Background and Objectives for the Systematic Review

Alcohol misuse, which includes the full spectrum from drinking above recommended limits (i.e., risky/hazardous drinking) to alcohol dependence,^1-3 is associated with numerous health and social problems, more than 85,000 deaths per year in the United States,^4,5 and an estimated annual cost to society of more than $220 billion.^6,7 Alcohol misuse is estimated to be the third leading cause of preventable mortality in the United States, following tobacco use and being overweight.⁸ Definitions of the spectrum of alcohol misuse (i.e., unhealthy alcohol use¹) continue to evolve. For the purposes of this report, we use the definitions described in Table 1.

Alcohol-use disorders (AUDs) include harmful use, alcohol abuse, and alcohol dependence;^12,13 they are relatively common in developed countries.¹² Prevalence of AUDs is higher for men than for women, with estimates indicating a lifetime risk of more than 20 percent for men.^12,14-16 Alcohol dependence has lifetime prevalence rates of about 17 percent for men and 8 percent for women.¹⁷

AUDs cause substantial morbidity and mortality—that is, threefold to fourfold increased rates of early mortality.^18-20 They are associated with hypertension, heart disease, stroke, cancer, liver cirrhosis, amnesias, cognitive impairment, sleep problems, peripheral neuropathy, gastritis and gastric ulcers, pancreatitis, decreased bone density, anemia, depression, insomnia, anxiety, suicide, and fetal alcohol syndrome.^12,21 In 2009, the number of alcoholic liver disease deaths was 15,183 and the number of alcohol-induced deaths, excluding accidents and homicides, was 24,518.⁸ Excessive alcohol consumption is also a major factor in injury and violence.²² Acute alcohol-related harm can be the result of fires, drowning, falls, homicide, suicide, motor vehicle crashes, child maltreatment, and pedestrian injuries.²³ In addition, AUDs can complicate the assessment and treatment of other medical and psychiatric problems.¹²

AUDs often begin in the teens and 20s and fluctuate over time, with periods of abstinence (perhaps following a crisis), subsequent periods of sobriety followed by temporary controlled drinking, and then enhanced likelihood of increasing intake and problems.¹² Twenty to 30 percent of people with AUDs achieve long-term remission without any formal treatment.^12,24,25

Some studies indicate that less than 10 percent of those with AUDs are able to achieve long periods of nonproblematic drinking.^26-30 Thus, the goal of treatment in the United States is typically abstinence, because of the belief that it is unlikely that those with AUDs can return to controlled, healthy alcohol use. However, controlled drinking and harm reduction are often goals of treatment in parts of Europe.^{12, 29}

Treatments for Alcohol-Use Disorders

Treatments for AUDs continue to evolve as research on the effectiveness of various treatments is published, and new treatments, including pharmacotherapy, are introduced and used more frequently. No single best approach has yet proven superior among the variety of available treatment options. Some common treatments for AUDs include cognitive behavioral therapy, motivational enhancement therapy, 12-step programs (e.g., Alcoholics Anonymous), and pharmacotherapy (disulfiram, naltrexone, acamprosate). Treatment may be delivered via intensive outpatient programs using group or individual counseling, alcoholism treatment centers, or other approaches.

Using complete abstinence as an outcome, from 15 to 35 percent of patients have been reported to achieve 1 year of sobriety following a variety of treatment approaches.³¹ Treatment approaches reviewed have included clinical trials of disulfiram, motivational enhancement therapy, cognitive behavioral therapy, and 12-step facilitation, as well as treatment as usual within alcoholism-treatment centers. Sobriety outcomes at 3 to 5 years or longer have been reported to be in a similar range.¹² However, the long-term efficacies of specific treatment approaches have not been systematically compared with one another in randomized trials, making interpretation and recommendations for specific interventions difficult.

Over the past 15 to 20 years, awareness has grown that treatment may still be beneficial even if complete abstinence is not achieved. As a result, research has used other outcomes to measure the effectiveness of treatment, which can be subsumed under the concept of harm reduction.³² These measures include significant increases in abstinent days or decreases in heavy drinking episodes, improved physical health, reductions in health care costs, and improvements in psychosocial functioning. Research using these nonabstinent outcomes provides additional evidence for the effectiveness of treatment for alcohol dependence. Miller et al. (2001)³¹ analyzed seven large multisite trials that tested the treatment approaches noted above. They found that whereas, in aggregate, about 25 percent of individuals maintained sobriety over 1 year, the remaining nonabstinent individuals showed substantial decreases in drinking days (from 63% pretreatment to 25% posttreatment) and a mean 57 percent decrease in drinks per drinking day.

Treatment outcomes can be affected by many factors, including the following: (1) AUDs are a heterogeneous group of disorders with considerable variability in outcome and prognosis; (2) comorbidities: multiple physical and emotional illnesses can influence treatment outcomes; (3) there are many forms of treatment, including multiple varieties of psychosocial interventions and several pharmacological interventions; and (4) patients have many pathways to treatment, ranging from voluntary care-seeking to legally mandated treatment. This complexity contributes to variance in treatment outcomes and lack of clarity about any particular best treatment. Nevertheless, many individuals with AUDs respond well to treatment.

Medications for Alcohol-Use Disorders

From the 1950s until the early 1990s, the pharmacotherapy for alcohol dependence consisted only of disulfiram: an aversive deterrent that produces significant physical symptoms, such as nausea or tachycardia, when alcohol is consumed. Disulfiram can be an effective adjunct to psychosocial treatment for alcohol dependence, though its effectiveness requires a high degree of patient motivation and adherence, thereby limiting its overall usefulness. Since the 1990s two oral medications—naltrexone and acamprosate—and one long-acting intramuscular formulation of naltrexone have been approved by the FDA for alcohol dependence. These medications are recommended for people with alcohol dependence, generally after a successful withdrawal from alcohol, and together with psychological intervention.¹³ Table 2 describes the medications available in the United States that are FDA approved for treatment of AUDs, their mechanism of action, and dosing. The medications are usually prescribed for 3 to 12 months. Table 3 describes medications that have been used (off-label) or studied for treatment of AUDs.

In clinical trials the FDA-approved medications have shown evidence for efficacy in enhancing abstinence, reducing relapse to heavy drinking, and reducing overall drinking behavior.³³ The average effect sizes for these medications are considered low to moderate (from 0.11 to 0.16 for effects on abstinence or heavy drinking) when heterogeneous populations of patients with alcohol dependence are studied.³³

Despite ongoing developments and advancements in treatment approaches, alcohol dependence represents one of the most undertreated disorders in the U.S. health care system; it is estimated that only 1 in 4 individuals with alcohol dependence receives treatment.¹⁷ Furthermore, of those patients who receive treatment, less than 1 in 10 receives medication as part of his or her treatment, which leads to a prescribing rate for the entire population of individuals with alcohol dependence of less than 1 in 100. Therefore, expanding awareness and access to this relatively new treatment modality has the potential to improve health outcomes and reduce the burden of this devastating illness that affects an estimated 8 million to 9 million U.S. citizens.

The use of medications for alcohol dependence has had a very slow uptake into clinical practice, including primary care practices. Very low prescribing rates for these medications indicate that primary care providers are rarely using these medications. This suggests that primary care clinicians are uncertain about how and when to use them (or may not believe evidence supports the use of these medications).

O'Malley and O'Connor³⁴ recently reviewed the issues surrounding the use of medications for alcohol dependence in primary care settings. They concluded that "the implementation and widespread use of medications to treat alcohol problems faces a unique set of barriers in primary care. Although primary care providers are proficient at prescribing a wide variety of medications, they generally are unfamiliar with medications for treating alcohol problems other than those used to treat alcohol withdrawal." They referenced a growing body of research to support basic screening methods, brief interventions, and especially medication therapy that has yet to have a major impact on how primary care providers care for individuals at risk for or with alcohol problems.³⁵

Existing Guidance

A 1999 Evidence Report for AHRQ examined the efficacy of disulfiram, opioid antagonists (naltrexone and nalmefene), acamprosate, serotonergic agents, and lithium in the treatment of alcohol dependence.³⁶ Naltrexone and acamprosate had the best evidence of efficacy, though the magnitude of effect was variable. Naltrexone and acamprosate were found to reduce drinking frequency and maintain abstinence, and naltrexone was found to reduce drinking quantity and prevent relapse (acamprosate trials did not measure the latter two outcomes). Included trials were mainly in substance abuse treatment settings, and cointerventions (e.g., counseling) were not described in much detail. Efficacy in primary care settings was unknown. Many additional trials have been published since that report was completed.

In 2011, the United Kingdom's National Institute for Clinical Excellence (NICE) released a set of clinical guidelines on the identification and treatment of people with alcohol dependence and harmful alcohol use.¹³ The guidelines include the following recommendations: (1) after a successful withdrawal for people with moderate or severe alcohol dependence, to consider offering acamprosate or oral naltrexone in combination with an individual psychological intervention (cognitive behavioral therapies, behavioral therapies, or social network and environment-based therapies) focused specifically on alcohol misuse; (2) to consider offering disulfiram in combination with a psychological intervention to service users who have a goal of abstinence but for whom acamprosate and oral naltrexone are not suitable, or prefer disulfiram and understand the relative risks of taking the drug; and (3) to have specialist and competent staff administer pharmacological interventions. A network meta-analysis of relapse-rate reduction using acamprosate, naltrexone, and placebo favored acamprosate but yielded wide credible intervals, probably due to the inclusion of only three studies.

The Veterans Administration (VA), National Institute on Alcohol Abuse and Alcoholism (NIAAA), and Substance Abuse and Mental Health Services Administration (SAMHSA) all have guidelines addressing the use of pharmacotherapy for alcohol dependence.^37-39 The VA guidelines recommend that oral naltrexone and/or acamprosate routinely be considered for patients with alcohol dependence (although acamprosate is currently a nonformulary medication for the VA), and that medications be offered in combination with addiction-focused counseling. At least 9 systematic reviews and 26 trials have been published since the last search date of the VA guidelines (October 2007).

Rationale for an Evidence Review

The treatment of alcohol dependence and the use of medications in the treatment of alcohol dependence are associated with uncertainty and variation across providers and settings. Many clinicians and treatment programs do not use medications for alcohol dependence despite evidence of efficacy, little evidence of harms, and FDA approval. The low use of medications for alcohol dependence could contribute to unnecessary morbidity and mortality.

Since the 1999 AHRQ report on medications for alcohol dependence, many new trials have been published: there has been more than a 10-fold increase in the number of individuals studied in controlled clinical trials of naltrexone and acamprosate, and a series of well-conducted trials have been completed with other pharmacotherapeutic agents that are not FDA approved for alcohol dependence. The need for a new and comprehensive comparative effectiveness review of medications for AUDs appears in order. Such a review will provide significant assistance to dissemination efforts to educate U.S. clinicians in the management of AUDs. The potential to improve the health and welfare of the U.S. population could be significant as well.

Other reasons for this review include the following: (1) intramuscular naltrexone (Vivitrol) is a fairly recently approved medication; (2) to include an assessment of studies using the medications in primary care settings, and to assess applicability of the evidence to primary care; (3) to assess whether some medications are more or less effective for adults with certain genetic polymorphisms (a literature that several Key Informants emphasized the need to synthesize and critique); and (4) to inform updates to clinical practice guidelines.

Key Questions

The draft key questions (KQs) were posted on the EHC website for public comment from September 20 through October 18, 2012. No changes were made based on public review of the draft KQs, PICOTS (populations, interventions, comparators, outcomes, timing, and setting) and analytic framework. The only comments we received were attempts to provide answers to the questions rather than to provide input about the draft KQs, analytic framework, or PICOTS.

Key Question 1:

• Which medications are efficacious for improving consumption outcomes for adults with alcohol-use disorders in outpatient settings?
• How do medications for adults with alcohol-use disorders compare for improving consumption outcomes in outpatient settings?

Key Question 2:

• Which medications are efficacious for improving health outcomes for adults with alcohol-use disorders in outpatient settings?
• How do medications for adults with alcohol-use disorders compare for improving health outcomes in outpatient settings?

Key Question 3:

• What adverse effects are associated with medications for adults with alcohol-use disorders in outpatient settings?
• How do medications for adults with alcohol-use disorders compare for adverse effects in outpatient settings?

Key Question 4:

• Are medications for treating adults with alcohol-use disorders effective in primary care settings?

Key Question 5:

• Are any of the medications more or less effective than other medications for men or women, older adults, young adults, racial or ethnic minorities, smokers, or those with co-occurring disorders?

Key Question 6:

• Are any of the medications more or less effective for adults with certain genetic polymorphisms (e.g., of the mu-opioid receptor gene [OPRM1]) compared with adults without such polymorphisms?

For the above KQs, the following PICOTS criteria apply:

• Population(s)
  • Adults (age 18 years or older) with alcohol-use disorders
• Interventions
  • Pharmacotherapy for relapse prevention or pharmacotherapy combined with various co-interventions (including both FDA-approved drugs and those being used off label).
  • Studies evaluating pharmacotherapy that utilized co-interventions with other treatments for AUDs (e.g., behavioral counseling, cognitive behavioral therapy, motivational enhancement therapy, psychosocial treatments, or self-help such as 12-step programs [e.g., Alcoholics Anonymous]) will be eligible for inclusion, as long as they meet other inclusion/exclusion criteria.
  • Medications approved by the FDA for treatment of alcohol dependence
    • acamprosate
    • disulfiram
    • naltrexone
  • Medications used off-label, or those under investigation
    • amitriptyline
    • aripiprazole
    • atomoxetine
    • baclofen
    • buspirone
    • citalopram
    • desipramine
    • escitalopram
    • fluoxetine
    • fluvoxamine
    • gabapentin
    • imipramine
    • nalmefene
    • olanzapine
    • ondansetron
    • paroxetine
    • prazosin
    • quetiapine
    • sertraline
    • topiramate
    • valproate
    • varenicline
    • vilozaxine
  • This review will not include pharmacotherapy for alcohol withdrawal.
• Comparators
  • For KQs 1 through 5, studies must compare one of the medications listed above with placebo or another medication.
  • For KQ 6, studies must compare people who have a genetic polymorphism with people who do not have the polymorphism.
• Outcomes
  • Consumption outcomes
    • abstinence/any drinking
      • rates of continuous abstinence
      • percentage of days abstinent
      • time to first drink/lapse
      • time to heavy drinking/relapse
    • reduction in alcohol consumption
      • number of heavy drinking days
      • percent of subjects with no heavy drinking days
      • number of drinking days
      • drinks per drinking day
      • drinks per week
  • Health outcomes
    • accidents
    • injuries
    • quality of life
    • function
    • mortality
  • Adverse effects of intervention(s)
    • withdrawals due to adverse events
    • nausea/vomiting
    • diarrhea
    • anorexia
    • palpitations
    • headache
    • dizziness
    • cognitive dysfunction
    • taste abnormalities
    • paresthesias (numbness, tingling)
    • metabolic acidosis
    • glaucoma
    • vision changes
    • suicidal ideation
    • insomnia
    • anxiety
    • rash
• Timing
  • Studies with at least 12 weeks of followup from the time of medication initiation.
• Setting
  • Outpatient health care (i.e., nonlaboratory) settings; KQ 4 applies to primary care settings only (i.e., internal medicine, family medicine, pediatrics, obstetrics/gynecology, or college and university health clinics).

Analytic Framework

Methods

A. Criteria for Inclusion/Exclusion of Studies in the Review

Table 4 presents the inclusion/exclusion criteria for this review. We do not repeat all of the PICOTS information related to the inclusion/exclusion criteria.

B. Searching for the Evidence: Literature Search Strategies for Identification of Relevant Studies to Answer the Key Questions

We will systematically search, review, and analyze the scientific evidence for each KQ. The steps that we will take to accomplish the literature review are described below.

To identify articles relevant to each KQ, we will begin with a focused MEDLINE search on alcohol-use disorders by using a variety of terms, medical subject headings (MeSH), and major headings; and by limiting the search to English-language, adult (18 and older), and human-only studies. Relevant terms are listed in Table 5. We will also search the Cochrane Library, the Cochrane Central Trials Registry, the Cumulative Index to Nursing and Allied Health Literature, EMBASE, and PsycInfo by using analogous search terms. We will conduct quality checks to ensure that the known studies (i.e., studies included in the previous review on pharmacotherapy for alcohol-use disorders and those identified during Topic Refinement) are identified by the search. If they are not, we will revise and rerun our searches.

We will not simply conduct one search starting from where the 1999 systematic review for AHRQ left off. Rather, because our review has some differences in scope (e.g., more included medications, questions about comparative effectiveness [KQs 1b, 2b, 3b], primary care [KQ 4], and genetic polymorphisms [KQ 6]), we will search the literature published since 1970. This search date was selected based on the earliest publications found during topic refinement, the earliest studies found in previous systematic reviews (which was from 1974), and expert opinion.

We will search the "gray literature" for unpublished studies relevant to this review and will include studies that meet all the inclusion criteria and contain enough methodological information for assessment of internal validity/quality. Gray literature sources will include ClinicalTrials.gov, the World Health Organization's International Clinical Trials Registry Platform, and pharmaceutical companies' scientific information packets (which will be requested by the Scientific Resource Center).

We reviewed our search strategy with the Technical Expert Panel (TEP) and did they did not have any recommendations to alter it. In addition, to attempt to avoid retrieval bias, we will manually search the reference lists of systematic reviews, landmark studies, and background articles on this topic to look for any relevant citations that might have been missed by electronic searches.

We will conduct an updated literature search (of the same databases searched initially) concurrent with the peer review process. Any literature suggested by Peer Reviewers or from the public will be investigated and, if appropriate, incorporated into the final review. Appropriateness will be determined by the same methods described above.

C. Data Abstraction and Data Management

All titles and abstracts identified through searches will be independently reviewed for eligibility against our inclusion/exclusion criteria by two trained members of the research team. Studies marked for possible inclusion by either reviewer will undergo a full-text review. For studies without adequate information to determine inclusion or exclusion, we will retrieve the full text and then make the determination. All results will be tracked in an EndNote® bibliographic database (Thomson Reuters, New York, NY).

We will retrieve and review the full text of all titles marked for possible inclusion during the title/abstract review phase. Each full-text article will be independently reviewed by two trained members of the team using the eligibility criteria described above. If both reviewers agree that a study does not meet the eligibility criteria, the study will be excluded. If the reviewers disagree, conflicts will be resolved by discussion and consensus or by consulting a third member of the review team. As described above, all results will be tracked in an EndNote database. We will record the reason that each excluded full-text publication did not satisfy the eligibility criteria so that we can later compile a comprehensive list of such studies.

For studies that meet our inclusion criteria, we will abstract important information into evidence tables. We will design data abstraction forms to gather pertinent information from each article, including characteristics of study populations (e.g., age, sex, race, ethnicity, and smoking status of enrolled populations; proportion with alcohol dependence and other AUDs; co-occurring disorders of enrolled populations; source of subject recruitment), interventions (e.g., dose and frequency of administration; type of provider prescribing the treatment; co-interventions), comparators, settings (e.g., primary care, substance abuse treatment settings), study designs, methods, and results. Trained reviewers will extract the relevant data from each included article into the evidence tables. All data abstractions will be reviewed for completeness and accuracy by a second member of the team.

D. Assessment of Methodological Risk of Bias of Individual Studies

To assess the risk of bias (i.e., internal validity) of studies, we will use predefined criteria based on the AHRQ Methods Guide for Comparative Effectiveness Reviews,⁴⁰ including questions to assess selection bias, confounding, performance bias, detection bias, and attrition bias (i.e., those about adequacy of randomization, allocation concealment, similarity of groups at baseline, masking, attrition, whether intention-to-treat analysis was used, method of handling dropouts and missing data, validity and reliability of outcome measures, and treatment fidelity). In general terms, results from a study assessed as having low risk of bias are considered to be valid. A study with moderate risk of bias is susceptible to some risk of bias but probably not enough to invalidate its results. A study assessed as high risk of bias has significant risk of bias (e.g., stemming from serious issues in design, conduct, or analysis) that may invalidate its results. We plan to exclude studies deemed high risk of bias from our main data synthesis and main analyses; we will include them only in sensitivity analyses.

Two independent reviewers will assess risk of bias for each study. Disagreements between the two reviewers will be resolved by discussion and consensus or by consulting a third member of the team.

E. Data Synthesis

If we find multiple similar studies for a comparison of interest, we will consider quantitative analysis (i.e., meta-analysis) of the data from those studies. To determine whether quantitative analyses are appropriate, we will assess the clinical and methodological heterogeneity of the studies under consideration following established guidance.⁴¹ We will do this by qualitatively assessing the PICOTS of the included studies, looking for similarities and differences. When quantitative syntheses are not appropriate (e.g., because of clinical heterogeneity, insufficient numbers of similar studies, or insufficiency or variation in outcome reporting), we will synthesize the data qualitatively.

For quantitative syntheses, we will use random-effects models to estimate pooled effects.⁴² For continuous outcomes (e.g., percentage of days abstinent) measured with the same scale, we will report the weighted mean difference (WMD) between intervention and control. If we combine multiple scales (e.g., different scales to measure quality of life) in one meta-analysis, we will use the standardized mean difference (SMD), Cohen's d. For binary outcomes (e.g., adverse events), we will calculate risk differences between groups or risk ratios (e.g., if mortality data are reported from studies with various followup durations, we will base the analysis on number of deaths per person-year and report a risk ratio). For each meta-analysis, we will conduct sensitivity analyses by adding studies excluded for having high risk of bias. To assess statistical heterogeneity, we will calculate the chi-squared statistic and the I² statistic.^{43, 44}

We plan to stratify analyses and/or perform subgroup analyses when possible and appropriate. Planned stratifications or categories for subgroup analyses include those listed for Key Question 5 as well as geographic location of studies (United States vs. all other countries).

If appropriate (based on our assessment of clinical and methodological heterogeneity, and availability of sufficient numbers of studies), we will conduct a network meta-analysis using Bayesian methods to compare the efficacy of medications. The analysis will include both head-to-head and placebo-controlled trials.

F. Grading the Strength of Evidence (SOE) for Individual Comparisons and Outcomes

We will grade the strength of evidence based on the guidance established for the Evidence-based Practice Center Program.⁴⁵ Developed to grade the overall strength of a body of evidence, this approach incorporates four key domains: risk of bias (includes study design and aggregate quality), consistency, directness, and precision of the evidence. It also considers other optional domains that may be relevant for some scenarios, such as a dose-response association, plausible confounding that would decrease the observed effect, strength of association (magnitude of effect), and publication bias.

Table 6 describes the grades of evidence that can be assigned. Grades reflect the strength of the body of evidence to answer KQs on the comparative effectiveness, efficacy, and harms of the interventions included in this review. Grades do not refer to the general efficacy or effectiveness of interventions. Two reviewers will assess each domain for each key outcome, and differences will be resolved by consensus.

We will grade the strength of evidence for alcohol-consumption measures, accidents, injuries, quality of life, and mortality.

G. Assessing Applicability

We will assess applicability of the evidence following guidance from the Methods Guide for Effectiveness and Comparative Effectiveness Reviews.⁴⁶ We will use the PICOTS framework to explore factors that affect applicability. Some factors identified a priori that may limit the applicability of evidence include the following: age of enrolled populations; sex of enrolled populations (e.g., few women may be enrolled in the studies); race/ethnicity of enrolled populations; smoking status of enrolled populations; co-occurring disorders of enrolled populations; setting; type of provider prescribing the treatment; and source of subject recruitment. Regarding the source of subject recruitment, studies of subjects recruited via advertisements may enroll people that have less severe disorders, and may be less applicable to patients with more severe forms of alcohol-use disorders.

References

1. Saitz R. Clinical practice. Unhealthy alcohol use. N Engl J Med. 2005 Feb 10;352(6):596-607. PMID: 15703424.
2. Whitlock EP, Green CA, Polen MR. Behavioral Counseling Interventions in Primary Care to Reduce Risky/Harmful Alcohol Use. Systematic Evidence Review No. 30. AHRQ Publication No. 04-0533B. (Prepared by Oregon Evidence-based Practice Center under Contract No. 290-97-0018, Task Order No. 2). Rockville, MD: Agency for Healthcare Research and Quality; April 2004.
3. U.S. Department of Veterans Affairs. AUDIT-C Frequently Asked Questions. Updated April 28, 2010. http://www.queri.research.va.gov/tools/alcohol-misuse/alcohol-faqs.cfm. Accessed June 27, 2011.
4. Mokdad AH, Marks JS, Stroup DF, et al. Actual causes of death in the United States, 2000. JAMA. 2004 Mar 10;291(10):1238-45. PMID: 15010446.
5. Whitlock EP, Polen MR, Green CA, et al. Behavioral counseling interventions in primary care to reduce risky/harmful alcohol use by adults: a summary of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med. 2004 Apr 6;140(7):557-68. PMID: 15068985.
6. Bouchery EE, Harwood HJ, Sacks JJ, et al. Economic costs of excessive alcohol consumption in the U.S., 2006. Am J Prev Med. 2011 Nov;41(5):516-24. PMID: 22011424.
7. Harwood HJ, Fountain D, Fountain G. Economic cost of alcohol and drug abuse in the United States, 1992: a report. Addiction. 1999 May;94(5):631-5. PMID: 10563025.
8. Centers for Disease Control and Prevention. FastStats: Alcohol Use. Updated January 27, 2012. http://www.cdc.gov/nchs/fastats/alcohol.htm. Accessed May 21, 2012.
9. Isaac M, Janca A, Sartorius N. ICD-10 symptom glossary for mental disorders. Geneva: Division of Mental Health, World Health Organization; 1994.
10. Janca A, Ustun TB, van Drimmelen J, et al. ICD-10 symptom checklist for mental disorders, version 1.1. Geneva: Division of Mental Health, World Health Organization; 1994.
11. American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 4th ed. Text rev. Washington, DC: American Psychiatric Publishing, Inc.; 2000.
12. Schuckit MA. Alcohol-use disorders. Lancet. 2009 Feb 7;373(9662):492-501. PMID: 19168210.
13. National Collaborating Centre for Mental Health, National Institute for Health & Clinical Excellence. Alcohol-use Disorders: The NICE Guidelines on Diagnosis, Assessment and Management of Harmful Drinking and Alcohol Dependence. The British Psychological Society and The Royal College of Psychiatrists 2011. http://www.nice.org.uk/nicemedia/live/13337/53190/53190.pdf
14. Hasin DS, Stinson FS, Ogburn E, et al. Prevalence, correlates, disability, and comorbidity of DSM-IV alcohol abuse and dependence in the United States: results from the National Epidemiologic Survey on Alcohol and Related Conditions. Arch Gen Psychiatry. 2007 Jul;64(7):830-42. PMID: 17606817.
15. Mertens JR, Weisner C, Ray GT, et al. Hazardous drinkers and drug users in HMO primary care: prevalence, medical conditions, and costs. Alcohol Clin Exp Res. 2005 Jun;29(6):989-98. PMID: 15976525.
16. Teesson M, Baillie A, Lynskey M, et al. Substance use, dependence and treatment seeking in the United States and Australia: a cross-national comparison. Drug Alcohol Depend. 2006 Feb 1;81(2):149-55. PMID: 16043307.
17. Hasin DS, Grant BF. The co-occurrence of DSM-IV alcohol abuse in DSM-IV alcohol dependence: results of the National Epidemiologic Survey on Alcohol and Related Conditions on heterogeneity that differ by population subgroup. Arch Gen Psychiatry. 2004 Sep;61(9):891-6. PMID: 15351767.
18. Mann K, Schafer DR, Langle G, et al. The long-term course of alcoholism, 5, 10 and 16 years after treatment. Addiction. 2005 Jun;100(6):797-805. PMID: 15918810.
19. Norstrom T. Per capita alcohol consumption and all-cause mortality in Canada, 1950-98. Addiction. 2004 Oct;99(10):1274-8. PMID: 15369565.
20. Rivara FP, Garrison MM, Ebel B, et al. Mortality attributable to harmful drinking in the United States, 2000. J Stud Alcohol. 2004 Jul;65(4):530-6. PMID: 15376828.
21. Corrao G, Bagnardi V, Zambon A, et al. A meta-analysis of alcohol consumption and the risk of 15 diseases. Prev Med. 2004 May;38(5):613-9. PMID: 15066364.
22. Cherpitel CJ, Ye Y. Alcohol-attributable fraction for injury in the U.S. general population: data from the 2005 National Alcohol Survey. J Stud Alcohol Drugs. 2008 Jul;69(4):535-8. PMID: 18612569.
23. Centers for Disease Control and Prevention (CDC). Alcohol-attributable deaths and years of potential life lost--United States, 2001. MMWR Morb Mortal Wkly Rep. 2004 Sep 24;53(37):866-70. PMID: 15385917.
24. Moos RH, Moos BS. Rates and predictors of relapse after natural and treated remission from alcohol use disorders. Addiction. 2006 Feb;101(2):212-22. PMID: 16445550.
25. Rumpf HJ, Bischof G, Hapke U, et al. Stability of remission from alcohol dependence without formal help. Alcohol Alcohol. 2006 May-Jun;41(3):311-4. PMID: 16490790.
26. Bodin MC, Romelsjo A. Predictors of abstinence and nonproblem drinking after 12-step treatment in Sweden. J Stud Alcohol. 2006 Jan;67(1):139-46. PMID: 16536138.
27. Cox WM, Rosenberg H, Hodgins CH, et al. United Kingdom and United States healthcare providers' recommendations of abstinence versus controlled drinking. Alcohol Alcohol. 2004 Mar-Apr;39(2):130-4. PMID: 14998830.
28. Dawson DA, Grant BF, Stinson FS, et al. Recovery from DSM-IV alcohol dependence: United States, 2001-2002. Addiction. 2005 Mar;100(3):281-92. PMID: 15733237.
29. Maisto SA, Clifford PR, Stout RL, et al. Drinking in the year after treatment as a predictor of three-year drinking outcomes. J Stud Alcohol. 2006 Nov;67(6):823-32. PMID: 17060998.
30. Schuckit MA. Drug and Alcohol Abuse: A Clinical Guide to Diagnosis and Treatment. 6th ed. New York: Springer; 2005.
31. Miller WR, Walters ST, Bennett ME. How effective is alcoholism treatment in the United States? J Stud Alcohol. 2001 Mar;62(2):211-20. PMID: 11327187.
32. O'Brien CP, McLellan AT. Myths about the treatment of addiction. Lancet. 1996 Jan 27;347(8996):237-40. PMID: 8551886.
33. Kranzler HR, Van Kirk J. Efficacy of naltrexone and acamprosate for alcoholism treatment: a meta-analysis. Alcohol Clin Exp Res. 2001 Sep;25(9):1335-41. PMID: 11584154.
34. O'Malley SS, O'Connor PG. Medications for unhealthy alcohol use: across the spectrum. Alcohol Res Health. 2011;33:300-12.
35. D'Amico EJ, Paddock SM, Burnam A, et al. Identification of and guidance for problem drinking by general medical providers: results from a national survey. Med Care. 2005 Mar;43(3):229-36. PMID: 15725979.
36. West SL, Garbutt JC, Carey TS, et al. Pharmacotherapy for Alcohol Dependence. Evidence Reports/Technology Assessments, No. 3. Agency for Health Care Policy and Research Report No.: 99-E004 Rockville, MD: 1999. http://www.ncbi.nlm.nih.gov/books/NBK32930/
37. U.S. Department of Veterans Affairs, U.S. Department of Defense. VA/DoD Clinical Practice Guideline for Management of Substance Use Disorders (SUD). 2009.http://www.healthquality.va.gov/sud/sud_full_601f.pdf<
38. Pettinati HM, Weiss RD, Miller WR, et al. COMBINE Monograph Series, Volume 2. Medical Management Treatment Manual: A Clinical Research Guide for Medically Trained Clinicians Providing Pharmacotherapy as Part of the Treatment for Alcohol Dependence. DHHS Publication No. (NIH) 04–5289. Bethesda, MD: National Institute on Alcohol Abuse and Alcoholism; 2004.
39. Center for Substance Abuse and Treatment. Incorporating alcohol pharmacotherapies into medical practice. (Treatment improvement protocol (TIP); no. 49). Substance Abuse and Mental Health Services Administration (SAMHSA) Rockville, MD: 2009.
40. Viswanathan M, Ansari MT, Berkman ND, et al. Assessing the Risk of Bias of Individual Studies in Systematic Reviews of Health Care Interventions. Agency for Healthcare Research and Quality Methods Guide for Comparative Effectiveness Reviews AHRQ Publication No. 12-EHC047-EF. Rockville, MD: March 2012. www.effectivehealthcare.ahrq.gov/.
41. West SL, Gartlehner G, Mansfield AJ, et al. Comparative Effectiveness Review Methods: Clinical Heterogeneity. Methods Research Report. Prepared by RTI International -- University of North Carolina Evidence-based Practice Center under Contract No. 290-2007-10056-I AHRQ Publication No. 10-EHC070-EF. Rockville, MD: Agency for Healthcare Research and Quality; September 2010.
42. Sutton AJ, Abrams KR, Jones DR, et al. Methods for Meta-Analysis in Medical Research (Wiley Series in Probability and Statistics - Applied Probability and Statistics Section). Wiley; 2000.
43. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002 Jun 15;21(11):1539-58. PMID: 12111919.
44. Higgins JP, Thompson SG, Deeks JJ, et al. Measuring inconsistency in meta-analyses. BMJ. 2003 Sep 6;327(7414):557-60. PMID: 12958120.
45. Owens DK, Lohr KN, Atkins D, et al. AHRQ series paper 5: grading the strength of a body of evidence when comparing medical interventions -- Agency for Healthcare Research and Quality and the Effective Health-Care Program. J Clin Epidemiol. 2010 May;63(5):513-23. PMID: 19595577.r
46. Atkins D, Chang S, Gartlehner G, et al. Chapter 6: Assessing the Applicability of Studies When Comparing Medical Interventions. In: Methods Guide for Effectiveness and Comparative Effectiveness Reviews. AHRQ Publication No. 11-EHC019-EF. Rockville, MD: Agency for Healthcare Research and Quality; March 2011.

Definition of Terms

See Table 1

Summary of Protocol Amendments

In the event of protocol amendments, the date of each amendment will be accompanied by a description of the change and the rationale.

Review of Key Questions

For all EPC reviews, key questions were reviewed and refined as needed by the EPC with input from Key Informants and the Technical Expert Panel (TEP) to assure that the questions are specific and explicit about what information is being reviewed. In addition, the key questions were posted for public comment and finalized by the EPC after review of the comments.

Key Informants

Key Informants are the end users of research, including patients and caregivers, practicing clinicians, relevant professional and consumer organizations, purchasers of health care, and others with experience in making health care decisions. Within the EPC program, the Key Informant role is to provide input into identifying the Key Questions for research that will inform healthcare decisions. The EPC solicits input from Key Informants when developing questions for systematic review or when identifying high priority research gaps and needed new research. Key Informants are not involved in analyzing the evidence or writing the report and have not reviewed the report, except as given the opportunity to do so through the peer or public review mechanism.

Key Informants must disclose any financial conflicts of interest greater than $10,000 and any other relevant business or professional conflicts of interest. Because of their role as end-users, individuals are invited to serve as Key Informants and those who present with potential conflicts may be retained. The TOO and the EPC work to balance, manage, or mitigate any potential conflicts of interest identified.

Technical Experts

Technical Experts comprise a multi-disciplinary group of clinical, content, and methodologic experts who provide input in defining populations, interventions, comparisons, or outcomes as well as identifying particular studies or databases to search. They are selected to provide broad expertise and perspectives specific to the topic under development. Divergent and conflicted opinions are common and perceived as health scientific discourse that results in a thoughtful, relevant systematic review. Therefore study questions, design and/or methodological approaches do not necessarily represent the views of individual technical and content experts. Technical Experts provide information to the EPC to identify literature search strategies and recommend approaches to specific issues as requested by the EPC. Technical Experts do not do analysis of any kind nor contribute to the writing of the report and have not reviewed the report, except as given the opportunity to do so through the peer or public review mechanism.

Technical Experts must disclose any financial conflicts of interest greater than $10,000 and any other relevant business or professional conflicts of interest. Because of their unique clinical or content expertise, individuals are invited to serve as Technical Experts and those who present with potential conflicts may be retained. The TOO and the EPC work to balance, manage, or mitigate any potential conflicts of interest identified.

Peer Reviewers

Peer reviewers are invited to provide written comments on the draft report based on their clinical, content, or methodologic expertise. Peer review comments on the preliminary draft of the report are considered by the EPC in preparation of the final draft of the report. Peer reviewers do not participate in writing or editing of the final report or other products. The synthesis of the scientific literature presented in the final report does not necessarily represent the views of individual reviewers. The dispositions of the peer review comments are documented and will, for CERs and Technical briefs, be published three months after the publication of the Evidence report.

Potential Reviewers must disclose any financial conflicts of interest greater than $10,000 and any other relevant business or professional conflicts of interest. Invited Peer Reviewers may not have any financial conflict of interest greater than $10,000. Peer reviewers who disclose potential business or professional conflicts of interest may submit comments on draft reports through the public comment mechanism.

EPC Team Disclosures

EPC core team members must disclose any financial conflicts of interest greater than $1,000 and any other relevant business or professional conflicts of interest. Related financial conflicts of interest which cumulatively total greater than $1,000 will usually disqualify EPC core team investigators.

Role of the Funder

This project was funded under Contract No. HHSA2902010008i from the Agency for Healthcare Research and Quality, U.S. Department of Health and Human Services. The Task Order Officer reviewed contract deliverables for adherence to contract requirements and quality. The authors of this report are responsible for its content. Statements in the report should not be construed as endorsement by the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services.