Unraveling Chronic Pain: From Mechanisms and Risks to Diagnosis and Treatment

Chronic pain is a globally prevalent and complex condition, encompassing three primary subtypes, that is, nociceptive, neuropathic, and nociplastic, each with distinct biopsychosocial mechanisms. Chronic pain was historically viewed as a monolithic symptom and managed with opioid-centric models, causing widespread therapeutic failure. While recognition of its heterogeneity has driven a paradigm shift toward precision medicine, tailoring multimodal strategies to the dominant pain mechanism, critical challenges persist. These include difficulty in identifying treatable root causes, limited long-term efficacy of therapies, and significant side-effect burdens. To address these gaps, this review systematically synthesized contemporary knowledge, predominantly from the last decade, on the molecular mechanisms, risk factors, diagnostic frameworks, and therapeutic modalities for chronic pain, framed by its pathophysiological subtypes. Furthermore, it explored two novel frontiers aimed at advancing personalized pain medicine. First, it proposed cold atmospheric plasma as an innovative therapeutic intervention capable of modulating key molecular pathways underlying diverse pain manifestations. Second, it introduced an original neurobiological model positing the hippocampus as a putative sensor for nociplastic pain, interfacing with higher-dimensional information fields. These insights may offer transformative potential for refining diagnostic and therapeutic strategies, potentially revolutionizing the management of chronic pain.