Medications to Treat Alcoholism

Medications To Treat Alcoholism Bankole A. Johnson, M.D., Ph.D., and Nassima Ait-Daoud, M.D. Advances in neurobiology support the development of medications to treat alcoholism by modifying the activity of specific chemical messengers (i.e., neurotransmitters) in the brain. Among the most promising new medications is acamprosate, which appears to decrease the intensity of craving after a person has stopped drinking. Naltrexone (ReVia™) has been shown to decrease alcohol consumption, although its practical effectiveness may be compromised by poor patient compliance and other factors. Ondansetron shows promise for decreasing drinking and increasing abstinence rates among early onset alcoholics, who respond poorly to psychosocial treatment alone. Researchers are investigating whether the use of specific medications in combination can further enhance their effectiveness. Additional research is needed to determine how medications interact with different psychosocial factors and treatments. KEY WORDS: drug therapy; AOD (alcohol and other drug) dependence; calcium acetylhomotaurinate; naltrexone; AOD craving; AOD abstinence; drug efficacy; antagonists; opioids; glutamate; serotonin; serotonin uptake inhibitors; dopamine; serotonin receptors; buspirone; combination drug therapy; patient compliance; literature review lthough psychosocial therapies persons may benefit from medications Opioid Antagonists help many alcohol-dependent designed to correct or ameliorate the A persons reduce alcohol con- biochemical abnormalities that pre- Opioid peptides are a class of neuro- sumption and maintain abstinence, 40 sumably underlie their susceptibility. transmitters that produce physiological to 70 percent of patients resume drink- This article reviews recent efforts to effects similar to those of morphine and ing within 1 year of such treatment develop medications to both reduce the (Swift 1999). Advances in neuroscience desire to drink and promote abstinence. research in the past decade suggest the Each section begins with a brief expla- BANKOLE A. JOHNSON, M.D., PH.D., is a possibility of developing medications nation of the probable role played by a professor of psychiatry and pharmacology to improve the efficacy of concurrent specific neurotransmitter system in the and deputy chairman for research and psychological or behavioral addiction development of addiction to alcohol NASSIMA AIT-DAOUD, M.D., is an instruc- therapies (Litten et al. 1996). These and other drugs (AODs). These neuro- tor at the University of Texas Health advances include research that impli- transmitter systems include opioids, Sciences Center, San Antonio, Texas. cates specific neurotransmitter systems glutamate, serotonin (5HT), and (see textbox, p. 100) in the development dopamine. Medications that affect the This research was supported by grants of addiction, suggesting that medica- function of these neurotransmitters to AA10522–05 and AA10522–0551 tions that modify the activity of these influence alcoholism are discussed, focus- from the National Institute on Alcohol systems may interfere with the developing on those medications that have Abuse and Alcoholism. The authors ment of alcoholism. In addition, some shown the most promise in clinical trials developed the 5HT3 hypothesis in collab- alcoholics may be biologically predis- on human subjects. Finally, the article oration with Martin Javors, Ph.D.; Julie posed to alcohol dependence. Those recommends areas for future research. Hensler, Ph.D.; and John Roache, Ph.D. Vol. 23, No. 2, 1999 99 heroin. In humans, opioid peptides modulate the effects of other neurotransmit- How Nerve Cells Communicate ters, thereby influencing a broad range of physiological functions (Froehlich 1997). All mental and bodily functions are integrated by orderly communication Alcohol consumption affects the pro- among nerve cells (i.e., neurons). The ends of adjacent neurons are generally duction, release, and activity of opioid separated from one another by microscopic gaps called synapses. Specialized peptides (Herz 1997). Opioid peptides chemicals called neurotransmitters carry messages across the synapse from appear to increase the rewarding effects the “sending” (i.e., presynaptic) area of one neuron to the “receiving” (i.e., of alcohol, nicotine, and opiates, con- postsynaptic) area of another neuron. The message is “received” when the tributing to the reinforcement of their neurotransmitter locks onto a binding site (i.e., receptor protein) on the post- use. Research suggests that this effect synaptic neuron. The binding of a neurotransmitter to its receptor causes a results from interaction with other neu- chemical change in the postsynaptic neuron, serving to stimulate, inhibit, or rotransmitter systems, particularly modulate a specific physiological function. A single neuron generally releases dopamine. For example, alcohol consump- either only one or a few types of neurotransmitters but may contain receptors tion by laboratory animals is reduced by that bind to several different neurotransmitters. Under normal circumstances, naltrexone (ReVia™) and naloxone, neurotransmitters released into synapses are quickly removed, either by antagonists of the mu receptor, one of chemical degradation or by the action of transporter molecules, which carry the major subtypes of opioid receptor in the neurotransmitters back into the presynaptic neuron. the brain (Froehlich 1997). These medications have been shown to block the alcohol-induced release of dopamine nounced increase in β-endorphin levels including both male and female alco- in the nucleus accumbens (Swift 1999). in response to alcohol administration holic subjects. An additional important Antagonists at the mu opioid receptor compared with persons who do not finding in this study was the interaction may also affect alcohol consumption have alcoholic relatives. Similarly, nal- between naltrexone use and the type of by suppressing general consummatory trexone’s propensity to reduce alcohol psychosocial therapy employed. The behaviors without altering motivational intake in humans is greater in persons cumulative rate of abstinence was high- or approach behaviors (for technical who have higher beta-endorphin levels est for patients who received naltrexone terms not defined in the text, see glos- (Gianoulakis et al. 1996). in conjunction with generalized sup- sary, pp. 100) (Boyle et al. 1998). In addi- The Food and Drug Administration portive psychotherapy. However, the tion, researchers (see Gianoulakis 1998) has approved naltrexone for the treatment combination of naltrexone and a more have proposed other mechanisms for of alcohol dependence based largely on intensive therapeutic program designed the effects of opioid peptides on alcohol evidence from two randomized, double- to teach specific coping skills was more consumption, including modulation of blind, placebo-controlled studies. In effective at preventing relapse among the body’s hormonal stress response. the first of these studies (Volpicelli et al. patients who sampled alcohol. Human laboratory studies exploring 1992), recently abstinent male patients Further research has demonstrated the effects of naltrexone on alcohol- undergoing psychosocial alcoholism that naltrexone-treated abstinent alco- induced mood and craving have pro- treatment who received 50 mg/day of holics report diminished craving for duced equivocal results (reviewed in naltrexone1 for 12 weeks reported less alcohol (O’Malley et al. 1996) and Litten and Allen 1998). One factor craving than subjects who received psy- those who sample alcohol after a period that may contribute to the discrepancy chosocial treatment alone. In addition, of abstinence experience less mood ele- among research results is a person’s the patients who received naltrexone vation from the alcoholic beverage than genetic susceptibility to alcoholism. maintained abstinence for longer peri- non-naltrexone-treated patients (Volpicelli In a recent study (King et al. 1997), ods and exhibited significantly reduced et al. 1995). Unfortunately, the protective nonalcoholic social drinkers (average relapse rates than the patients who did effects of naltrexone appear to dissipate consumption of two drinks per day) not receive naltrexone (i.e., only 23 over time; O’Malley and colleagues consumed an alcoholic beverage 3 to 4 percent of naltrexone-treated patients (1996) found no difference in abstinence hours after taking naltrexone. Compared compared with 54 percent of placebo- rates between naltrexone- and placebo- with subjects who did not have any treated patients experienced relapse). treated patient groups 5 months after alcoholic relatives, subjects with family Among patients who sampled alcohol naltrexone treatment was terminated. histories of alcoholism (i.e., high-risk while still in treatment, only 50 percent The major obstacle to the practical subjects) experienced less of alcohol’s of the naltrexone-treated patients clinical effectiveness of naltrexone appears stimulant effects but reported increased relapsed, compared with 95 percent to be poor patient compliance. In a 3- tension, fatigue, and confusion. of the patients who received a placebo month followup study, Volpicelli and Consistent with the above results, (Volpicelli et al. 1992). persons at genetically high risk for devel- O’Malley and colleagues (1992) β 1This is the standard dose of naltrexone (under the oping alcoholism have lower levels of - obtained comparable results in the sec- brand name Trexan®) used for

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