Which moderating factors influence autonomic imbalance in chronic musculoskeletal pain? A domain-specific systematic review and multilevel meta-regression of heart rate variability

Chronic musculoskeletal pain (CMP) involves autonomic dysregulation quantifiable with heart rate variability (HRV), but findings are heterogeneous and the influence of HRV protocols and clinical characteristics remain unclear. This study aimed to quantify autonomic imbalance in CMP and identify methodological and clinical moderators of between-study heterogeneity. A systematic review, meta-analysis, and multilevel meta-regression following PRISMA was conducted. Electronic databases were searched for studies comparing resting-state HRV between adults with CMP and healthy controls. Effect sizes (Hedges g) were pooled with random-effects models. Individual HRV indices were meta-analyzed and then aggregated into functional domains (vagal, global, sympathovagal balance) for multilevel meta-regression including recording duration, pain condition, posture, and sex distribution as moderators. Twenty-six studies (3641 participants: 1207 CMP, 2434 controls) were included. Patients showed reduced vagal indices and global variability and higher sympathovagal balance across time, frequency, and nonlinear domains. Domain-aggregated effects indicated impaired vagal modulation (g = -0.52, 95% CI -0.67 to -0.37), reduced global variability, and elevated sympathovagal balance, with substantial heterogeneity. Multilevel meta-regression identified a significant recording duration × condition interaction (β = 0.154, P < 0.001): in fibromyalgia, longer recordings were associated with greater vagal impairment (β = -0.078, P < 0.001), whereas regional pain conditions were adequately characterized by shorter protocols. CMP is characterized by consistent HRV reductions, most prominently vagal withdrawal. Heterogeneity across studies reflects condition-specific autonomic phenotypes: fibromyalgia shows systemic dysregulation detectable with extended recordings, whereas regional pain conditions display more localized HRV alterations. Protocol standardization must be condition-tailored rather than universal.