Systematic review data puts the prevalence of central sensitization features among knee osteoarthritis patients at approximately 36 percent by validated instrument. More than one in three patients carrying an orthopedic diagnosis you trust, presenting with pain that structural intervention may only partially address. The joint pathology on the imaging is real. The dominant pain mechanism is incompletely characterized.
In my last piece, I argued that glucagon-like peptide-1 (GLP-1) pharmacology and neurotechnology are approaching chronic pain from opposite directions, and that whoever demonstrates durable pain reduction will reshape the standard of care. But a prior question sits in front of that argument, one that neither industry has answered publicly because the answer is commercially inconvenient: A substantial proportion of the patients both technologies are targeting have nociplastic features, and the interventions being deployed against them were designed primarily for peripheral structural or nociceptive targets.
Nociplastic pain is the International Association for the Study of Pain’s (IASP) mechanistic descriptor for pain arising from altered nociception in the absence of clear evidence of ongoing tissue damage or somatosensory nerve injury. It is not a wastebasket. It is not a euphemism for psychiatric illness, drug-seeking behavior, or pain a clinician cannot explain. It is a recognized, biologically grounded phenotype that coexists with nociceptive and neuropathic mechanisms in the same patient, often simultaneously, with a clinical signature that becomes legible once you know what to look for.
Pain disproportionate to identifiable structural pathology. Sleep dysfunction, fatigue, cognitive symptoms, hypersensitivity to pressure, heat, light, sound, and odor. Fibromyalgia, irritable bowel, headache, and other overlapping pain conditions appearing in the same history. A reported inciting event such as infection, surgery, trauma, or sustained psychological stress, followed by pain that persists long past what the original injury adequately explains.
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These are not random comorbidities stacked on a structural diagnosis. In many patients they are convergent expressions of dysregulated sensory processing: increased excitatory neurotransmission, impaired descending inhibition, glial activation, neuroinflammation, and altered endogenous pain-modulatory function operating in concert.
Conditioned pain modulation provides one measurable window into this biology. Normally, one painful stimulus suppresses the perception of another through endogenous inhibitory mechanisms. In many chronic pain patients that inhibitory response is diminished or absent. The brake system is offline. Procedures aimed at peripheral structure do not bring it back.
This has concrete surgical implications. A 2022 meta-analysis of patients undergoing total knee arthroplasty found significantly worse postoperative pain outcomes among those with preoperative central sensitization features. The implication is not that surgery is contraindicated whenever nociplastic findings are present. Mixed pain states are common, and peripheral pathology can be clinically significant even when central sensitization is also operating. The implication is that identifying an anatomic abnormality on imaging does not establish that a procedure directed at that abnormality will address the dominant pain generator. Similar concerns have emerged across other structurally directed interventions, though the evidence base varies by procedure and the strength of association differs across studies.
Medicare policy has begun to reflect part of this. Current facet-joint local coverage determination (LCD) guidance states explicitly that procedures performed for generalized pain conditions such as fibromyalgia or chronic centralized pain syndromes are generally not considered medically reasonable and necessary. This is a specific coverage statement, not a broad Centers for Medicare & Medicaid Services (CMS) determination about nociplastic pain or interventional medicine generally. But it encodes a principle that should precede every procedure we authorize: An anatomic finding justifies an intervention only if that anatomy is plausibly the dominant source of the patient’s pain.
The GLP-1 data sits inside this same unresolved question. The STEP 9 trial randomized 407 patients with obesity and knee osteoarthritis to semaglutide 2.4 mg or placebo. The semaglutide group reported Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain improvement of 41.7 points versus 27.5 in the placebo group, a 14-point difference, alongside weight reduction of 13.7 percent versus 3.2 percent. The trial establishes superior pain outcomes. It does not establish the mechanism producing them, and the mechanistic question is the scientifically productive one.
Preclinical and translational research has identified biologically plausible GLP-1 receptor signaling pathways involving microglial activity, IL-10 mediation, beta-endorphin release, neuroinflammation modulation, and central sensory processing. A 2026 review reached the appropriately cautious conclusion: The mechanistic evidence is compelling at the preclinical level, but direct analgesic efficacy at systemic clinical doses has not been established in humans independently of weight reduction, mechanical unloading, and metabolic improvement. Whether some STEP 9 responders improved through mechanisms beyond weight reduction, and whether patients with significant central sensitization features responded differently than those without, are questions the trial was not designed to answer. Future studies should be.
Neurotechnology faces an equivalent gap. Closed-loop spinal cord stimulation, noninvasive brain stimulation, and AI-guided neuromodulation target neural processing rather than peripheral anatomy, which makes them in principle more relevant to nociplastic mechanisms than most structural interventions. Identifying which patients have predominantly nociplastic physiology, and therefore which are most likely to benefit, is not yet standard practice in most implanting centers. The same diagnostic question precedes both pharmacological and device-based approaches: What combination of mechanisms is operating in this patient?
No single validated biomarker currently answers that question definitively. The IASP clinical framework relies on pain distribution, exclusion of adequately explanatory nociceptive or neuropathic pathology, evidence of evoked hypersensitivity, and associated systemic symptoms. Quantitative sensory testing, conditioned pain modulation assessment, validated questionnaires, and pain-distribution mapping each contribute information. None is sufficient alone. Physician pattern recognition integrated across the full clinical picture remains the essential step, and it has to happen before the intervention decision, not after a series of failed ones.
Consider the patient with osteoarthritis, poor sleep, widespread hypersensitivity, cognitive symptoms, irritable bowel, and persistent pain after technically successful procedures. The available framing in most clinical settings is binary: find another structural lesion to treat, or imply the pain is psychological. Neither is adequate for a large subset of these patients.
The nervous system itself may have become dysregulated, altering nociceptive gain, weakening endogenous inhibition, and sustaining pain that peripheral pathology alone no longer predicts or explains. Giving that process a biologically coherent name does not invalidate the patient’s suffering. It redirects clinical resources toward what the pain is actually running on.
In 2021, approximately 51.6 million American adults reported chronic pain. As new pharmacological and neurotechnological approaches enter this space, the pull will be toward asking which technology produces superior outcomes. The prior question is whether we can characterize the dominant pain mechanisms in an individual patient before selecting the intervention.
The structural lesion is sometimes the primary driver. The nerve injury sometimes is. In a significant and measurable proportion of patients, altered central nociceptive processing has become the dominant mechanism, and technically proficient peripheral intervention will not reach it.
Before the next procedure, two questions are worth separating: Is there a lesion I can treat? And is that lesion the mechanism generating this patient’s pain?
Asking both is where precision pain medicine actually starts.
Amir Friedman is a pain physician, physician-scientist, and investigator with 25 years of clinical experience and more than 10,000 patients treated. He trained in surgery, anesthesiology, critical care, and pain medicine at the University of Southern California and the University of California, Los Angeles.
His work focuses on chronic pain, neuromodulation, regenerative medicine, longevity, men’s health, and emerging approaches to chronic disease. He writes about neuroscience, AI-enabled medicine, and the challenge of translating innovation into meaningful patient care.
Friedman also applies his experience in complex chronic illness and care delivery through his work with Broadway Community Care Centers in California, advancing integrated behavioral health care models designed to improve access, coordination, and outcomes for underserved communities. He can be found on LinkedIn.
