Naltrexone and the Treatment of Alcohol Dependence.

Although current treatments for alcohol dependence(1) can safely and effectively help patients stop drinking alcohol, they are only modestly successful in reducing patients' tendencies to relapse, or return to excessive alcohol consumption. About one-half of all patients who complete an inpatient or residential psychosocial treatment program relapse within the first 3 months of treatment, causing this period of recovery to be critical for maintaining abstinence (Miller and Hester 1986; Nathan 1986). Because of the high relapse rates that occur early in recovery, considerable interest has developed in finding medications that help prevent a quick return to alcohol abuse. A longer period of abstinence is considered to increase eventual treatment success. The most commonly used and researched pharmacological agents include disulfiram; lithium; and those that increase activity of the serotonin system (i.e., the system that affects mood states), such as fluoxetine (Prozac(R)) (see the article by Anton, pp. 265-271). However, none of these compounds have been shown in studies to work better than placebo in a clinical population. A promising new approach to the problem of relapse is the use of opiate antagonists. These substances block specific portions of neurons in the brain--opiate receptors--that are stimulated by opioids,(2) such as morphine. Opiate receptors also are targets for alcohol's activity in the brain. Blocking the receptors seems to prevent many of the positive consequences of drinking alcohol, such as the alcohol "high," thereby decreasing the likelihood of excessive alcohol consumption. One opiate antagonist, naltrexone, appears to be a safe and effective adjunct for the early treatment of alcohol dependence. This article reviews research suggesting that opiate antagonists reduce excessive alcohol consumption in animal models and presents supporting data from two clinical samples of alcohol-dependent patients given the drug naltrexone. Finally, the article describes how naltrexone may work to reduce excessive drinking. EXPERIMENTAL BACKGROUND For one-quarter of a century, researchers have shown that alcohol consumption can alter the activity of opiate receptors (Cohen and Collins 1970; Davis and Walsh 1970). These receptors exist in the brain and normally are stimulated by naturally occurring substances (endogenous opioids) that are released by neurons in response to physical and emotional pain. Drugs, such as morphine, that mimic the effects of endogenous opioids also may stimulate opiate receptors. Other drugs, such as alcohol, may enhance opiate receptor activity indirectly, perhaps by stimulating the release of endogenous opioids. In support of this theory, animal studies have demonstrated important interactions between alcohol consumption and increases in opiate receptor activity. Specifically, alcohol consumption stimulates opiate receptor activity; is influenced by the use of opiates, such as morphine; and is reduced by opiate antagonists, such as naltrexone (figure 1).(Figure 1 omitted) Each of these findings is described below. Alcohol's Effects on Opiate Receptor Activity Several mechanisms by which alcohol may indirectly affect opiate receptor activity have been suggested, but the one presented here appears most important in understanding alcohol dependence. Accumulating evidence, including studies in humans, shows that alcohol stimulates the release of endogenous opioids, such as beta-endorphin, normally used by the body to mitigate pain, and other endorphins that produce pleasurable effects (see reviews by Gianoulakis 1993; Volpicelli et al. 1994). This release of endorphins may explain why some strains of rats and some people drink excessive amounts of alcohol. For example, rats bred to have a high preference for alcohol show enhanced beta-endorphin release when they consume alcohol compared with rats bred for a low preference for alcohol (deWaele et al. …