Innate Immune Signalling Genetics of Pain, Cognitive Dysfunction and Sickness Symptoms in Cancer Pain Patients Treated with Transdermal Fentanyl

PLoS One. 2015 Sep 2;10(9):e0137179. doi: 10.1371/journal.pone.0137179. eCollection 2015.

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.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Cutaneous
  • Adult
  • Aged
  • Aged, 80 and over
  • Analgesics, Opioid / administration & dosage
  • Analgesics, Opioid / adverse effects
  • Analgesics, Opioid / blood
  • Analgesics, Opioid / therapeutic use*
  • Cognition Disorders / complications*
  • Cognition Disorders / genetics
  • Cognition Disorders / immunology
  • Female
  • Fentanyl / administration & dosage
  • Fentanyl / adverse effects
  • Fentanyl / blood
  • Fentanyl / therapeutic use*
  • Humans
  • Immunity, Innate / drug effects
  • Karnofsky Performance Status
  • Male
  • Middle Aged
  • Myeloid Differentiation Factor 88 / genetics
  • Neoplasms / complications*
  • Neoplasms / genetics
  • Neoplasms / immunology
  • Pain / complications*
  • Pain / drug therapy*
  • Pain / genetics
  • Pain / immunology
  • Pain Management
  • Polymorphism, Single Nucleotide
  • Young Adult

Substances

  • Analgesics, Opioid
  • Myeloid Differentiation Factor 88
  • Fentanyl

Grant support

The Norwegian Research Council and the European Union’s 6th framework (Contract No. 037777; http://www.forskningsradet.no/en/Home_page/1177315753906; PK OD SK) and the National Health and Medical Research Council of Australia (Project Grant 1011521; https://www.nhmrc.gov.au/; AAS) financially supported the EPOS study.