The Stress-Pain Connection in Chronic Primary Pain: A Systematic Review and Meta-Analysis of Physiological Stress Markers in Relation to Experimental Pain Responses

Dysfunctioning of stress systems, i.e., the autonomic nervous system (ANS) and hypothalamic-pituitary-adrenal (HPA) axis, has been implicated in chronic pain. However, the exact interplay between (re)activity and recovery of stress and pain systems in chronic pain remains unclear. A systematic review and meta-analysis was pre-registered on PROSPERO (CRD42024495934). Six databases were searched to identify relevant literature. Risk of bias (RoB) was evaluated with the Newcastle-Ottawa Scale, and certainty of evidence (CoE) with GRADE. Clusters of interactions between physiological markers of stress and experimental outcomes of pain were formed based on the timing of the stress measurements. Fifty-two studies (5 cross-sectional, 47 case-control; n = 2,657) were included and scored on average 9/12 (range: 2-11) on RoB. Overall CoE was very low to moderate. Qualitative analyses showed significant correlations between lower mean arterial pressure and higher pain sensitivity at baseline in individuals with chronic primary pain, which was supported by a meta-analysis. Furthermore, meta-analyses showed that higher pain sensitivity was associated with higher cortisol levels at baseline, lower high-frequency heart rate variability during recovery, and higher heart rate at multiple timepoints of the stress system response. Other associations did not yield significance. Taken together, these findings suggest that dysfunction of the ANS and HPA axis is linked to heightened pain sensitivity in chronic primary pain populations. However, the level of evidence remains low due to methodological heterogeneity, highlighting the need for studies combining stress markers and pain measures to provide insights into underlying stress-pain mechanisms.