Abstract
BACKGROUND: The cortisol awakening response (CAR) is a core biomarker of hypothalamic-pituitary-adrenal (HPA) axis regulation. To date, however, studies of HPA-axis function among patients with chronic pain are scarce and show equivocal results. The objectives of this study were to investigate the association between CAR and pain-related outcomes and to investigate potential sex differences in patients with knee osteoarthritis (KOA). METHODS: In this cross-sectional study, KOA patients (N = 96) completed self-report questionnaires assessing pain and psychosocial factors and underwent Quantitative Sensory Testing (QST) to assess pressure pain threshold (PPT). Additionally, salivary cortisol samples (N = 60) were collected to assess HPA-axis function at 6 time points (awakening, 15- and 30-minute post-awakening, 4 PM, 9 PM and bedtime). The CAR was calculated by examining increases in salivary cortisol from awakening to 30 min post awakening and the total post-awakening cortisol concentration by calculating the lower areas under the curve of cortisol with respect to ground (AUC(G)). RESULTS: Patients with a relatively blunted CAR had significantly higher anxiety levels and lower PPT than patients with relatively normal CAR. Similarly, patients with a relatively reduced AUC(G) had significantly higher pain interference and anxiety levels compared to patients with relatively normal AUC(G). PPT was positively correlated with CAR and AUC(G) and negatively correlated with pain severity and anxiety(.) Men with KOA had significantly lower anxiety, higher PPT and higher CAR and AUC(G) than women with KOA. Mediation analysis results revealed a significant indirect effect of PPT on the relationship between sex and AUC(G.) CONCLUSIONS: The findings of this study suggest that neuroendocrine factors such as CAR and AUC(G) may contribute to individual differences in pain-related outcomes in patients with KOA. Additionally, our results show sex differences in the magnitude of morning HPA activation and pain-related outcomes. Finally, our findings are suggestive of a sex-dependent relationship between post-awakening cortisol concentrations and pain perception. Future research should examine these associations across various pain populations.