US Pharm. 2009;34(11):60-65.
Alcohol dependence is a serious health concern that is associated with many long-term consequences. Alcohol dependence not only affects an individual's physical health, but also may impact mental health and social well-being. Alcohol use is common in the American population. According to the 2008 National Survey on Drug Use and Health, more than 50% of Americans aged 12 and older reported drinking, 23% reported binge drinking, and 6.9% were heavy alcohol drinkers.1 The prevalence rate of alcohol abuse or dependence in the United States is estimated at 5% to 14%.1-3
Alcohol dependence is a chronic disorder that may require maintenance treatment, similar to other medical conditions such as hyperlipidemia and diabetes.4 It is believed that multiple neurotransmitters such as endogenous opioids, dopamine, serotonin, gamma-aminobutyric acid (GABA), and glutamate may be either directly or indirectly affected by alcohol.4 Risk factors such as genetics, environmental factors, and cultural attitudes may play a significant role in the development of alcohol dependence.2
The intent of this article is to review the pharmacologic management of alcohol dependence; therefore alcohol withdrawal, although a crucial part of treatment, will not be discussed.
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
Combination Treatment
It has been proposed that combination therapy may result in improved efficacy compared with monotherapy.17,21,22 Owing to their different mechanisms of action, it may be theoretically appropriate to combine these agents for added benefit. Based on the literature, the combination of disulfiram and naltrexone appears to offer no additional benefits over treatment with either medication alone.23 Studies examining the combination of disulfiram and acamprosate indicate that this combination may result in improved efficacy, but there is not much literature regarding concomitant use of these drugs.21
The bulk of the literature centers on the combination of naltrexone and acamprosate. The COMBINE trial concluded that the concomitant use of these two medications appeared to be safe and well tolerated, but provided no additional therapeutic benefit versus naltrexone alone.17 In another trial, 160 patients were randomized to receive acamprosate, naltrexone, naltrexone plus acamprosate, or placebo.22 The combination group had significantly lower relapse rates compared with the placebo group and the acamprosate group, but the combination was not more effective than naltrexone only.22
Overall, the combination of naltrexone and acamprosate appears to be safe and well tolerated, but there may be an increase in certain adverse effects, such as diarrhea and nausea.22 The combination seems to provide some benefit compared with acamprosate alone. Combination therapy may be a valid option for some patients who are not responding to monotherapy. Further research is needed to clarify the utility of combination therapy in the treatment of alcohol dependence.
Off-Label and Investigational Treatments
Recently there has been a growing interest in exploring other potential treatments for alcohol dependence. Most new research focuses on agents that are proposed to target neurotransmitters that are affected by alcohol. These different classes of medications have been used off-label in the hope that some new agents may provide promising treatments in the future.
Topiramate, oxcarbazepine, lithium, carbamazepine, gabapentin, and divalproex are some of the mood stabilizers and anticonvulsants that have been evaluated for the treatment of alcohol dependence.4,6,10 It is believed that some anticonvulsants, such as topiramate, are responsible for enhancing GABA activity and antagonizing glutamate activity, which may lead to decreased alcohol consumption.4,10,24 Topiramate appears to be the best studied of the anticonvulsants thus far. Several randomized, controlled trials of topiramate have reported positive drinking outcomes (such as decreased heavy drinking days and drinks per day) and increased abstinent days compared with placebo.10,24,25 One trial found that patients treated with topiramate achieved 26% more abstinent days than patients given placebo.24 Topiramate appears to hold promise as a treatment for alcohol dependence.
Most of the other abovementioned drugs, such as oxcarbazepine and divalproex, do not have conclusive data concerning their utility in treating alcohol dependence, and further research is needed.10 Lithium currently does not have supportive evidence as a treatment for alcohol dependence.7
Serotonergic agents constitute another medication class that has been researched for its value in treating alcohol dependence. It is theorized that serotonin plays a role in alcohol consumption.4,26 Literature exists concerning the use of selective serotonin reuptake inhibitors (SSRIs) for the treatment of alcohol dependence; however, results are inconsistent and do not support the use of SSRIs to treat alcohol dependence as a primary condition.4,6,7,26 It is thought that SSRIs may improve psychiatric illness, which may have an effect on drinking behavior.27 Ondansetron has been associated with positive drinking outcomes such as fewer drinks per day, fewer drinks per drinking day, more abstinent days, and more abstinent days per week.6
Dopamine antagonists may be involved in the treatment of alcohol dependence. Olanzapine has exhibited some positive outcomes.10 Other agents, such as baclofen and galantamine, also have been researched, but data regarding their use are either mixed or negative.10
Currently, there are only a few options available for the treatment of alcohol dependence. The agents mentioned above may hold some promise for the future, but more research is needed. Many of the current trials of these agents are methodologically weak or have inconclusive findings. For those reasons, further investigation is needed before these agents can be recommended or used for the treatment of alcohol dependence. There is a great need for the discovery of new potential options to treat alcohol dependence.
Conclusion
Alcohol dependence is a chronic disorder that has many consequences. Optimal treatment with pharmacologic agents may help achieve desired outcomes. The currently available treatments for alcohol dependence are all valid options, and their use should be individualized. Pharmacists can optimize treatment by recommending agents based on the expected outcomes associated with each medication. Pharmacists also can provide care by educating patients regarding expected outcomes, adverse effects, and precautions associated with the pharmacologic agents.
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