Under pressure: lessons from and beyond entrapment neuropathies

Entrapment neuropathies are the most prevalent focal neuropathic pain conditions globally and impose a substantial individual and socioeconomic burden. Traditionally conceptualised as purely mechanical compression syndromes, this view is increasingly challenged by converging evidence from human tissue analyses, advanced neuroimaging, and deep clinical phenotyping. Entrapment neuropathies are now recognised as biologically dynamic disorders shaped to different extents by microvascular compromise, demyelination, axonal degeneration, immune dysregulation, neuroinflammation, central nervous system adaptations, and psychosocial influences. Varying combinations and dominance of biopsychosocial processes give rise to marked clinical heterogeneity even within the same diagnostic label. This mechanistic diversity helps explain common diagnostic discordances, including extraterritorial symptom spread, normal electrodiagnostic findings despite clinical symptoms indicative of entrapment neuropathies, and imaging-clinical presentation mismatch. It also challenges one-size-fits-all treatment approaches, which have largely failed in entrapment neuropathies.Uniquely, entrapment neuropathies provide a natural human model of focal nerve injury in the context of neuropathic pain. Surgical decompression allows integration of tissue-level biology with precise clinical phenotypes and offers time-locked insights into recovery. Lessons derived from this model extend beyond entrapment neuropathies and can inform broader understanding of neuropathic and nerve-related musculoskeletal pain conditions. Here, we synthesise contemporary mechanistic insights, examine how biological heterogeneity translates into distinct clinical phenotypes, and discuss potential implications for mechanism-informed management.