The Stress-Pain Connection in Chronic Primary Pain: A Systematic Review and Meta-Analysis of Physiological Stress Markers in Relation to Experimental Pain Responses
Bibliographic record
Abstract
ABSTRACT 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. HIGHLIGHTS – Sympathetic cardiovascular dominance appears to be associated with enhanced pain sensitivity in chronic primary pain – A dysregulation in baroreflex activity might be present in chronic primary pain – HPA axis dysfunctioning seems to be related to enhanced pain sensitivity in chronic primary pain – Need for more standardized and comprehensive mapping of stress-pain interactions to unravel underlying mechanisms
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.015 | 0.036 |
| Meta-epidemiology (narrow) | 0.002 | 0.001 |
| Meta-epidemiology (broad) | 0.016 | 0.026 |
| Bibliometrics | 0.005 | 0.006 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.003 | 0.001 |
| Open science | 0.002 | 0.002 |
| Research integrity | 0.002 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".