Efficacy and Comparative Effectiveness

We found moderate SOE that both acamprosate and oral naltrexone (50 mg per day) are effective for improving alcohol consumption outcomes (Table 37). Numbers needed to treat (NNT) to prevent 1 person from returning to any drinking were 12 and 20, respectively. For return to heavy drinking, evidence did not support the efficacy of acamprosate, whereas oral naltrexone (50 mg per day) was efficacious with an NNT of 12. Relatively limited evidence from well-controlled trials does not adequately support the efficacy of disulfiram compared with placebo for preventing return to any drinking or for other alcohol consumption outcomes. Some disulfiram trials reported fewer drinking days for subjects who returned to any drinking and who had a complete set of assessment interviews, and suggest that disulfiram may have a role in the treatment of AUDs for some individuals.

Table 37

Summary of findings and strength of evidence for efficacy of FDA-approved medications for alcohol dependence.

We found insufficient direct evidence to conclude that treatment with acamprosate or naltrexone leads to improvement in health outcomes—i.e., accidents, injuries, quality of life (QoL), function, or mortality. Very few trials reported any health outcomes, and the included trials were not designed or powered to assess impact on health outcomes—they typically focused on alcohol consumption outcomes. It is noteworthy that the largest pharmacotherapy trial in alcohol dependence, COMBINE, did report some evidence of improvement in QoL with naltrexone plus behavioral intervention (on the 12-item Short-Form Health Survey [SF-12v2] physical health scale), but the difference between groups did not reach a clinically meaningful threshold.¹⁹³ Evidence from epidemiologic literature consistently relates high average alcohol consumption and heavy per-occasion use to an increased risk of health problems, such as cancers of the oral cavity, esophagus, larynx, colon, rectum, liver, and breast; liver cirrhosis; chronic pancreatitis; coronary heart disease; stroke; depression; preterm birth complications; fetal alcohol syndrome; and injuries and violence.^{13,24,220-222} Such epidemiologic evidence would suggest that improving alcohol consumption outcomes is likely to result in improved health outcomes. A recent model estimated that increasing treatment coverage to 40 percent of all people with alcohol dependence in the European Union would reduce alcohol-attributable mortality by 13 percent for men and 9 percent for women.²²³ Further, a cost study based on the COMBINE trial reported that several treatment combinations that include pharmacotherapy led to reduced median social costs associated with health care, arrests, and motor vehicle accidents compared with medical management plus placebo.²²⁴

Our meta-analyses of 4 head-to-head randomized controlled trials (RCTs) comparing acamprosate with naltrexone,^61,65,74,79 all rated as low risk of bias, found no statistically significant difference between the two medications for improvement in alcohol consumption outcomes (Table 38). The COMBINE study was one of the 4 RCTs.⁶⁵ It found that “patients receiving medical management with naltrexone, combined behavioral intervention (CBI), or both fared better on drinking outcomes than those who received placebo, but acamprosate showed no evidence of efficacy, with or without CBI.”

Table 38

Summary of findings and strength of evidence for comparative effectiveness of acamprosate and naltrexone.

For the vast majority of medications used off-label, and those under investigation, the evidence either was insufficient to determine whether they are efficacious for reducing alcohol consumption or the evidence suggested that they are not efficacious for people with AUDs. We found some exceptions. First, for topiramate, we found moderate SOE supporting efficacy for reducing drinking days, heavy drinking days, and drinks per drinking day—based on the results of 2 RCTs rated as low or medium risk of bias (total N=521).^175,179 The included RCTs did not report data for return to any drinking or return to heavy drinking. Second, for nalmefene, we found moderate SOE supporting efficacy for reducing heavy drinking days per month (WMD -2.0; 95% CI, -3.0 to -1.0) and drinks per drinking day (WMD, -1.0; 95% CI, -1.8 to -0.3).^159,160 We found insufficient evidence of efficacy for nalmefene for other consumption outcomes (return to any drinking and return to heavy drinking) and low SOE that nalmefene is not efficacious for reducing drinking days (WMD, -1.1; 95% CI, -7.6 to 5.4). Finally, limited evidence from 2 small RCTs (total N=88) supports efficacy of valproic acid for reducing return to heavy drinking, heavy drinking days, and drinks per drinking day (low SOE for all).

Harms

Adverse events were often not collected using standardized measures, and methods for systematically capturing adverse events were often not reported. Studies were generally not designed primarily to assess adverse events; the vast majority focused on alcohol consumption outcomes. Evidence for many potential adverse events was insufficient to determine whether the risk was increased or not, often primarily because of lack of precision. For most of the specific adverse events, point estimates favored placebo (i.e., there were more adverse events with medications), but the differences were not statistically significant.

In head-to-head studies, the risk of withdrawal due to adverse events was not significantly different between acamprosate and naltrexone, whereas the risks of headache and vomiting were higher for those treated with naltrexone. Compared with placebo, patients treated with acamprosate had a higher risk of anxiety, diarrhea, and vomiting; those treated with naltrexone had a higher risk of dizziness, nausea, and vomiting; and those treated with nalmefene had a higher risk of dizziness, headache, insomnia, nausea, and vomiting. Trials of topiramate reported increased risk of many adverse events, including paresthesias, taste perversion, anorexia, difficulty with concentration/attention, nervousness, dizziness, pruritis, psychomotor slowing, and weight loss.^175,179 A single trial that reported adverse effects for valproic acid compared with placebo found a higher rate of nausea for patients treated with valproic acid.

According to the package insert,²²⁵ acamprosate is contraindicated for people with severe renal impairment (creatinine clearance 30 mL per minute or less) and requires dose adjustments for moderate renal impairment (creatinine clearance between 30 and 50 mL per minute). Precautions are listed to monitor for depression and suicidal ideation. Common side effects include diarrhea and somnolence.

Oral naltrexone is contraindicated for patients with acute hepatitis or liver failure, and for those currently using opioids or with anticipated need for opioids.^226,227 It can precipitate severe withdrawal for patients dependent on opioids.^226,227 Precautions are listed in the package insert for other hepatic disease, renal impairment, and history of suicide attempts or depression. Patients should be advised to carry a wallet card to alert medical personnel because larger doses may be required and respiratory depression may be deeper and more prolonged if opioid analgesia is needed. Serious adverse events include precipitation of severe withdrawal if the patient is dependent on opioids, and hepatotoxicity (although it is not believed to be a hepatotoxin at the recommended doses). Common side effects include nausea, vomiting, decreased appetite, headache, dizziness, fatigue, somnolence, and anxiety. Injectable naltrexone can also cause injection site reactions. The prescribing information for injectable naltrexone is somewhat different.²²⁷ For example, contraindications for injectable naltrexone include patients receiving opioid analgesics, with current physiologic opioid dependence, with acute opioid withdrawal, or who have failed a naloxone challenge test. It is not contraindicated for patients with acute hepatitis or liver failure, or for those with anticipated need for opioids.

Primary Care Settings

Evidence from primary care settings was scant. One trial (N=100) that recruited subjects primarily by advertisement in two family medicine settings in the United States found no significant treatment effect when comparing acamprosate with placebo.⁶⁹ The only other trial meeting our inclusion criteria that was conducted partly in primary care settings compared nalmefene with placebo in 15 sites (about half were primary care settings) in Finland.¹⁵⁸

Some included studies conducted in non-primary care settings used interventions that may be adaptable for delivery in primary care. For example, in the COMBINE study,⁶⁵ providers delivered a medical management intervention of up to 9 manual-guided counseling visits. The first visit was approximately 45 minutes and followup visits were about 20 minutes each. Medical management included advice for reducing drinking, inquiries about medication side-effects, and emphasis on the importance of taking medications as prescribed. Another trial (included in Key Question [KQ] 1 but not in KQ 4) that compared naltrexone with placebo for 12 weeks in the United States described the use of a “primary care model.”¹⁰¹ Although the trial did not take place in a primary care setting (it was a treatment research center), and the investigators were from a department of psychiatry, the psychosocial co-intervention was delivered by a nurse practitioner with a primary care background, and the trial may have implications for how psychosocial co-interventions could be provided in primary care settings.

In terms of implementing treatment programs for AUDs in primary care, we identified four other publications that did not meet our inclusion criteria (due to the study design or comparators) that may have important implications for primary care settings.^228-231 While these studies found conflicting results, they demonstrated the feasibility of managing AUDs in primary care. In general, these interventions involve formal clinic structure, staffing, and protocols. They used variations of chronic care management, multidisciplinary team-based care, and care-coordination between primary care providers and mental health providers (e.g., physicians coordinating with social workers to connect patients to community resources or provide counseling).

First, a nested sequence of three U.S.-based RCTs compared naltrexone plus “primary care management” (PCM) with naltrexone plus cognitive behavioral therapy.²²⁸ PCM was provided by nurse practitioners, physician assistants, and one internist in an initial 45-minute visit, followed by 15- to 20-minute sessions in weeks 1, 2, 3, 4, 6, 8, and 10. The study found no difference in response to treatment, as measured by avoiding persistent heavy drinking, between those who received PCM and those who received cognitive behavioral therapy (84.1 percent versus 86.5 percent). Among responders enrolled in a maintenance trial, it found higher response for those who received naltrexone and PCM than for those who received placebo and PCM (80.8 percent versus 51.9 percent, p=0.03). Second, a pragmatic trial with 149 general practitioners in France who were “used to managing alcohol-dependent patients in their daily practice” randomized patients (N=422) to acamprosate plus standard care or standard care alone.²²⁹ Standard care in France was described as typically consisting of outpatient detoxification followed by a rehabilitation program (involving some type of psychotherapy). The trial reported better outcomes for the acamprosate group for the Alcohol-Related Problems Questionnaire score, the number of subjects with no alcohol-related problems, and for all secondary outcome measures, including QoL. Third, another U.S-based RCT (N=163) compared a primary-care based alcohol care management (ACM) program with a specialty outpatient addiction treatment program.²³⁰ A greater proportion of the ACM group received naltrexone than the specialty treatment group (65.9 percent versus 11.5 percent), the ACM group had a higher proportion of participants engaged in treatment over the 26 weeks (OR, 5.36; 95 % CI, 2.99 to 9.59), and the percentage of heavy drinking days was lower in the ACM group (OR, 2.16; 95 % CI, 1.27 to 3.66). Overall abstinence did not differ between groups. Fourth, the U.S.-based AHEAD trial (N=563) compared chronic care management (CCM) that included longitudinal care coordinated by a primary care clinician with no CCM for people with alcohol or drug dependence who were not currently engaged in primary care.²³¹ Of those enrolled, 12 percent had alcohol dependence without also meeting criteria for other drug dependence. CCM included motivational enhancement therapy; relapse prevention counseling; on-site medical, addiction, and psychiatric treatment; social work assistance; and referrals. The no-CCM group received a primary care appointment and a list of treatment resources including a telephone number to arrange counseling. The trial found no difference between groups for the primary outcome of abstinence over 12 months.

Barriers to prescribing medications for AUDs in primary care may include lack of familiarity with the medications, lack of confidence in their effectiveness, or inability to provide suitable psychosocial co-interventions (e.g., due to competing demands or insufficient practice resources, personnel, or training). Like behavioral counseling interventions for risky drinking delivered in primary care, implementing the use of medications and psychosocial co-interventions for AUDs in primary care might require development of support systems and additional provider and staff training.^13,232 Further, primary care providers are typically trained to refer patients with AUDs for specialized treatment. O'Malley and O'Connor recently reviewed the issues surrounding the use of medications for alcohol dependence in primary care settings.³⁴ 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.²³³

Subgroups and Genetic Polymorphisms

We did not find any convincing evidence that either naltrexone or acamprosate are more or less effective (compared with each other) for men or women, older adults, young adults, racial or ethnic minorities, smokers, or those with co-occurring disorders. We found no studies that assessed the clinical utility of genotype-guided dosing strategies or genotype-guided medication selection, and none that randomized by genotype. All included studies were either subgroup analyses of trials or prospective cohort studies of people treated with a medication, and all assessed the association between genotype and response to medication (i.e., clinical validity). For most polymorphism-medication pairs, we found just 1 eligible study, and we graded the SOE as insufficient.

We found 7 eligible studies assessing variation in naltrexone response related to mu-opioid receptor gene (OPRM1) polymorphisms. Our meta-analyses for return to any drinking and return to heavy drinking found no significant difference between A-allele homozygotes and those with at least one G allele, both without and with inclusion of studies rated as high or unclear risk of bias. Of note, the total number of subjects contributing data to the analyses was relatively low, and firm conclusions are limited by the imprecision of the results. Point estimates for return to heavy drinking suggest it is possible that patients with at least one G allele of A118G polymorphism of OPRM1 might be more likely to respond to naltrexone, but confidence intervals were wide; additional studies are needed to improve confidence in the estimate of the effect.

Findings in Relation to What Is Already Known

Existing guidelines and systematic reviews support our main findings.^{16,37,38,46-48} As described in the introduction, the U.S. Department of Veterans Affairs (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.^46-48 The various guidelines recommend that naltrexone and/or acamprosate routinely be considered for patients with alcohol dependence in combination with addiction-focused counseling.

Whereas we did not find statistically significant effects on alcohol consumption outcomes for injectable naltrexone,fewer studies and subjects were available for injectable naltrexone; thus, analyses have less precision.

Applicability

Most studies reported that all subjects met criteria for alcohol dependence. We did not identify any studies that evaluated medications and reported them to be efficacious for people with alcohol use disorders who did not meet criteria for alcohol dependence (i.e., people with alcohol abuse or harmful alcohol use). The included literature used definitions from DSM-III or DSM–IV. DSM-5 (2013) describes a single alcohol use disorder category measured on a continuum from mild to severe, and no longer has separate categories for alcohol abuse and dependence.¹² Using DSM-5 terminology, most participants in the included studies likely had moderate to severe AUDs. Thus, applicability of our findings to people with mild AUDs is uncertain. The mean age of subjects was generally in the 40s, with very few studies enrolling slightly younger or older populations. Thus, it is uncertain whether the medications have similar efficacy for older (e.g., those 65 and older) or younger (e.g., in the 20s) subgroups as they have for patients enrolled in the trials. We did not find evidence to confirm or refute whether treatments are more or less efficacious for many other subgroups, including gender groups, racial or ethnic minorities, smokers or nonsmokers, and those with certain coexisting conditions.

Although the majority of included trials assessing the efficacy of acamprosate were conducted in Europe (16 of 22) and a minority were conducted in the United States (4 of 22), the opposite was true for naltrexone (27 of 44 in the United States and 8 of 44 in Europe). Further, the few studies of acamprosate conducted in the United States did not find it to be efficacious. It is unclear whether the different results were due to population differences or other factors. The European trials of acamprosate typically identified patients from inpatient settings or treatment programs, whereas the U.S.-based trials of acamprosate relied on advertisements and referrals. It is possible that this resulted in populations with differing AUD severity and differing potential for benefit. For example, studies of subjects recruited via advertisements may enroll people who have less severe disorders, and may be less applicable to patients with more severe forms of alcohol-use disorders.

Most studies required patients to abstain for at least a few days prior to initiating medication, and the medications are generally recommended for maintenance of abstinence. Acamprosate and injectable naltrexone are only approved for use in patients who have established abstinence, though the duration of required abstinence is not set. However, some studies enrolling patients who were not yet abstinent have reported reduction in heavy drinking with naltrexone^97,234 or acamprosate.⁷³