Influence of COMT (rs4680) and OPRM1 (rs1799971) on Cancer Pain, Opioid Dose, and Adverse Effects

Background: The influence of pharmacogenomics on opioid response, particularly with COMT (rs4680) and OPRM1 (rs1799971) variants, has been studied individually and in combination. However, most studies are in a noncancer context and not all their possible variant combinations have been examined. Objectives: This study examined COMT (rs4680) and OPRM1 (rs1799971), and their allele combinations, in advanced cancer to examine associations with pain scores, opioid dose, and adverse effects. Setting/Subjects: This multicenter prospective cohort study recruited patients receiving opioids for advanced cancer pain in Melbourne, Australia. Clinical data (demographics, opioids), validated instruments (pain and adverse effects), and blood (DNA) were collected. Descriptive analyses were used. Univariate and multivariate logistic regression analyses were used to evaluate associations between clinical outcomes (opioid dose, pain, adverse effects) and genotypes of interest. Results: Fifty-four participants were recruited to the study. Those with COMT A allele required lower opioid doses [130 mg (interquartile range [IQR] 67.5,230) versus 180 mg (IQR 55,322.5), p = 0.047] and experienced greater adverse effects [sickness response aOR (adjusted odds ratio) 7.1 (95% CI 1.51,33.41), p = 0.01]. Those with the COMT GG/OPRM1 G allele combination required higher opioid doses [322.5 mg (IQR 264,360) versus 125 mg (65,225), (p = 0.04)]. Those with COMT AG/OPRM1 AA experienced higher average pain [aOR 1.55 (95% CI 1.03, 2.33), p = 0.04] and moderate-severe nausea [aOR 5.47 (95% CI 1.35, 22.21), p = 0.02] but reduced drowsiness [aOR 0.25 (95% CI 0.06, 1.02), p = 0.05]. Conclusions: Patients with cancer with the COMT alternate (A) allele have greater sickness response adverse effects, which may be responsible for the lower opioid doses observed. Significant results of two new COMT/OPRM1 genotype combinations are presented that have not previously been studied, with plausible phenotype descriptions suggested.