Innate Immune Signalling Genetics of Pain, Cognitive Dysfunction and Sickness Symptoms in Cancer Pain Patients Treated with Transdermal Fentanyl.
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.
Discipline of Pharmacology, School of Medicine, University of Adelaide, Adelaide, Australia; Centre for Personalised Cancer Medicine, University of Adelaide, Adelaide, Australia.
Daniel T
DT
Barratt
Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway; Department of Anaesthesiology and Intensive Care Medicine, St Olavs University Hospital, Trondheim, Norway.
Pål
P
Klepstad
Department of Anaesthesiology and Intensive Care Medicine, St Olavs University Hospital, Trondheim, Norway; Department of Cancer Research and Molecular Medicine, European Palliative Care Research Centre, Norwegian University of Science and Technology, Trondheim, Norway.
Ola
O
Dale
Department of Cancer Research and Molecular Medicine, European Palliative Care Research Centre, Norwegian University of Science and Technology, Trondheim, Norway.
Stein
S
Kaasa
Discipline of Pharmacology, School of Medicine, University of Adelaide, Adelaide, Australia; Department of Clinical Pharmacology, Royal Adelaide Hospital, Adelaide, Australia; Centre for Personalised Cancer Medicine, University of Adelaide, Adelaide, Australia.
Andrew A
AA
Somogyi
D000279:Administration, Cutaneous; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D003072:Cognition Disorders / Q000150:complications* / Q000235:genetics / Q000276:immunology; D005260:Female; D005283:Fentanyl / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D017567:Karnofsky Performance Status; D008297:Male; D008875:Middle Aged; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics; D009369:Neoplasms / Q000150:complications* / Q000235:genetics / Q000276:immunology; D010146:Pain / Q000150:complications* / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D059408:Pain Management; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult
D000701:Analgesics, Opioid; D053594:Myeloid Differentiation Factor 88; D005283:Fentanyl