Genetic variability of tramadol pharmacokinetic genes and pain treatment outcome after breast cancer surgery.

Abstract

e23133 Background: Tramadol is a treatment of choice for pain management after axillary lymph node dissection in breast cancer patients. Tramadol is metabolized via CYP2D6 and UGT2B7, while ABCB1, ABCC2 and SLC22A1 are involved in transport of tramadol metabolites. Genetic variability of metabolizing enzymes or drug transporters may therefore affect efficacy and adverse effects of tramadol. The aim of this study was to evaluate the association of genetic variability in tramadol pharmacokinetics pathway on long-term outcome of tramadol pain treatment after breast cancer surgery. Methods: The study included 102 breast cancer patients treated with either 75 or 37.5 mg of tramadol for pain relief after breast cancer surgery including axillary lymph node dissection as part of a randomized clinical trial KCT 04/2015-DORETAonko/si at Institute of Oncology Ljubljana. All patients were genotyped for 14 polymorphisms in ABCB1, ABCC2, CYP2D6, SLC22A1 and UGT2B7 genes, as well as for CYP2D6 duplication and deletion. CYP2D6 phenotype was predicted from the genotype data and patients were categorized as poor (PM), intermediate, extensive or ultrarapid metabolizers. The association of genetic factors with pain one year after treatment was evaluated using logistic regression and Mann-Whitney test. Results: One year after treatment, 21 (20.8%) patients were still experiencing chronic and 25 (24.8%) neuropathic pain. CYP2D6 PMs were significantly more likely to experience chronic and neuropathic pain after tramadol treatment (OR = 5.96, 95% CI = 1.22-29.13, p = 0.027 and OR = 9.31, 95% CI = 1.65-50.59, p = 0.011, respectively), even after adjustment for tramadol dose (p = 0.032 and p = 0.016, respectively). PMs also had higher average pain intensity compared to others regardless of tramadol dose (p = 0.042). In patients receiving lower tramadol dose, ABCB1 rs1128503, rs2032582 and rs1045642 were associated with more chronic pain in the dominant model (p = 0.004, p = 0.004 and p = 0.047, respectively). Conclusions: Genetic variability in tramadol pharmacokinetics pathway may be associated with pain treatment outcome in breast cancer patients, therefore pharmacogenetic testing could enable more effective tramadol treatment. Clinical trial information: EudraCT 2015-000992-28.