Residency · Residency · Neurology
Migraine: Pathophysiology and Acute Treatment
Introduction
Migraine is a primary headache disorder affecting approximately 12% of the global population and is a leading cause of disability worldwide. Understanding its neurovascular pathophysiology and applying evidence-based acute treatment strategies are fundamental skills for every neurologist.
Epidemiology
Migraine affects 18% of women and 6% of men, with peak prevalence between ages 25 and 55 years. It ranks as the second leading cause of years lived with disability globally according to the Global Burden of Disease Study. The socioeconomic burden is significant, encompassing missed work, reduced productivity, and healthcare utilization. Migraine remains underdiagnosed and undertreated across all populations.
Pathophysiology
Trigeminovascular System
The trigeminovascular system is the key pain-generating pathway in migraine. Activation of trigeminal afferents innervating dural and meningeal blood vessels releases vasoactive neuropeptides including CGRP, substance P, and neurokinin A. Calcitonin gene-related peptide (CGRP) is the most important mediator, causing vasodilation, neurogenic inflammation, and central sensitization. Trigeminal signals relay to the trigeminocervical complex, which comprises the spinal trigeminal nucleus caudalis and C1-C2 dorsal horn.
Cortical Spreading Depression (CSD)
Cortical spreading depression is the electrophysiological substrate of migraine aura. It consists of a wave of neuronal and glial depolarization that spreads across the cortex at 2-6 mm/min, followed by prolonged suppression of activity. CSD activates trigeminovascular afferents, providing the link between aura and headache. Visual aura reflects CSD propagation across the occipital cortex.
Central Sensitization
Repeated trigeminal activation leads to central sensitization in the trigeminocervical complex and thalamus. This manifests clinically as cutaneous allodynia (pain from normally non-painful stimuli such as brushing hair). Once allodynia is established, it predicts poor response to triptans, emphasizing the importance of treating early before sensitization develops.
Brainstem and Hypothalamic Generators
PET studies demonstrate activation of the dorsal pons and hypothalamus during migraine attacks. The hypothalamus may drive premonitory symptoms including yawning, food cravings, and mood changes.
Clinical Features
Migraine Without Aura (ICHD-3 Criteria)
Diagnosis requires at least 5 attacks lasting 4-72 hours with at least 2 of the following: unilateral location, pulsating quality, moderate-to-severe intensity, or aggravation by routine physical activity. Additionally, at least 1 of the following must be present: nausea and/or vomiting, or photophobia and phonophobia.
Migraine With Aura
Diagnosis requires at least 2 attacks with fully reversible visual, sensory, or speech/language symptoms. The aura develops gradually over 5 or more minutes, with each symptom lasting 5-60 minutes. Headache follows the aura within 60 minutes or accompanies it. Visual aura is the most common form, manifesting as scintillating scotoma, fortification spectra, or zigzag lines.
Phases of Migraine
The prodrome (hours to days before headache) includes fatigue, yawning, food cravings, mood changes, and neck stiffness. The aura phase lasts 5-60 minutes and may produce visual, sensory, language, or motor symptoms. The headache phase lasts 4-72 hours with pain and associated features. The postdrome (hours to days after headache resolution) includes fatigue, cognitive difficulty, and mood changes.
Acute Treatment
Treatment Principles
Treatment should be initiated early, within 1 hour of onset and before central sensitization develops. Adequate doses via appropriate route are essential. Associated symptoms (nausea, vomiting) should be treated concurrently. Acute medication use must be limited to fewer than 10 days per month (for triptans and combination analgesics) or fewer than 15 days per month (for simple analgesics) to prevent medication overuse headache (MOH).
| Acute Treatment Class | Examples | Mechanism | Key Considerations |
|---|---|---|---|
| Triptans | Sumatriptan, rizatriptan, eletriptan, zolmitriptan | 5-HT1B/1D agonist | Contraindicated in CV disease; less effective after allodynia |
| Gepants | Ubrogepant, rimegepant | CGRP receptor antagonist | No vasoconstrictive effect; safe in CV disease |
| Ditans | Lasmiditan | 5-HT1F agonist | No vasoconstriction; sedation; Schedule V |
| NSAIDs | Ibuprofen 400–600 mg, naproxen 500 mg | COX inhibition | Mild-to-moderate attacks; GI/renal risks |
| Dopamine antagonists (ED) | Metoclopramide IV, prochlorperazine IV | D2 antagonist + antiemetic | First-line parenteral therapy |
| Adjuncts | Dexamethasone 10 mg IV | Anti-inflammatory | Reduces recurrence within 72 hours |
First-Line: Triptans
Triptans are selective 5-HT1B/1D receptor agonists, including sumatriptan, rizatriptan, eletriptan, zolmitriptan, naratriptan, almotriptan, and frovatriptan. Their mechanism involves constricting meningeal vessels, inhibiting CGRP release, and blocking trigeminovascular transmission. Sumatriptan 100 mg oral or 6 mg subcutaneous are the most extensively studied. They are contraindicated in uncontrolled hypertension, coronary artery disease, stroke history, hemiplegic migraine, and basilar migraine. They are most effective when taken early and less effective once allodynia has developed.
CGRP Receptor Antagonists (Gepants)
Ubrogepant and rimegepant are oral small-molecule CGRP receptor antagonists. They have no vasoconstrictive effects, making them safe in cardiovascular disease. They can be used for acute treatment, and rimegepant is also approved for prevention with every-other-day dosing. Their efficacy is comparable to triptans for many patients.
Ditans
Lasmiditan is a selective 5-HT1F receptor agonist with no vasoconstrictive properties. It is effective for acute migraine but CNS side effects (dizziness, sedation) limit use. It is a Schedule V controlled substance, and driving must be avoided for 8 hours after dosing.
NSAIDs and Combination Analgesics
Ibuprofen 400-600 mg, naproxen 500 mg, or diclofenac 50 mg are effective for mild-to-moderate migraine. Aspirin 900-1000 mg is an evidence-based option. The acetaminophen-aspirin-caffeine combination is superior to its individual components. An antiemetic (metoclopramide, ondansetron) should be added for nausea.
Emergency Department and Rescue Therapies
IV metoclopramide 10-20 mg or prochlorperazine 10 mg are first-line parenteral therapies. IV ketorolac 30 mg is an effective adjunct. IV magnesium sulfate 1-2 g is particularly useful for migraine with aura. Dexamethasone 10 mg IV reduces headache recurrence within 72 hours. Opioids and butalbital-containing compounds should be avoided because they are associated with MOH and poor outcomes.
Medication Overuse Headache
Medication overuse headache is defined as chronic headache (15 or more days per month) with regular overuse of acute medications for more than 3 months. It is most commonly caused by triptans, combination analgesics, opioids, and butalbital. Treatment requires withdrawal of the offending medication with bridge therapy (corticosteroids, nerve blocks) and initiation of preventive therapy. CGRP-targeted preventive therapies may be particularly effective in MOH.
Clinical Pearls
Migraine should be treated early and adequately because allodynia signals central sensitization and reduced triptan efficacy. Gepants offer a non-vasoconstrictive alternative for patients with cardiovascular risk factors. Acute medication use must be limited to avoid medication overuse headache, and patients should be counseled on frequency tracking. Parenteral dopamine antagonists (metoclopramide, prochlorperazine) are the most effective ED treatments for migraine.
References
- Goadsby PJ, Holland PR, Martins-Oliveira M, et al. Pathophysiology of migraine: a disorder of sensory processing. Physiol Rev. 2017;97(2):553-622.
- Marmura MJ, Silberstein SD, Schwedt TJ. The acute treatment of migraine in adults: the American Headache Society evidence assessment of migraine pharmacotherapies. Headache. 2015;55(1):3-20.
- Dodick DW, Lipton RB, Ailani J, et al. Ubrogepant for the treatment of migraine. N Engl J Med. 2019;381(23):2230-2241.
- Friedman BW, Irizarry E, Solorzano C, et al. Randomized study of IV prochlorperazine plus diphenhydramine vs IV hydromorphone for migraine. Neurology. 2017;89(20):2075-2082.