On the Role of Genetic Testing for Personalized Drug Overdose Management

Abstract

Author Reply: We thank our colleagues for their interest in our study entitled "Opioid Receptor Polymorphism A118G Associated with Clinical Severity in a Drug Overdose Population." Our results add to the growing literature over the past decade that implicate a handful of promising single nucleotide polymorphisms (SNPs) of the mu opioid receptor gene (OPRM1) as candidates for clinically relevant variability in baseline mesolimbic reward neurobiology (dopamine-opioid interaction), opioid sensitivity, and addiction [1]. Our findings warrant further research to understand the mechanisms underlying specific at-risk overdose populations. We completely concur that results of our pilot study, as with all such investigations, will require validation in larger populations, an effort which is currently being addressed at our institution. Confirming our results would have significant impact in the field of addiction to pave the way for personalized prescription practices not only for opioids, but for those at risk for drug overdose.Our data which demonstrated higher overdose severity in G allele subjects, not limited to opioid drugs, is likely due to dopamine-opioid interactions in the mesolimbic/striatal pathways relevant to reward and habit formation. Indeed, several lines of evidence have established significant disturbances of the opioid system in association with various drugs of abuse [2,3]. We therefore chose not to limit the analysis to only opioids given the biologic plausibility of enhanced abuse and addiction behaviors which apply for all drugs, not limited to opioids. To address our colleagues' suggestion to eliminate sympathomimetics, such as cocaine, from the analysis, we would argue that it is equally plausible that OPRM1 variants affect the same reward pathways for sympathomimetics, and thus arbitrary removal of these exposures would actually introduce, not eliminate, bias.A question was also raised as to whether the 118G allele confers resistance rather than increased susceptibility as suggested by the findings of our study. Consistent with the results of our study, multiple investigations have reported an