---

🧠 Migraine Medicine — Detailed Notes

---

1. Overview & Classification

Repeated attacks lasting 4–72 h with ≥2 of: unilateral pain, throbbing, aggravated by movement, moderate/severe intensity — PLUS ≥1 of: nausea/vomiting, photophobia & phonophobia.

---

2. Pathophysiology

2a. Vascular & Neural Mechanisms

• Migraine with aura: begins as cortical spreading depression — hypoperfusion spreading forward over the cortex, persisting through the aura and into the headache phase
• Migraine without aura: no hypoperfusion, but pain arises from extracranial and intracranial arterial vasodilation
• Vasodilation leads to release of neuroactive molecules: substance P, neurokinin A, and CGRP (calcitonin gene-related peptide)

2b. Serotonin (5-HT) Hypothesis

• Plasma/platelet 5-HT concentrations vary with migraine phases
• Urinary 5-HT and metabolites are elevated during most attacks
• Migraine can be precipitated by agents that release 5-HT (e.g., reserpine, fenfluramine)
• 5-HT1B/1D receptor agonists (triptans) are highly effective acutely

2c. CGRP Role

• CGRP is a potent vasodilatory and proinflammatory neuropeptide
• Plasma CGRP levels are elevated during acute migraine attacks
• Successful triptan treatment correlates with decreased blood levels of CGRP
• CGRP blockade is now a central therapeutic strategy

2d. Brainstem Involvement

• PET studies show hypothalamic, dorsal midbrain, and dorsolateral pontine activation during migraine (including the noradrenergic locus coeruleus)
• Lateralization of pontine changes correlates with side of head pain in hemicranial migraine

---

3. Acute Treatment of Migraine

Strategy

• Nonspecific (symptomatic): NSAIDs, analgesics, antiemetics
• Migraine-specific: Triptans, ergot alkaloids, ditans (lasmiditan), CGRP receptor antagonists (gepants)

---

3.1 Triptans (5-HT1B/1D Receptor Agonists) — First-Line

• Potent agonists at 5-HT1B and 5-HT1D receptors
• Two proposed mechanisms:
  1. Vasoconstriction of intracranial blood vessels (including AV anastomoses), restoring normal blood flow
  2. Presynaptic inhibition — block release of proinflammatory neuropeptides (substance P, CGRP) at trigeminal perivascular nerve terminals

• Effective for acute treatment of migraine with or without aura
• NOT for prophylaxis
• Start treatment as soon as possible after headache onset
• Effective in ~70% of patients
• Sumatriptan 6 mg SC: onset ~20 min; oral: 1–2 h
• Frovatriptan has the longest half-life (>24 h) — useful for menstrual migraine
• Headache may recur within 24–48 h; a second dose is usually effective

• Sumatriptan: SC injection (fastest), intranasal, oral, oral + naproxen combination
• Zolmitriptan: oral tablet or nasal spray
• All others: oral only

• Chest, neck, throat, jaw pressure/pain sensations
• Dizziness, malaise
• Elevated blood pressure

• Coronary artery disease (or significant risk factors without prior cardiac evaluation) — due to coronary vasospasm risk
• Do not use within 24 h of ergot alkaloids — risk of coronary ischemia

---

3.2 Ergot Alkaloids

• Complex action at 5-HT1 receptors, α-adrenergic receptors, and dopamine receptors
• 5-HT1 agonism on intracranial blood vessels → vasoconstriction

• Available sublingually, orally (+ caffeine), suppository
• Most effective in early stages of migraine
• Strict daily and weekly dosage limits due to risk of dependence and rebound headaches

• IV or intranasal
• Efficacy similar to sumatriptan
• Reserved for severe migraine
• Common adverse effect: nausea
• IV protocol for severe migraine in ED: prochlorperazine 5 mg + DHE 0.5 mg over 2 min

• Angina and peripheral vascular disease (significant vasoconstrictors)
• Pregnancy
• Do not combine with strong CYP3A4 inhibitors — risk of life-threatening peripheral ischemia

---

3.3 Ditans — Lasmiditan (5-HT1F Agonist)

• Selective 5-HT1F receptor agonist
• Reduces activation of trigeminal nerve system pain pathways
• Does NOT cause vasoconstriction — unlike triptans and ergots

• Oral agent for acute migraine
• Indicated for patients with contraindications or intolerance to triptans (e.g., cardiovascular disease)

• Potential for abuse — classified as a controlled substance
• Can cause significant driving impairment — patients must avoid hazardous activities

---

3.4 CGRP Receptor Antagonists (Gepants)

• Ubrogepant — acute treatment only
• Rimegepant — acute treatment AND prevention
• Atogepant — prevention only
• Vazgepant (intranasal) — investigational for acute treatment

• Block CGRP receptor signaling, reducing vasodilation and neuroinflammation in the trigeminal system

• Oral agents indicated for acute migraine in patients with contraindications or intolerance to triptans
• Rimegepant and atogepant also used for prevention

• Nausea, somnolence (incidence is low)

• Ubrogepant: contraindicated with strong CYP3A4 inhibitors

---

3.5 NSAIDs and Analgesics

• Both the severity and duration of a migraine attack can be reduced significantly by NSAIDs
• Agents: ibuprofen, naproxen, aspirin, indomethacin, ketorolac, diclofenac
• Naproxen combined with sumatriptan (Treximet) is FDA-approved
• For mild to moderate migraine: combination of acetaminophen + aspirin + caffeine is FDA-approved
• Useful adjunct with triptans for more severe migraine

---

3.6 Antiemetics / Dopamine Receptor Antagonists

• Drug absorption is impaired during migraine (reduced gastric motility), even without overt nausea
• Oral dopamine antagonists (metoclopramide 10 mg, prochlorperazine 10 mg, domperidone 10 mg) enhance gastric absorption of co-administered drugs AND reduce nausea
• Parenteral forms (chlorpromazine, prochlorperazine, metoclopramide IV/IM) can provide significant acute migraine relief; can be combined with parenteral triptans/DHE
• RCT evidence shows prochlorperazine is superior to hydromorphone in ED setting

---

3.7 Opioids

• Modestly effective; IV meperidine 50–100 mg used in ED
• Not recommended for recurrent headache:
  • Do not address underlying headache mechanism
  • May decrease future triptan response
  • Opioid craving/withdrawal can worsen migraine
• Reserve for: severe but infrequent headaches unresponsive to other approaches, or when other therapies are contraindicated

---

3.8 Neuromodulation (Acute)

• Single-pulse transcranial magnetic stimulation (sTMS): FDA cleared; 2 pulses at attack onset
• Non-invasive vagus nerve stimulator (nVNS): FDA cleared; 1–2 doses of 120 s each
• Remote electrical neuromodulation: smartphone-app-controlled stimulation of upper arm, 30–45 min
• Transcutaneous supraorbital nerve stimulation: 60 min
• These offer non-pharmaceutical options

---

4. Preventive (Prophylactic) Treatment of Migraine

When to Initiate Prophylaxis

• ≥4 migraine days/month
• Attacks unresponsive or poorly responsive to acute treatments
• Attacks causing significant disability or neurologic compromise

General principles

• Most agents must be taken daily
• Lag of 2–12 weeks before effect is seen
• Once effective, continue for 6–12 months, then slowly taper
• Probability of success with any one drug: ~40–50%
• Topiramate and valproate are now less attractive in females of reproductive age (fetal developmental concerns)

---

Harrison's Table: Preventive Treatments in Migraine

---

4.1 Beta-Blockers — Drugs of Choice for Prophylaxis

• Propranolol and metoprolol are the first-line agents
• Mechanism in migraine prophylaxis is not entirely clear (likely not serotonin-related)
• Contraindicated in asthma, heart block, severe depression

4.2 Antidepressants

• Amitriptyline (TCA): most studied; effective regardless of comorbid depression
• Nortriptyline, venlafaxine: alternatives
• Low doses used; benefit unrelated to antidepressant effect

4.3 Anticonvulsants

• Topiramate and Divalproex/valproate: FDA-approved for migraine prevention
• Topiramate: paresthesias, cognitive slowing ("cognitive fog"), weight loss, angle-closure glaucoma
• Valproate: weight gain, teratogenicity — avoid in pregnancy and reproductive-age women

4.4 Calcium Channel Blockers

• Verapamil — used especially when other agents fail or are contraindicated

4.5 CGRP Monoclonal Antibodies (Anti-CGRP mAbs)

• Erenumab (targets CGRP receptor), fremanezumab, galcanezumab, eptinezumab (target CGRP ligand)
• Subcutaneous (monthly or quarterly) except eptinezumab (IV quarterly)
• Highly effective; often work within the first month
• Excellent tolerability profile
• Have significantly changed the landscape of preventive treatment

4.6 OnabotulinumtoxinA (Botox)

• FDA-approved for chronic migraine only (≥15 headache days/month)
• Placebo-controlled trials in episodic migraine were negative
• Injected into pericranial and neck muscles every 12 weeks

4.7 Other Agents

• Candesartan (ARB): shows preventive efficacy; well-tolerated
• Cyproheptadine: significant 5-HT antagonism; used especially in children
• Melatonin: controlled trial evidence; not FDA-approved for this indication
• Phenelzine (MAOI): reserved for very refractory cases; tyramine-containing foods contraindicated

---

5. Medication-Overuse Headache (MOH)

• Acute medications, especially opioids and barbiturate-containing analgesics, can aggravate headache frequency
• Results in refractory daily or near-daily headache (transformation of migraine)
• Patients with ≥2 headache days/week should be counseled about frequent analgesic use
• MOH is not a separate entity — it reflects migraine biology's reaction to certain medications

---

6. Special Situations

Menstrual Migraine (Catamenial Migraine)

• In ~15% of female migraineurs, attacks are exclusively perimenstrual
• Related to estrogen withdrawal (though hormonal influence is complex)
• Frovatriptan (longest-acting triptan, t½ >24 h) is particularly useful for perimenstrual prophylaxis

Migraine in Pregnancy

• Migraine tends to improve in 2nd and 3rd trimester in 75–80% of women
• Topiramate and valproate are contraindicated in pregnancy
• DHE is contraindicated in pregnancy
• NSAIDs generally avoided in 3rd trimester

Migraine with Cardiovascular Risk Factors

• Triptans require cardiac evaluation before use in patients with CAD risk
• Lasmiditan is preferred as it causes no vasoconstriction
• Gepants are also an option (no vasoconstriction)

---

7. Summary Table: Acute Treatment

---

8. Summary Table: Prophylactic Treatment

---

• Lippincott Illustrated Reviews: Pharmacology — Ch. 39
• Goodman & Gilman's Pharmacological Basis of Therapeutics — Ch. 5 (5-HT drugs)
• Harrison's Principles of Internal Medicine 22e — Ch. 441
• Adams and Victor's Principles of Neurology, 12e — Ch. on Headache
• Katzung's Basic and Clinical Pharmacology, 16e — CGRP section