setting such as a primary care physician's office. We recommend that these two issues - use of the medication with varying intensities of psychosocial treatment, and studies of these medications in primary care settings - be the subjects of future research since both factors may substantially affect the cost and generalizability of medication use.

Another issue that emerges from the naltrexone trials is the importance of ensuring patient compliance with the medication in order to detect and obtain a pharmacologic effect. The 1997 Volpicelli, et al., report is noteworthy here, as it documented limited effects of naltrexone in the overall trial but significant naltrexone effects in subjects considered compliant with pharmacotherapy. These findings suggest that studies of intervention methods designed to enhance compliance with pharmacotherapy represent another important area for future research in alcohol dependence.

Disulfiram

The efficacy grade for disulfiram was a B. Sufficient data of reasonable quality were available to evaluate efficacy, but the results were inconsistent across studies and even within studies. Given these diverse findings from clinical trials, the role of disulfiram in the treatment of alcoholism remains ambiguous.

Disulfiram has been available for the treatment of alcoholism for close to 50 years, and initially there was great hope that it might revolutionize the treatment of the disease. Many articles were published about disulfiram's effectiveness, but the majority were about open trials or case series and subject to all the biases associated with such designs. The completion of double-blind, placebo-controlled trials provided the first opportunity for the field to evaluate the efficacy of disulfiram in a scientifically controlled fashion. Perhaps surprisingly, given the longevity of the clinical use of the drug, the results of these trials were not uniformly supportive of the efficacy of disulfiram. For example, no evidence was found that disulfiram enhanced abstinence, although two studies, including the large, high-quality trial by Fuller, Branchey, Brightwell, et al. (1986) and a study by Chick, Gough, Falkowski, et al. (1992), did find that disulfiram was associated with fewer drinking days.

Disulfiram is unique among the pharmacotherapeutic agents reviewed because it is the only medication that attempts to exert a therapeutic effect by producing a negative consequence should alcohol be consumed. This action, in turn, complicates interpretation of double-blind, placebo-controlled clinical trials because subjects receiving placebo are faced with the same psychological deterrent effect as those receiving disulfiram. Subjects who then take their medication and believe they are on disulfiram might be discouraged from drinking regardless of whether they are on placebo or disulfiram. In fact, Fuller, Branchey, Brightwell, et al. (1986) found that, independent of drug condition, subjects who complied with treatment demonstrated much higher abstinence rates than those who did not. The compliance factor was stronger than the medication factor when abstinence was the measured outcome.

Subjects who sample alcohol while on a sensitizing dose of disulfiram will experience adverse reactions, so this effect should reinforce the psychological deterrent effect and represent a true pharmacological effect of the drug. One of the few positive outcomes for disulfiram in some of the controlled trials is that subjects on disulfiram had significantly fewer drinking days. This effect might arise if subjects who were not deterred from drinking by the threat of a disulfiram-ethanol reaction were deterred from drinking further when they experienced adverse responses upon drinking. This cannot be ascertained from the trials, but it may represent a useful hypothesis to test.

With compliance emerging as an important factor in the use of disulfiram, the question of how to maximize compliance becomes an important consideration. Supervised disulfiram administration is one method to enhance compliance, but this method has been studied in only one controlled trial (Chick, Gough, Falkowski, et al., 1992). In that trial patients receiving disulfiram drank less alcohol and drank less frequently although their rates of abstinence were not reported. However, the patients were unblinded to their medication condition once randomization had occurred, so this trial does not meet the criteria for a double-blind, placebo-controlled trial.

Finally, the use of disulfiram implants has also been tested as a method to ensure compliance. These trials have produced mixed although primarily negative findings. Again, the issue of the psychological deterrent effect must be considered in the results of these trials and their general failure to find significant drug effects.

The problem of the bioavailability of disulfiram implants is, perhaps, the most substantive methodological concern. The trials generally implanted standard disulfiram tablets at doses of 800 to 1000 mg at the beginning of the trial and then followed patients for up to 48 weeks. The bioavailability of disulfiram under these conditions would not be expected to be adequate to ensure a sensitizing effect late in the course of treatment. Johnsen, Stowell, Bache-Wiig, et al. (1987) found no differences in response to repeated ethanol challenges between disulfiram and sham implant subjects over a 20-week trial. Efforts to improve disulfiram implants continue; only when this methodology is shown to provide adequate disulfiram bioavailability can the effectiveness of implants be better evaluated.

Lithium

The lithium data are sufficient to suggest that lithium is not an effective treatment for primary alcoholism, and lithium received a grade of C. The results from the highest-quality controlled study in alcoholics without comorbid mood disorders were negative (Dorus, Ostrow, Anton, et al., 1989). Even the data on use of lithium in depressed alcoholic populations are mixed, and we did not review the efficacy of lithium with respect to misuse of alcohol in bipolar subjects. Based on all the lithium studies that were reviewed, additional investigation of lithium in primary alcoholics without mood disorders is likely to be of little value.

Serotonergic Agents

Duration of Pharmacotherapy and Length of Studies

Combination Therapies

Combination treatment regimens may be more effective than monotherapy, especially when medications with differing mechanisms of action are assessed. The gains that can be obtained with this approach are illustrated by the pharmacotherapy of acquired immunodeficiency syndrome (AIDS) where combination therapy is yielding significant improvements in outcome. The trade-offs with combination therapy may be increases in adverse effects of medications and direct costs. To the extent that interest is rising in the use of multiple pharmaceutical agents in a variety of medical disciplines, practitioners and patients will need to have a better sense of what harms, as well as benefits, should be expected.

We recommend that investigators direct their efforts to combination therapy in two ways. First, more attention should be given to searching specifically for combination treatments in new or forthcoming publications of ongoing and future trials. Second, studies on promising combination therapies should be deliberately designed and supported, so that systematic information can be marshaled about this aspect of care, rather than relying on what may appear to be rather serendipitous "combinations" in existing work. Combination pharmacotherapy studies may require special funding mechanisms, including strong Federal support, as they are less likely to be funded by the pharmaceutical industry. Of note is that the NIAAA has recently funded a multisite study of the combination therapy of naltrexone and acamprosate compared with each drug alone and with placebo in alcohol-dependent subjects.

Co-Interventions

A majority of investigators believe that psychosocial co-interventions are essential to the success of pharmacotherapy in alcohol-dependent individuals. Unfortunately, these interventions often are not described in sufficient detail to permit the interventions to be characterized adequately for comprehensive reviews and analyses of the existing literature or to allow replication of the intervention in other studies or settings. Thus, we make three recommendations on this point. The first two relate more to thorough reporting of results than to the conduct of the research, although by implication investigators will need to ensure that adequate documentation is kept about the co-interventions. The third recommendation relates to types of studies that should be carried out to broaden the scope of understanding about the use of pharmacotherapies in all types of settings and patients.

First, we recommend that all future studies describe the timing and content of the intervention and the training of the therapists. Second, we recommend that those reporting on the studies include an assessment of patient compliance with the psychosocial intervention. Third, testing interventions that can be performed outside specialized treatment centers, such as brief motivational enhancement, will substantially aid the generalizability of information about the effectiveness (if not efficacy) of pharmacologic treatments for patients with this disorder. Thus, we recommend that investigators begin to design, and funding agencies support, studies of interventions that heretofore have not been well studied (if at all).

Treatment in a Variety of Settings

As noted elsewhere, most of our literature review and synthesis has focused on efficacy studies - i.e., the knowledge base derived from randomized controlled trials (RCTs). As is well understood, such studies may have serious limitations in terms of constraints on the types of patients included in the trials; they also may be carried out in specialized centers by practitioners with exceptionally high professional qualifications. In short, they may not provide as much information on the effectiveness of the pharmacologic agent among "ordinary" patient populations in "average" settings and circumstances.

The practical drawback to this fact is that, in the case of pharmaceuticals, once the FDA has approved a medication, any physician in any practice setting may prescribe it. Thus, we can expect to see considerable diffusion of at least certain kinds of medications to patient groups in which the drug in question has not been tested (or at least tested adequately). Moreover, most alcohol-dependent patients currently are not under treatment in centers similar to those in which the reviewed trials took place.

In short, we cannot generalize our findings and conclusions (much) beyond the existing trial data. This leaves important questions about the extent to which our findings will be applicable to the broader population of patients, centers and settings, and clinicians for whom the various medications reviewed here might be considered. For example, we might ask: Are similar outcomes possible in the offices of trained primary care physicians or in community mental health centers?

To address these questions, we recommend that a broader set of studies, conducted as trials if possible or as well-designed longitudinal cohort studies, be carried out in a wider array of typical settings in which patients with alcoholism receive care. These studies should include primary care physicians as the principal source of care; in some circumstances, other primary care clinicians may also be involved in the studies (e.g., psychiatric nurse practitioners for co-interventions). The aim is to replicate the types of trials that already have been conducted on the key drugs (particularly naltrexone and acamprosate), to the extent possible, with studies that will inform providers, patients, and policymakers about the effectiveness of these agents as they may be used by physicians, other providers, and treatment centers of all types. This body of work will provide information about the pharmaceutical interventions themselves; it also will yield data that may indicate whether this nation will have to devote substantially more resources to upgrading substance abuse treatment centers in the coming years.

Common Outcome Measurements and Definitions

We were hindered in our attempts to perform a meta-analysis of the efficacy of pharmacotherapy for alcohol dependence in part by the multiple and disparate outcomes that were used in the trials. The use of various outcomes across studies and differing methods of measuring those outcomes impede the clinical community in evaluating the relative efficacy of treatments. Similarly, differences in defining relapse rates and heavy drinking and in measuring craving also create problems for efficiently abstracting, comparing, or interpreting data across this body of literature. The problems are in two areas: ambiguous descriptions of the outcomes that are measured (including different usages of the same term, such as "relapse") and different choices of endpoints (some of which may be idiosyncratic to a particular study).

We recommend that investigators, professional societies involved in alcohol research, and the appropriate Federal funding agencies work together with investigators to ensure that future studies will have reasonably comparable outcomes. We also recommend that some attention be given to ensuring that outcomes important to patients and their families always be included in these studies. Very precise definitions of outcomes that are measured (i.e., clarity in describing the outcomes) will foster this goal. We also recommend that journal editors insist on unambiguous descriptions of all outcomes, so that even unusual or special ones can be completely understood by readers and reviewers of these articles. This is particularly germane to the measurement of craving.

High Dropout Rates

Many alcohol studies are hindered by high dropout rates. Many trials had dropout rates of 40 percent or more. This level of attrition seriously undermines the confidence that one can place in the work. This is especially true in the following circumstances:

• The original sample sizes are small.

• The dropout rates between experimental and control or comparison groups differ.

• Those lost to followup cannot be compared adequately with those who complete the study on a full range of baseline characteristics.

• Those lost to followup for different reasons (e.g., death, institutionalization, adverse side effects, or unknown) cannot be compared with each other on baseline characteristics.

We recognize that these patient populations (especially those outside specialized centers and those included in community-oriented or effectiveness studies) may be difficult to retain in studies, and that the challenge of doing so is only greater as researchers attempt to address some of our other recommendations (e.g., a broader set of treatment settings, longer treatment, and longer followup). Nevertheless, we recommend that alcohol investigators work with survey researchers to develop and apply methods of reducing dropout and loss to followup. In addition, they should devote some resources simply to determining the reasons for dropout from their efficacy trials or effectiveness studies, with a view to providing this information in published articles. This will enable readers and reviewers to gain a better appreciation of the dynamics of the studies (and the patient population), but it also will provide feedback on which issues need to be addressed (especially problematic circumstances affecting patients) that would permit researchers to target resources effectively to reduce dropout rates in future studies.

Pharmacokinetics

As can be inferred from our presentation in Chapter 1 on the presumptive mechanisms by which the various pharmacologic agents studied here affect patients with alcohol dependence, especially at the biochemical level, little is understood about exactly what these agents do and why (at least in humans). The theory on these matters is quite rich; the empirical data are relatively thin. Part of the deficit in the knowledge base relates specifically to the relationship of blood levels and active or toxic metabolites to treatment response; data of these sorts are essentially absent in the reported trials.

We recommend that alcohol researchers address this information gap by incorporating data into clinical trials on the pharmacokinetics of the compound under study. This would include basic information such as steady-state levels of the parent compound, measurement of metabolites as appropriate, and investigation of how drug-drug interactions may affect blood levels. Such data may lead to insights as to why some patients do not respond to a given agent while other patients develop toxicity. Advances in these areas will help the pharmacotherapy of alcoholism mature as a discipline.

Relationship of Pharmacotherapy to Patient Heterogeneity and Disease Biology

As can be inferred from the recommendations to this point, we believe that the heterogeneity of patients with alcoholism is substantial; this heterogeneity includes genetic, biological, environmental, and sociodemographic characteristics. Similarly, the underlying biology of this disease is itself now thought to exhibit signs of heterogeneity (as noted in Chapter 1 about the concept of "alcoholisms"). Putting these facts together suggests that how this disorder (or disorders) plays out in different populations may be a remarkably complex, multifaceted process. Coupling this observation with the multiple mechanisms by which pharmacotherapies may act at the basic biological (or psychological) level suggests that more attention must be paid to the combinations of patient characteristics, the disease they exhibit, and the specific treatments that are provided. Thus, we recommend that researchers devote more attention and resources into characterizing the biological/clinical, sociodemographic, and other attributes of their patient populations, specifying to the extent possible the manifestations of alcoholism(s) in these patients, and measuring the relationship between these sets of factors (on the one hand) and the response to pharmacotherapies (on the other). Some areas of particular concern include the growing number of patients with dependence on multiple substances and what implications this codependency has for pharmacotherapy and the effects of psychiatric comorbidity on pharmacotherapy outcomes. We recognize that this area of investigation may require maturation of the research on the heterogeneity of alcoholism.

I. STUDY CHARACTERISTICS

Blinding:	Single	Double	Not stated	None
Length of Efficacy Study
Blinded period of study:		_____	Weeks	Months
Unblinded period of study:		_____	Days	Weeks	Unspecified	None
Total length of Active Drug Treatment:			_____	Weeks	Months
Dose Titration Used?		Yes	No/Not stated
Recruitment Setting:		Inpatient	Outpatient	Not stated
Pre-Treatment:
Detox	Yes	No	Not stated
Abstinent	Yes	No	Not stated
	___	Days	Weeks	Months	Not stated

Psychosocial Treatment Inpatient Day hospital Outpatient Mixed None

Practice Setting:
Number of Sites: ___________

University Affiliation:	Academic	Non-academic	Not stated
Geographic Locale:	United States	Europe	Other	Not stated

Not Stated

Definition of Alcohol Dependence:
(Describe how authors define alcoholism or alcohol dependence. EXCLUDE ARTICLES THAT USE HEAVY SOCIAL DRINKING OR ALCOHOL ABUSE):

• Criteria for Alcohol Dependence Diagnosis:

• DSM-III

• DSM-III-R

• DSM-IV

• ICD-9

• ICD-10

• National Council on Alcoholism

• If none of the above are checked, specify criteria for alcohol dependence diagnosis:

• How were criteria assessed: (Check all that apply)

• Structured interview with individual (self-report) (e.g., SCID)

• Diagnostic Interview Schedule (DIS)

• Computerized Diagnostic Interview Schedule (CDIS)

• Structured interview with proxy

• Clinical observation/interview

• Other (specify) ____________________

• Not stated/Don't know

• Inclusion Criteria

• Age

• Sex

• Medical illnesses (both specified and unspecified)

• Psychiatric illness -> Depression Anxiety

• Laboratory values

• Pattern of alcohol consumption

• Length of abstinence

• Other

• Not stated

• Exclusion Criteria

• Age

• Sex

• Medical illnesses (both specified and unspecified)

• Non-alcohol drug abuse

• Psychiatric illness

• Previous alcoholism treatment

• Current medications

• Laboratory values

• Pregnant/lactating women

• Length of abstinence

• Other

• Not stated

• Author's Definition of Relapse: (Check all that apply)

• Any alcohol consumption

• Number of drinks in a given unit of time (specify) ___________________________

• Number of days of drinking in a given unit of time (specify) ________________________

• Blood alcohol level/Breathalizer

• Other

• Not stated

• How relapse measured: (Check all that apply)

• Structured interview with individual (self-report)

• Unspecified self-report

• Structured interview with proxy

• Clinical observation/interview

• Liver function tests

• Carbohydrate deficient transferrin (CDT)

• Other (specify) _________________

• Not stated

• Not measured

• Craving

• Analog scale

• Ordinal scale

• Other (specify) _____________________________________

• Not stated/Don't know

• Not measured

Compliance with Treatment	Method Used ( all that apply)	Specify Acceptable Range	Measured in Both Placebo and Active ( )
Urine marker, e.g., % visits with active drug
Blood levels, e.g., mg/ml
Pill count, e.g., % of drug taken
Self-report of compliance
Proxy report of compliance
Visit attendance, i.e., % visits with appropriate treatment
Other (specify) _____________________________

Statistical Analysis

• Statistical Methods:

• Student's t-test

• Fisher's Exact Test

• Kaplan Meier

• Chi-square

• ANOVA

• ANACOVA (Analysis of covariance) or ANCOVA

• MANCOVA

• Regression

• Non-parametric tests (Rankings such as Wilcoxen, Mann-Whitney U, etc.)

• Multiple comparisons

• Other (specify) __________

• Not stated

Specifies Intent to Treat Analysis? Yes No Not stated

History of Alcohol Dependence of Control Group: Not stated

[Control Group]

Age at onset:	Mean ______	Range ______	Std Dev: ______	Not stated
Years since onset of alcohol dependence:	Mean ______	Range ______	Std Dev: ______	Not stated

II. Characteristics of the Study Population

(Any control/comparison group should be listed first.)

[Control Group]

CONTROL Group No Control Group

Drug intervention(s) of Control Group:	Frequency of administration comparable to intervention groups?
Placebo	Yes No
No Drug

Psychosocial intervention(s) of Control Group:	Program Intensity ( )
	Alcoholics Anonymous
Group program/counseling
Individualized program/counseling
Family counseling
Unspecified
None
Contract Yes No Not stated

Total Number of Controls: Not stated

Screened _____

Initially entered trial _____ (after randomization)

Final number at end of trial _____

Note:

Information on dropouts and loss to followup on randomized subjects only, to explain difference between number entered and final number.

• Dropout:Number _____Rate _____ Not statedDropout due to adverse events:Number _____Rate _____ Not statedLoss to followup:Number _____Rate _____ Not stated

Family History of Alcohol Dependence or Alcoholism of Control Group: Not stated Number ___________ Percent ___________

Not stated
Addiction Severity at Study Entry of Control Group	Check all that apply ( )

Not stated
Comorbidities of Control Group:	Check all that apply ( )	Number	Percentage

Number of Prior Substance Abuse Treatment Experiences of Control Group:

• Not measured

• Mean _____ Range _____ Standard deviation _____

Patients with prior treatments	Number	Percentage
None
One or More
Unspecified Substance Abuse

INTERVENTION Group 1

Drug intervention(s) of Intervention Group 1:	Maximum dose/day	Units	Dosage varies ( )
Disulfiram		mg Other (specify) ________________
Naltrexone		mg Other (specify) ________________
Acamprosate		mg Other (specify) ________________
Serotonergic Agent: ___________________________		mg Other (specify) ________________
Lithium (all types)		mg Other (specify) ________________
Placebo		mg Other (specify) ________________

Psychosocial intervention(s) of Intervention Group 1:	Program Intensity ( )
	Required attendance	Encouraged attendance
Alcoholics Anonymous
Group program/counseling
Individualized program/counseling
Family counseling
Unspecified
None
Contract Yes No Not stated

Total Number of Patients in Intervention Group 1: Not stated

Screened _____

Initially entered trial _____ (after randomization)

Final number at end of trial _____

Note:

Information on dropouts and loss to followup on randomized subjects only, to explain difference between number entered and final number.

• Dropout:Number _____Rate _____ Not statedDropout due to adverse events:Number _____Rate _____ Not statedLoss to followup:Number _____Rate _____ Not stated

Demographic information for randomized population only.

	N	%	Mean Age	Age SD	% White	% Black	% Hispanic	% Native American	% Other
Total
Males
Females

History of Alcohol Dependence of Control Group: Not stated

Age at onset:	Mean ______	Range ______	Std Dev: ______	Not stated
Years since onset of alcohol dependence:	Mean ______	Range ______	Std Dev: ______	Not stated

Family History of Alcohol Dependence or Alcoholism of Intervention Group 1:
Not stated Number _____ Percent _____

Not stated
Addiction Severity at Study Entry of Intervention Group 1	Check all that apply ( )

Not stated
Comorbidities of Intervention Group 1:	Check all that apply( )	Number	Percentage

Number of Prior Substance Abuse Treatment Experiences of Intervention Group 1:
Not measured

Mean _____

Range _____

Standard deviation _____

Patients with prior treatments	Number	Percentage
None
One or More
Unspecified Substance Abuse

INTERVENTION Group 2

Drug intervention(s) of Intervention Group 2:	Maximum dose/day	Units	Dosage varies ( )
Disulfiram		mg Other (specify) ________________
Naltrexone		mg Other (specify) ________________
Acamprosate		mg Other (specify) ________________
Serotonergic Agent: __________________________		mg Other (specify) ________________
Lithium (all types)		mg Other (specify) ________________
Placebo		mg Other (specify) ________________

Psychosocial intervention(s) of Intervention Group 2:	Program Intensity ( )
	Required attendance	Encouraged attendance
Alcoholics Anonymous
Group program/counseling
Individualized program/counseling
Family counseling
Unspecified
None
Contract Yes No Not stated

Total Number of Patients in Intervention Group 2: Not stated

Screened _____

Initially entered trial _____ (after randomization)

Final number at end of trial _____

• Note: Information on dropouts and loss to followup on randomized subjects only, to explain difference between number entered and final number.

• Dropout:Number _____Rate _____ Not statedDropout due to adverse events:Number _____Rate _____ Not statedLoss to followup:Number _____Rate _____ Not stated

Demographic information for randomized population only.

	N	%	Mean Age	Age SD	% White	% Black	% Hispanic	% Native American	% Other
Total
Males
Females

History of Alcohol Dependence of Intervention Group 2: Not stated

Age at onset:	Mean ______	Range ______	Std Dev: ______	Not stated
Years since onset of alcohol dependence:	Mean ______	Range ______	Std Dev: ______	Not stated

Family History of Alcohol Dependence or Alcoholism of Intervention Group 2:
Not stated
Number _____ Percent _____

Not stated

Not stated
Comorbidities of Intervention Group 2:	Check all that apply ( )	Number	Percentage

Number of Prior Substance Abuse Treatment Experiences of Intervention Group 2:
Not measured

• Mean _____ Range _____ Standard deviation _____

Patients with prior treatments	Number	Percentage
None
One or More
Unspecified Substance Abuse

INTERVENTION Group 3

Drug intervention(s) of Intervention Group 3:	Maximum dose/day	Units	Dosage varies ( )
Disulfiram		mg Other (specify) ________________
Naltrexone		mg Other (specify) ________________
Acamprosate		mg Other (specify) ________________
Serotonergic Agent:		mg Other (specify) ________________
Lithium (all types)		mg Other (specify) ________________
Placebo		mg Other (specify) ________________

Psychosocial intervention(s) of Intervention Group 3:	Program Intensity ( )
	Required attendance	Encouraged attendance
Alcoholics Anonymous
Group program/counseling
Individualized program/counseling
Family counseling
Unspecified
None
Contract > Yes No Not stated

Total Number of Patients in Intervention Group 3: Not stated

• Screened _____ Initially entered trial _____ (after randomization) Final number at end of trial _____

• Note: Information on dropouts and loss to followup on randomized subjects only, to explain difference between number entered and final number.

• Dropout:Number _____Rate _____ Not statedDropout due to adverse events:Number _____Rate _____ Not statedLoss to followup:Number _____Rate _____ Not stated

Demographic information for randomized population only.

	N	%	Mean Age	Age SD	% White	% African Americans	% Hispanic	% Native American	% Other
Total
Males
Females

History of Alcohol Dependence of Intervention Group 3: Not stated

Age at onset:	Mean ______	Range ______	Std Dev: ______	Not stated
Years since onset of alcohol dependence:	Mean ______	Range ______	Std Dev: ______	Not stated

Family History of Alcohol Dependence or Alcoholism of Intervention Group 3:
Not stated
Number _____ Percent _____

Not stated

Not stated

Number of Prior Substance Abuse Treatment Experiences of Intervention Group 3:
Not measured

Mean _____

Range _____

Standard deviation _____

Patients with prior treatments	Number	Percentage
None
One or More
Unspecified Substance Abuse

III. Results

What were the changes in outcome(s) that resulted from the intervention for each group? These should be recorded in units used as the outcome measure(s) (e.g., reduction in the number of standard drinks consumed per time period, time to relapse, number of episodes of heavy drinking per time period, etc.). Any measures of central tendency or dispersion (i.e., standard deviation) should be reported. Test statistics and significance levels should be included.

[Control Group]

CONTROL GROUP Enter information for all outcomes that apply:

Alcohol Intake of Control Group

Not Stated

Not Stated

Not Stated

Not Stated

Not Stated

Not Stated

Not Stated

Not Stated

Intervention Group 1

Enter information for all outcomes that apply:
Alcohol Intake of Intervention Group 1

Not Stated

Not Stated

Not Stated

Not Stated

Not Stated

Not Stated

Not Stated

Not Stated

Intervention Group 2

Enter information for all outcomes that apply:

Alcohol Intake of Intervention Group 2

Not Stated

Not Stated

Not Stated

Not Stated

Not Stated

Not Stated

Not Stated

Not Stated

Intervention Group 3

Enter information for all outcomes that apply:

Alcohol Intake of Intervention Group 3

Not Stated

Not Stated

Not Stated

Not Stated

Not Stated

Not Stated

Not Stated

Not Stated

IV. Study Summary

Analysis by Groups on Side Effects: (Article must provide a rate or percent by treatment group or have sufficient information so that rates or percents can be calculated in order to check "yes" and flag.)

• Yes (flag article)

• No

• Not stated

Factors Controlled for in the Analysis

• Age

• Sex

• Family history of alcoholism

• Others (Specify) ____________

• Not stated

Limitations Noted in Article by Authors No limitations in the article

• Sub-therapeutic dosing

• Alcohol consumption unverified

• High dropout rate

• Low severity of alcohol dependence

• Compliance problem

• Others (Specify) ____________

Limitations Noted by Reviewer No limitations by reviewer

• Sub-therapeutic dosing

• Alcohol consumption unverified

• High dropout rate

• Low severity of alcohol dependence

• Compliance problem

• Others (Specify) ____________

Conclusions Noted in Article

• Intervention(s) showed efficacy

• Intervention(s) did not show efficacy

• Others (Specify) ____________

• Not stated

Attachments: Comorbid Groups Followup Results

Comments

• Subgroup analysis

• Additional outcomes recorded here

V. Quality Rating Scale

for Alcohol Dependence
Pharmacotherapy Review

Category 4: Internal Validity (5 points)
	No	Yes	NA
Are potential confounding effects addressed (differences between two groups such as age, gender, type of alcohol dependence, other substance abuse)?	0	1
	No	Yes
Was the co-intervention (e.g., psychotherapy) similar between two study groups?	0	1
	No	Yes
Was the co-intervention (e.g., psychotherapy) compliance monitored?	0	1
	No	Yes
Was a concurrent control group present?	0	2

Category 7: Statistical Conclusions (5 points)
	No	Yes	NA
If multiple univariate tests performed, multiple comparisons taken into account?	0	1
	No	Yes
Power analysis performed?	0	1
	No	Yes
In regression analysis, is number of variables in model less than 1/10th of the sample size?	0	1
	No	Yes
Are statistically significant findings clinically significant?	0	1
	No	Yes
Are statistical tests used appropriate to the data?	0	1

[Control Group]

Reviewer ___ ___ ___	Date ___ ___ / ___ ___	Unique Article ID	|__|__|__| (ProCite #, 3 digits)
Comorbid Condition:	depression anxiety other (Specify) _______________
IIA. CHARACTERISTICS OF THE COMORBID STUDY POPULATION
(Any control/comparison group should be listed first.)

COMORBID CONTROL Group No Control Group

Drug intervention(s) of Comorbid Control Group:	Frequency of administration comparable to intervention groups?
Placebo	Yes No
No Drug

Psychosocial intervention(s) of Comorbid Control Group:	Program Intensity ( )
	Alcoholics Anonymous
Group program/counseling
Individualized program/counseling
Family counseling
Unspecified
None
Contract Yes No Not stated

Total Number of Comorbid Controls: Not stated

Dropout:	Number _____	Rate _____	Not stated
Dropout due to adverse events:	Number _____	Rate _____	Not stated
Loss to followup:	Number _____	Rate _____	Not stated

Demographic information for randomized population only.

History of Alcohol Dependence of Comorbid Control Group: Not stated

• Age at onset:Mean ______Range ______Std Dev: ______ Not statedYears since onset of alcohol dependence:Mean ______Range ______Std Dev: ______ Not stated

Family History of Alcohol Dependence or Alcoholism of Comorbid Control Group:
Not stated Number _____ Percent _____

Not stated

Not stated

Number of Prior Substance Abuse Treatment Experiences of Comorbid Control Group:
Not measured

• Mean _____ Range _____ Standard deviation _____

COMORBID INTERVENTION Group 1

Drug intervention(s) of Comorbid Intervention Group 1:	Maximum dose/day	Units	Dosage varies ( )
Disulfiram		mg Other (specify) ______________
Naltrexone		mg Other (specify) ______________
Acamprosate		mg Other (specify) ______________
Serotonergic Agent: _________________		mg Other (specify) ______________
Lithium (all types)		mg Other (specify) ______________
Placebo		mg Other (specify) ______________

Psychosocial intervention(s) of Comorbid Intervention Group 1:	Program Intensity ( )
	Required attendance	Encouraged attendance
Alcoholics Anonymous
Group program/counseling
Individualized program/counseling
Family counseling
Unspecified
None
Contract Yes No Not stated

Total Number of Patients in Comorbid Intervention Group 1: Not stated

• Screened _____ Initially entered trial _____ (after randomization)Final number at end of trial _____

• Note: Information on dropouts and loss to followup on randomized subjects only, to explain difference between number entered and final number.

• Dropout:Number _____Rate _____ Not statedDropout due to adverse events:Number _____Rate _____ Not statedLoss to followup:Number _____Rate _____ Not stated

Demographic information for randomized population only.

History of Alcohol Dependence of Comorbid Intervention Group 1: Not stated

• Age at onset:Mean ______Range ______Std Dev: ______ Not statedYears since onset of alcohol dependence:Mean ______Range ______Std Dev: ______ Not stated

Family History of Alcohol Dependence or Alcoholism of Comorbid Intervention Group 1:
Not stated

Not stated

Not stated

Number of Prior Substance Abuse Treatment Experiences of Comorbid Intervention Group 1:
Not measured

• Mean _____ Range _____ Standard deviation _____

COMORBID INTERVENTION Group 2

Drug intervention(s) of Comorbid Intervention Group 2:	Maximum dose/day	Units	Dosage varies ( )
Disulfiram		mg Other (specify) ______________
Naltrexone		mg Other (specify) ______________
Acamprosate		mg Other (specify) ______________
Serotonergic Agent: _________________		mg Other (specify) ______________
Lithium (all types)		mg Other (specify) ______________
Placebo		mg Other (specify) ______________

Psychosocial intervention(s) of Comorbid Intervention Group 2:	Program Intensity ( )
	Required attendance	Encouraged attendance
Alcoholics Anonymous
Group program/counseling
Individualized program/counseling
Family counseling
Unspecified
None
Contract Yes No Not stated

Total Number of Patients in Comorbid Intervention Group 2: Not stated

Dropout:	Number _____	Rate _____	Not stated
Dropout due to adverse events:	Number _____	Rate _____	Not stated
Loss to followup:	Number _____	Rate _____	Not stated

Demographic information for randomized population only.

History of Alcohol Dependence of Comorbid Intervention Group 2: Not stated

• Age at onset:Mean ______Range ______Std Dev: ______ Not statedYears since onset of alcohol dependence:Mean ______Range ______Std Dev: ______ Not stated

Family History of Alcohol Dependence or Alcoholism of Comorbid Intervention Group 2:
Not stated

• Number _____ Percent _____

Not stated

Not stated

Number of Prior Substance Abuse Treatment Experiences of Comorbid Intervention Group 2:
Not measured

• Mean _____ Range _____ Standard deviation _____

COMORBID INTERVENTION Group 3

Drug intervention(s) of Comorbid Intervention Group 3:	Maximum dose/day	Units	Dosage varies ( )
Disulfiram		mg Other (specify) ______________
Naltrexone		mg Other (specify) ______________
Acamprosate		mg Other (specify) ______________
Serotonergic Agent: _________________		mg Other (specify) ______________
Lithium (all types)		mg Other (specify) ______________
Placebo		mg Other (specify) ______________

Psychosocial intervention(s) of Comorbid Intervention Group 3:	Program Intensity ( )
	Required attendance	Encouraged attendance
Alcoholics Anonymous
Group program/counseling
Individualized program/counseling
Family counseling
Unspecified
None
Contract Yes No Not stated

Total Number of Patients in Comorbid Intervention Group 3: Not stated

Dropout:	Number _____	Rate _____	Not stated
Dropout due to adverse events:	Number _____	Rate _____	Not stated
Loss to followup:	Number _____	Rate _____	Not stated

Demographic information for randomized population only.

History of Alcohol Dependence of Comorbid Intervention Group 3: Not stated

• Age at onset:Mean ______Range ______Std Dev: ______ Not statedYears since onset of alcohol dependence:Mean ______Range ______Std Dev: ______ Not stated

Family History of Alcohol Dependence or Alcoholism of Comorbid Intervention Group 3:
Not stated

• Number _____ Percent _____

Not stated

Not stated

Number of Prior Substance Abuse Treatment Experiences of Comorbid Intervention Group 3:
Not measured

• Mean _____ Range _____ Standard deviation _____

Comorbid Control Group

Enter information for all outcomes that apply:

Alcohol Intake of Comorbid Control Group

Not Stated

Not Stated

Not Stated

Not Stated

Not Stated

Not Stated

Not Stated

Not Stated

COMORBID INTERVENTION Group 1

Enter information for all outcomes that apply:

Alcohol Intake of Comorbid Intervention Group 1

Not Stated

Not Stated

Not Stated

Not Stated

Not Stated

Not Stated

Not Stated

Not Stated

COMORBID INTERVENTION Group 2

Enter information for all outcomes that apply:

Alcohol Intake of Comorbid Intervention Group 2

Not Stated

Not Stated

Not Stated

Not Stated

Not Stated

Not Stated

Not Stated

Not Stated

COMORBID INTERVENTION Group 3

Enter information for all outcomes that apply:

Alcohol Intake of Comorbid Intervention Group 3

Not Stated

Not Stated

Not Stated

Not Stated

Not Stated

Not Stated

Not Stated

Not Stated

Followup Control Group

Enter information for all outcomes that apply:

Alcohol Intake of Followup Control Group

Not Stated

Not Stated

Not Stated

Not Stated

Not Stated

Not Stated

Not Stated

Not Stated

FOLLOWUP INTERVENTION Group 1

Enter information for all outcomes that apply:

Alcohol Intake of Followup Intervention Group 1

Not Stated

Not Stated

Not Stated

Not Stated

Not Stated

Not Stated

Not Stated

Not Stated

FOLLOWUP INTERVENTION Group 2

Enter information for all outcomes that apply:

Alcohol Intake of Followup Intervention Group 2

Not Stated

Not Stated

Not Stated

Not Stated

Not Stated

Not Stated

Not Stated

Not Stated

FOLLOWUP INTERVENTION Group 3

Enter information for all outcomes that apply:

Alcohol Intake of Followup Intervention Group 3

Not Stated

Not Stated

Not Stated

Not Stated

Not Stated

Not Stated

Not Stated

Not Stated