The relationship between single nucleotide polymorphisms in ARRB2, KCNJ6 and BDNF genes and methadone response for pain management in palliative care.

Abstract

Background: Pain has a negative impact on cancer patients’ quality of life. It is highly prevalent within this vulnerable population, with an estimated 70 to 90% of patients with advanced cancer experiencing pain. It is the most feared symptom of advanced cancer. Opioids are recommended for moderate to severe pain in palliative care. Methadone has advantages over other opioids, but it is associated with significant interindividual variability and complex pharmacokinetic and pharmacodynamic parameters, which makes dosing challenging in practice. There is limited pharmacogenetic research on cancer pain. However, recent research on single nucleotide polymorphisms (SNPs) and pharmacodynamics has shown that SNPs contribute to interindividual variability in response to opioids. The aim of this study was to investigate the relationship between SNPs in the three genes, namely KCNJ6, BDNF and ARRB2 and their influence on interindividual variability in methadone dosing requirements for pain management in advanced cancer. Methods: Fifty-five participants were recruited from the palliative and supportive care services at Mater Adults Hospital and St Vincent’s Private Hospital, Brisbane, in a prospective multi-centre, open labelled, dose individualisation study. Patients were prescribed varying doses of oral methadone by specialist palliative care clinicians for the management of pain. Patient characteristics were collected at baseline, with pain scores recorded using the Brief Pain Inventory, on a numerical rating scale of 0 to 10. Genotyping was conducted using pyrosequencing for both BDNF and KCNJ6 and TaqMan assays were used for ARRB2. Results: Forty-six participants were included in the final study and received an average methadone dose of 17.7 mg. The mean pain score was 4.2 out of 10. The mean age of the population was 60.7 years. The patient characteristics measured in this study were not found to be covariates affecting methadone dose, response or pain scores. A patient was considered to be experiencing high pain if they had a pain score of > 4/10. There was a significant association between high pain scores and the following SNPs in BDNF and ARRB2: rs1491850 (p = 0.033), rs3786047 (p = 0.011), rs1045280 (p = 0.004) and rs2036657 (p = 0.05). SNPs in KCNJ6, BDNF and ARRB2 did not show significant associations with methadone dose. Conclusion: These findings suggest that specific SNPs in BDNF and ARRB2 may play a role in methadone response and that genetics may be an important factor in interindividual variability. In the future, the SNPs in these genes could be factored into a multimodal treatment algorithm for cancer pain.