Allodynia in migraine patients with fibromyalgia comorbidity: focus on small fiber pathology

Background: Cutaneous allodynia is a clinical marker of central sensitization in migraine and is associated with greater migraine severity and poorer outcomes. Fibromyalgia (FM) is a frequent comorbidity of migraine that may further enhance central sensitization, whereas small fibre pathology (SFP) has been identified in a substantial proportion of FM patients. Whether FM comorbidity and peripheral small-fibre abnormalities contribute to cutaneous allodynia in patients with migraine remains unclear. We investigated cutaneous allodynia and migraine characteristics in patients with migraine with and without FM and, within the FM cohort, according to skin biopsy findings. Methods: In this retrospective cross-sectional study, 212 patients with migraine were included: 106 patients with FM who had undergone skin biopsy (65 with pathological and 41 with normal biopsy findings) and 106 patients without FM with the same sex distribution and comparable age. FM and migraine were diagnosed according to current clinical criteria. Cutaneous allodynia was assessed using a standardized clinical checklist. Skin biopsy was performed at the proximal thigh and distal leg, and SFP was defined by reduced intraepidermal nerve fibre density (IENFD). The comparison between patients with and without FM was the primary analysis; comparisons according to skin biopsy findings and correlations with IENFD were secondary analyses. Migraine characteristics, allodynia, and migraine-related disability were compared across groups. Results: The proportion of chronic migraine (CM) was similar in patients with and without FM (19.8% vs. 21.7%; p=0.866). Cutaneous allodynia was more frequent in patients with FM than in those without FM (82.1% vs. 64.2%; p=0.005), and moderate-to-severe allodynia affected 50.9% vs. 16.0% of patients, respectively (p<0.001). Median allodynia scores were 6 (interquartile range [IQR] 4-8) in patients with FM and pathological biopsy findings, 6 (3-7) in those with normal biopsy findings, and 3 (2-5) in patients without FM (p<0.001; ε2=0.133), with no difference between the two FM subgroups; allodynia scores were not associated with proximal or distal IENFD. Greater allodynia was associated with greater migraine-related disability among participants with available Migraine Disability Assessment (MIDAS) data, including after adjustment for age, headache frequency, and FM status (partial ρ=0.267, p=0.002). Conclusions: FM comorbidity identifies patients with migraine with a greater burden of cutaneous allodynia, independently of migraine chronification. This sensory hypersensitivity was not clearly related to the presence or extent of structural small-fibre loss, supporting a predominant contribution of central sensitization. Structural and functional assessments of small fibres, including trigeminal territories, may further clarify the contribution of peripheral abnormalities to migraine-related allodynia in FM.