Shaping the boundaries of neuropathic and nociplastic pain

This Ph.D. research examines the role of small fiber pathology in the development of nociplastic and neuropathic pain, with a focus on sensory and autonomic aspects of small fiber damage. Neuropathic pain arises from somatosensory system injury, whereas nociplastic pain lacks clear tissue or nerve damage, often making diagnosis one of exclusion. This project compares small fiber pathology (observed in fibromyalgia syndrome, which lacks traditional neuropathic indicators yet shows reduced intraepidermal nerve fiber density) with small fiber neuropathy, marked by peripheral nerve damage affecting pain and sensory function. The research employed quantitative sensory testing (QST), skin biopsy, cardiovascular reflex tests, and heart rate variability analysis. The first study evaluates differences in QST sensory profiles between patients with small fiber neuropathy and small fiber pathology, indicating distinct pathophysiological mechanisms underlying these conditions. The second study explores pain in long COVID, demonstrating that it can present as either small fiber neuropathy with associated neuropathic pain or as nociplastic pain, unaccompanied by nerve damage. Two additional studies innovatively investigated autonomic small fibers, revealing their involvement in fibromyalgia beyond pain perception alone. Findings suggest that small fiber pathology in fibromyalgia patients contribute to autonomic imbalances, triggering central sympathetic hyperactivity and chronic orthostatic intolerance. These data support the role of small fiber damage in nociplastic pain conditions, indicating an increasingly blurred boundary with neuropathic pain.