Triggers such as irregular sleep, caffeine fluctuation or an estrogen drop activate the meningeal nociceptors of the trigeminal nerve, whose endings then release large amounts of CGRP.Migraine is not a simple headache — it is an inflammatory pathway in the trigeminovascular system:
Triggers (highly individual):
· Irregular sleep / crossing time zones / weekend "sleep-in" · Caffeine fluctuation (withdrawal is a more common trigger than intake) · Menstrual cycle + estrogen drop · Individual food triggers (alcohol / red wine / aged cheese / chocolate / / nitrites) · Flickering light / strong odours / sudden temperature change · Neck and shoulder tension.
Trigger → trigeminovascular activation:
· The V1 branch of the trigeminal nerve innervates the meninges + extracranial vessels · Meningeal nociceptors are activated at a low threshold · In migraine with aura, cortical spreading depression (CSD): a wave of decreased visual-cortex neuronal activity → indirectly activates the trigeminal system.
· A 37-amino-acid neuropeptide, discovered in 1983 · Stored in large quantities at trigeminal nerve endings + surges during a migraine attack · A potent vasodilator (~ 100 × histamine) · A pro-inflammatory mediator — initiates neurogenic inflammation · Goadsby's 1990s series: jugular CGRP concentrations rise sharply during attacks and fall after triptan acute rescue.
2 · pain cascade
CGRP dilates meningeal vessels, sets off neurogenic inflammation and sensitises the trigeminal pathway, producing throbbing pain that worsens with any head movement.Downstream cascade after CGRP release:
① Vascular effect:
· CGRP → strong dilation of the middle meningeal artery and extracranial vessels · Fluctuating vascular tone + pulsing sensation = the physical basis of the "throbbing" pain quality.
② Neurogenic inflammation:
· CGRP → activates mast cells + macrophages → release histamine + + cytokines · Inflammation around the meningeal vasculature, not parenchymal injury · This inflammation further sensitises the peripheral trigeminal: previously non-painful stimuli (drum-membrane pulsation, head position change) become painful → "any head movement hurts".
③ Trigeminocervical complex (TCC):
· Trigeminal-meningeal signal → trigeminal ganglion → TCC (brainstem + upper cervical cord) · Central sensitisation here: in chronic migraineurs, the TCC remains hyper-responsive even between attacks → the anatomical basis of "chronic migraine" (Burstein review).
④ Ascending propagation:
· TCC → thalamus → cortex → subjective pain + photophobia + phonophobia + nausea (central autonomic) · Cortical spreading depression (CSD): visual aura (~ 25% of migraineurs) = a wave of altered cortical neuronal activity spreading at ~ 1 cm / 4 min.
Triptans (the 1990s revolution) — 5-HT₁B/D agonists:
· Constrict intracranial vessels + suppress CGRP release (dual mechanism) · Acute-attack relief backed by a large body of randomized trials, but coronary-constriction warning + not for prevention.
CGRP is the core: this is why anti-CGRP monoclonal antibodies are the first class of migraine preventives designed by mechanism (rather than borrowed from anti-epileptic / anti-depressant drugs).
3 · anti-CGRP mAb
Anti-CGRP monoclonal antibodies prevent migraine by blocking the CGRP receptor or binding the CGRP ligand itself, and small-molecule gepants offer an oral option.In 2018-2019 the FDA approved 4 CGRP mAbs — a paradigm shift in migraine prevention:
① Erenumab (Aimovig, Amgen):
· Target: CGRP receptor (CGRP-R) — the only receptor-targeted member · Dosing: 70 / 140 mg once monthly, self-administered subcutaneously · STRIVE / ARISE trials: monthly migraine days -3 to -4 (baseline 8-9), 50% responder rate ~ 50% (placebo ~ 27%) · Class side effects: injection-site reactions + stubborn constipation (CGRP plays a physiological role in the gut; blocking it makes constipation the most predictable reaction).
② Fremanezumab (Ajovy, Teva):
· Target: CGRP ligand · Dosing: 225 mg monthly or 675 mg quarterly · HALO trial: similar reduction in attacks · Side effects: injection-site reactions; constipation milder than with erenumab.
③ Galcanezumab (Emgality, Lilly):
· Target: CGRP ligand · Dosing: 240 → 120 mg monthly · EVOLVE trial: monthly migraine days -3 to -4 · Extra indication: cluster-headache prevention (the only approved mAb).
④ Eptinezumab (Vyepti, Lundbeck):
· Target: CGRP ligand · Dosing: 100 / 300 mg IV every quarter (the only IV) · PROMISE trial: takes effect on day 1 — suitable for patients with dense attacks.
Gepants (small-molecule CGRP-R antagonists):
· Ubrogepant (Ubrelvy): acute rescue — pairs with triptan intolerance / coronary contraindication · Atogepant (Qulipta): daily oral prevention — same indications as mAbs but oral, a patient preference option · Rimegepant (Nurtec ODT): dual rescue + prevention indication (75 mg every other day) · Post-2024: gepant pricing + oral convenience means mAbs no longer hold a monopoly — more choice.
4 · clinical landscape
CGRP drugs suit frequent, disabling migraine, while traditional preventives and the riboflavin, magnesium and trio still have a place, weighed by evidence, cost and side effects.Real indications for CGRP-class drugs (AHS 2024 position statement):
· ≥ 4 migraine days / month + functional impact — ⚠️ no requirement to have failed 2 or more traditional classes first: the 2024 AHS update is titled around CGRP-targeting therapies being a first-line option, and states they should be considered first-line without a requirement for prior failure · Chronic migraine (≥ 15 headache days / month) is a priority · Cluster headache (galcanezumab) · MOH (medication-overuse headache): use cautiously, taper OTC analgesics first.
Traditional preventives still have a place:
· β-blockers (propranolol): backed by multiple randomized trials, cheap, first choice in cardiovascular comorbidity (HTN + migraine) · Topiramate: backed by multiple randomized trials; lowers weight / affects cognition (the "dopamax" side effect) · Tricyclics (amitriptyline): fewer randomized trials; useful when treating insomnia + depression together · Botox (onabotulinumtoxinA): backed by large randomized trials for chronic migraine, 31 fixed injection points.
Relation to nutritional prevention (the riboflavin + magnesium + trio):
· Riboflavin (B2) 400 mg/day — Schoenen 1998: one small randomized trial · Magnesium 400-600 mg elemental Mg/day — Peikert 1996: one randomized trial; this is above the tolerable upper intake level () for supplemental magnesium (350 mg a day), so take it under medical guidance · CoQ10 100-300 mg/day — Sándor 2005: one small randomized trial
· The trio fits patients with ≥ 1-2 attacks/month but < 4 (below the CGRP indication threshold), or as synergistic add-on to CGRP / traditional drugs · Trio vs CGRP: moderate certainty (only a few small randomized trials each) vs high (multiple large randomized trials), but cheap + safe + self-managed = a reasonable 8-12-week first-line trial.
Class side effects (shared across mAbs):
· Constipation — the CGRP-R pathway is physiologically active in the gut; blocking it → constipation (especially erenumab) · Injection-site reactions · Rare cardiovascular event signal — under post-marketing surveillance, related to ligand-blockade vascular effects, not yet confirmed as causal · Pregnancy / lactation: not recommended; effective contraception advised.
Economics:
· CGRP mAb out-of-pocket ~ ¥6000-12000 / year (now available in China) · One year of the trio out-of-pocket ~ ¥200-500 · Multiple large trials + high cost vs a few small trials + low cost is a real trade-off.
Red flags — immediate neurology referral:
· Thunderclap sudden severe headache → rule out SAH · First-ever attack ≥ age 50 → rule out intracranial pathology · CGRP-class drug + cardiovascular event: consult neurology + cardiology.