Treatment of Alcohol Dependence With Medications Treatment of Alcohol Dependence With Medications In recent years, the development of new medica- on alcohol. One such medication, acamprosate, tions to treat alcohol dependence, representing holds promise in reducing the return to drink- the combined efforts of neuroscientists and ing, following a brief period of abstinence, clinical researchers, has begun a new era in that typifies alcohol dependence. Moreover, alcoholism treatment. Until 1995, the only investigators are examining the possibility that medical treatment approved for use in the United combining a medication that reduces the risk States (disulfiram) simply provoked intense of relapse (such as acamprosate) with one that physical symptoms such as vomiting upon the reduces the risk of heavy drinking should relapse ingestion of alcohol. In contrast, newer drugs for occur (such as an opiate antagonist) may increase alcoholism treatment operate at the molecular treatment effectiveness. level of the brain processes that promote and maintain addiction. The targeted actions of these Pharmacology research has focused not only newer drugs offer the possibility of more effective on drugs to treat alcoholism itself, but also on treatment options for the millions of alcohol- medications for coexisting conditions that can dependent persons in our Nation. threaten recovery. Current research continues to show that antidepressants, both old and new, are Over the past decade, advances in knowledge of powerful agents for helping persons with alcohol the biology underlying drinking behavior have dependence who also suffer from depression to laid the groundwork for new pharmacologic gain and maintain abstinence from alcohol. treatments for alcohol dependence. For example, Patients with untreated depression often relapse it is now known that multiple chemical messenger to drinking, whereas those who take antidepres- systems in the brain, called neurotransmitter sants generally participate more in treatment systems, are involved in problem drinking. programs and respond better. Recent studies Several medications that affect different neuro- in this area have strengthened the findings of transmitter systems have been tested in humans. previous research by using larger, more diverse patient samples and new types of antidepressants. In particular, one area of research has focused on a class of medications called “opiate antagonists.” Medications hold great promise but at present These medications interfere with neurotransmitter cannot replace psychological treatments for systems that produce pleasurable effects, such as people with alcohol dependence. These two feelings of euphoria, upon the use of alcohol and classes of treatment strategies are complementary other drugs. If patients resume drinking while rather than competitive, in that studies suggest taking opiate antagonists, they are not rewarded that pharmacologic agents may be combined with the expected “high” from the alcohol. Two effectively with skilled counseling to improve of these drugs, naltrexone and nalmefene, have treatment outcomes (O’Malley et al. 1992, 1996). shown promising results for treating alcohol This section focuses on recent advances in dependence. In 1995 naltrexone (ReVia) was pharmacotherapy research in two main areas: approved by the U.S. Food and Drug Admin- (1) medications specifically used to treat alcohol istration (FDA) for treating alcohol dependence, dependence, and (2) medications to treat some while nalmefene is in the testing phase of patients who suffer not only from alcohol development. dependence but also from psychiatric disorders, primarily depression. (For an update on research In addition, researchers are evaluating medica- on psychological treatments, see the previous tions that target different neurotransmitter section “Treatment of Alcohol Dependence systems involved in maintaining dependence With Psychological Approaches” in this chapter.) 451 Chapter 8: Treatment Research Medications for Alcohol Dependence Naltrexone. Studies in humans also support the hypothesis that opiate antagonists reduce the In 1992, alcohol researchers proposed the pleasurable effects associated with alcohol’s attributes of a “perfect medication” for treating stimulation of the endogenous opioid system and alcohol dependence (Volpicelli et al. 1992). The related reward systems. Patients given naltrexone drug they were seeking would reduce the craving described less euphoria, or “high,” from drinking for alcohol so that an individual would be less than did patients taking a placebo (Volpicelli et motivated to drink. The ideal drug also would al. 1995b). Similarly, social drinkers given block the reinforcing effects of alcohol so that if naltrexone in a laboratory told researchers they the individual resumed drinking, pleasant effects felt fewer stimulant effects of alcohol and more would not be felt. In addition, the medication of its sluggish, sedative effects (Swift 1995; Swift would have few, if any, side effects. With these et al. 1994). Thus, by reducing the positive goals in mind, researchers have made significant reinforcement of drinking and increasing un- progress in recent years. pleasant effects, naltrexone may help abstinent individuals who relapse to refrain from heavy Blocking the Reward: Opiate Antagonists drinking. The treatment of alcohol dependence has In another study, social drinkers who were benefited from decades of research that have pretreated with naltrexone waited longer to have led to an understanding of the mechanics of both their first and their second drinks (Davidson addiction and of the way in which certain et al. 1996b). This finding suggests that opiate medications can counter the effects of addictive antagonists block both the chemical changes in drugs. Substances like heroin and morphine, the brain elicited by environmental cues before called opiates, act like chemicals the brain drinking and the “priming” effects of alcohol produces naturally, called endogenous opioids, during drinking—phenomena associated with the which stimulate pleasurable feelings and suppress urge to drink and loss of control over drinking. pain. Medications known as opiate antagonists Researchers who reexamined data (O’Malley et bind with the brain’s receptors for endogenous al. 1995) from two previous clinical trials of opioids, thus blocking the desired effects of naltrexone (O’Malley et al. 1992; Volpicelli et al. heroin and similar drugs while having no effect 1992) found that patients with alcoholism who themselves. took naltrexone and who ultimately returned to drinking refrained a longer time until their first Alcohol is not an opiate-like substance, and drink and their first episode of heavy drinking researchers do not know the exact mechanism by than did patients who took a placebo. Among which opiate antagonists affect drinking. Animal the patients in the study who drank, those studies suggest, however, that these medications using naltrexone drank less frequently and on block some of alcohol’s rewarding effects. When a significantly smaller percentage of days than researchers administered an opiate antagonist did placebo-treated patients, and they were less (naltrexone) to rats that were later given alcohol, likely to relapse to heavy drinking. the medication decreased the amount of alcohol- induced dopamine, a neurotransmitter involved Persons with alcoholism share two core symptoms: in motivation and reinforcement that is available the tendency to drink more than they intend in a reward center in the brain (Benjamin et al. to and drinking at levels that lead to medical, 1993). Moreover, rats given larger doses of psychological, or social problems, such as missing naltrexone showed even greater decreases in dopa- work and failing to fulfill family responsibilities. mine. This “dose-dependent” effect demonstrated Naltrexone appears to have a significant effect that the opioid system is an important target for on both of these symptoms of alcohol depen- medications to control alcohol consumption and dence. In two early studies, the researchers reward. Recent studies on two opiate antagonists, gave naltrexone to recently detoxified outpatient naltrexone and nalmefene, are summarized below. 452 Treatment of Alcohol Dependence With Medications volunteers who came from diverse racial/ethnic with alcoholism found no serious adverse events and economic backgrounds and who had received associated with naltrexone treatment (Croop et different types and intensities of behavioral al. 1995). Although no systematic studies have treatments for alcoholism (O’Malley et al. 1992; ascertained the range of doses that might be Volpicelli et al. 1992). Regardless of differences used to treat alcoholism, the typical dose is in demographic traits and behavioral treatments, 50 milligrams per day (mg/day). At a much patients given naltrexone had similar outcomes higher dose—300 mg/day—naltrexone is across all groups: they drank less frequently, and associated with adverse liver effects (hepato- when they drank, they consumed less alcohol. toxicity). The drug label notes that this medica- tion is not appropriate for patients with acute No medication can be fully effective unless it hepatitis or liver failure. is used as directed, that is, taken as scheduled and for the full course of treatment. The degree Follow-up studies of patients who have used to which patients are compliant in taking a medication can yield important information medication as directed is