Pharmacogenetics and personalizing perioperative analgesia in children

Abstract

Safe and effective perioperative analgesia is an important unmet critical medical need in children. Up to 50% of children experience inadequate perioperative pain relief and serious side effects from opioids. Morphine, the most commonly used “gold standard” opioid for managing perioperative pain in children, has a narrow therapeutic index and a large inter-patient variability in response. Frequent genetic variations in response to morphine are clinically significant with inadequate pain relief at one end of the spectrum of responses and serious side effects such as respiratory depression at the other. The central hypothesis is that differences in specific single nucleotide polymorphisms (SNPs) of genes involved in pain perception (COMT), opioid transport (ABC B1) and opioid receptor signaling (OPRM1) contribute significantly to effective analgesia and adverse effects from morphine in children. The specific aims are 1. to identify genetic profiles that will predict children's pain sensitivity and pain relief from morphine, and 2. to identify children who are genetically predisposed to risk of serious side effects from morphine. After obtaining IRB approval and informed consent/assent, 108 children, 6-15 years, who had received morphine for tonsillectomy were analyzed. COMT genes had strong associations with perioperative morphine requirement and rescue analgesic interventions. COMT rs6269 (AG and GG genotypes) and rs4818 (CC genotype)and rs4633 (TT genotype) are 3 times more likely to require rescue analgesic interventions compared to other genotypes. ABCB1 gene had strong associations with opioid induced respiratory depression and PONV. The odds of respiratory depression and PONV in TT genotype of ABCB1 SNP, rs1045642 are >2 times compared to TC and CC genotypes. These findings are expected to become the foundation for personalized pain management and enable clinicians to individualize the use of morphine to maximize pain relief while minimizing the likelihood of adverse effects in children.