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Jonas DE, Amick HR, Feltner C, et al. Pharmacotherapy for Adults With Alcohol-Use Disorders in Outpatient Settings [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2014 May. (Comparative Effectiveness Reviews, No. 134.)
Pharmacotherapy for Adults With Alcohol-Use Disorders in Outpatient Settings [Internet].
Show detailsBackground
Alcohol misuse, which includes the full spectrum from drinking above recommended limits (i.e., risky or 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.
Table 1
Definitions of the spectrum of alcohol misuse.
Alcohol-use disorders (AUDs) include harmful use, alcohol abuse, and alcohol dependence;15,16 they are relatively common in developed countries.15 Prevalence of AUDs is higher for men than for women, with estimates indicating a lifetime risk of more than 20 percent for men.15,17-19 Alcohol dependence has lifetime prevalence rates of about 17 percent for men and 8 percent for women.20
Alcohol use disorders cause substantial morbidity and mortality—that is, threefold to fourfold increased rates of early mortality.21-23 They are associated with hypertension, heart disease, stroke, cancer (e.g., mouth, throat, espophagus, colon, liver, and breast), 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.15,24 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.25 Acute alcohol-related harm can be the result of fires, drowning, falls, homicide, suicide, motor vehicle crashes, child maltreatment, and pedestrian injuries.26 In addition, AUDs can complicate the assessment and treatment of other medical and psychiatric problems.15
Alcohol use disorders 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.15 Twenty to 30 percent of people with alcohol use disorders achieve long-term remission without any formal treatment.15,27,28
Some studies indicate that less than 10 percent of those with AUDs are able to achieve long periods of nonproblematic drinking.29-33 Thus, the goal of treatment in the United States has traditionally been complete abstinence, because of the belief that it is unlikely that those with alcohol use disorders can return to controlled, healthy alcohol use. However, controlled drinking and harm reduction are often goals of treatment in parts of Europe.15,32
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. Treatment may be delivered via individual outpatient counseling, intensive outpatient programs using group or individual methods, alcoholism treatment centers, or other approaches. Most treatment is currently delivered in specialty settings rather than in primary care settings. Primary care providers are typically trained to refer patients with AUDs for specialized treatment, and primary care providers are generally unfamiliar with medications for treating AUDs.34
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.35 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.15
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.36 These measures include significant increases in abstinent days or decreases in heavy drinking episodes, improved physical health, and improvements in psychosocial functioning. Research using these outcomes can provide additional evidence for the effectiveness of treatment for alcohol dependence.
Variation in response to the medications has been described,37-39 some of which may be related to genetic polymorphisms. For example, some previous studies have reported associations between mu-opioid receptor gene (OPRM1) polymorphisms and clinical response to the opiate antagonist naltrexone.40,41 In theory, it makes sense that OPRM1 polymorphisms could alter the response to naltrexone because its mechanism of action is to competitively bind to opioid receptors and block the effects of endogenous opioids. Further, it has the highest affinity for the mu-opioid receptor. However, some studies of OPRM1 polymorphisms did not find an association with response to naltrexone.42,43
Pharmacological Interventions 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. Since the 1990s, two oral medications (naltrexone and acamprosate) and one long-acting intramuscular formulation (of naltrexone) have been approved by the U.S. Food and Drug Administration (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.16 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, though much longer courses of treatment are not uncommon in clinical practice. 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.39 Many additional medications have been used off-label or studied for treatment of AUDs. These include antidepressants, mood stabilizers, anticonvulsants, alpha-adrenergic blockers, antipsychotics, and anxiolytics.
Table 2
Medications that are FDA approved for treating adults with alcohol-use disorders.
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 fewer than 1 in 3 individuals with AUDs receives treatment.17 Furthermore, of those patients who receive treatment, data from the Veterans Health Administration show that less than 1 in 10 receives medication as part of his or her treatment.44,45 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.
Existing Guidance
The Veterans Administration (VA), National Institute on Alcohol Abuse and Alcoholism (NIAAA), and Substance Abuse and Mental Health Services Administration (SAMHSA) all have guidelines, manuals, or protocols addressing the use of pharmacotherapy for alcohol dependence.46-48 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. The NIAAA Medical Management Treatment Manual provides direction for clinicians to provide medical management, combined behavioral intervention (CBI), and medical treatment with naltrexone or acamprosate as provided in the COMBINE trial.47 The SAMHSA treatment improvement protocol provides basic information, guidelines, tools, and resources to help health care practitioners treat patients with AUDs and includes chapters on acamprosate, disulfiram, oral naltrexone, and injectable naltrexone.
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.16 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 (extended release naltrexone injection is not available in the United Kingdom) 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 for people who have a goal of abstinence but for whom acamprosate and oral naltrexone are not suitable, or who prefer disulfiram and understand the relative risks of taking the drug; and (3) to have specialist and competent staff administer pharmacological interventions.
Scope and Key Questions
The use of medications for alcohol-use disorders is associated with uncertainty and variation across providers and settings. In recent years, many new trials of medications for alcohol-use disorders have been published. Since the 1999 Agency for Healthcare Research and Quality (AHRQ) report on medications for alcohol dependence,49,50 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 treating alcohol dependence. Other reasons for conducting a new review on this topic include the following: (1) to assess the comparative effectiveness of the FDA approved medications; (2) to determine whether any agents that are not FDA approved have evidence supporting their efficacy; (3) to evaluate the evidence on intramuscular naltrexone (Vivitrol®), a fairly recently approved medication; (4) to evaluate whether or not trials provide evidence of effectiveness in primary care settings; (5) to assess whether some medications are more or less effective for adults with specific genotypes; and (6) to provide a comprehensive review on medications for AUDs that is relevant for clinicians, researchers, and policymakers.
We approach each Key Question (KQ) by considering the relevant Populations, Interventions, Comparators, Outcomes, Timing, and Settings (PICOTS). Our report focuses on clinically relevant medications (those that are commonly used, those with sufficient literature for systematic review, and those of greatest interest to clinicians and to the developers of guidelines). Our report is limited to people with AUDs; it does not address people with risky or hazardous alcohol use (for whom medications are likely not an appropriate intervention).
The main objective of this report is to conduct a systematic review and meta-analysis of the comparative effectiveness and harms of medications for adults with alcohol-use disorders. In this review, we address the following KQs:
KQ 1a: Which medications are efficacious for improving consumption outcomes for adults with alcohol-use disorders in outpatient settings?
KQ 1b: How do medications for adults with alcohol-use disorders compare for improving consumption outcomes in outpatient settings?
KQ 2a: Which medications are efficacious for improving health outcomes for adults with alcohol-use disorders in outpatient settings?
KQ 2b: How do medications for adults with alcohol-use disorders compare for improving health outcomes in outpatient settings?
KQ 3a: What adverse effects are associated with medications for adults with alcohol-use disorders in outpatient settings?
KQ 3b: How do medications for adults with alcohol-use disorders compare for adverse effects in outpatient settings?
KQ 4: Are medications for treating adults with alcohol-use disorders effective in primary care settings?
KQ 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?
KQ 6: Are any of the medications more or less effective for adults with specific genotypes (e.g., related to polymorphisms of the mu-opioid receptor gene [OPRM1])?
Analytic Framework
We developed an analytic framework to guide the systematic review process (Figure 1).
![Figure 1 is titled “Analytic framework for pharmacotherapy for adults with alcohol-use disorders in outpatient settings.” The framework begins on the left with our patient population of interest: adults with alcohol-use disorders. We also specify the following subgroups of interest: men or women, older adults (age 65 or older), young adults ages 18 to 25, racial or ethnic minorities, smokers, those with co-occurring disorders, and those with certain genetic polymorphisms (e.g., of the mu-opioid receptor gene [OPRM1]). The arrow connecting the main population with the box containing the subgroups is labeled “KQ 5 and 6.”An arrow with the word “pharmacotherapy” goes from the population on the left to a box containing the words “alcohol consumption outcomes.” The following are bulleted below the box title: “Abstinence/any drinking (including time to first drink, time to relapse)” and “Reduction in alcohol consumption (including number of heavy drinking days, number of drinking days, drinks per drinking day, and drinks per week.” “KQ 1” is also above this arrow, to indicate that the first Key Question focuses on pharmacotherapy and alcohol consumption outcomes. A curvy arrow labeled “KQ3” descends from the “pharmacotherapy” arrow to an elliptical shape with the words “adverse effects of treatment” to illustrate the focus of KQ3. A dashed line ascends from the “pharmacotherapy” arrow to a diamond shape containing the words “primary care settings.” This dashed line is labeled “KQ 4.” From the “alcohol consumption outcomes” box, a dashed line going to the right connects it to a box labeled “health outcomes.” Health outcomes listed in this box are accidents, injuries, quality of life, and mortality. There is an arrow that connects the “pharmacotherapy” arrow to the “health outcomes” box; it is labeled “KQ 2.” A dashed line connects the “KQ 2” arrow to the “primary care settings” diamond.](/books/NBK208579/bin/introductionf1.gif)
Figure 1
Analytic framework for pharmacotherapy for adults with alcohol-use disorders in outpatient settings.
KQ 1 assesses which medications are efficacious and how they compare with one another for improving alcohol consumption outcomes. KQ 2 examines which medications are efficacious and how they compare with one another for improving health outcomes. KQ 3 examines harms. KQ 4 focuses on evidence for primary care settings. KQ 5 assesses whether the medications are more or less effective compared with each other for a variety of subgroups. KQ 6 assesses whether any of the medications are more or less effective for adults with specific genotypes than for adults with different genotypes.
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