Chronic pain affects a large portion of the global population and represents a major public health burden due to its impact on physical function, mental health, and quality of life. Importantly, many individuals experience persistent pain despite minimal or absent ongoing tissue damage, and structural abnormalities on imaging frequently fail to correlate with symptom severity. This mismatch highlights the need for mechanistic frameworks that explain chronic pain beyond peripheral pathology. A narrative review was conducted using PubMed and Google Scholar with keywords including chronic pain, central sensitization, neuroplasticity, predictive processing, and nociplastic pain. Peer-reviewed human and translational studies published within the past decade examining mechanistic contributors to chronic pain were included, while non-peer-reviewed sources and studies not directly addressing pain mechanisms were excluded. This narrative review examines interacting mechanisms that may contribute to chronic pain persistence. Central sensitization describes increased nociceptive gain within spinal and supraspinal pathways, explaining phenomena such as hyperalgesia and allodynia but lacking reliable biomarkers and standardized diagnostic criteria. Neuroplasticity research demonstrates structural and functional reorganization within pain-related brain networks. Predictive processing proposes that pain perception is shaped by expectations, prior learning, and threat appraisal, offering insight into cognitive amplification of pain. Stress and emotional circuits further interact with these mechanisms through limbic activation, fear learning etc. Despite advances in each domain, significant limitations remain, including unclear transition mechanisms from acute to chronic pain. Integrating cellular, neural, cognitive, and stressrelated processes into a unified framework may improve mechanistic understanding and guide future diagnostic and therapeutic strategies.
