TREATMENT OF ALCOHOLISM
After detoxification, psychosocial therapy either in intensive inpa-tient or in outpatient rehabilitation programs serves as the primary treatment for alcohol dependence. Other psychiatric problems, most commonly depressive or anxiety disorders, often coexist with alcoholism and, if untreated, can contribute to the tendency of detoxified alcoholics to relapse. Treatment for these associated disorders with counseling and drugs can help decrease the rate of relapse for alcoholic patients.
Three drugs—disulfiram, naltrexone, and acamprosate—have FDA approval for adjunctive treatment of alcohol dependence.
Naltrexone, a relatively long-acting opioid antagonist, blocks the effects at μ opioid receptors . Studies in experi-mental animals first suggested a link between alcohol consump-tion and opioids. Injection of small amounts of opioids was followed by an increase in alcohol drinking, whereas adminis-tration of opioid antagonists inhibited self-administration of alcohol.Naltrexone, both alone and in combination with behavioral counseling, has been shown in a number of short-term (12- to 16-week) placebo-controlled trials to reduce the rate of relapse to either drinking or alcohol dependence and to reduce craving for alcohol, especially in patients with high rates of naltrexone adher-ence. Naltrexone was approved in 1994 by the FDA for treatment of alcohol dependence.Naltrexone is generally taken once a day in an oral dose of 50 mg for treatment of alcoholism. An extended-release formula-tion administered as an IM injection once every 4 weeks is also effective. The drug can cause dose-dependent hepatotoxicity and should be used with caution in patients with evidence of mild abnormalities in serum aminotransferase activity. The combina-tion of naltrexone plus disulfiram should be avoided, since both drugs are potential hepatotoxins. Administration of naltrexone to patients who are physically dependent on opioids precipitates an acute withdrawal syndrome, so patients must be opioid-free before initiating naltrexone therapy. Naltrexone also blocks the therapeu-tic analgesic effects of usual doses of opioids.
Acamprosate has been used in Europe for a number of years to treat alcohol dependence and was approved for this use by the FDA in 2004. Like ethanol, acamprosate has many molecular effects including actions on GABA, glutamate, serotonergic, noradrenergic, and dopaminergic receptors. Probably its best-characterized actions are as a weak NMDA-receptor antagonist and a GABAA-receptor activator. In European clinical trials, acam-prosate reduced short-term and long-term (more than 6 months) relapse rates when combined with psychotherapy. In a large American trial that compared acamprosate with naltrexone and with combined acamprosate and naltrexone therapy (the COMBINE study), acamprosate did not show a statistically sig-nificant effect alone or in combination with naltrexone.
Acamprosate is administered as 1–2 enteric-coated 333 mg tablets three times daily. It is poorly absorbed, and food reduces its absorption even further. Acamprosate is widely distributed and is eliminated renally. It does not appear to participate in drug-drug interactions. The most common adverse effects are gastrointestinal (nausea, vomiting, diarrhea) and rash. It should not be used in patients with severe renal impairment.
Disulfiram causes extreme discomfort in patients who drink alco-holic beverages. Disulfiram alone has little effect; however, flush-ing, throbbing headache, nausea, vomiting, sweating, hypotension, and confusion occur within a few minutes after an individual tak-ing disulfiram drinks alcohol. The effects may last 30 minutes in mild cases or several hours in severe ones. Disulfiram acts by inhibiting aldehyde dehydrogenase. Thus, alcohol is metabolized as usual, but acetaldehyde accumulates.
Disulfiram is rapidly and completely absorbed from the gastro-intestinal tract; however, a period of 12 hours is required for its full action. Its elimination rate is slow, so that its action may persist for several days after the last dose. The drug inhibits the metabolismof many other therapeutic agents, including phenytoin, oral anti-coagulants, and isoniazid. It should not be administered with medications that contain alcohol, including nonprescription medications such as those listed in Table 63–3. Disulfiram can cause small increases in liver function tests. Its safety in pregnancy has not been demonstrated.
Because adherence to disulfiram therapy is low and because the evidence from clinical trials for its effectiveness is weak, disulfiram is no longer commonly used.
Several other drugs have shown efficacy in maintaining abstinence and reducing craving in chronic alcoholism, although none has FDA approval yet for this use. Such drugs include ondansetron, a serotonin 5-HT3-receptor antagonist; topi-ramate, a drug used for partial and generalized tonic-clonic sei-zures ; and baclofen, a GABA B receptor antagonist used as a spasmolytic . Based on evidence from model systems, efforts are underway to explore agents that modu-late cannabinoid CB1 receptors, corticotropin-releasing factor receptors, and GABA receptor systems, as well as several other possible targets. Rimonabant, a CB1 receptor antagonist, has been shown to suppress alcohol-related behaviors in animal models and is being tested in clinical trials of alcoholism.