Migraine Prophylaxis

Indications for Prophylactic Treatment

• Attacks occur 4 or more days/month (some sources say 2+ times/month with significant disability)
• Attacks are severe, prolonged, or unresponsive to acute therapies
• Complicated migraine (hemiplegic, basilar, migraine with prolonged aura)
• Significant disability or impact on quality of life

Four Drugs Used in Migraine Prophylaxis

Also approved: CGRP monoclonal antibodies (erenumab, galcanezumab, fremanezumab, eptinezumab), oral CGRP antagonists (rimegepant, atogepant), and onabotulinumtoxin A (for chronic migraine ≥15 headache days/month).

MOA of Each Drug (Briefly)

1. Propranolol (Beta-blocker)

• Blocks beta-adrenergic receptors, reducing noradrenergic neurotransmission
• Decreases central neuronal excitability and cortical spreading depression susceptibility
• May reduce platelet aggregation and serotonin-induced vasoconstriction
• Starting dose: 10-20 mg 2-3x/day; titrate up to 240 mg/day
• Beta-blockers with intrinsic sympathomimetic activity (ISA) (e.g., pindolol) are not effective - only ISA-lacking agents work

2. Valproate / Divalproex (Anticonvulsant)

• Enhances GABA-ergic inhibition in the brain
• Blocks voltage-gated sodium channels and T-type calcium channels
• Reduces trigeminovascular activation and neurogenic inflammation
• Dose: 250 mg 3-4x daily

3. Amitriptyline (Tricyclic antidepressant)

• Blocks reuptake of norepinephrine and serotonin
• Has antihistaminic (H1), anticholinergic, and sodium channel-blocking properties
• Modulates descending pain control pathways
• Dose: 25-125 mg at night

4. Verapamil (Calcium channel blocker)

• Blocks L-type voltage-gated calcium channels
• Prevents serotonin release and neurovascular instability
• Stabilizes neuronal membranes; reduces vasospasm
• Dose: 320-480 mg/day (lag of days-to-weeks before benefit)

Adverse Effects - Propranolol (Detailed)

Precautions for Propranolol

• Asthma / COPD: Absolute contraindication - can precipitate fatal bronchospasm
• Diabetes: Masks tachycardia warning signs of hypoglycemia; use with caution in insulin-dependent diabetics
• Heart block, sick sinus syndrome, severe bradycardia: Contraindicated
• Peripheral vascular disease / Raynaud's: Worsens symptoms
• Pregnancy: Category C; neonatal bradycardia and IUGR reported
• Depression: May worsen; consider amitriptyline instead
• Do NOT stop abruptly - taper gradually to avoid rebound effects
• Young patients often intolerant due to fatigue and exercise intolerance
• Topiramate and valproate: avoid in females of reproductive age due to teratogenicity (neural tube defects with valproate; cleft palate with topiramate)

Sumatriptan (KDT)

MOA - Mechanism of Action

1. Cranial vasoconstriction - Activates 5-HT1B receptors on intracranial blood vessel walls (particularly the dilated meningeal and dural vessels during a migraine attack), causing vasoconstriction and reversing the vasodilation that underlies migraine pain
2. Inhibition of trigeminal neurotransmitter release - Activates presynaptic 5-HT1D receptors on trigeminal nerve terminals, blocking the release of pro-inflammatory neuropeptides (substance P, CGRP = calcitonin gene-related peptide), thereby reducing neurogenic inflammation
3. Inhibition of trigeminal pain transmission - Acts at central 5-HT1D receptors in the trigeminal nucleus caudalis to reduce pain signal propagation

Triptans are selective for 5-HT1B/1D (unlike ergotamine which is non-selective across multiple serotonin receptor subtypes).

Adverse Effects of Sumatriptan

Precautions / Contraindications for Sumatriptan

• Ischemic heart disease (CAD), angina, previous MI
• Cerebrovascular disease (history of stroke or TIA)
• Peripheral vascular disease
• Uncontrolled hypertension
• Hemiplegic migraine or migraine with brainstem aura (previously basilar migraine) - risk of stroke
• Concurrent or recent use of ergotamine/ergot derivatives (within 24 hours) - additive vasospasm
• MAOIs (within 2 weeks) - risk of serotonin syndrome

• Concurrent SSRIs/SNRIs - potential for serotonin syndrome (many patients use these together; clinical judgment required)
• Pregnancy - Category C; no clear increase in adverse outcomes shown but caution advised; classified as compatible by American Academy of Pediatrics
• Elderly patients - increased cardiovascular risk
• Hepatic impairment - reduce dose (extensively metabolized by MAO-A)
• Do NOT use in the aura phase - triptans are ineffective if given during aura (before headache); administer at headache onset
• Do NOT combine triptans from different classes on same day without guidance

• With ergotamine-containing medications: do NOT use within 24 hours (additive coronary vasoconstriction)
• With MAOIs: contraindicated
• With strong CYP interactions (varies by specific triptan)

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