Migraine Onset — Cranial Vasodilation & Trigeminal Activation
Dilated meningeal vessels and firing trigeminal fibers drive throbbing pain.
- ~14%: Migraine prevalence (of adults worldwide)
- 4–72 h: Attack duration untreated (per episode)
- +30–60%: Vessel dilation (meningeal artery diameter)
- ↑↑: CGRP release (neuropeptide surge)
The trigeminovascular cascade
Trigeminal fibers release CGRP, dilating meningeal vessels.
Neurogenic inflammation
Plasma proteins leak, sensitizing pain-sensing nerve endings.
Central sensitization risk
Delay lets brainstem neurons become hyperexcitable.
Early Triptan Dosing — The Golden Hour
Dosing within an hour of onset gives triptans their best chance to work.
- <1 h: Optimal dosing window (from pain onset)
- ~14%: Sumatriptan oral bioavailability (first-pass metabolism)
- ~2 h: Time to peak plasma (oral tablet)
- ~10 min: Subcutaneous onset (faster route)
Why timing matters
Early dosing beats a vessel wall that is not yet fully dilated.
Formulation choices
Oral, nasal spray, and injection trade speed for convenience.
Absorption during nausea
Gastric stasis during attacks slows oral absorption.
5-HT1B/1D Receptor Agonism
Triptans mimic serotonin, binding receptors on vessels and nerve terminals.
- 5-HT1B/1D: Primary receptor targets (Gi-coupled GPCRs)
- ~2.5 h: Sumatriptan half-life (plasma clearance)
- 2 sites: Receptor location (vascular smooth muscle + nerve)
- ↓ cAMP: Signal effect (via Gi inhibition)
5-HT1B on vessels
Receptor activation contracts vascular smooth muscle directly.
5-HT1D on nerve terminals
Presynaptic binding blocks CGRP and substance P release.
Selectivity matters
Cranial selectivity limits broader cardiovascular side effects.
Vasoconstriction & Neurogenic Inflammation Block
Vessel diameter falls back toward baseline as inflammatory signaling quiets.
- up to 90%: Vessel diameter recovery (toward baseline)
- ↓ sharply: CGRP suppression (presynaptic block)
- 10–15 min: Onset of relief (SC route) (fastest formulation)
- ~70–80%: Response rate, early dose (pain relief at 2 h)
Mechanical relief
Smaller vessel diameter reduces pulsatile stretch on nerve endings.
Inflammatory quieting
Reduced CGRP lowers plasma protein leakage around vessels.
Dose-timing dependence
Late dosing yields slower, weaker constriction response.
Attack Resolution — Pain-Free Outcome
Early, adequate dosing gives the best odds of a pain-free two-hour outcome.
- ~50–60%: Pain-free at 2 h (early dose) (clinical trial data)
- ~30–40%: Recurrence rate (within 24 h)
- 2 of 3: Consistent response (attacks, same patient)
- ~20–30%: Late-dose response (lower efficacy)
What determines success
Early timing and adequate dose drive resolution probability.
Recurrence risk
Headache can return as drug levels decline within a day.
Missed-window outcomes
Skipped or delayed dosing leaves the attack largely unresolved.