Immuno-Inflammatory Mechanisms in the Chronification of Pain
Marcelo A. A. Moncada, Marco A. Narváez Tamayo, Miguel A. Narvaez Encinas, Matteo Luigi Giuseppe Leoni, Giustino Varrassi
Abstract
Chronic pain affects 20% of the global population, with current treatments achieving meaningful relief in less than 30% of patients. Growing evidence indicates that immuno-inflammatory mechanisms critically mediate the transition from acute to chronic pain, extending beyond sustained nociceptive input. This narrative review synthesizes current understanding of cellular and molecular immuno-inflammatory processes underlying pain chronification, emphasizing therapeutic implications of immune-neural interactions. Peripheral tissue injury triggers coordinated immune responses involving pro-inflammatory cytokines such as interleukin (IL)-1β, IL-6, tumor necrosis factor alpha (TNF-α), and algesic mediators that sensitize nociceptors. Infiltrating macrophages, T lymphocytes, and mast cells perpetuate pro-nociceptive environments. Centrally, microglial and astrocytic activation induces persistent neuroinflammation, synaptic remodeling, and enhanced excitatory neurotransmission while impairing descending inhibition. The balance between pro-inflammatory T helper 1 and T helper 17 (Th1/Th17) and anti-inflammatory T helper 2 and regulatory T cell (Th2/Treg) responses determines pain outcomes. Critically, premature suppression of acute inflammation with nonsteroidal anti-inflammatory drugs (NSAIDs) or corticosteroids may paradoxically promote chronification by disrupting endogenous resolution pathways mediated by specialized pro-resolving mediators and regulatory immune cells. Local inflammation proves more relevant than systemic inflammation for pain persistence. The gut-brain-immune axis emerges as a novel therapeutic target, with microbiota composition influencing pain susceptibility through immunomodulation. Finally, chronic pain represents a failure of natural resolution mechanisms rather than prolonged nociceptive activation. Understanding temporal dynamics of immune responses, individual variability, and sex-specific mechanisms opens avenues for precision medicine approaches. Future strategies should restore homeostatic mechanisms rather than simply suppress symptoms, incorporating biomarker-guided treatment selection and multimodal interventions targeting the complex immuno-inflammatory cascade.