After the withdrawal phase of treatment, the risk of relapse and return to heavy drinking remains high. FDA-approved medications for alcoholism have been primarily studied in relapse prevention. As revealed in the large multisite National Institute on Alcohol Abuse and Alcoholism–funded Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence (COMBINE) study17 and consistent with established interventions for other chronic neuropsychiatric disorders (eg, schizophrenia, MDD) available treatments are beneficial for some patients with AUDs. There is a critical need to develop more effective and personalized treatments that reduce the risk of relapse and harm from excessive alcohol intake.
Naltrexone/nalmefene. The μ-opioid receptor antagonist naltrexone is the most extensively studied treatment for alcohol dependence and should be considered as first-line treatment. Findings from 2 meta-analyses as well as the COMBINE study indicate that patients who received naltrexone had more days abstinent from alcohol and fewer heavy drinking days than patients who received placebo.17-19 However, the effect size is moderate, and naltrexone is not effective for all patients. Recent research with naltrexone has focused on alternative delivery strategies and identifying moderators of treatment response.
One alternative delivery strategy is to use targeted μ-opioid receptor antagonists. With this strategy, naltrexone is limited to days when or situations in which the patient is at higher risk for heavy drinking. Targeted opioid receptor antagonists are likely to be most effective in heavy drinkers who are not physically dependent and in vulnerable individuals during high-risk situations.
Several studies have shown this strategy to be effective. A large, multisite RCT of targeted nalmefene demonstrated fewer heavy drinking days and lower laboratory levels of markers for chronic hepatotoxicity.20 A more recent study of targeted naltrexone showed a decrease in the mean number of weekly drinks and in the final week of this 12-week open-label study, a decrease in daily drinks.21
Long-acting injectable naltrexone (190 or 380 mg) was approved in 2006 by the FDA for alcohol dependence. A single monthly intramuscular injection of naltrexone has been shown to be more effective than monthly placebo injections in decreasing drinking in alcohol-dependent patients.22 There is also a clear dose response; the higher dose is more effective in promoting abstinence. Unfortunately, the widespread use of this medication has been limited, possibly because of its high cost and reports of injection site complications.23
Another active area of research has been on moderators of naltrexone’s effects. Although results vary, a family history of alcoholism and antisocial behavior has been reported to decrease drinking in persons treated with naltrexone.24-26 The pharmacogenetics of naltrexone response, particularly at the μ-opioid receptor gene, OPRM1, has also been extensively studied because functional variants of the μ-opioid receptor may be related to treatment response. A common functional variant in OPRM1—identified more than 10 years ago—is the response to naltrexone seen in persons who carry at least 1 copy of the 118G haplotype.27-29 Results from a PET study suggest that 118G carriers release more dopamine in response to alcohol, which is mediated via endogenous opioids. A future area of practical treatment may be the pharmacogenetic stratification of alcohol-dependent persons by OPRM1 genotype.
Acamprosate. This medication was approved by the FDA in 2004. Several US studies subsequently demonstrated little to no effect over placebo. Nevertheless, a recent Cochrane review that evaluated all the studies to date found acamprosate to have a modest effect on promoting abstinence after detoxification and suggested that acamprosate may be beneficial in some patients who do not respond to other treatments.30 Acamprosate also has the added advantage of being the only FDA-approved medication that is not metabolized in the liver; thus, it may be of use in patients with chronic liver disease, such as hepatitis B or C.