What are the most effective preventative medications for a patient with frequent or severe migraines, listed in order of efficacy?

Migraine Preventative Medications Ranked by Efficacy

First-Line Agents (Highest Efficacy)

The most effective preventative medications for migraine, based on the strongest evidence and FDA approval, are propranolol, timolol, topiramate, and divalproex/sodium valproate—all demonstrating consistent efficacy in reducing migraine frequency by ≥50% in clinical trials. 1, 2, 3, 4, 5

1. Propranolol (80-240 mg/day)

• Propranolol is the gold standard first-line agent with FDA approval, the strongest evidence base, and proven efficacy across multiple randomized controlled trials. 2, 3, 4, 5
• Dosing: Start at 80 mg daily and titrate to 120-160 mg daily (most patients achieve control at 160 mg daily), with a maximum of 240 mg/day. 2, 6
• Requires 2-3 months at therapeutic dose before declaring treatment failure. 2, 3
• Contraindications: bradycardia, second or third-degree heart block, asthma, uncontrolled diabetes. 2, 3

2. Timolol (20-30 mg/day)

• Timolol shares equal first-line status with propranolol, with FDA approval and strong evidence for efficacy. 2, 3, 4, 5
• May have fewer CNS side effects than propranolol (less fatigue, depression, insomnia). 2

3. Topiramate (50-100 mg/day, typically 50 mg twice daily)

• FDA-approved with strong evidence for both episodic and chronic migraine prevention. 3, 4, 5, 7
• Particularly advantageous for patients with comorbid obesity due to associated weight loss. 3
• Requires 2-3 months for adequate trial. 3
• Common adverse effects include cognitive slowing, paresthesias, and kidney stones. 3

4. Divalproex Sodium/Sodium Valproate (500-1500 mg/day for divalproex; 800-1500 mg/day for valproate)

• FDA-approved with strong evidence for migraine prevention. 3, 4, 5, 7
• Strictly contraindicated in women of childbearing potential due to teratogenic effects. 3
• Adverse effects include weight gain, hair loss, tremor, and hepatotoxicity. 2, 3

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Second-Line Agents (Probably Effective)

5. Amitriptyline (30-150 mg/day)

• Optimal choice for patients with comorbid depression, anxiety, or mixed migraine/tension-type headache. 2, 3, 4, 8, 5
• Probably effective based on clinical evidence, though not FDA-approved for migraine. 4, 5
• Adverse effects include sedation, dry mouth, weight gain, and anticholinergic effects. 2

6. Metoprolol

• Established efficacy and commonly used off-label for migraine prevention. 3, 4
• Alternative beta-blocker when propranolol is not tolerated. 3

7. Venlafaxine (SNRI)

• Probably effective for migraine prevention, particularly useful for patients with comorbid depression. 4, 7

8. Atenolol and Nadolol

• Probable efficacy for migraine prevention based on limited evidence. 3, 4, 5

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Third-Line Agents (Limited Evidence or Reserved for Refractory Cases)

9. CGRP Monoclonal Antibodies (Erenumab, Fremanezumab, Galcanezumab)

• Strong recommendation for patients who have failed 2-3 oral preventive medications or have contraindications to first-line agents. 3
• Administered monthly via subcutaneous injection with efficacy assessment requiring 3-6 months. 3
• Significantly more expensive ($5,000-$6,000 annually) than oral agents but similar efficacy. 3

10. OnabotulinumtoxinA

• FDA-approved specifically for chronic migraine prophylaxis only (≥15 headache days/month), NOT for episodic migraine. 3
• Efficacy assessment requires 6-9 months. 1, 3

11. Candesartan

• First-line agent particularly useful for patients with comorbid hypertension. 3
• Limited evidence compared to beta-blockers and topiramate. 3, 4, 5

12. Flunarizine (5-10 mg/day, where available)

• Effective second-line agent with efficacy comparable to propranolol and topiramate. 3
• Not available in the United States. 3
• Contraindicated in active Parkinsonism, history of extrapyramidal disorders, and current depression. 3

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Agents with Weak or Insufficient Evidence

13. Gabapentin

• Fair evidence of effectiveness but should only be considered if propranolol fails or is contraindicated. 2, 4, 5

14. Lisinopril

• Weak evidence for episodic migraine prevention. 2, 3, 5

15. Verapamil

• Mixed data and expert opinion; can be considered when other medications cannot be used but should not be prioritized over propranolol. 2, 4, 5

16. Oral Magnesium

• Weak evidence but may be considered as adjunctive therapy. 3, 5

17. Riboflavin (Vitamin B2)

• Potentially useful first-line preventive intervention based on more than one randomized trial. 1, 5

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Ineffective Agents (Do Not Use)

• Acebutolol, oxcarbazepine, lamotrigine, and telmisartan are ineffective for migraine prevention. 4

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Critical Implementation Principles

• Indications for preventive therapy: ≥2 migraine attacks per month with disability lasting ≥3 days, use of acute medications >2 days per week, failure of acute treatments, or uncommon migraine conditions. 2, 3
• Adequate trial duration: Allow 2-3 months at therapeutic dose for oral agents before declaring treatment failure. 2, 3
• Start low, titrate slowly: Begin with low doses and gradually increase to minimize side effects and improve tolerability. 2, 3
• Medication overuse headache: Ensure patients are not using acute medications >2 days per week, as this interferes with preventive therapy effectiveness. 1, 3
• Comorbidity-driven selection: Choose agents that treat both migraine and coexisting conditions (e.g., propranolol for hypertension, amitriptyline for depression, topiramate for obesity). 3, 8, 7