Targeting Central Sensitization for Pain Management in Knee Osteoarthritis: A Narrative Review of Mechanisms and Clinical Applications of Neuromodulation.

Chronic refractory pain in knee osteoarthritis (KOA) is among the leading causes of physical disability worldwide. While KOA is traditionally characterized by articular cartilage degradation, subchondral bone remodeling, synovial inflammation, and periarticular soft tissue lesions, the structural damage frequently dissociates from the symptomatic pain severity. Emerging neurobiological evidence suggests that central sensitization (CS)-the pathological neuroplastic remodeling of the central nociceptive networks-may play a pivotal role in the exacerbation and maintenance of KOA pain. Conventional therapeutic approaches primarily act on peripheral joints. Consequently, these approaches often yield suboptimal analgesic efficacy in patients who have already developed deep-rooted CS, while also carrying risks of potential side effects. Given these clinical challenges, neuromodulation has emerged as a potential alternative or adjunctive analgesic strategy. By directly manipulating neural activity to potentially reverse maladaptive plasticity, these modalities may provide a novel framework targeting CS structurally and functionally, potentially addressing the limitations of conventional medicine. Recent technological advancements have accelerated the exploration of both non-invasive techniques-including transcutaneous electrical nerve stimulation (TENS), transcranial direct current stimulation (tDCS), and repetitive transcranial magnetic stimulation (rTMS)-and invasive procedures, such as spinal cord stimulation (SCS) and dorsal root ganglion stimulation (DRGS). From the perspective of combating CS, this narrative review summarizes the mechanistic basis and clinical evidence of diverse neuromodulatory applications in KOA pain management. Furthermore, we propose the integration of Quantitative Sensory Testing (QST) for the phenotypic stratification of sensitization in patients, which may facilitate a paradigm shift toward precision neuromodulation in KOA.