COMT and OPRM1 Polymorphisms and their Effect on Post-Operative Pain in Children Undergoing General Anesthesia

Abstract

Introduction: Inadequately treated post-operative pain in children undergoing surgery is a significant clinical challenge. Recent studies show that pain sensitivity and analgesic requirements differ between people based on their genetic makeup. There are two main genes involved in pain sensitivity and opioid requirements: COMT and OPRM1. Research indicates that Single Nucleotide Polymorphisms (SNPs) in these genes alter responses to pain and opioid requirements. COMT SNPs include: rs6269, rs4633, rs4818 and rs4680, and OPRM1 SNPs include: rs1799971. The effect of these polymorphisms on postoperative pain in children is not very well studied. Hence, the specific aims of this study were to investigate whether the OPRM1 and COMT SNPs influence postoperative pain scores, postoperative sedation score, postoperative opioid requirements, length of stay in the PACU, signs of respiratory depression (RD) and postoperative nausea and vomiting (PONV) in children between the ages of 8 and 18 undergoing all types of surgery under general anesthesia. Methods: This is a prospective observational genotype-blinded cohort conducted on children between the ages of 8-18 undergoing surgeries at the American University of Beirut Medical Center (AUBMC). Blood was collected for DNA extraction, and genotyping for the OPRM1 A118G (rs1799971) SNP and four COMT SNPs (rs4680, rs6269, rs4633, and rs4818) was performed using TaqMan real-time PCR allele discrimination assay. Postoperative pain was assessed using the Numerical Rating Scale (NRS), and opioid consumption was recorded. COMT haplotypes were constructed using BEAGLE and Haploview. Two types of analyses were conducted for COMT polymorphisms: diplotype-based analysis and phenotype-based analysis. Linear and logistic regression analyses were performed to evaluate associations between genetic variants and postoperative outcomes while adjusting for confounders. Results: A total of 66 patients were included in this preliminary analysis. Genotype and haplotype distributions for COMT and OPRM1 were consistent with Hardy–Weinberg equilibrium, and the allele frequencies were similar to Europeans. After adjusting for confounders for COMT, patients with the GCGG/GCGG diplotype had significantly higher pain scores only before the time of their discharge from the PACU (60 minutes) in comparison with other diplotypes. No significant associations between COMT phenotypes and postoperative outcomes were observed in the phenotype-based analysis. Similarly, for OPRM1, 118G allele carriers had significantly higher pain scores only before the time of their discharge from the PACU (60 minutes) in comparison with 118G non-carriers (AA genotype). No significant association was found between COMT and OPRM1 polymorphisms and postoperative opioid consumption. There was very little variability in length of stay in the Post-Anesthesia Care Unit (PACU), and the incidence of the following postoperative outcomes: postoperative sedation levels, postoperative nausea and vomiting (PONV), and respiratory depression was very low. Conclusion: These preliminary findings suggest that COMT and OPRM1 genetic polymorphisms may influence postoperative pain responses in children between the ages of 8 and 18 undergoing general anesthesia. These associations highlight the importance of pharmacogenetics in optimizing individualized treatments for postoperative pain among patients. Recruitment for this study continues to reach statistical power for a more definitive analysis.