Abstract
Skeletal muscle injuries, whether acute or chronic, are a major clinical challenge due to their high incidence, persistent pain, and risk of functional impairment. While pharmacological interventions like NSAIDs and opioids remain mainstays for pain management, their prolonged use is limited by adverse effects and potential interference with muscle regeneration. Emerging evidence underscores the importance of balanced inflammatory responses in tissue repair, highlighting the need for alternative strategies. Manual therapy and exercise therapy modulate nociceptive signaling through biomechanical, biochemical, and neurocognitive mechanisms, including inhibition of central sensitization and activation of descending analgesic pathways, while advanced tissue engineering approaches (3D bioprinting, exosome therapy, and genetic engineering) directly target inflammation, enhance vascular and neuromuscular regeneration, and restore structural integrity of injured muscle. This review synthesizes current knowledge on the mechanisms underlying acute and chronic muscle injury-associated pain, emphasizing the roles of peripheral sensitization, neuroinflammation, and maladaptive central plasticity, and further delineates how specific non-pharmacological interventions are mechanistically tailored to counteract these processes.