Genetic Basis for Predicting Response to Naltrexone in the Treatment of Alcohol Dependence

Abstract

Alcohol use disorders (alcohol abuse and dependence) affect 15–20 million Americans at any given time. Despite this and the US$185 billion cost tag owing to lost wages, accidents, reduced productivity, property, personal damage and so on, most people remain untreated [1]. In the past 10 years or so, a number of medications have been reported to be efficacious in reducing drinking, promoting abstinence and reducing relapse [2,3]. One of the most widely studied medications in the treatment of alcoholism is the opioid receptor antagonist, naltrexone. Many studies, carried out in a number of countries, have substantiated the effectiveness of naltrexone for the treatment of alcohol dependence [4–6], with small to medium effect sizes over placebo treatment. One of the largest studies ever carried out on the pharmacotherapy of alcoholism in the USA, the federally funded Combined Pharmacotherapies and Behavioral Intervention for Alcohol Dependence (COMBINE) study, found that naltrexone was better than placebo, but only in the absence of specialty counseling, which itself was found effective. When medical management (MM) was combined with naltrexone, the overall global response rate was 71%, compared with 58% when MM was combined with a placebo. There was also a reduction in heavy drinking, and a greater numer of abstinent days in the active naltrexone plus MM group. Of course, the question asked most often is, why do some people respond to naltrexone and others do not? A corollary is, can you predict who will respond better to this medication? It is clear that, while some alcoholics do very well on naltrexone, others do not. A number of phenotypic characteristics of alcohol dependent individuals might be associated with better response, including level of craving, cognitive function, family history and gender [7–11]. More recently, the focus has turned to variability in the μ-opioid receptor in the brain, the receptor to which the endogenous opioid β-endorphin binds, and the likely main site of action of naltrexone, an antagonist/blocker of this receptor. An asparagine-to-aspartate amino acid substitution in the μ-opioid type 1 (OPRM1) receptor at the 40 position (asn40asp), as a result of an A to G substitution at the 118 position in exon 1 of the OPRM1 gene, causes structural variation on the extra-membrane portion of the receptor in the β-endorphin binding region. This variation has been reported to increase β-endorphin binding and G-protein-coupled adenylate cyclase production [12] and receptor levels [13], but these findings might be cell specific [14]. In addition, individuals with the asn40asp SNP show a different response to alcohol [15], alcohol cues [16], differential neural activation to pain [17] and hypothalamic adrenal response to opioid antagonists [18]. In summary, accumulated evidence suggests that this single polymorphism has functional activity at both the cellular and clinical level.