Trial reportNeurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology2026
Neurovascular-immune mediator dynamics in migraine: State-dependent effects of caffeine.
Trial report in Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Authors and funding
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Abstract
backgroundMigraine is a complex neurovascular disorder involving interactions between trigeminovascular, endothelial, and neuroimmune pathways. Dysregulation of key mediators-calcitonin gene-related peptide (CGRP), nitric oxide (NO), endothelin-1, interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α)-is central to its pathophysiology. However, their phase-dependent dynamics and acute responsiveness to caffeine remain unclear. This study evaluated phase-specific alterations in these mediators and their intra-individual response to caffeine.
methodsA total of 327 participants (174 migraine patients and 153 healthy controls) were included. Migraine patients were assessed across interictal and ictal phases using a within-subject design. During ictal attacks, participants underwent a randomized, double-blind, placebo-controlled crossover intervention with 200 mg caffeine or placebo. Blood samples were collected at baseline (T0) and 60 min post-intervention (T1). Mediators were measured using ELISA and analyzed with linear mixed-effects models.
resultsCGRP, NO, IL-6, and TNF-α were significantly elevated during migraine, particularly in the ictal phase, while endothelin-1 was reduced. Caffeine significantly decreased CGRP and NO levels and increased endothelin-1 compared with placebo. IL-6 and TNF-α showed modest reductions. Responses varied between individuals, with greater effects observed in those with higher baseline levels.
conclusionsMigraine is characterized by dynamic, phase-dependent neurovascular and inflammatory alterations. Acute caffeine administration modulates key mediators, promoting a shift toward a more vasoconstrictive vascular balance and reduced trigeminovascular activation. These effects are influenced by baseline mediator levels, highlighting the importance of state-dependent responsiveness. The findings emphasize the need for temporally sensitive and individualized approaches in understanding migraine pathophysiology and therapeutic modulation.
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