Migraine

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Migraine

Definition & Classification

Migraine is a recurrent, primary headache disorder of moderate-to-severe intensity. The term derives from the Greek hemikranios ("half head"), reflecting the unilateral pain present in ~60-75% of attacks. A full migraine attack can have up to four phases:

Premonitory phase - mood changes, food cravings, yawning, polyuria, photophobia (hours before pain)
Aura - focal neurological symptoms preceding or accompanying the headache
Headache phase - throbbing/pulsatile pain + photophobia, phonophobia, nausea/vomiting
Postdrome - fatigue, cognitive fog after the pain resolves

ICHD-3 Major Types:

Migraine without aura (common migraine) - ~70% of migraineurs
Migraine with aura (classic migraine) - visual, sensory, or speech disturbances preceding headache
Chronic migraine - headaches on ≥15 days/month for >3 months, with ≥8 meeting migraine criteria

The POUND mnemonic for clinical diagnosis (LR+24 if 4/5 criteria met):

Pulsatile quality
One-day duration (4-72 hours)
Unilateral location
Nausea or vomiting
Disabling intensity

(Bradley and Daroff's Neurology in Clinical Practice; Tintinalli's Emergency Medicine)

Epidemiology

12% 1-year prevalence in the general population; 18% in women, 6% in men
Peaks in the fourth decade of life (~24% of women, 7% of men)
Lifetime prevalence: ~33% women, ~13% men
The WHO classifies migraine among the most disabling medical conditions worldwide
Indirect economic burden: ~$13 billion/year in the US from lost productivity
Genetic component: First-degree relatives of migraineurs with aura are ~4x more likely to develop migraine with aura

(Bradley and Daroff's Neurology, p. 170-176)

Pathophysiology

Migraine has a complex, multifactorial pathogenesis involving neural, vascular, and neurochemical elements.

Cortical Spreading Depression (CSD)

The aura is explained by CSD - a slow wave of neuronal and glial depolarization that propagates across the cortex at ~3 mm/min, followed by prolonged suppression of neural activity. CSD activates trigeminovascular fibers and is believed to initiate the headache cascade.

Trigeminovascular Activation

The key mechanism of migraine pain involves activation of trigeminal sensory fibers innervating the meningeal blood vessels. This releases neuropeptides (substance P, CGRP - calcitonin gene-related peptide) causing:

Vasodilation of meningeal vessels
Neurogenic inflammation (plasma protein extravasation)
Sensitization of trigeminal neurons → central sensitization → allodynia

Serotonin (5-HT) Role

Key evidence that 5-HT is a key mediator:

Plasma/platelet 5-HT concentrations fluctuate with migraine phases
Urinary 5-HT metabolites are elevated during attacks
Agents that release 5-HT (e.g., reserpine, fenfluramine) can precipitate migraine
5-HT1B/1D agonists (triptans) are highly effective acute treatments

(Goodman & Gilman's Pharmacological Basis of Therapeutics; Bradley and Daroff's Neurology)

Clinical Features

Feature	Description
Pain character	Throbbing/pulsatile, moderate-severe
Location	Unilateral (60-75%), can be bilateral
Duration	4-72 hours (untreated)
Associated symptoms	Nausea, vomiting, photophobia, phonophobia, osmophobia
Aggravating factor	Routine physical activity
Allodynia	Skin sensitivity in ~70% during attacks

Aura (when present):

Visual: fortification spectra (scintillating scotoma), photopsia - most common
Sensory: unilateral paresthesias/numbness
Speech: dysphasia
Aura lasts 5-60 minutes, typically precedes headache by <1 hour

Acute Treatment

Step 1: Mild-Moderate attacks - Analgesics/NSAIDs

Agent	Dose
Acetaminophen	1000 mg
Aspirin	500-1000 mg
Ibuprofen	200-400 mg
Naproxen sodium	550 mg
Diclofenac potassium	50-100 mg
Acetaminophen/Aspirin/Caffeine	500/500/130 mg (Excedrin)

Step 2: Moderate-Severe attacks - Triptans (5-HT1B/1D agonists)

Triptans are first-line abortive therapy. They work by:

Constricting dilated intracranial blood vessels (5-HT1B)
Inhibiting trigeminal nociceptive transmission (5-HT1D)
Blocking release of vasoactive neuropeptides

Drug	Route	Dose	Max/24h
Sumatriptan (Imitrex)	SC / oral / nasal	6 mg SC; 25-100 mg oral	12 mg SC / 200 mg oral
Rizatriptan (Maxalt)	Oral / ODT	5-10 mg	30 mg
Eletriptan (Relpax)	Oral	20-40 mg	80 mg
Almotriptan (Axert)	Oral	6.25-12.5 mg	25 mg
Frovatriptan (Frova)	Oral	2.5 mg	7.5 mg
Naratriptan (Amerge)	Oral	1-2.5 mg	5 mg
Zolmitriptan (Zomig)	Oral / nasal	2.5-5 mg	10 mg

Contraindications to triptans: ischemic heart disease, uncontrolled hypertension, hemiplegic migraine, basilar migraine, pregnancy, concurrent MAOI use.

Ergotamines (DHE - Dihydroergotamine): 5-HT agonist with α-adrenergic activity. Available IV/IM/SC/nasal spray. Useful for refractory attacks; contraindicated in pregnancy.

(Bradley and Daroff's Neurology; Goodman & Gilman's)

Emergency Department (ED) Treatment

Most ED patients have failed outpatient abortive therapy and need rescue therapy:

IV dopamine antagonists (first-line in ED): prochlorperazine, metoclopramide, droperidol
IV NSAIDs: ketorolac
Diphenhydramine (25-50 mg IV): combined with antiemetics to prevent akathisia
Dexamethasone (10 mg IV): reduces risk of headache recurrence post-discharge
Opioids/barbiturates: NOT recommended routinely; use only if standard treatments fail

(Tintinalli's Emergency Medicine)

Preventive Treatment

Indicated when migraines are frequent (≥4/month), severely disabling, or not responding to acute therapy.

First-Line Preventives

Class	Agents	Notes
Beta-blockers	Propranolol, metoprolol, timolol	Best evidence; avoid in asthma, depression
Antidepressants	Amitriptyline (TCA), venlafaxine	Also treat comorbid depression/anxiety
Antiepileptics	Valproate, topiramate	Topiramate also approved for episodic migraine
Calcium channel blockers	Verapamil, flunarizine	Especially with aura

Newer Preventives - CGRP-Targeted Therapies

CGRP (calcitonin gene-related peptide) is a key neuropeptide in migraine pathogenesis. Targeted therapies include:

Anti-CGRP monoclonal antibodies: erenumab (targets CGRP receptor), fremanezumab, galcanezumab, eptinezumab (targets CGRP ligand) - monthly SC or quarterly IV injections
Gepants (small-molecule CGRP receptor antagonists): rimegepant, atogepant - both acute and preventive use

Non-Pharmacological Prevention

Identify and avoid triggers (sleep deprivation, stress, skipped meals, certain foods/alcohol, hormonal changes)
Regular sleep schedule, exercise, stress management
Biofeedback, cognitive behavioral therapy

Special Populations

Pregnancy

Triptans: contraindicated
Ergotamines: absolutely contraindicated
Safe options: acetaminophen, metoclopramide (Category B), corticosteroids, opioids (short-term)
NSAIDs: safe until third trimester only

Menstrual Migraine

Attacks cluster around menstruation (days -2 to +3). May benefit from short-course triptan prophylaxis during the perimenstrual window. A 2024 meta-analysis confirmed efficacy of both acute and preventive treatments for menstrual migraine.

Migraine vs. Other Headaches (Key Differentials)

Feature	Migraine	Tension	Cluster
Character	Pulsating	Pressing/tightening	Stabbing/boring
Location	Unilateral (usually)	Bilateral	Unilateral (periorbital)
Severity	Moderate-severe	Mild-moderate	Excruciating
Nausea/Vomiting	Yes	Absent	Absent
Photophobia	Yes	Mild (one)	Absent
Autonomic features	Absent	Absent	Yes (lacrimation, rhinorrhea, Horner's)
Activity effect	Worse	Not worse	Restless/agitated

Key Sources:

Bradley and Daroff's Neurology in Clinical Practice (primary neurology reference above)
Goodman & Gilman's Pharmacological Basis of Therapeutics (triptan mechanism)
Tintinalli's Emergency Medicine (ED management)
Recent systematic review on migraine aura phenomenology (Joppekova et al., J Headache Pain 2025, PMID 40597581)

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