Migraine

Definition & Classification

1. Premonitory phase - hours to days before: yawning, fatigue, food cravings, mood changes, neck stiffness
2. Aura - present in ~25-30% of migraineurs; typically 5-60 minutes
3. Headache phase - the main attack
4. Postdrome - hours of fatigue, cognitive fog after pain resolves

• Duration: 4-72 hours
• At least 2 of: unilateral location, pulsating quality, moderate/severe intensity, aggravated by routine activity
• At least 1 of: nausea/vomiting, photophobia + phonophobia

Epidemiology

• 1-year prevalence: ~12% of the general population (18% women, 6% men)
• Female:male ratio ~3:1; peaks in the 4th decade
• ~27.9 million affected in the United States
• 2% of the population has chronic migraine
• WHO ranks migraine among the most disabling medical conditions globally

• 90% of patients report impaired function during attacks; 53% require bed rest

• Indirect economic costs: estimated ~$13 billion/year in the US

Pathophysiology

• A slow wave of neuronal depolarization spreading across the cortex at ~2-4 mm/min
• This matches the "marching" quality of migraine aura (visual scotoma, paresthesias)
• The oligemia following CSD does not respect vascular territories - arguing against pure vasospasm
• CSD activates trigeminal afferents, which then release neuropeptides including CGRP

• Trigeminal nerve endings innervate intracranial dural vessels
• Stimulation causes release of CGRP, substance P, and neurokinin A
• CGRP causes vasodilation and sensitizes meningeal nociceptors
• Central sensitization in the trigeminocervical complex then amplifies pain
• Peripheral sensitization leads to cutaneous allodynia (touching skin becomes painful) in ~70% of attacks

• CGRP (calcitonin gene-related peptide) - elevated during migraine attacks; central to modern treatment
• Serotonin (5-HT) - modulates trigeminovascular pathway; basis for triptan therapy
• Voltage-gated Ca²⁺ channels (CACNA1A gene mutations in FHM1), Na⁺/K⁺-ATPase (FHM2), and sodium channels (FHM3)

Triggers

• Hormonal changes (menstruation, oral contraceptives, hormone replacement)
• Stress and stress let-down
• Sleep disruption (too much or too little)
• Alcohol (especially red wine)
• Dietary: aged cheeses, nitrates, chocolate, dairy, caffeine or caffeine withdrawal
• Skipping meals/fasting
• Sensory: bright lights, strong smells, loud sounds
• Weather/barometric pressure changes

Treatment

Acute (Abortive) Treatment

1. NSAIDs

• Aspirin, ibuprofen, naproxen, diclofenac
• Most effective when taken early in the attack
• FDA-approved combination: acetaminophen + aspirin + caffeine (e.g., Excedrin Migraine) for mild-moderate attacks
• Aspirin + metoclopramide is effective and well-studied

2. Triptans (5-HT1B/1D agonists) - First-line specific therapy

• 7 agents available: sumatriptan (prototype), eletriptan, rizatriptan, zolmitriptan, almotriptan, naratriptan, frovatriptan
• Abort or markedly reduce migraine in ~70% of patients
• Mechanism: Activate 5-HT1B/1D receptors on trigeminal nerve endings → vasoconstriction + inhibition of CGRP/substance P release
• Available as oral, SC injection (fastest ~20 min), intranasal
• Frovatriptan has longest half-life (>24h) - useful for menstrual migraine
• Caution: Avoid in patients with coronary artery disease (cardiovascular events); may cause chest/neck pressure sensations
• Per 2025 ACP guidelines, triptan + NSAID combination provides the best net benefit for acute attacks

3. CGRP Receptor Antagonists - Gepants

• Rimegepant, ubrogepant - indicated for acute migraine
• Particularly useful when triptans are contraindicated (cardiovascular disease) or not tolerated
• Advantage over triptans: gepants can be re-dosed at 2 hours effectively (unlike triptans)
• Rimegepant and atogepant also approved for preventive use

4. Ditans (5-HT1F agonists)

• Lasmiditan - does NOT cause vasoconstriction; safer in patients with cardiovascular risk
• 5-HT1F receptors are present on trigeminal neurons but absent from cardiovascular tissue
• Causes CNS dizziness/sedation; driving restricted for 8 hours post-dose

5. Ergot Alkaloids

• Ergotamine (sublingual/oral) and dihydroergotamine (DHE - IV/IM/intranasal)
• Complex receptor binding: 5-HT1, α-adrenergic, dopamine receptors
• Strict dose limits due to risk of dependence and medication overuse headache (MOH)
• DHE is particularly effective for status migrainosus (parenteral)

6. Dopamine Antagonists (Antiemetics)

• Prochlorperazine, metoclopramide, chlorpromazine
• Treat associated nausea AND have direct anti-migraine effects
• Often used IV in the emergency setting

• Mild attacks: NSAIDs ± antiemetic
• Moderate attacks: Triptans ± NSAID
• Severe attacks: Parenteral DHE, IV antiemetics, IV ketorolac
• Status migrainosus: IV DHE, IV valproate, IV dexamethasone (short-term)

Preventive (Prophylactic) Treatment

• Beta-blockers: propranolol, metoprolol, timolol
• Antiepileptics: valproate (divalproex), topiramate
• Antidepressants: amitriptyline (TCA), venlafaxine (SNRI)
• ACE inhibitors (lisinopril) or ARBs (candesartan) as alternatives

• Erenumab (anti-CGRP receptor) - monthly SC injection
• Fremanezumab - monthly or quarterly SC injection
• Galcanezumab - monthly SC injection
• Eptinezumab - quarterly IV infusion
• These have transformed prevention; some patients achieve "migraine freedom"

• Atogepant, rimegepant - daily oral preventives

• Identify and avoid triggers
• Regular sleep schedule
• Regular aerobic exercise
• Biofeedback, cognitive behavioral therapy (CBT)
• Magnesium, riboflavin (B2), CoQ10 - moderate evidence
• Acupuncture

Special Populations

• Timed NSAIDs or frovatriptan (perimenstrual days) for prevention
• Meta-analysis (2024, PMID: 39227797) supports both acute and preventive treatment approaches

• Avoid: ergotamines, valproate, topiramate (teratogenic), triptans (relative contraindication, though sumatriptan has the most safety data)
• Safer options: acetaminophen, magnesium, metoclopramide
• CGRP antibodies not recommended (insufficient data)

• Avoid ergotamines; NSAIDs safe; cautious use of triptans acceptable; sumatriptan SC preferred

Migraine and Comorbidities

Monitoring and Assessment Tools

• Medication overuse headache (MOH): Triptans/ergots >10 days/month, analgesics >15 days/month for >3 months
• Chronic migraine: ≥15 headache days/month for >3 months, ≥8 of which are migraine