Pharmacogenetics of the μ-opioid receptor and the treatment of addictions

10.2217/17410541.4.2.xxx © 2 Pr oo f Evaluation of: Munafò MR, Elliot KM, Murphy MFG, Walton RT, Johnstone EC: Association of the μ-opioid receptor gene with smoking cessation. Pharmacogenomics J. (2007). This well-designed study examined shortand long-term outcome data from a large clinical trial comparing nicotine-replacement therapy (NRT) with placebo in order to test the association between the μ-opioid receptor gene and treatment outcomes. In addition to a significant effect of NRT compared with placebo across time periods, analyses revealed a significant genotype × treatment interaction at 12-week follow-up, such that participants who were homozygous for the A allele were more likely to report smoking abstinence in the NRT condition versus placebo compared with carriers of the G allele. These results did not persist after NRT was discontinued, although its temporal contiguity to treatment suggests it is a true pharmacogenetic effect. Importantly, these findings stand in contrast to previous research in the field. Moreover, the study reported provocative interactions between gender and μ-opioid receptor gene status with regard to long-term treatment outcome, and between abstinence and gender with regard to changes in body mass index. Munafò and colleagues’ study has a number of strengths and its overall findings underline the complex ways in which genotype, gender and body mass index may interact in smoking-cessation treatment. The significance of these findings is discussed in the context of pharmacogenetics research in the field of substance-use disorders. uth or In light of the large observed interindividual variability in clinical response to pharmacotherapies for addictive behaviors, such as nicotine and alcohol dependence, recent research has focused on identifying moderators of medication response, including genetic variants, as a means of optimizing treatments in the future. In a well-designed study, Munafò and colleagues examined the role of a functional polymorphism of the μ-opioid receptor gene (OPRM1) in treatment outcomes in a large, double-blind, placebo-controlled trial of nicotine-replacement therapy (NRT) for smoking cessation [1]. Most candidate-gene pharmacogenetic studies to date have focused on genetic factors influencing medication efficacy and toxicity, emphasizing polymorphisms that have an effect on pharmacokinetics (e.g., drug metabolism) or pharmacodynamics (e.g., drug sensitivity) [2]. Based on previous research, Munafò and colleagues selected the A118G single nucleotide polymorphism (SNP) of OPRM1 located in position +118 in exon I, whereby a nonsynonymous mutation results in an aminoacid substitution from asparagine to aspartate. This polymorphism has been shown to be functionally significant, with studies suggesting that the SNP affects receptor-binding affinity [3], messenger RNA and protein yield [4]. At the behavioral level, carriers of the G allele have been found to exhibit greater sensitivity to the subjective effects of alcohol [5], greater relative reinforcement value of nicotine (in women) [6] and greater levels of short-term smoking abstinence to NRT [7]. Taken together, previous studies have suggested that this candidate SNP is functional at molecular and behavioral levels and may be especially relevant to the study of addictive behaviors, given the putative role of the opioidergic system in the reward mechanisms for several substances of abuse, including alcohol and nicotine. Munafò and colleagues examined shortand long-term outcome data from a large clinical trial comparing NRT with placebo to test the association between the OPRM1 genotype and treatment outcomes in this trial. In addition, the study examined body mass index (BMI) and gender as variables that may predict treatment outcome and may interact with the genotype of interest. The authors did not put forth specific hypotheses regarding the nature of the relationships among genotype, treatment outcome, BMI and gender. However, based on the literature carefully reviewed in their introduction, it would be reasonable to hypothesize that carriers of the G allele