Migraine Therapeutics

Migraine Pathophysiology & Overview - Brain's Ache Saga

• Definition: Episodic headache disorder; with or without aura (transient focal neurological symptoms).
• Neurovascular Theory: Primary neuronal dysfunction triggers secondary vascular changes.
• Cortical Spreading Depression (CSD): Self-propagating wave of neuronal/glial depolarization; underlies migraine aura.
  • Activates trigeminal nerve afferents.
• Trigeminovascular System Activation: Central to pain.
• Key Mediators:
  • CGRP (Calcitonin Gene-Related Peptide): Potent vasodilator; neurogenic inflammation.
  • Serotonin (5-HT): Imbalance; 5-HT1B/1D/1F receptor agonism is a key therapeutic target.
  • Substance P, Neurokinin A.

⭐ Activation of the trigeminovascular system releases CGRP, a key player in migraine pain.

Acute Migraine Treatment - Attack Abort!

• Care Approaches:
  • Stratified: Match initial treatment to attack severity.
  • Step-care: Start with simple analgesics, escalate if no response.

  ⭐ Stratified care is often preferred for faster relief and improved outcomes in moderate to severe attacks.

• Non-Specific Analgesics (Limit use to <15 days/month to avoid MOH):
  • NSAIDs: Ibuprofen, Naproxen, Diclofenac, Aspirin.
  • Paracetamol.
• Antiemetics (Adjunctive for N/V; some have intrinsic anti-migraine effects):
  • Metoclopramide, Domperidone, Prochlorperazine.
• Migraine-Specific Agents (Limit use to <10 days/month to avoid MOH):
  • Triptans (5-HT1B/1D Agonists → vasoconstriction, ↓CGRP release):
    • E.g., Sumatriptan, Rizatriptan, Zolmitriptan, Naratriptan, Eletriptan.
    • ADRs: 'Triptan sensations' (chest tightness), flushing.
    • CIs: CAD, stroke/TIA, uncontrolled HTN, hemiplegic/basilar migraine.
    • 📌 Mnemonic: 'A TRIP to the ANus constricts vessels' (vasoconstriction).
  • Ergot Alkaloids (Non-selective 5-HT1, $\alpha$-adrenergic, dopaminergic):
    • Ergotamine, Dihydroergotamine (DHE).
    • ADRs: N/V, ergotism.
    • CIs: CAD, PVD, HTN, pregnancy, potent CYP3A4 inhibitors.
  • CGRP Antagonists (Gepants) (Small molecule CGRP receptor antagonists):
    • Ubrogepant, Rimegepant.
    • Advantages: No vasoconstriction.
  • 5-HT1F Receptor Agonists (Ditans) (Selective 5-HT1F agonist):
    • Lasmiditan.
    • Advantages: No vasoconstriction; useful if triptans CI due to CV risk.
    • ADRs: Dizziness (driving impairment warning).
• Medication Overuse Headache (MOH):
  • Prevention: Limit acute meds (simple analgesics <15 days/month; triptans/ergots/combo <10 days/month).

Preventive Migraine Treatment - Shield Up Strategies

Indications: ≥4 headache days/month, ≥2 with disability, debilitating attacks, or acute med issues.

• Oral Prophylactics (selected by comorbidity/ADR profile):
  • Beta-blockers: Propranolol, Metoprolol. MOA: ?Modulate adrenergic/serotonergic systems. ADRs: Fatigue, bradycardia, hypotension. CIs: Asthma, heart block.
  • Antidepressants: Amitriptyline (TCA). MOA: NE & 5-HT reuptake inhibition. ADRs: Sedation, anticholinergic, weight gain. Venlafaxine (SNRI) alternative.
  • Anticonvulsants:
    • Topiramate: MOA: Blocks Na+/Ca2+ channels, ↑GABA. ADRs: Paresthesia, cognitive slowing ('Dopamax'), weight loss, kidney stones. Teratogenic.
    • Valproic Acid: MOA: ↑GABA, blocks Na+/T-type Ca2+ channels. ADRs: Weight gain, tremor, hepatotoxicity. ⚠️ Highly teratogenic.

      ⭐ 📌 Valproic Acid: Highly teratogenic (neural tube defects) - Black Box Warning.

• Injectable Prophylactics:
  • CGRP Monoclonal Antibodies: Erenumab (receptor), Fremanezumab, Galcanezumab (ligand). SC monthly/quarterly. ADRs: Injection site reactions, constipation (Erenumab).
  • OnabotulinumtoxinA: For chronic migraine (≥15 headache days/month). MOA: Inhibits CGRP release. Admin: 31 specific sites.
• Other Options: Candesartan (ARB), Riboflavin (Vit B2), Coenzyme Q10, Magnesium.
• Menstrual Migraine Prophylaxis: Frovatriptan, NSAIDs perimenstrually.

High‑Yield Points - ⚡ Biggest Takeaways

• Triptans (5-HT1B/1D agonists) are first-line for acute migraine attacks; contraindicated in CAD/PVD.
• Ergotamine (non-selective 5-HT agonist) causes significant vasoconstriction and nausea; less preferred.
• CGRP antagonists ("-gepants" for acute, "-mabs" for prophylaxis) are novel targeted therapies.
• Prophylaxis mainstays: Propranolol, Amitriptyline, Topiramate, Valproate, CGRP mAbs.
• Risk of Serotonin Syndrome with concurrent use of triptans/ergots and SSRIs/SNRIs.
• Medication Overuse Headache (MOH) is a critical concern with frequent acute drug use (≥10-15 days/month).