Genetic Influences of OPRM1, OPRD1 and COMT on Morphine Analgesia in a Multi-Modal, Multi-Tissue Human Experimental Pain Model

Abstract

Human studies on experimentally induced pain are of value to elucidate the genetic influence on morphine analgesia under controlled conditions. The aim of this study was to investigate whether genetic variants of mu-, kappa- and delta-opioid receptor genes (OPRM1, OPRK1 and OPRD1) and catechol-O-methyltransferase gene (COMT) are associated with the morphine analgesia. The study was a randomized, double-blind, two-way, crossover, single-dose study conducted in 40 healthy participants, where morphine was compared with placebo. Pain was induced by contact heat, muscle pressure, bone pressure, rectal stimulations (mechanical, electrical and thermal) and cold pressor test (immersion of the hand into ice water). Sixteen genetic polymorphisms of four candidate genes were explored. Variability in morphine analgesia to contact heat stimulation was associated with COMT rs4680 (p = 0.04), and rectal thermal stimulation was associated with OPRM1 rs9479757 (p = 0.03). Moreover, in males, variability in morphine analgesia to rectal thermal stimulation was associated with OPRD1 polymorphisms: rs2234918 (p = 0.01) and rs533123 (p = 0.046). The study was explorative and hypothesis-generating due to the relatively small study size. However, results suggest that genetic variants in the COMT and OPRM1 irrespective of gender, and OPRD1 in males may contribute to the variability in morphine analgesia in experimental pain models.