Therapeutic Modalities: Pharmacological - Alcohol Use Disorders

Therapeutic Modalities: Pharmacological

Although the benzodiazepines have played a key role in the treatment of alcohol withdrawal, pharmacotherapy has not yet had a demonstrable effect on other aspects of alcoholism treat-ment. Disulfiram, an alcohol-sensitizing drug, has been ap-proved for clinical use in the USA since the 1940s, but it has not been widely prescribed. During the past decade, however, medications have begun to play a more important role both in the treatment of comorbid psychiatric disorders in alcoholics and in the rehabilitation of alcohol dependence. In dually diagnosed patients, medications that reduce psychiatric symptomatology may also reduce the risk of drinking. Independent of their effects on comorbid psychopathology, medications that reduce drinking may enhance the alcoholic’s participation in psychosocial treat-ment. This rationale is similar to that underlying the combination of medications with psychotherapy in the treatment of depressive or anxiety disorders.

Alcohol-sensitizing Drugs

Medications such as disulfiram or calcium carbimide cause an unpleasant reaction when combined with alcohol. The efficacy of such drugs in the prevention or limitation of relapse in alcoholics has not been demonstrated. However, these drugs may be of util-ity in selected samples of alcoholics with whom special efforts are made to ensure compliance.

Disulfiram (Antabuse) is the most commonly used alco-hol-sensitizing medication and the only one approved for use in the USA. When given in a single daily dose of 125 to 500 mg, disulfiram binds irreversibly to ALDH, permanently inactivat-ing this enzyme. When alcohol is consumed, it is metabolized to acetaldehyde which accumulates due to inhibition of the enzyme that metabolizes it. Elevated levels of acetaldehyde are responsi-ble for the aversive effects associated with the disulfiram-ethanol reaction (DER).

In addition to its effects on ALDH, disulfiram inhibits a variety of other enzymes. Disulfiram also reduces clearance rates of a number of medications. Common side effects of di-sulfiram include drowsiness, lethargy and fatigue. More seri-ous adverse effects, such as optic neuritis, peripheral neuropa-thy and hepatotoxicity are rare. The exacerbation of psychotic symptoms in patients with schizophrenia, and occasionally their appearance in other individuals as well as the development of depression, may be linked to inhibition of the enzyme dopamine-beta-hydroxylase. As with its neuropathic effects, the psychiatric effects of disulfiram are uncommon and may only occur at higher dosages of the medication.

Disulfiram is usually given orally. Although the daily dos-age prescribed in the USA has been limited to 250–500 mg/day, some patients require in excess of 1 g/day of disulfiram to reach blood levels sufficient to produce the DER. The requirement that disulfiram undergo bioactivation before it can inhibit ALDH may explain the need for a higher dosage in some patients. At the dos-age that is used clinically, faulty bioactivation in some individu-als may yield too low a concentration of the active metabolite to inhibit ALDH.

Given the limited efficacy of disulfiram for the preven-tion of relapse, it should not be used as a first line treatment for alcohol dependence. However, if a patient has not responded to other pharmacological treatments and is motivated to take disulfiram, it may be beneficial. Whenever disulfiram is prescribed patients should be warned about its hazards, includ-ing the need to avoid over-the-counter (OTC) preparations with alcohol and drugs that interact adversely with disulfiram, as well as the potential for a DER to result from alcohol used in food preparations.