Mechanisms of pain occurrence in osteoarthritis: peripheral triggers, sensitization, and the path to persistence

Osteoarthritis (OA) is a joint disease, and pain drives disability. Radiographic severity correlates poorly with pain intensity, indicating that OA pain cannot be explained by cartilage loss alone. This narrative review focuses on OA pain occurrence, the events that translate joint pathology into episodic activation of nociceptive pathways. We synthesize evidence that pain occurrence is initiated and shaped by peripheral mechanisms, including algogenic signaling in tissues, access of nociceptors to pain sources, and sensitization related lowering of activation thresholds. Key triggers include inflammatory and lipid mediators, neurotrophin-dependent sensitization, and joint acidosis. Proton-sensing channels and receptors are implicated in pH-driven nociceptor activation (preclinical evidence), though direct causal demonstration in human OA remains limited. Neurovascular remodeling and sympathetic-sensory crosstalk have been associated with increased nerve density and excitability in preclinical models, and synovial immune dysregulation may contribute to a permissive microenvironment, with human evidence largely observational or inferential. Systemic factors, particularly obesity and metabolic dysfunction, bias joint biology toward heightened pain responsiveness via adipokines and inflammation. Persistent peripheral input may promote central sensitization and pain chronicity. We discuss implications of targeting peripheral mechanisms to reduce pain occurrence and prevent transition to refractory, centrally amplified pain states. Inferences are limited by cross-sectional designs, intensity-dominant outcomes, limited phenotype stratification, and translational gaps between experimental models and the prolonged course of OA in humans. Peripheral and central processes are often inferred indirectly and co- occur, complicating attribution along pain trajectories. Longitudinal, stage and phenotype stratified cohorts integrating imaging, molecular and sensory phenotyping, plus occurrence oriented outcomes, are needed.