Polymorphisms Associated With Higher Opioid Requirements in Advanced Cancer

DNA Sequencing
DNA Sequencing
Two single nucleotide polymorphisms in the gene encoding for TAO kinase 3 were found to be associated with higher opioid dose requirements in patients with cancer pain.

Two single nucleotide polymorphisms (SNPs) in the gene encoding for TAO kinase 3 (TAOK3) — rs1277441 and rs795484 — were found to be associated with higher opioid dose requirements in patients with pain secondary to advanced cancer, according to a study published in the Journal of Pain and Symptom Management.

Genetic variability in genes encoding for cell surface receptors and transporters, as well as proteins involved in drug (particularly opioids) metabolism may play a role in individual variations in opioid dose requirements, as indicated by the wide range in oral morphine equivalent daily dose (MEDD) required for effective analgesia in patients with advanced cancer. TAOK3 is a protein kinase thought to be involved in the regulation of µ-opioid receptors.

Investigators examined the role of 2 SNPs in the TAOK3 gene — found to be associated with higher MEDD requirements after surgery in a Genome-Wide Association Study — in opioid dose requirements in patients with cancer. A total of 110 individuals with cancer pain (mean age, 58.8 years; 41.6% men; mean admission duration, 23.6 days) receiving opioid treatment at a tertiary palliative care unit were enrolled in the retrospective cohort study. 

Study participants had minor allelic frequencies for the 2 common SNPs examined (rs1277441: C/T and rs795484: A/G) comparable with those in the general population. The cohort had a mean overall MEDD of 480 mg (standard deviation [SD], 1.189 mg), a median overall MEDD of 166 mg (interquartile range, 52-468 mg), a 3-day average maximum MEDD value of 602 mg (SD, 1.412 mg), and a median value of 210 mg (interquartile range, 64-597 mg).

Study participants had minor allele frequencies of 0.29 and 0.28 for rs1277441 and rs795484, respectively, with perfect linkage disequilibrium (r2 = 0.97). Both SNPs were significantly associated with a mean overall MEDD ≥800 mg, defined as high opioid dose requirements. For rs1277441, mean MEDD values ≥800 mg were found to have a greater association with a CC genotype (minor allele, 44% of patients), compared with TT (7%) and CT (18%) genotypes (P =.013). For the rs795484 SNP, MEDD ≥800 mg had greater association with the AA genotype (57%) compared with the GG (7%) and GA (18%) genotypes (P =.004). Study participants homozygous for rs1277441 and rs795484 (8.2% of patients) were found to receive greater number of opioid medications compared with the rest of the cohort (P =.021 for rs795484 and P =.055 for rs1277441).

Study strengths included a unique patient sample comprising individuals with more complex pain and higher opioid dosage requirements than the general population and a focus on 2 TAOK3 SNPs.

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Study limitations included retrospective data collection that prevented precise elucidation of pain etiologies, the inability to ascertain that the pain was cancer-related, the lack of SNP analysis related to opioid metabolism, and a small sample size that may limit the generalizability of these results.

“Identification of patients with genotypes associated with high opioid requirements could allow for individualized and possibly more effective approaches to pain management (‘precision medicine’),” noted the authors. They recommended that future studies attempt to replicate these results using larger sample sizes.

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Gutteridge T, Kumaran M, Ghosh S, et al. Single nucleotide polymorphisms in TAOK3 are associated with high opioid requirement for pain management in patients with advanced cancer admitted to a tertiary palliative care unit [published online July 19, 2018]. J Pain Symptom Manage. doi:10.1016/j.jpainsymman.2018.07.011