Supplementary Material for: The Involvement of the Hypothalamus-Pituitary-Adrenal Axis in the Development of Hyperalgesia During the Early Postoperative Period in Postmenopausal Patients

Introduction: Hyperalgesia frequently occurs after surgery and is associated with adverse effects on surgical outcomes. Thus, we aimed to examine whether the hypothalamus-pituitary-adrenal (HPA) axis function after surgery is involved in the development of postoperative hyperalgesia. Methods: Surgery- and pain-related variables were measured 24 and 48 hours after the first and second total knee arthroplasties (TKAs) in postmenopausal patients undergoing one-week-interval staged bilateral TKA. Two sets of saliva samples were consecutively collected from patients before (pre-T1) and one week after (post-T1) the first TKA (n = 69). HPA axis function was analyzed in a subgroup of 20 patients with a typical cortisol awakening response (CAR) in both sets of saliva samples. Results: Surgery-related variables were comparable between the first and second TKAs. However, pain-related variables (pain ratings and the amount of opioid analgesics consumed) were greater after the second than the first TKA. Cortisol and dehydroepiandrosterone (DHEA) secretion during the post-awakening period (CARauc and Daucawk, respectively) was higher at post-T1 than at pre-T1, but the molar CARauc/Daucawk ratio was comparable between the time points examined. No relationship was observed between the pre-T1 CARauc and pain ratings after the first TKA. However, post-T1 CARauc showed a positive correlation with pain ratings after the second TKA. Postoperative pain ratings were negatively correlated with Daucawk and positively correlated with the molar CARauc/Daucawk ratio at all examined time points. Discussion/Conclusion: The results suggest that adrenocortical steroidogenic activity favoring the production of cortisol over DHEA after surgery may contribute to the development of hyperalgesia during the early postoperative period.引言：痛觉超敏常发生于术后，并与手术预后不良相关。因此本研究旨在探讨术后下丘脑-垂体-肾上腺（hypothalamus-pituitary-adrenal, HPA）轴功能是否参与术后痛觉超敏的发生发展。 方法：对接受间隔1周分期双侧全膝关节置换术（total knee arthroplasty, TKA）的绝经后患者，分别在首次及二次全膝关节置换术后24小时、48小时记录手术相关及疼痛相关变量。本研究连续采集了69例首次全膝关节置换术前（pre-T1）及术后1周（post-T1）的患者唾液样本，共两组。针对两组唾液样本中均检测到典型皮质醇觉醒反应（cortisol awakening response, CAR）的20例患者亚组，开展下丘脑-垂体-肾上腺轴功能分析。 结果：首次与二次全膝关节置换术的手术相关变量无显著差异。但二次术后的疼痛相关变量（疼痛评分及阿片类镇痛药使用量）均高于首次术后。觉醒后时段的皮质醇与脱氢表雄酮（dehydroepiandrosterone, DHEA）分泌量（分别对应CARauc与Daucawk）在post-T1时均高于pre-T1，但摩尔浓度下的CARauc/Daucawk比值在两个时间点无显著差异。首次全膝关节置换术后的疼痛评分与pre-T1时的CARauc无显著相关性。然而，post-T1时的CARauc则与二次全膝关节置换术后的疼痛评分呈显著正相关。在所有检测时间点，术后疼痛评分均与Daucawk呈显著负相关，与摩尔浓度下的CARauc/Daucawk比值呈显著正相关。 讨论与结论：本研究结果提示，术后肾上腺皮质类固醇生成活动偏向于皮质醇而非脱氢表雄酮的合成，或可参与术后早期痛觉超敏的发生发展。