Chronic Migraine as an Emergent Systems Failure: Integrating Upstream Neuroimmunology, Gut–Brain Dysregulation, and Computational Chronification
Abstract
Chronic migraine affects 1–2% of the global population and is the leading cause of neurological disability in women younger than 50. Calcitonin gene–related peptide (CGRP)-targeting monoclonal antibodies and gepants represent the first disease-specific preventive therapies, yet in the registration trials in chronic migraine roughly six in ten treated patients still fail to reach a 50% reduction in monthly headache days, and medication-overuse headache compounds the problem. The therapeutic ceiling of single-target CGRP pharmacology suggests that chronification is governed by mechanisms upstream of, parallel to, and beyond the trigeminovascular neuropeptide loop. This narrative review synthesises converging evidence from 2020–2026 and proposes a multi-stratum model of chronic migraine as an emergent systems failure. In the trigeminocervical complex, the alarmin high-mobility group box 1 (HMGB1) is proposed as an upstream catalyst of Toll-like receptor 4 (TLR4) signalling to CGRP; in a nitroglycerin-induced chronic-migraine model in mice, pharmacological HMGB1 inhibition with glycyrrhizin attenuated mechanical hypersensitivity and reduced phosphorylated ERK, inducible nitric oxide synthase and CGRP release, though this is a single-laboratory result with a non-selective inhibitor. Clinical data from patients with medication-overuse headache reveal elevated circulating lipopolysaccharide, HMGB1, and HIF-1α, consistent with intestinal barrier failure feeding systemic…
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Evidence Hub reads this as a cohort study, done in people. Its evidence level is 3 of 5 (Moderate · trial / cohort / secondary analysis). Trials without a large randomized design, cohorts and secondary analyses give moderate evidence.
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