Medications for Alcohol Dependence Three medications are now FDA approved for treatment of

Medications for Alcohol Dependence Three medications are now FDA approved for treatment of

alcohol dependence: disulfiram, naltrexone, and acamprosate. Disulfiram binds irreversibly to aldehyde dehydrogenase, the enzyme that catalyzes the oxidation of acetaldehyde (a metabolite of alcohol) to acetic acid. It therefore changes the body’s response to alcohol. Ingestion of alcohol results in the accumulation of acetaldehyde, causing an extremely dysphoric experience of palpitations, hypotension, nausea and vomiting, and diaphoresis. This is self-limiting but it can produce substan- tial stress to the cardiovascular system, particularly with high doses both of alcohol and of disulfiram. This is generally not dangerous in young, healthy individuals, but could lead to

239 cardiovascular collapse and death in patients with significant

DRUGS FOR TREATING SUBSTANCE ABUSE DISORDERS

cardiovascular or renal disease. Disulfiram has also been asso- ciated with liver toxicity, and education of the patient about signs of liver failure and periodic monitoring of liver functions are advisable.

When the FDA approved disulfiram as a treatment for alcoholism, standards for efficacy studies were lower than they are today. The best evidence suggests that, although disulfiram is associated with a reduction in the number of drinking days in alcoholics who drink while taking it, compliance with medi- cation, not the effects of disulfiram, is probably important for

a better outcome. In the view of many clinicians, disulfiram may nonetheless provide an important disincentive to drink in well-motivated patients. There is evidence that using disulfiram as part of

a contract involving the spouse offers the prospect of good results: the alcoholic agrees to allow the spouse to witness disul- firam ingestion and the spouse agrees to refrain from comment on the alcoholic’s drinking. If disulfiram is taken regularly, it will prevent drinking, since even a small amount of intake will make the patient sick.

The usual dose of disulfiram is 250 mg/day; this maintains inhibition of acetaldehyde dehydrogenase while minimizing side effects such as lethargy. Some patients will report being able to drink without consequence on 250 mg per day. This may simply mean the patient is not actually taking the medication regularly, and should prompt gentle inquiry into compliance. However, some patients do need higher doses, up to 500 mg per day. In rare cases, drug-induced psychosis may occur due

is also a risk of interactions between disulfiram and medica- tions (e.g., tricyclic antidepressant and phenytoin levels are increased). Patients should be made aware that alcohol is a component of products other than beverages (e.g., shaving lotions). Significant inhibition of acetaldehyde dehydrogenase, and therefore the risk of reactions if alcohol is ingested, lasts for up to two weeks after stopping disulfiram.

It is believed that the reinforcing effects of alcohol may be mediated by endogenous opiate systems and this hypothesis underlies the use of naltrexone in alcohol relapse prevention.

240 HANDBOOK OF PSYCHIATRIC DRUGS

Naltrexone combined with structured psychosocial treatment has been associated with improvements in complete absti- nence, less craving for alcohol when the patient was abstinent, and less drinking once drinking began. Psychosocial treat- ments that have proven particularly effective in combination with naltrexone are those, such as cognitive behavioral relapse prevention, that emphasize coping skills for handling various sources of relapse risk. The recommended dose is 50 mg per day. This agent differs from disulfiram in that there is no added ill effect once drinking begins. It may limit the severity of binges and diminish preoccupation with alcohol in absti- nent alcoholics. Nausea has been a common side effect early in naltrexone treatment for alcoholism, but is generally mild and clears with continued use. Naltrexone can produce liver toxicity, which is dose dependent, has mainly been observed at much higher doses (200 or 300 mg per day), and resolves with dose reduction. Elevated liver enzymes, which do not resolve with dose reduction or discontinuation, represent another likely cause of hepatitis (e.g., viral, alcoholic).

Acamprosate has been approved for a number of years in Europe, and it recently received FDA approval. Its mecha- nism is not well understood but is thought to involve inter- ference with excitatory amino acid mechanisms that may be involved in relapse. Clinical trials have shown a modest effect in reducing relapse risk, and studies are underway to determine if it may have complementary effects to those of naltrexone and whether the combination of the two may increase effec- tiveness. Acamprosate is supplied in 333 mg tablets, and the recommended dosage is two tablets, three times daily. Blister packs, organized according to the daily schedule of dosing, can be helpful to patients in maintaining compliance. Acam- prosate is generally safe and well tolerated. Diarrhea is the most common side effect.

In the same way that any given antidepressant medica- tion will be helpful to some depressed patients but not others, naltrexone and acamprosate may similarly have little effect in some patients but work well in others. As of yet, there are no reliable predictors of which alcohol-dependent patient will benefit from these medications, but clinicians should be encouraged to attempt adequate trials (effective dose, for at

241 least a month) of these medications for patients with problem

DRUGS FOR TREATING SUBSTANCE ABUSE DISORDERS

drinking, and not be discouraged by the fact that some patients will not benefit.