Evidence for the Efficacy of Naltrexone in the Treatment of Alcohol Dependence (Alcoholism)

1 From Snake Pits to Science About 14 million American adults meet diagnostic criteria for alcohol abuse or alcohol dependence (alcoholism). And, every year, more than 1.5 million seek treatment for their alcohol-related problems (Highlights. 2000; Kurtzweil 1996). Throughout history, attempts to treat alcoholics have been illconceived and gave disappointing results. A first treatment for chronic drunkenness may have been devised by ancient Romans, who lowered habitual drunkards into snake-filled pits, thinking the terror would shock them into abandoning their wayward practices (Sournia 1990). By the close of the 19th Century, Merck’s Manual of the Materia Medica (1899) was recommending such nostrums for alcoholism as arsenic, bromides, cocaine, chloral hydrate, opium, and strychnine. Roughly 50 years later, in 1948, disulfiram became the U.S. Food and Drug Administration (FDA) approved drug for alcoholism treatment (Kurtzweil 1996). It induces nausea, vomiting, and other aversive reactions in those who drink alcohol while taking the medication. After nearly another half-century passed, in late 1994, naltrexone became only the second drug approved to date for alcoholism by the first FDA (Kurtzweil 1996). This new indication was authorized in part because of naltrexone’s accumulated record of safety during extensive prior use for opioid detoxification and in the treatment of heroin addiction (Naltrexone. 1997; Miller 1997, p75). A deciding factor, however, was results from two pivotal studies demonstrating naltrexone’s usefulness as part of a clinical program for treating alcoholism (O’Malley et al. 1992; Volpicelli et al. 1992). In its approval, the FDA recommended that naltrexone also be used with adjunctive psychosocial therapies for alcoholism. Naltrexone’s pharmacologic actions are fairly straightforward. Alcohol is a complex substance, affecting a number of chemical systems in the brain. Among other effects, it is suspected that, when an alcoholic imbibes, the brain’s opioid system releases endorphins triggering reinforcement that entices the person to drink more (Goldstein 1997; Naltrexone.1997; O’Brien 1997; O’Malley 1998, Swift 1995). Unlike earlier drugs used to treat alcoholism, naltrexone is not addictive and does not react aversively with alcohol. It blocks opioid receptors in the brain (it is an antagonist), and this has been proposed as stemming the endorphin-mediated reinforcing effects of drinking alcohol. The validity of this concept has been supported by observations that alcoholics experience increased opioid system activity in response to alcohol (Herz 1997; Miller 1997). Some controversy has surrounded the use of naltrexone for alcoholism (Freed and York, 1997). First, healthcare providers, and patients themselves, sometimes question the value of using any drug to treat drug or alcohol addiction. Second, research on the effectiveness of naltrexone and how best to use it in treating alcoholism has evolved rapidly during just the past decade and cumulative findings are not widely known or appreciated. In this era of managed care and increasing pressures of accountability, healthcare providers need credible scientific information for decision-making purposes in recommending medications such as naltrexone. They need to respond authoritatively to questions such as: • Where did you learn that naltrexone is effective in treating alcoholism? • How do you know the information is reliable and valid? • What results do you expect from using naltrexone? These questions serve as the foundation of this clinical update report. The goal is to provide healthcare providers with useful, evidence-based answers. Treatment Expectations It has been stressed that both alcoholics and alcohol abusers need treatment, although the goals may differ. According to the FDA, “In most cases of alcohol abuse, the goal is to limit drinking, while for alcoholism, it is to stop drinking altogether” (Kurtzweil 1996). The immediate goal of most recovery programs is alcohol abstinence, yet that is often too strict a standard. According to some studies, about half of patients experience a relapse to heavy drinking within 12 weeks of beginning treatment, and up to 90% will relapse at least once during four years following treatment. (Kurtzweil 1996; Nathan 1986; Volpicelli et al. 1992). When sustained abstinence cannot be achieved, other goals, such as reducing the number, frequency, or severity of relapses could be of significant clinical value. A great potential benefit of naltrexone, in combination with appropriate psychosocial therapy, would be providing the patient relief from the self-destructive cycle of intoxication to enhance engagement in treatment and achieve long-term recovery objectives (Miller 1997, p59). Volpicelli et al. (1992) have suggested that the ideal pharmacological agent for use in alcoholism treatment would, first, decrease alcohol craving and reduce the initial motivation to drink. Second, if drinking does occur, the agent should block the reinforcing or desirable qualities of alcohol to decrease further drinking behavior, so a “lapse” does not progress to a relapse. Naltrexone’s ability to fulfill those requirements is examined in the research evidence. Evidence Selection The various types of research study designs may be ranked according to a “hierarchy of evidence,” based on their relative strengths for providing results that are likely to be valid and free of bias. Randomized controlled clinical trials (RCTs) are considered by many as the “gold standard” when addressing questions of a drug’s therapeutic efficacy (Guyatt and Drummond 1993; Sackett et al. 1997), and are the focus of this report. Naltrexone Clinical RCTs Through year 2001 there were 14 clinical RCTs to assess the effectiveness of naltrexone for treating alcoholism, enrolling 2127 subjects, and conducted in five countries. Table 1 presents summaries of those trials. For some of the earlier studies, multiple published articles have discussed data from the same treatment population and are grouped together. Unless noted otherwise, all of the RCTs reported in Table 1 had the following characteristics in common: • Subjects met criteria for alcohol dependence according to the Diagnostic and Statistical Manual of Mental Disorders 3rd or 4th editions (DSM 1987, 1994), had a recent history of alcohol intoxication, and were between 18 and 65 years of age. • Subjects were excluded if they had significant liver disease, a psychiatric diagnosis beyond alcohol dependence that was being treated with psychotropic medication, or substance abuse (other than alcohol and excluding nicotine or occasional marijuana use). Pregnant women or those likely to become pregnant while on naltrexone also were excluded. • Subjects were withdrawn (detoxified) from alcohol and abstinent for a period of time prior to administration of study medication. An exception was the RCT by Heinala et al. (2001), in which prior alcohol abstinence was not required. • Subjects were randomly assigned to treatment groups and there were no significant demographic differences between groups at the start. • Naltrexone (NTX) was compared to an identical-appearing inert substance (placebo, PBO). The naltrexone dose was equivalent to 50 mg/day, except in the study by Monterosso et al. (2001; 100 mg/day). • Neither subjects nor investigators knew if NTX or PBO was being taken (double-blind).