Medication for alcohol use disorder: Which agents work best?

Historically, alcohol use disorder (AUD; classified as alcohol abuse or dependence in DSM-IV-TR) has been treated with psychosocial therapies, but many patients treated this way relapse into heavy drinking patterns and are unable to sustain sobriety (Box 1¹). Although vital for treating AUD, psychosocial methods have, to date, a modest success rate. Research has demonstrated that combining pharmacotherapy with psychosocial programs is effective for treating AUD.²

Patients and clinicians might associate AUD medications with so-called aversion therapy because, for many years, the only treatment was disulfiram, which causes unpleasant physical effects when consumed with alcohol. However, newer medications help patients maintain abstinence by targeting brain neurotransmitters relevant to addiction neurocircuitry, such as dopamine, serotonin, _ϒ-aminobutyric acid (GABA), glutamate, and opioid.³ These medications may help patients with AUD achieve sobriety, avoid relapse, decrease heavy drinking days, and delay time to recurrent drinking.

In this article, we review FDA-approved medications (Table 1)^4-6 and off-label agents (Table 2)^3,7-18 and provide recommendations for treating patients with AUD (Box 2).^19-21

FDA-approved treatments

Naltrexone is an opiate antagonist that blocks the mu receptor and is believed to interrupt the dopamine reward pathway in the brain for alcohol. A meta-analysis of 2,861 patients in 24 combined randomized controlled trials (RCTs) demonstrated naltrexone to be an effective short-term (12 weeks) treatment for alcoholism, significantly decreasing relapses.²² The large multisite COMBINE study (N = 1,383) showed that naltrexone, 100 mg/d, and medical treatment without behavioral treatment over 16 weeks was more effective than placebo in increasing percentage of days abstinent (80.6% vs 75.1%, respectively) and reducing the percentage of patients experiencing heavy drinking days (66.2% vs 73.1%, respectively).² Patients who have a family history of AUD or strong cravings, or both, may benefit most from naltrexone.^3,7,23 Despite evidence of the effectiveness of naltrexone for AUD, not all studies have yielded positive results.²⁴

Common side effects of naltrexone, if present, appear early in treatment and include GI upset (eg, nausea, vomiting, abdominal pain), headache, and fatigue.^2,3,22,23 Hepatotoxicity has been reported with dosages of 100 to 300 mg/d, but lab values typically normalize when naltrexone is discontinued.^2,3,23 Monitor markers of liver function including _ϒ-glutamyltransferase, aspartate aminotransferase, alanine aminotransferase, and bilirubin before and during naltrexone treatment (we check patients 1 to 3 months after starting treatment and yearly thereafter). Obtain a negative urine drug screen for opioids before administering naltrexone, because if opioids were consumed recently naltrexone could precipitate withdrawal. Because of the unknown teratogenicity of naltrexone, women of childbearing age should undergo pregnancy testing before and periodically during naltrexone therapy.

Naltrexone also is available in a once-monthly, 380-mg injectable formulation. Studies show that, similar to its oral counterpart, injectable naltrexone effectively reduces heavy drinking days and number of drinks a day compared with placebo.^25,26 Advantages of injectable naltrexone are its extended steady release of medication and its efficacy for patients who do not adhere to oral dosing.^7,27 Side effects are similar to oral naltrexone, except for injection site reactions and pain.

Contraindications to naltrexone include current opioid use because its antagonistic effects on opioid receptors render opioid analgesia ineffective. Patients who have used opioids within 7 to 10 days or who may be surreptitiously using opioids should not take naltrexone because it may cause opioid withdrawal. Some patients may try to override the opioid receptor blockade of naltrexone with higher opioid doses, which could result in overdose.

Naltrexone is approved for treating opioid use disorder and may be useful for persons with comorbid opioid use disorder and AUD, if the patient has been adequately detoxified from opioids and intends to abstain from these drugs. Patients who have extensive liver damage secondary to acute hepatitis or uncompensated cirrhosis would not be good candidates for naltrexone because of a risk of hepatotoxicity.^2,3,22

Because of ease of dosing, we recommend naltrexone as a first-line treatment for AUD, unless the patient requires opioids or has severe liver disease. We recommend increasing naltrexone from 50 mg to 100 mg before switching to acamprosate, based on European studies.

Acamprosate is a glutamate antagonist that is thought to modulate overactive glutamatergic brain activity that occurs after stopping chronic heavy alcohol use. In a meta-analysis of 17 studies (N = 4,087), continuous abstinence rates at 6 months were significantly higher in acamprosate-treated patients (36.1%) than in patients receiving placebo (23.4%).²⁸ In a review of European studies, acamprosate benefited patients who have increased anxiety, physiological dependence, negative family history of AUD, and late age of onset (age >25) of alcohol dependence.⁷ However, in the COMBINE trial acamprosate was no more effective than placebo.²