Mediators of the Pain-Depression Relationship in Adults with Chronic Pain: A Systematic Review and Exploratory Meta-Analyses.

Abstract

<b>Background/Objectives</b>: Pain intensity and depressive symptoms are closely associated in adults with chronic pain (CP), contributing to greater disability, poorer treatment outcomes, and increased healthcare costs. However, the mechanisms underlying this symptom-level relationship remain incompletely understood. This systematic review and meta-analysis aimed to (i) identify all candidate factors mediating the effect of pain intensity on depressive symptoms, or vice versa, in adults with CP and (ii) estimate the magnitude of indirect, direct and total effects reported across eligible studies. <b>Methods</b>: Seven databases were searched in May-July 2023 and updated in May-June 2024. Observational studies and randomized controlled trials evaluating mediators of the relationship between pain intensity and depressive symptoms, or vice versa, in adults with CP were eligible. Data extraction and methodological appraisal were performed independently by three reviewers. Findings were synthesized narratively using vote counting and displayed using harvest plots. When appropriate, meta-analyses were conducted using regression coefficients, standard errors and sample sizes to estimate pooled indirect, direct and total effects. <b>Results</b>: The search identified 6826 studies, of which 34 (47 mediation models) met the inclusion criteria. Twenty-nine studies (combined <i>n</i> = 13,587) examined the effect of pain intensity on depressive symptoms, identifying 24 candidate mediators. Exploratory meta-analyses were feasible only for pain catastrophizing (indirect effect [IE]: &#x3b2; = 0.150; 95% confidence interval [CI]: 0.066, 0.233) and helplessness (IE: &#x3b2; = 0.101; CI: 0.066, 0.137). The pooled estimate for pain catastrophizing showed substantial heterogeneity and was highly influenced by a single study. Sleep quality, pain self-efficacy and pain interference showed preliminary evidence of mediation in narrative synthesis. Nine studies (combined <i>n</i> = 1359) investigated the effect of depressive symptoms on pain intensity, identifying 12 candidate mediators. Pain catastrophizing was the most consistently supported mediator, although quantitative synthesis was not feasible. <b>Conclusions</b>: Several potentially modifiable mediators of the pain-depression relationship were identified and may represent targets for multidisciplinary interventions. However, quantitative findings remain preliminary because of the limited number of studies, substantial heterogeneity for some mediators, and the predominance of cross-sectional evidence. Robust three-wave longitudinal mediation studies with adequate statistical power, standardized measures and reporting, and theory-driven models are needed to establish the temporal validity of candidate mediators and strengthen causal inferences.