What is the most effective preventive therapy for migraine?

Best Preventive Therapy for Migraine

Beta-blockers (propranolol 80-240 mg/day or timolol 20-30 mg/day), topiramate (50-100 mg/day), or candesartan are the first-line preventive medications for migraine, with the choice depending on patient comorbidities. 1, 2

Indications for Starting Preventive Therapy

Preventive therapy should be initiated when patients experience:

• ≥2 migraine attacks per month causing disability lasting ≥3 days, despite optimized acute treatment 1, 2
• Use of abortive medications more than twice weekly (≥10 days/month for triptans or ≥15 days/month for NSAIDs), which risks medication-overuse headache 1, 2
• Contraindication to or failure of acute treatments, making preventive therapy the primary management strategy 1, 2
• Uncommon migraine conditions including hemiplegic migraine, migraine with prolonged aura, or migrainous infarction 1, 2

First-Line Preventive Medications

Beta-Blockers (Strongest Evidence)

• Propranolol 80-240 mg/day has the most robust evidence with consistent efficacy demonstrated across multiple randomized controlled trials 1, 2
• Timolol 20-30 mg/day also has strong evidence for efficacy 1, 2
• Alternative beta-blockers including atenolol, bisoprolol, metoprolol, and nadolol have moderate evidence supporting their use 1, 2
• Beta-blockers with intrinsic sympathomimetic activity (acebutolol, alprenolol, oxprenolol, pindolol) are ineffective and should be avoided 1
• Common adverse effects include fatigue, depression, nausea, dizziness, and insomnia, though these are generally well-tolerated 1

Topiramate

• Topiramate 50-100 mg/day (typically 50 mg twice daily) is a first-line option with strong evidence for both episodic and chronic migraine 1, 2
• Particularly beneficial in patients with obesity due to associated weight loss 2
• Common adverse effects include cognitive inefficiency ("word-finding difficulty"), paresthesias, fatigue, and weight loss 2
• Teratogenic potential requires careful counseling in women of childbearing age 1

Candesartan

• Candesartan is a first-line angiotensin receptor blocker particularly useful for patients with comorbid hypertension 1, 2
• Provides dual benefit of migraine prevention and blood pressure control 1, 2

Second-Line Preventive Medications

Amitriptyline

• Amitriptyline 30-150 mg/day has consistent evidence for efficacy, particularly in patients with mixed migraine and tension-type headache 1, 2
• Optimal choice for patients with comorbid depression, anxiety, or sleep disturbances, as it addresses both migraine and mood disorders simultaneously 2
• Common adverse effects include drowsiness, weight gain, and anticholinergic symptoms (dry mouth, constipation, urinary retention) 1
• Lacks robust evidence specifically for chronic migraine prophylaxis; efficacy is mainly demonstrated in episodic migraine 2

Flunarizine

• Flunarizine 5-10 mg once daily (typically at night) is an effective second-line calcium channel blocker where available 1, 2
• Proven efficacy comparable to propranolol and topiramate in multiple placebo-controlled trials 2
• Common adverse effects include sedation, weight gain, and abdominal pain 2
• Serious adverse effects include depression and extrapyramidal symptoms, particularly in elderly patients 2
• Absolute contraindications include active Parkinsonism or history of extrapyramidal disorders; current depression is a relative contraindication 2

Sodium Valproate/Divalproex Sodium

• Sodium valproate 800-1500 mg/day or divalproex sodium 500-1500 mg/day have good evidence for efficacy 1, 2
• Strictly contraindicated in women of childbearing potential due to teratogenic effects (neural tube defects) 1, 2
• Adverse events include weight gain, hair loss, tremor, and hepatotoxicity 1

Third-Line Preventive Medications: CGRP Monoclonal Antibodies

• Erenumab, fremanezumab, galcanezumab, and eptinezumab should be considered when first- and second-line oral preventives have failed or are contraindicated 1, 2
• Administered monthly via subcutaneous injection (or quarterly for some formulations) 2
• Efficacy assessment requires 3-6 months before determining success or failure 2
• Significantly more expensive than oral agents, with annualized costs of $5,000-$6,000 2
• In Europe, regulatory restrictions limit their use to patients in whom other preventive drugs have failed or are contraindicated 1

Implementation Strategy

Starting and Titrating Preventive Therapy

• Start with a low dose and titrate slowly until clinical benefits are achieved or side effects limit further increases 2
• Allow an adequate trial period of 2-3 months at therapeutic dose before determining efficacy for oral agents 1, 2
• For CGRP monoclonal antibodies, assess efficacy only after 3-6 months 2
• Simplified dosing schedules (once daily or less) improve treatment adherence 1

Monitoring and Duration

• Use headache diaries to track attack frequency, severity, duration, disability, treatment response, and adverse effects 2
• Calculate percentage reduction in monthly migraine days or monthly headache days of moderate-to-severe intensity to quantify success 1
• Consider pausing preventive treatment after 6-12 months of successful therapy to determine if it can be discontinued 1, 2

Algorithm for Selecting First-Line Agent Based on Comorbidities

• Hypertension present → initiate propranolol, timolol, or candesartan 1, 2
• Obesity present → initiate topiramate (promotes weight loss) 2
• Depression, anxiety, or sleep disturbance present → initiate amitriptyline 2
• No significant comorbidities → initiate propranolol or topiramate (strongest evidence base) 1, 2
• Elderly patients → avoid flunarizine due to increased risk of extrapyramidal symptoms and depression 2
• Women of childbearing potential → avoid valproate/divalproex due to teratogenicity 1, 2

Non-Pharmacological Preventive Options

• Neuromodulatory devices can be considered as adjuncts to medication or as stand-alone treatments when medications are contraindicated 1, 2
• Biobehavioral therapy (cognitive behavioral therapy, biofeedback, relaxation training) has evidence supporting its use alongside medication 1, 2
• Acupuncture has some supporting evidence, though not superior to sham acupuncture in controlled trials 1, 2
• Limited to no evidence exists for physical therapy, spinal manipulation, and dietary approaches 1

Critical Pitfalls to Avoid

• Inadequate duration of preventive trial (less than 2-3 months at therapeutic dose) leads to premature abandonment of effective therapy 2
• Starting with too high a dose causes poor tolerability and discontinuation; always start low and titrate slowly 2
• Failing to recognize medication-overuse headache from frequent use of acute medications (≥10 days/month for triptans, ≥15 days/month for NSAIDs) interferes with preventive treatment efficacy 2
• Using valproate in women of childbearing potential despite absolute contraindication due to teratogenicity 1, 2
• Avoiding beta-blockers with intrinsic sympathomimetic activity (acebutolol, alprenolol, oxprenolol, pindolol), which are ineffective 1
• Failure of one preventive class does not predict failure of others; multiple trials may be required to find the optimal agent for an individual patient 1, 3, 4