601. GENETIC POLYMORPHISMS ASSOCIATED WITH OPIOID SENSITIVITY IN PATIENTS UNDERGOING PALLIATIVE CARE AND GENERAL ANAESTHESIA

Abstract Background Opioids are almost mandatorily used for analgesia for cancer pain and postoperative pain, although opioid analgesics commonly induce side effects, such as drowsiness, nausea, vomiting, and constipation. Considerable individual differences are widely observed in the main and side effects of opioids, which could hamper effective treatment of pain by opioid analgesics. Among these side effects, postoperative nausea and/or vomiting (PONV) is known as one of the most frequent side effects following general anaesthesia involving administration of opioids, although individual differences have also been observed in the incidence of PONV. Aims & Objectives To explore potential candidate genetic variants responsible for the inter-subject differences in requirements of opioid analgesics for the treatment of cancer pain and the incidence of nausea/vomiting as a side effect of opioids, we conducted genome-wide association studies (GWAS) in a total of 428 and 806 patients with written informed consent who underwent palliative care and general anaesthesia involving administration of opioids, respectively, to identify potential genetic variants that may significantly contribute to these traits. Method In the patients who underwent general anaesthesia, GWAS was also conducted only in patients with propofol, which was the most common type of anaesthesia in the subjects, as well as the entire 806 patient subjects. Candidate genetic variants, mostly single nucleotide polymorphisms (SNPs), were explored in trend/additive, dominant, and recessive genetic models in both patient subjects. Results For the analysis of patients who underwent palliative care, a GWAS on requirements of opioids for the treatment of cancer pain showed a strong association with two intronic SNPs, rs1283671 and rs1283720, in the ANGPT1 gene that encodes a secreted glycoprotein that belongs to the angiopoietin family. These two SNPs were strongly associated with average daily opioid requirements for the treatment of pain in both additive and recessive models (P < 5.0000 × 10−8). Several other SNPs were also significantly associated with the phenotype. However, no SNPs showed genome-widely significant associations with nausea as a side effect of opioids in this patient group. For the analysis of patients who underwent general anaesthesia, two SNPs, rs2776262 and rs140703637 (exm2274524) SNPs in the LOC100506403 and CNTN5 gene regions, were significantly associated with frequency of nausea in additive or recessive and dominant models, respectively (P < 7.812 × 10-8) as a result of GWAS in all patients. In another GWAS only in patients with propofol, rs7212072 and rs12444143 SNPs in the SHISA6 and RBFOX1 gene regions, respectively, were significantly associated with frequency of nausea in additive model as well as the rs2776262 SNP in additive and recessive models, and rs1752136 and rs45574836 (exm1401859) SNPs in the LOC105370198 and ATP8B3 gene regions, respectively, were significantly associated with vomiting in trend model. Among these SNPs, clinical and SNP data were available only for the rs45574836 SNP in independent subjects who underwent laparoscopic gynecological surgery, and the association was replicated in these subjects. Discussion & Conclusions The results suggest that these SNPs could serve as markers that predict opioid sensitivity. Our findings will provide valuable information for achieving satisfactory pain control in palliative care and prophylactic treatment for PONV.