Barratt Daniel T, Klepstad Pål, Dale Ola, Kaasa Stein, Somogyi Andrew A
Discipline of Pharmacology, School of Medicine, University of Adelaide, Adelaide, Australia; Centre for Personalised Cancer Medicine, University of Adelaide, Adelaide, Australia.
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.
PLoS One. 2015 Sep 2;10(9):e0137179. doi: 10.1371/journal.pone.0137179. eCollection 2015.
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.
癌症和化疗常见的不良症状是一项重大的健康负担；其中最主要的是疼痛，包括透皮芬太尼在内的阿片类药物是主要的治疗手段。先天性免疫激活通常与癌症患者报告的疼痛、阿片类镇痛、认知功能障碍和疾病样症状有关。我们旨在确定神经免疫激活途径中的基因多态性是否会改变癌症疼痛患者在疼痛控制、认知功能障碍和其他不良症状方面的血清芬太尼浓度-反应关系。对468例接受透皮芬太尼治疗的癌症疼痛患者进行了19个基因中31个单核苷酸多态性的基因分型：CASP1、BDNF、CRP、LY96、IL6、IL1B、TGFB1、TNF、IL10、IL2、TLR2、TLR4、MYD88、IL6R、OPRM1、ARRB2、COMT、STAT6和ABCB1。分别使用套索回归和向后逐步广义线性回归来确定疼痛控制（平均简明疼痛量表<4）、认知功能障碍（简易精神状态检查表≤23）、疾病反应和阿片类药物不良事件主诉的非遗传和遗传预测因素。血清芬太尼浓度并不能预测这些结果在患者之间的变异性，遗传因素也不能预测疼痛控制、疾病反应或阿片类药物不良事件主诉。与野生型患者（69/325）相比，携带MYD88 rs6853变异体的患者出现认知功能障碍的可能性（11/111）只有一半，在考虑主要非遗传预测因素（年龄、卡诺夫斯基功能评分）时，相对风险为0.45（95%置信区间：0.27至0.76）。这支持了先天性免疫信号传导参与认知功能障碍，并将MyD88信号通路确定为预测和减轻癌症疼痛患者认知功能障碍负担的潜在重点。
