Pharmacologic Management of Alcohol Dependence

Krina H. Patel, PharmD

Disclosures

US Pharmacist. 2009;34(11):1-4. 

In This Article

Pharmacologic Therapy

The ultimate goals for patients with alcohol dependence are to achieve abstinence and prevent relapse. Currently, the four pharmacologic agents that may aid in accomplishing these goals are disulfiram, oral naltrexone, injectable extended-release naltrexone, and acamprosate.

Disulfiram

Disulfiram is an aversion-based treatment that acts by blocking aldehyde dehydrogenase (ALDH). This results in an increase in acetaldehyde levels when alcohol is consumed and induces negative effects such as dizziness, flushing, nausea, vomiting, hypotension, arrhythmia, convulsions, respiratory depression, and myocardial infarction.[4–6] The effects of this drug are sufficiently unpleasant to the patient to serve as a deterrent to consuming alcohol.

Disulfiram in the absence of alcohol tends to cause minimal effects; however, drowsiness, metallic aftertaste, and hepatotoxicity may occur.[5] Severe cardiovascular disease and concurrent use of metronidazole are two major contraindications associated with disulfiram.[5] It is important not to administer disulfiram until the patient has abstained from alcohol for at least 12 hours. Furthermore, since disulfiram irreversibly inhibits ALDH, alcohol consumption must be avoided for 2 weeks after the last dose.[5]

There is a substantial amount of literature regarding the use of disulfiram for alcohol dependence, but many of these trials have significant methodologic weaknesses.[6,7] Some of the data are inconsistent and may be conflicting.[4,6] A Veterans Administration Cooperative Study assessed 605 subjects assigned to disulfiram 250 mg, disulfiram 1 mg, or placebo.[8] This study, conducted over 1 year, concluded that there were no significant between-group differences in abstinence rates or time to first drink. The study did find, however, that patients receiving disulfiram 250 mg who ended up drinking reported fewer drinking days compared with the other two groups.[8]

Disulfiram is still utilized despite the conflicting data. Disulfiram's unique mechanism of action may be a powerful advantage for patients. Disulfiram may help with drinking outcomes such as reduced drinking days or frequency; however, other outcomes, such as time to first drink, abstinence, and alcohol consumption per unit of time, lack consistent evidence.[4,6] Although not appropriate for all patients, disulfiram has a place in therapy for individuals seeking help with cessation of heavy drinking.

Naltrexone

Naltrexone is a competitive opioid receptor antagonist. Endogenous opioids are released in response to alcohol intake, thereby causing alcohol's acute rewarding properties. Naltrexone's mechanism of action reduces cravings and also is likely to minimize the "high" that individuals experience with alcohol intake, which may result in lower alcohol consumption.[7,9–12]

Naltrexone's adverse-effect profile tends to be mild, but gastrointestinal side effects, headache, dizziness, anxiety, and decreased appetite may occur.[5] Rarely, naltrexone may cause dose-related hepatotoxicity, so frequent monitoring is recommended. Owing to naltrexone's mechanism of action, current opiate treatment may induce withdrawal symptoms, so patients should be opioid-free for at least 7 to 10 days before naltrexone is initiated.[5]

Several studies have concluded that naltrexone is an effective treatment option for alcohol dependence. In a 12-week, double-blind, placebo-controlled trial, 70 male patients were treated with naltrexone or placebo.[9] Patients who received naltrexone experienced fewer cravings and consumed less alcohol. The percentage of patients who relapsed was significantly less in the naltrexone group compared with the placebo group (54% vs. 23%). Additionally, 95% of placebo patients who sampled alcohol relapsed, versus 50% of naltrexone patients.[9] Another trial established that naltrexone was superior to placebo when outcomes such as number of drinking days, abstinence rates, relapse rates, and severity of alcohol-related problems were compared.[12] This study found that abstinence rates were higher in the naltrexone group versus the placebo group (61% vs. 19%).[12]

There are also some less compelling data regarding naltrexone. One trial evaluated the use of naltrexone for 3 months or 12 months in 627 veterans.[13] Naltrexone was not significantly better than placebo in decreasing percentage of drinking days or drinks per day, and it did not improve days to relapse. The trial concluded that the use of naltrexone in this population base was not supported.[13]

Overall, naltrexone is an effective treatment option for patients with alcohol dependence. Based on the literature, naltrexone can help improve outcomes by lessening cravings, decreasing heavy alcohol consumption, decreasing relapse, and potentially enhancing abstinence rates.[7,9–12]

Intramuscular (IM) Naltrexone

In 2006, the FDA approved a long-acting IM formulation of naltrexone. Previous trials of naltrexone suggested that nonadherence to treatment may be a concern, resulting in decreased effectiveness and suboptimal treatment outcomes.[10,14] Use of the IM formulation may help overcome problems with adherence. One concern regarding this formulation is the potential for injection-site reactions such as cellulitis, hematoma, and necrosis.[5]

Several trials support positive outcomes associated with the use of IM naltrexone. In one multicenter, randomized, placebo-controlled trial, 315 patients received either IM naltrexone or placebo.[15] The trial, conducted over 3 months, found that IM naltrexone significantly improved abstinence rates compared with placebo (18% vs. 10%), and also prolonged the time to first drinking day.[15] Overall, IM naltrexone appears to be a safe and effective treatment option that may be especially beneficial for patients who have adherence problems.[16]

Acamprosate

In 2004, acamprosate became available in the U.S. for the treatment of alcohol dependence. It is hypothesized that acamprosate restores GABA and glutamate imbalances caused by alcohol intake.[5,11] It also is proposed that acamprosate has some effects on the N-methyl-D-aspartic acid receptor.[11]

Some common adverse effects associated with acamprosate are diarrhea, headache, insomnia, anxiety, and muscle weakness.[5] Patients treated with acamprosate should try their best to avoid alcohol; however, alcohol intake does not affect the pharmacokinetics of acamprosate, and therefore no disulfiram-type reaction will occur.[5] In addition, acamprosate may be a safer option than disulfiram or naltrexone in patients with hepatic impairment. The drug should be used with caution in patients with renal impairment, however.[5]

Currently, there is insufficient U.S. literature strongly evidencing the effectiveness of acamprosate, although an adequate amount of European literature supports its use.[17–20] The COMBINE study, conducted in the U.S., concluded that acamprosate failed to show evidence of efficacy with regard to time to first heavy drink or abstinent days.[17] In another U.S.-based double-blind, placebo-controlled study, patients received acamprosate 2 g, acamprosate 3 g, or placebo.[18] This study found that percentage of abstinent days did not differ among treatment groups; however, a post-hoc analysis that controlled baseline covariates and measured highly motivated patients as a subset found that acamprosate yielded a greater number of abstinent days than placebo.[18]

A European meta-analysis of 20 trials suggested that continuous abstinence rates at 6 months were significantly higher for acamprosate-treated patients versus patients given placebo (36.1% vs. 23.4%).[19] Data also indicate that acamprosate confers improved abstinence rates for up to 48 weeks.[20]

It is not clear why outcomes associated with acamprosate are inconsistent between the U.S. and European studies. Certain factors, such as the severity of the alcohol dependence, may be potential reasons.[4] Based on the literature, acamprosate is associated with an improved rate of complete abstinence and may have other positive outcomes, such as decreased drinking frequency and rate of relapse.[7,18–20] The drug appears to be a logical option given the evidence of lasting effects and improved drinking outcomes.[20]

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