Small nerve fibre pathology in non-neuropathic chronic pain conditions: a systematic review and meta-analysis

Small nerve fibre pathology has been observed in several chronic pain conditions not typically classified as neuropathic (e.g., fibromyalgia). This systematic review compared morphometric data of small nerve fibres in people with non-neuropathic chronic pain conditions, defined using ICD-11 classifications, with pain-free controls. MEDLINE, EMBASE, Cochrane, Web of Science, and CINAHL were searched. Two independent reviewers performed screening, risk of bias assessment, and data extraction. Outcomes of interest were intraepidermal nerve fibre density (IENFD) and metrics derived from corneal confocal microscopy (CCM), compared by meta-analysis. Quality of evidence was assessed using Grades of Recommendation, Assessment, Development, and Evaluation. Fifty-two studies were included, examining fibromyalgia (N = 28), complex regional pain syndrome I (N = 5), migraine (N = 4), and other conditions (N = 15). Intraepidermal nerve fibre density was assessed in 41 studies and CCM in 14 studies. Risk of bias was low in 24 studies and moderate in 28. Meta-analysis revealed lower IENFD (fibres/mm 2 ) at the distal leg (MD: -3.06 [95% CI: -3.80 to -2.31]; I 2 = 74%; 16 studies; 1123 participants) and proximal thigh (MD: -3.77 [-5.10 to -2.43]; I 2 = 86%; 12 studies; 896 participants) and reduced corneal nerve fibre density (MD: -7.14 [-13.56 to -0.72]; I 2 = 98%; 8 studies; 768 participants) in participants with non-neuropathic chronic pain compared with controls. Innervation measures differed in participants with chronic pain vs controls for other IENFD and CCM metrics. Quality of evidence ranged from high to low. Associations between clinical features (e.g., pain, disability) and IENFD/CCM data were less commonly examined, mostly indicating no relationships. There is morphological evidence of small nerve fibre pathology in non-neuropathic chronic pain conditions; however, the clinical significance of these findings is unclear.