State-dependent roles of inflammation across pain conditions: insights from human transcriptomics

Inflammation is widely viewed as a driver of pain, yet clinical and transcriptomic studies report conflicting associations. A clearer understanding of how inflammatory processes relate to pain across clinical contexts is essential for improving diagnosis, treatment, and prevention of chronic pain.

We analysed whole-blood RNA sequencing from seven human cohorts spanning four pain conditions, including acute, postoperative, chronic localised, and chronic widespread pain in almost 500 blood samples with corresponding pain intensity scores. Using gene-level meta-analyses, pathway enrichment, and immune cell-specific gene ontologies, we tested how inflammatory responses relate to current pain, future pain trajectories, and within-person changes over time.

Inflammation emerged as one of the strongest biological correlates of pain across all cohorts, yet its association direction depended on the pain state. In acute musculoskeletal and postoperative pain, higher inflammatory activation, which correlated with enhanced neutrophil and macrophage function, was associated with greater pain intensity but also correlated with better subsequent recovery, consistent with an adaptive inflammatory response. In chronic localised pain, this relationship was disrupted and inverted: higher inflammatory activity was linked to lower pain intensity and associated with worse long-term outcomes. In chronic widespread pain, macrophage-related inflammatory activity remained positively associated with both pain severity and persistence, suggesting progression toward a maladaptive immune state.

These findings indicate that inflammation is not uniformly detrimental in pain but plays distinct roles depending on disease stage and context. Inflammation might support resolution during acute injury yet become dysregulated in chronic and nociplastic pain. Recognising these context-dependent roles could help explain conflicting findings in the literature and guide more precise use of anti-inflammatory therapies.