Genetic basis for predicting response to naltrexone in the treatment of alcohol dependence

Abstract

PharmacogenomicsVol. 9, No. 6 EditorialFree AccessGenetic basis for predicting response to naltrexone in the treatment of alcohol dependenceRaymond F AntonRaymond F AntonCenter for Drug and Alcohol Programs, 67 President Street, MSC 861, Charleston, SC 29425, USA. Search for more papers by this authorEmail the corresponding author at antonr@musc.eduPublished Online:3 Jun 2008https://doi.org/10.2217/14622416.9.6.655AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInReddit 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.In a post-hoc analysis of several combined clinical trial data sets, an initial report suggested that the asp40 OPRM1 SNP was associated with naltrexone response in Caucasian alcoholics [19]. However, the retrospective nature of the report, along with an incomplete factorial analysis, led to cautious acceptance as to the validity of the findings. A second post-hoc study of a multisite clinical trial conducted by US Veteran’s Administration investigators [20] did not find a significant interaction between the OPRM1 SNP status and treatment response to naltrexone [21]. However, only approximately a third of the subjects were available for genotyping, and there was a main effect of naltrexone in this sub-sample, contrary to a lack of statistical effect in the main trial, leading to a cautious interpretation of these results.The NIH (National Institute on Alcohol Abuse and Alcoholism [NIAAA]) funded COMBINE Study, carried out at 11 academic medical centers, randomized 1383 individuals with alcohol dependence to either naltrexone, acamprosate, both medications or their inactive placebos, while providing MM to all subjects and an intensive outpatient specialized counseling called combined behavioral intervention (CBI) therapy to half of all subjects in each medication group [22]. Over 1000 subjects had DNA available for analysis, and of those, 604 Caucasians had been randomized to receive naltrexone or placebo and MM with or without CBI therapy. As mentioned previously, in the original study intent-to-treat-analysis, naltrexone was statistically superior to placebo only in the group that received MM without specialized counseling/CBI. This was interpreted as being the most pure pharmacological effect, since CBI was more effective than placebo in its own right and might have obscured the efficacy of naltrexone.In the genetic sub-study we wondered whether the asp40 SNP would be associated with naltrexone response in both counseling groups (MM alone or MM with CBI) or just in the MM alone group, where the pure pharmacological response was initially detected. In fact, it was found that the gene (asn40asn vs asp40) by naltrexone (active versus placebo) interaction was present only in the MM-alone group [23], the group that showed a significant naltrexone over placebo effect in the original intention-to-treat (ITT) analysis. This suggested that for a naltrexone by gene effect to be observed, it may need to be examined under conditions free of other therapeutic influences that might obscure naltrexone’s effectiveness. In the MM-only group, the difference in good clinical outcome to naltrexone in those with at least one asp40 allele was almost double that in all other groups: approximately 87% good response in the asp40 naltrexone group versus approximately 50% response in all of the other groups (those asp40 individuals treated with placebo and those asn40asn individuals treated with either naltrexone or placebo). This translated into an odds ratio of a better response of 5.74 (CI: 1.88–17.54) to naltrexone if an individual had the asp40 SNP. This effect could not be accounted for by any baseline difference in drinking, alcoholism severity or any other demographic variable that we examined. Also, this effect was not accounted for by a differential side-effect profile of naltrexone, nor compliance in those with or without the asp40 SNP. In addition, the gene by naltrexone interaction was present across several drinking variables, including heavy drinking days and percent days abstinent over time.The limitations of the data from the COMBINE study include the following: • Lack of a priori randomization by OPRM1 genotype• Post-hoc analysis (using, however, a similar analytic strategy and variables as the main trial)• Limitation to Caucasians (although adding the 72 African–Americans, 110 Hispanics and 45 other ethnic/racial subjects into the analysis did not significantly alter the findings).While examination of baseline and other important variables within the study (e.g., retention, compliance, side effects) did not point to randomization bias, only a priori randomization based on genotype could completely address the concern that some unrecognized randomization bias might have lead to the observed gene by naltrexone interaction effect.Where does this leave us? For now, it appears that the OPRM1 asp40 SNP is worthy of more study. Given the magnitude of the gene by naltrexone effect observed in the COMBINE study, early adopters might consider it strong enough to utilize in the selection of treatment for alcoholics. Since CBI therapy worked as well as naltrexone in the main analysis, one could make a case for reserving naltrexone treatment for those that have the asp40 SNP and would prefer pharmacotherapy to behavioral intervention. Others might choose to wait for more replication and/or biological correlation. For instance, our group is currently exploring whether asp40 compared with asn40asn individuals differ in naltrexone dampening of alcohol-cue-induced brain activation of reward systems [24], and whether this has any effect on drinking under controlled conditions [25]. Others are currently evaluating the ability of the asp40 allele to predict naltrexone response in a clinical trial [26] modeled after the COMBINE study.If these studies, and others, further corroborate the cumulative evidence to date, the OPRM1 asp40 by naltrexone interaction will be a milestone in the treatment of alcoholism, providing the first evidence of a ‘personalized treatment approach’ to this condition. This might allow many more individuals suffering from this devastating disorder to seek treatment and have successful outcomes.Note from the authorThe A118G (Asn40Asp) OPRM1 SNP referred to in this report is the OPRM1 SNP (rs1799971) that has been updated in public informatics databases (ABI, NCBI, HapMap) over time as the following A304G (Asn102Asp) or A355G (Asn102Asp).Financial & competing interests disclosureWithin the past 12 months, the author or an immediate member of family has a financial relationship or interest with a proprietary entity producing healthcare goods or services. The author has received research grants from Bristol-Myers Squibb, Hythiam and Eli Lilly, Inc. and has acted on the speakers bureau for Alkermes and Cephalon. He has also acted as a consultant for Bristol-Myers Squibb, Alkermes, Cephalon, Solvay Pharmaceuticals, Sanofi-Aventis, Novartis and acted on the advisory committee or Board for Hythiam. 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The author has received research grants from Bristol-Myers Squibb, Hythiam and Eli Lilly, Inc. and has acted on the speakers bureau for Alkermes and Cephalon. He has also acted as a consultant for Bristol-Myers Squibb, Alkermes, Cephalon, Solvay Pharmaceuticals, Sanofi-Aventis, Novartis and acted on the advisory committee or Board for Hythiam. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.PDF download