The κ-opioid receptor gene as a predictor of response in a cocaine vaccine clinical trial

Abstract

We examined the pharmacogenetic association between a variant in the κ-opioid receptor (OPRK1) gene and the response to treatment with a cocaine vaccine tested in a recent clinical trial (October 2003 to April 2005). This gene has a protective allele for opioid addiction that may act by the inhibiting dopamine activation associated with reinforcement. Sixty-nine DNA samples were obtained from 114 cocaine-dependent and opioid-dependent patients who were enrolled in a 16-week phase IIb randomized double-blind placebo-controlled trial and received five vaccinations over the first 12 weeks. We genotyped 66 of these patients for the rs6473797 variant of the OPRK1 gene and compared vaccine patients with placebo patients in terms of cocaine-free urines over time. Using repeated measures analysis of variance corrected for population structure, it was seen that vaccine pharmacotherapy reduced cocaine-positive urines significantly on the basis of the OPRK1 genotype. Among patients treated with the cocaine vaccine, those who were homozygous for the protective A allele of rs6473797 had the proportion of positive urines drop from 78 to 51% on using the vaccine (point-wise P<0.0001, experiment-wise P<0.005), whereas the positive urines of individuals carrying the nonprotective, risk G allele dropped from 82 to 77%. Strong treatment by single nucleotide polymorphism interactions reflected a lower baseline and significant reduction for placebo patients with the risk G allele (P<0.00001). This study indicates that a patient's OPRK1 genotype could be used to identify a subset of individuals for whom vaccine treatment may be an effective pharmacotherapy for cocaine dependence.