What medications are used for migraine prophylaxis?

Medications for Migraine Prophylaxis

For migraine prophylaxis, start with propranolol (80-240 mg/day), timolol (20-30 mg/day), or topiramate (100 mg/day) as first-line agents, with the choice guided by patient comorbidities and tolerability concerns. 1, 2

First-Line Prophylactic Medications

Beta-Blockers

• Propranolol (80-240 mg/day) and timolol (20-30 mg/day) have the strongest evidence for efficacy and are FDA-approved for migraine prophylaxis. 3, 1, 2
• Alternative beta-blockers with moderate evidence include atenolol, metoprolol, nadolol, and bisoprolol, though these have less robust data. 3, 1
• Avoid beta-blockers with intrinsic sympathomimetic activity (acebutolol, alprenolol, oxprenolol, pindolol) as they are ineffective for migraine prevention. 3
• Common adverse effects include fatigue, depression, nausea, dizziness, and insomnia, though these are generally well-tolerated. 3

Topiramate

• Topiramate 100 mg/day (typically 50 mg twice daily) is a first-line agent with high-quality evidence demonstrating efficacy comparable to beta-blockers. 1, 4, 5
• Topiramate reduces monthly migraine frequency by approximately 2 attacks per month and increases the 50% responder rate by 168 more patients per 1,000 compared to placebo. 5
• Start at 25 mg/day and titrate by 25 mg weekly to the target dose of 100 mg/day; doses of 200 mg/day show no additional efficacy but significantly more adverse effects. 4, 6
• Topiramate is particularly useful for patients concerned about weight gain, those who are overweight, or those with coexisting epilepsy, as it causes weight loss rather than gain. 4
• Common adverse effects include paresthesias (dose-related and most common cause of discontinuation), cognitive dysfunction, fatigue, decreased appetite, nausea, and taste perversion. 4, 5
• Topiramate is strictly contraindicated in women of childbearing potential due to teratogenic effects including neural tube defects. 1

Candesartan

• Candesartan is a first-line agent, particularly useful for patients with comorbid hypertension. 1

Second-Line Prophylactic Medications

Antidepressants

• Amitriptyline (30-150 mg/day) is the only antidepressant with consistent evidence for migraine prophylaxis and may be particularly effective in patients with mixed migraine and tension-type headache. 3, 1
• Common adverse effects include drowsiness, weight gain, and anticholinergic symptoms (dry mouth, constipation, urinary retention). 3
• Fluoxetine (20-40 mg/day) has limited evidence showing modest effect. 3

Anticonvulsants

• Divalproex sodium (500-1500 mg/day) and sodium valproate (800-1500 mg/day) have good evidence for efficacy but are strictly contraindicated in women of childbearing potential due to teratogenic effects. 3, 1
• Adverse effects include weight gain, hair loss, tremor, and teratogenic potential. 3
• These agents may be especially useful in patients with prolonged or atypical migraine aura. 3
• Gabapentin has limited evidence for moderate efficacy, while carbamazepine and vigabatrin are ineffective. 3

NSAIDs

• Naproxen or naproxen sodium have modest evidence for prophylactic effect based on meta-analysis of placebo-controlled trials. 3
• Side effects include gastrointestinal symptoms (nausea, vomiting, gastritis, blood in stool) reported in 3-45% of participants. 3

Serotonergic Agents

• Flunarizine (10 mg/day) has proven efficacy and is commonly used where available, though not in the United States. 3, 1
• Adverse effects include sedation, weight gain, abdominal pain, depression, and extrapyramidal symptoms (particularly in elderly patients). 3
• Methysergide has strong evidence for efficacy but carries risk of retroperitoneal and retropleural fibrosis with long-term use; therapy must be discontinued for 3-4 weeks after each 6-month course. 3

Third-Line Prophylactic Medications

CGRP Monoclonal Antibodies

• CGRP monoclonal antibodies (erenumab, fremanezumab, galcanezumab, eptinezumab) should be considered when first- and second-line treatments have failed or are contraindicated. 1
• Efficacy assessment requires 3-6 months of treatment, longer than the 2-3 months needed for oral agents. 1

Implementation Strategy

Initiation and Titration

• Start with a low dose and titrate slowly until clinical benefits are achieved or adverse effects limit further increases. 3, 1
• Allow an adequate trial period of 2-3 months before determining efficacy for oral agents. 3, 1
• Once preventive treatment is established, avoid overuse of acute medications (limit to no more than twice weekly) to prevent medication-overuse headache. 3, 1

Duration and Discontinuation

• After 6-12 months of successful therapy (defined as significant reduction in monthly migraine days), consider tapering or discontinuing treatment to determine if it can be stopped. 3, 1
• A useful measure of success is calculating the percentage reduction in monthly migraine days. 1

Indications for Preventive Therapy

• Consider preventive therapy for patients with ≥2 migraine attacks per month with disability lasting ≥3 days per month. 1
• Patients using abortive medication more than twice per week should receive preventive treatment to avoid medication-overuse headache. 1
• Patients with contraindications to or failure of acute treatments warrant preventive therapy. 1
• Patients with uncommon migraine conditions (hemiplegic migraine, prolonged aura, migrainous infarction) are candidates for prevention. 1

Critical Pitfalls to Avoid

• Do not fail to recognize medication-overuse headache from frequent use of acute medications, which can interfere with preventive treatment efficacy. 1
• Avoid inadequate trial duration (less than 2-3 months for oral agents); premature discontinuation prevents accurate efficacy assessment. 1
• Do not start with excessively high doses, which leads to poor tolerability and treatment discontinuation. 1
• In women of childbearing potential, absolutely avoid valproate/divalproex and topiramate due to teratogenic effects. 3, 1