Targeting Central Sensitization: Neuromodulation Emerges as a Precision Strategy for Knee Osteoarthritis Pain

Knee osteoarthritis (搜索)搜索该疾病 (KOA) is a degenerative joint disease predominantly affecting middle-aged and older adults and is recognized as a leading cause of chronic pain and disability. With global aging and rising obesity, KOA prevalence has increased year by year, affecting approximately 370 million people by 2021. According to the Global Burden of Disease Study 2021 in The Lancet Rheumatology, KOA cases are projected to increase by 74.9% versus 2020. Although KOA involves structural degeneration—including cartilage wear, osteophyte formation, and synovial inflammation—chronic knee pain is considered a primary driver of impaired daily function, emotional comorbidities such as anxiety and depression, and medical consultation.

A long-standing contradiction has characterized the clinical diagnosis and treatment of KOA-related pain: the degree of structural damage in patients' knee joints often shows a marked inconsistency with the severity of their subjective pain, a phenomenon referred to as "clinico-radiological dissociation." Many patients with severe structural degeneration do not experience overt pain, whereas some patients with mild degeneration report severe pain symptoms. This discrepancy suggests that chronic pain in KOA may not be simply caused by peripheral nociceptive input from the joint.

Central Sensitization as a Core Pathogenic Mechanism

Accumulating evidence suggests that the development and maintenance of persistent KOA pain arise from the complex interplay of multiple factors, involving ongoing peripheral nociceptive input, local inflammatory responses, neuropathic mechanisms, psychological factors, and motor control abnormalities. A growing body of studies further suggests that central sensitization (搜索)搜索该疾病 (CS), triggered by abnormalities in the pain transmission network, serves as one of the key mediators of this complex pathological process.

CS represents pathological neuroplastic changes in the central nervous system (CNS) induced by persistent peripheral nociceptive stimuli, spanning multiple levels including the spinal dorsal horn, brainstem descending modulatory system, and cerebral cortex. These changes manifest as hyperresponsiveness and amplified signaling of nociceptive neurons to normal or subthreshold stimuli, ultimately leading to decreased pain thresholds, hyperalgesia, and allodynia. Furthermore, the pain distribution often extends beyond the anatomical boundaries of the affected joint, presenting as widespread pain.

At the spinal level, rapid, repetitive stimulation (>0.3 Hz) continuously transmitted via C fibers to the spinal dorsal horn elicits the "wind-up" effect, a form of short-term synaptic plasticity that enhances the responsiveness of spinal neurons. Glutamate binds to and activates N-methyl-D-aspartate (NMDA) receptors on spinal dorsal horn neurons, which is widely considered a key molecular mechanism mediating the "wind-up" effect. If peripheral abnormal stimulation persists, the "wind-up" effect can further develop into long-term potentiation (LTP) in the spinal dorsal horn through calcium-mediated cascading molecular reactions.

At the supraspinal level, long-term persistent nociceptive input is believed to lead to downregulation of the descending pain inhibitory system, characterized by downregulation of endogenous opioid receptors and impaired conditioned pain modulation (CPM) function. Long-term KOA pain can also induce structural changes and functional remodeling in the brain, with the primary motor cortex (M1) and primary somatosensory cortex (S1) potentially exhibiting reduced gray matter volume and abnormal functional connectivity.

Limitations of Current Treatments

Despite the diverse clinical treatments available for KOA pain, achieving durable and safe pain control remains challenging. Current strategies include non-pharmacological interventions such as exercise therapy, pharmacological options including non-steroidal anti-inflammatory drugs (搜索)搜索该药品 (NSAIDs), and total knee arthroplasty (TKA) for end-stage patients. However, their limitations are increasingly apparent. Oral NSAIDs, the most commonly used pharmacological agents for KOA pain, may cause gastrointestinal discomfort and renal impairment with long-term use. Opioids (搜索)搜索该药品, while effective for pain relief, carry significant risks of addiction and tolerance. TKA is associated with high costs, trauma, and potential complications such as infection and implant loosening.

Given the limitations of peripheral-targeted therapies, novel analgesic strategies directly modulating central pain processing networks are urgently required. Neuromodulation techniques have exhibited unique clinical potential for chronic pain and have emerged as a research focus in KOA pain management. As defined by the International Neuromodulation Society (搜索)搜索该词条 (INS), neuromodulation refers to "the alteration of nervous system function by the exogenous direct application of chemical or physical (electric, magnetic, optogenetic, thermal, or mechanical) treatments to neuronal targets."

Non-Invasive Neuromodulation Strategies

Transcutaneous electrical nerve stimulation (TENS) delivers mild pulsed electrical currents to the skin surface to stimulate nerves, intervening in pain transmission processes. Based on frequency, it is primarily classified into low-frequency TENS (LF-TENS, <10 Hz) and high-frequency TENS (HF-TENS, >50 Hz). Small-scale single-center randomized controlled trials (RCTs) have indicated that compared with placebo groups, HF-TENS (80 Hz) not only increases local pressure pain threshold (PPT) in the affected knee but also significantly elevates PPT at distant reference sites such as the tibialis anterior muscle. These observations are consistent with the hypothesis that TENS may act at spinal and supraspinal sites. In contrast, LF-TENS exhibits regulatory potential more oriented toward the brain, with a preliminary exploratory study reporting that LF-TENS induces sustained changes in cortical state, significantly increasing α oscillation amplitude in the contralateral primary sensorimotor cortex (S1/M1).

Repetitive transcranial magnetic stimulation (rTMS) generates an alternating magnetic field over a specific scalp area, inducing currents in the underlying cerebral cortex that modulate neuronal excitability. High-frequency stimulation (≥5 Hz) induces a long-term potentiation (LTP)-like effect and increases cortical excitability, whereas low-frequency stimulation (≤1 Hz) induces long-term depression (LTD) and suppresses neuronal activity. A small-scale single-center RCT in patients with KOA showed that 12 weeks of high-frequency rTMS combined with quadriceps strength training effectively improved pain, muscle strength, and joint function in KOA patients.

Transcranial direct current stimulation (tDCS) delivers weak currents (1–2 mA) to the cerebral cortex via scalp electrodes, modulating cortical excitability in a polarity-dependent manner. A systematic review and meta-analysis exploring the analgesic effects of tDCS in KOA demonstrated that tDCS markedly alleviated pain symptoms in KOA patients, yet yielded no significant improvements in secondary outcomes including physical function, joint stiffness, and quality of life. A small-scale single-center RCT reported that active tDCS combined with exercise therapy not only substantially ameliorated pain and physical function in KOA patients, but more importantly, effectively elevated PPT at multiple periknee sites and notably restored CPM function.

Invasive Neuromodulation Techniques

For refractory KOA pain predominantly driven by CS, spinal cord stimulation (SCS) and dorsal root ganglion stimulation (DRGS) may serve as promising non-pharmacological interventions to avoid opioid dependence induced by long-term high-dose opioid administration.

SCS delivers electrical current to the spinal cord to produce analgesic effects, grounded in the classic Gate Control Theory, which suppresses ascending pain signal transmission via activation of large-diameter Aβ fibers. In a monosodium iodoacetate (MIA)-induced rat model of KOA, preclinical findings have helped elucidate the mechanistic differences between these two techniques. SCS ameliorates both knee dysfunction and plantar hyperalgesia, suggesting that SCS may broadly suppress the abnormal excitability of CS-associated neurons at the spinal central level via activating spinal inhibitory pathways. In contrast, DRGS only relieves mechanical and thermal hyperalgesia on the ipsilateral stimulated side, with no meaningful analgesic effect on the contralateral side, suggesting that DRGS may indirectly mitigate the severity of CS primarily through blockade of persistent afferent input of peripheral nociceptive signals at the nerve root level.

Toward Precision Pain Management

The current clinical evidence for neuromodulation techniques targeting CS in KOA pain management remains largely at a preliminary stage of investigation. Available studies are predominantly characterized by small sample sizes, single-center designs, and short follow-up durations, with marked heterogeneity in stimulation parameters and outcome measures, which may collectively complicate the interpretation of the genuine neurobiological efficacy of these interventions.

Quantitative sensory testing (QST), as a widely used phenotyping tool for sensitization, presents notable practical barriers to routine clinical implementation, including reliance on specialized equipment and trained personnel, a lack of globally standardized population-based normative reference values, and variable inter-examiner and multi-center reliability.

Future research may benefit from exploring the development of a clinically applicable precision neuromodulation framework for KOA patients with CS, with interventions potentially tailored to individual dominant pain mechanisms. This framework could employ simplified bedside QST as the primary stratification tool, complemented by the Central Sensitization (搜索)搜索该疾病 Inventory (CSI) as a self-report screening measure, to tentatively stratify patients into sensitized and non-sensitized phenotypes. Reduced PPT at distal sites, facilitated mechanical temporal summation (MTS), and impaired CPM may be suggestive of a centrally driven pain pattern.

Ultimately, integrating baseline sensory phenotypes, central pathological indicators, and cortical excitability metrics such as TMS-evoked motor evoked potentials (MEPs) as treatment response predictors could potentially support the construction of a multidimensional predictive system, potentially facilitating the transition from empirical general protocols to mechanism-guided individualized neuromodulation. Nevertheless, the optimal combination and clinical translation of these specific components in KOA populations remain to be definitively clarified through rigorously designed, large-scale RCTs.