The Involvement of the Hypothalamus-Pituitary-Adrenal Axis in the Development of Hyperalgesia during the Early Postoperative Period

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.Surgery- and pain-related variables were measured 24 and 48 h after the first and second total knee arthroplasties (TKAs) in postmenopausal patients undergoing 1-week-interval staged bilateral TKA. Two sets of saliva samples were consecutively collected from patients before (pre-T1) and 1 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 the sets of saliva samples.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.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.