Intact Conditioned Pain Modulation Despite Altered Pain Sensitivity in Migraine Across Phases and Sites

OBJECTIVES: Altered endogenous pain-inhibitory pathways have been proposed as a mechanistic contributor to migraine. However, results from conditioned pain modulation (CPM) paradigms are inconsistent, potentially reflecting limited assessment of trigeminal nociception and a paucity of data stratified by migraine phase. Accordingly, this study aimed to evaluate the site- and phase-dependence of CPM and somatosensory sensitivity in migraine. METHODS: In a cross-sectional study, 50 adults with migraine and 50 age-/sex- headache-free controls underwent assessor-blinded, standardized CPM and quantitative sensory testing (QST) at a trigeminal site (V1, forehead) and an extra-trigeminal site (C6, forearm). CPM was calculated as the change in heat pain thresholds measured during a heterotopic ischemic conditioning stimulus relative to baseline. QST captured thermal, pressure and mechanical pain measures, also including mechanical pain sensitivity and allodynia. Repeated-measures ANOVAs tested effects of CPM, site, diagnosis and migraine phase (peri-ictal vs. interictal). RESULTS: A robust inhibitory CPM effect was observed in both migraine and control groups, with no between-group or phase-specific differences across sites (all p > 0.05). Compared with controls and not considering the stimulated region, migraine was associated with lower pressure pain thresholds (p < 0.001) and higher mechanical pain sensitivity (p = 0.001), alongside elevated central sensitization and catastrophizing scores (p < 0.001). Across migraine phases, pain sensitivity measures were largely stable; however, trigeminal mechanical pain sensitivity was selectively higher during the peri-ictal phase (p = 0.017). CONCLUSIONS: CPM appears preserved in migraine across phases and anatomical territories, whereas sensory alterations may be modality- and region-specific, supporting a pain sensitivity amplification phenotype rather than a generalized deficit in endogenous inhibition. SIGNIFICANCE STATEMENT: Patients with migraine could inhibit pain similarly to controls, but they present in general lower pressure and mechanical pain thresholds in contrast to controls and increased mechanical sensitivity on the forehead during the peri-ictal phase. This suggests that migraine involves specific changes in pain processing rather than a general disruption of the descending inhibitory system.