BENZODIAZEPINE TREATMENT FOR ALCOHOL-DEPENDENT PATIENTS

Alcohol & Alcoholism Vol. 33. No. 6. pp. 563-575, 1998 REVIEW BENZODIAZEPINE TREATMENT FOR ALCOHOL-DEPENDENT PATIENTS MICHEL LEJOYEUX*, JACQUELYN SOLOMON and JEAN ADES 1 Department of Psychiatry, Hopital Bichat. Claude Bernard, 75877 Paris Cedex 18 and 'Department of Psychiatry, Louis Mouner Hospital, Colombes, France (Received 16 June 1997; accepted 29 April 1998) Abstract — Benzodiazepines (BZDs) are the preferred pharmacological agents for treatment of acute alcohol withdrawal. Treatment with BZDs can be administered on an out-patient basis for subjects experiencing mild to moderate withdrawal and on an in-patient basis for the most severe forms of withdrawal. The efficacy of BZDs for long-term treatment of alcoholism has been more controversial Controlled studies indicate that BZD treatment does not improve abstinence rate. Most reviews of drug treatment of alcoholism conclude that routine use of BZDs is not indicated on a long-term basis. However, the clinical reality is that many alcoholics are treated by BZDs during detoxification and then continue to receive them for the treatment of anxiety disorders or insomnia, often secondary to alcohol dependence. After a review of the biological properties of BZDs related to their therapeutic issues, this review discusses the major indications for BZD treatment of alcoholism. BZDs are first prescribed to prevent and treat symptoms of alcohol withdrawal. Indication of BZD administration during alcohol withdrawal and criteria of choice of an agent according to its half-life or its route of administration are discussed. The different protocols of BZD treatment during withdrawal are considered (e.g. loading techniques, symptom-triggered therapy). The use of BZDs in the treatment of anxiety associated with alcohol dependence is examined. Among unwanted effects, risk of abuse, memory impairment, confusion, and delirium are described. Finally, practical guidelines for the use of BZDs in the treatment of alcoholism are proposed. INTRODUCTION Benzodiazepines (BZDs) are a group of chemical compounds that were first synthesized in the 1880s and shown to have tranquillizing actions in the 1950s (Nutt et al., 1989). In 1960, when chlordiazepoxide, the first BZD, was introduced in the United States (Ciraulo et al., 1988), several highly favourable reviews were published on its efficacy in treating the symptoms observed during alcohol detoxification. Despite the availability of other drugs (i.e. /?-blockers, clonidine), BZDs remain the preferred pharmacological agents for the treatment of acute alcohol withdrawal (Fuller and Gordis, 1994). Treatment with BZDs can be administered on an out-patient basis for subjects •Author to whom correspondence should be addressed. experiencing mild to moderate withdrawal and on an in-patient basis for the most severe forms of withdrawal. The majority of patients can be treated safely on an ambulatory basis (Shaw, 1995). The efficacy of BZDs for long-term treatment of alcoholism has been more controversial. The earlier studies were optimistic, but later controlled studies indicated that BZD treatment did not improve abstinence rate. Most reviews of drug treatment of alcoholism conclude that routine use of BZDs is not indicated on a long-term basis. However, the clinical reality is that many alcoholics are treated with BZDs during detoxification and then continue to receive them for the treatment of anxiety disorders or insomnia which are often secondary to alcohol dependence. General practitioners and psychiatrists are often in the position of evaluating the risks and benefits 563 © 1998 Medical Council on Alcoholism 564 M. LEJOYEUX et al. of BZD use in the post-withdrawal phase of treatment. The possible inherent danger of prescribing a potential drug of abuse to subjects with a history of abusing one substance should be considered in the light of yet other liabilities, e.g. not using an anxiolytic agent when it could be helpful, a potential increase in quality of life, and adherence to treatment. This review discusses both biological issues related to the effects of BZDs and their actions on withdrawal symptoms and on anxiety associated with alcohol abuse or dependence, and therapeutic issues concerning their indication in the treatment of alcohol withdrawal and in the long-term treatment of alcohol dependence. BIOLOGICAL ISSUES BZDs and ethanol share several biological modes of action. These similarities explain how and why ethanol antagonizes symptoms of withdrawal: by acting upon y-aminobutyric acid (GABA) receptors, noradrenergic systems, activation of the hypothalamic-pituitary-adrenal (HPA) axis, and kindling phenomenon (Table 1). Ethanol and BZDs also undergo pharmacokinetic interactions which influence their actions. The following are brief accounts of all these aspects. GABA Effects of ethanol. Ethanol acts, at least in part, at the BZD/GABA-chloride receptor complex (Tabakoff and Hoffman, 1992). Chronic ethanol administration increases the binding of [3H]Ro15-4513 (a partial inverse agonist of the BZD receptor) in the cerebral cortex and cerebellum of rats. Using polyclonal antibodies, Mhatre and Ticku (1993) have shown that chronic ethanol ingestion also produces a decrease in the expression of GABAA receptor subunit. This effect may underlie the molecular basis for alcohol tolerance and withdrawal. During alcohol withdrawal, the GABA receptor complex becomes acutely devoid of ethanol's enhancing effect on chloride flux, so there is a subsequent decrease in GABA functioning. The alcohol-withdrawal syndrome is characterized by reduced coupling of the GABAA BZD receptor to the chloride channel (Adinoff, 1994). As GABA is the major inhibitory neurotransmitter in the central nervous system (CNS), this reduction of coupling results in disinhibition. A reduction in GABAinduced chloride flux has been associated with seizures, anxiety, and anxiety-related symptoms such as tremors, diaphoresis, and tachycardia. Actions of BZDs. BZDs may ameliorate the symptoms of alcohol withdrawal by substituting the GABA-enhancing effects of ethanol. BZDs have been demonstrated to decrease the signs of ethanol withdrawal through the GABA/BZD receptor, in that diazepam's ameliorating effects on withdrawal-associated tremor in rats is antagonized by Ro-15-1788 (Nutt et al., 1989). BZDs also act through the increase in the affinity of GABA to the GABAA receptor. Noradrenergic activity Effects of ethanol. Acute ingestion of alcohol increases locus coeruleus activity. Locus coeruleus neurons are activated and noradrenaline activity is increased (Valentino and Aston-Jones, 1995). Lactate infusion, which stimulates the Table 1. Biological effects of benzodiazepines (BZDs) Effect of ethanol GABA Acute ingestion stimulates GABA activity Withdrawal decreases GABA functioning Noradrenaline Overactivity during alcohol ingestion and withdrawal Stimulation during withdrawal Increase in corticosteroid levels Re (...truncated)