Benzodiazepine Treatment of the Ethanol Withdrawal Syndrome

2015

The objective of drug treatment in ethanol withdrawal is the relief of subjective symptoms, the prevention or treatment of more serious complications such as seizures or delirium tremens, and the preparation for long-term rehabilitation with minimal hazard of new dependence problems or direct toxicity related to drug treatment. The ideal drug for alcohol withdrawal should have a rapid onset and long duration of action, wide margin of safety, metabolism not dependent on liver function, and absence of abuse potential. The various benzodiazepines offer many of these advantages; the selection of the most appropriate benzodiazepine will depend on the clinical situation.

Withdrawal severity can be quickly and reliably determined upon admission by measuring breath alcohol concentration and administering an objective rating scale, such as the CIWA-A (Clinical Institute Withdrawal Assessment of Alcohol). Patients in mild ethanol withdrawal (CIWA-A<20) and without a prior history of withdrawal seizures can generally be treated conservatively (fluids, multivitamins, reassurance, antacids, thiamine). Treatment without medication offers the patient an opportunity to exercise nonpharmacological control over his or her life as well as to avoid adverse effects, such as acute memory impairment, which frequently accompany the administration of benzodiazepines and may interfere with the rehabilitation process.

Alcoholics with a moderate to severe withdrawal syndrome (CIWA-A > 20), demonstrating signs and symptoms such as autonomic hyperactivity, psychological distress, and perceptual distortions, generally require pharmacotherapy. Since the introduction of chloral hydrate and paraldehyde in 1880 for the treatment of alcohol withdrawal, the use of over 150 different drugs and drug combinations has been described in the literature for this indication.

Several controlled studies have demonstrated the efficacy of benzodiazepines in the treatment of alcohol withdrawal, including the prevention and treatment of withdrawal seizures and delirium tremens. Other drugs used in the treatment of ethanol withdrawal, such as beta Mockers, chlormethiazole, chloral hydrate, bromocriptine, antihistamines, phenothiazines, paraldehyde, magnesium, and ethanol, are either less efficacious or less safe than benzodiazepines. Although medications such as carbamazepine and clonidine may be as effective and well tolerated as the benzodiazepines, this review is limited to the treatment of ethanol withdrawal with benzodiazepines.

Patients in moderate withdrawal (CIWA-A 20-25) frequently require only minimal pharmacological intervention. Diazepam 10 mg every 6 hr p.o. p.r.n. or chlordiazepoxide 25 mg p.o. p.r.n. may be administered until either symptoms increase in severity (CIWA-A >25), at which time a loading dose strategy should be instituted (see below), or the withdrawal symptoms begin to decrease (CIWA-A < 15).

A safe and effective treatment of patients in severe alcohol withdrawal (CIWA-A >25) is the diazepam-loading procedure. In this paradigm, 10 mg of diazepam p.o. is administered to the patient every hour until symptoms are suppressed (CIWA-A < 10) or the patient becomes sedated. Diazepam is the benzodiazepine of choice as it has a wide margin of safety and is quickly absorbed when administered p.o. The subsequent rapid distribution of diazepam to the brain allows for the patient to be evaluated for signs of toxicity prior to the next dose. Coexisting illnesses should be considered if withdrawal is not sufficiently reduced after six doses. The reemergence of symptoms should be treated with 20 mg diazepam every 6 hr p.r.n.

The effects of diazepam and its metabolite, desmethyldiazepam, persist for relatively long periods of time. (The half-lives of diazepam and desmethyldiazepam are 33 and 90 hr on the average, respectively.) This permits a withdrawal relatively free of cyclical variations, from drug-induced “highs” to re-emergence of withdrawal symtpoms. The prolonged effect also tends to eliminate the need for additional doses following the initial dose. In addition to the rapid amelioration of withdrawal symptoms, this treatment strategy therefore tends also to decrease the drug-seeking behavior frequently observed in withdrawing alcoholics.

Diazepam may also be administered intravenously or intramuscularly in nauseated patients. Intramuscular absorption is faster and more complete from the deltoid than the gluteal or vastus lateralis muscles.

A similar regimen as described for diazepam can be followed using 25 mg chlordiazepoxide instead of 10 mg diazepam. Although chlordiazepoxide is less preferable due to its slower absorption and distribution, it has a duration of action and metabolic pathways roughly similar to those of diazepam. As both diazepam and chlordiazepoxide undergo oxidation by the liver, there is a two-to threefold decrease in clearance in patients with alcoholic cirrhotic liver disease. Other benzodiazepines not significantly oxidized by the liver, such as oxazepam and lorazepam, should therefore be considered in these patients. Oxazepam and lorazepam should be administered every 6 hr (oxazepam 15-60 mg, lorazepam 1-3 mg), as they both have shorter half-lives (8 and 10 hr, respectively) than diazepam and chlordiazepoxide. Tapering of either lorazepam or oxazepam should begin on the second day. Tapering should be accomplished by decreasing the dose, not by increasing the interval between doses. Other benzodiazepines, such as halazepam and clobazam, have been reported to be therapeutically equivalent to chlordiazepoxide in the treatment of ethanol withdrawal.

The benzodiazepines produce similar side-effects. Memory impairment is common and may hamper efforts toward rehabilitation during the first several days of hospitalization. Several studies in normal volunteers have reported that lorazepam produces more prolonged impairment of cognitive-psychomotor performance than other benzodiazepines, indicative of a relative lack of acute tolerance to these effects of lorazepam. Minor cardiovascular and respiratory depression may occur with high doses of benzodiazepines, although this is unusual when benzodiazepines are administered alone. In combination with ethanol, however, benzodiazepines have an additive effect, possibly due to an interaction with ethanol at the GABA/ benzodiazepine receptor. The patient requiring treatment for ethanol withdrawal prior to the BAC reaching zero should therefore be administered benzodiazepines with caution. Symptoms of ethanol intoxication such as drowsiness, lethargy, ataxia, diplopia, and confusion are also similar to the symptoms observed following benzodiazepine overdose. It is therefore important to determine the proper etiology of any disturbance in CNS functioning. Inhibition of the gag reflex has also been reported following diazepam administration, increasing the risk of aspiration in nauseated patients who are administered the drug.

The benzodiazepines are themselves potential substances of abuse (see below). Deutsch and Watson have reported that rats treated with diazepam during ethanol withdrawal demonstrate a higher intake of ethanol in a subsequent free-choice situation than rats treated with placebo. Although an analogous phenomenon has not been reported clinically, this study suggests that the ethanol withdrawal syndrome should be treated with nonpharmacological methods when appropriate. It is possible, however, that the experience of withdrawal that is unmodified by pharmacological agents could also aggravate the subsequent course of the illness ().

 

Selections from the book: “Recent Developments in Alcoholism. Volume 7. Treatment Research: Alcoholics Anonymous. The Family. Serotonin and Preference. Clinical Pharmacology.” Edited by Marc Galanter. An Official Publication of the American Medical Society on Alcoholism, the Research Society on Alcoholism, and the National Council on Alcoholism. 1989.