When imaging is normal, but biology is not: Aligning diagnostics of pain states with nociceptive biology

Pain is the leading reason people seek medical care. Yet, the diagnosis of acute and chronic pain states remains tied to a structural paradigm that equates real disease with visible anatomical abnormality on imaging or systemic laboratory changes. When scans are normal and routine lab tests are unremarkable, patients with severe pain are often labeled nonspecific or functional, as if the absence of structural findings implied an absence of underlying biology. This approach ignores convergent evidence that nociception, the neural process required for pain, operates through molecular, cellular, and network-level mechanisms within a distributed apparatus spanning peripheral nociceptors, dorsal root ganglia, spinal circuits, and supraspinal networks, at scales and in compartments that conventional diagnostics were never designed to detect. Mechanistic studies already demonstrate microstructural, neuroimmune, electrophysiological, and metabolic abnormalities in people with chronic pain whose imaging and systemic laboratory results appear normal. Current policies that discourage imaging in conditions such as low back pain correctly recognize the weak correlation between structural findings and pain but mistakenly treat this as evidence that imaging has no diagnostic role, rather than that structural imaging is poorly matched to nociceptive physiology. We argue that chronic pain diagnostics should be realigned with nociceptive biology, using existing and emerging tools to detect physiologic nociceptive pathology even when structural imaging is normal. PERSPECTIVE: This paper challenges the structural paradigm for diagnosing painful states, arguing that normal imaging does not imply normal biology. It calls for aligning diagnostics with nociceptive physiology, recognizing molecular, cellular, and network mechanisms of pain, and advancing emerging imaging technologies to detect nociceptive pathology currently invisible to conventional structural imaging.