Abstract
Common adverse symptoms of cancer and chemotherapy are a major health burden; chief among these is pain, with opioids including transdermal fentanyl the mainstay of treatment. Innate immune activation has been implicated generally in pain, opioid analgesia, cognitive dysfunction, and sickness type symptoms reported by cancer patients. We aimed to determine if genetic polymorphisms in neuroimmune activation pathways alter the serum fentanyl concentration-response relationships for pain control, cognitive dysfunction, and other adverse symptoms, in cancer pain patients. Cancer pain patients (468) receiving transdermal fentanyl were genotyped for 31 single nucleotide polymorphisms in 19 genes: CASP1, BDNF, CRP, LY96, IL6, IL1B, TGFB1, TNF, IL10, IL2, TLR2, TLR4, MYD88, IL6R, OPRM1, ARRB2, COMT, STAT6 and ABCB1. Lasso and backward stepwise generalised linear regression were used to identify non-genetic and genetic predictors, respectively, of pain control (average Brief Pain Inventory < 4), cognitive dysfunction (Mini-Mental State Examination ≤ 23), sickness response and opioid adverse event complaint. Serum fentanyl concentrations did not predict between-patient variability in these outcomes, nor did genetic factors predict pain control, sickness response or opioid adverse event complaint. Carriers of the MYD88 rs6853 variant were half as likely to have cognitive dysfunction (11/111) than wild-type patients (69/325), with a relative risk of 0.45 (95% CI: 0.27 to 0.76) when accounting for major non-genetic predictors (age, Karnofsky functional score). This supports the involvement of innate immune signalling in cognitive dysfunction, and identifies MyD88 signalling pathways as a potential focus for predicting and reducing the burden of cognitive dysfunction in cancer pain patients.
Highlights
Common symptoms of cancer and its treatment are themselves a major health burden; chief among these is pain [1]
No major nongenetic predictors of pain control were identified by Lasso regression, including serum fentanyl concentrations
CRP rs2794521 variant genotype was associated with reduced pain control, cross-validation performance of this model was no better than randomised controls (median (25–75th percentile) CVE = 0.249 (0.247–0.251))
Summary
Common symptoms of cancer and its treatment are themselves a major health burden; chief among these is pain [1]. Transdermal fentanyl is a strong opioid analgesic targeted to patients with stable opioid requirements [4]. It is commonly prescribed for the treatment of moderate to severe cancer pain [3], but has similar limitations to oral morphine with respect to inadequate pain control and adverse effects [5]. Clinical experience shows that individualisation is the key to successful opioid treatment. This is due to opioids’ narrow therapeutic index, as well as the large interindividual variability in their pharmacokinetics (PK) and pharmacodynamics (PD), and patients’ pain sensitivity, phenotype, perception and acceptance. Genetics can contribute to variability in these factors and variable opioid response [6]
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