Stress and pain systems : a meta-analysis of their complex physiological interplay

Background and aims: Besides psychological distress, (dys)functioning of stress systems, i.e. the autonomic nervous system (ANS) and hypothalamic-pituitary-adrenal (HPA-)axis, has been implicated in pain. However, the exact interplay between (re)activity of stress and pain systems in chronic pain remains unclear. This study will synthesize the evidence regarding their interactions in chronic pain. Methods: A systematic review and meta-analysis was pre-registered on PROSPERO (CRD42024495934). Six databases were searched to identify studies examining at least one physiological stress marker of ANS or HPA-axis reflecting basal levels (i.e., before a stressor), reactivity (i.e., during a stressor) and/or recovery (i.e., after a stressor), and one experimental outcome measure of pain in adults with chronic primary pain. Risk of bias (RoB) was evaluated with the Newcastle-Ottawa Scale, and certainty of evidence (CoE) with GRADE. Results: Forty-six studies (3 cross-sectional, 43 case-control; n=2407) were included and scored averagely 9/12 (5-11) on RoB. Overall CoE was (very) low. At baseline, qualitative analyses showed significant correlations between lower mean arterial pressure and higher pain sensitivity in patients with chronic pain which was confirmed in the meta-analyses (r=.301-.353, p=.02-.033). Furthermore, meta-analyses showed that higher cortisol levels were associated with lower pressure pain thresholds (PPTs) at baseline (r=.218, p=.01). Higher heart rate was associated with lower PPTs, and lower highfrequency heart rate variability measured at recovery level with lower cold pain tolerance (r=.309-.525, p=.001-.028). Conclusions: Dysregulation of baroreceptor and HPA-axis functioning seems to be related to higher pain sensitivity at baseline, and autonomic dysfunction might be related to higher pain sensitivity under acute stress in patients. However, the evidence is low and limited.