What are the first‑line preventive medications for a patient with frequent or disabling migraines (≥4 migraine days per month) and how should they be initiated and titrated?

First-Line Preventive Medications for Frequent Migraine

Beta-blockers (propranolol 80–240 mg/day, metoprolol, atenolol, or bisoprolol), topiramate 50–100 mg/day, or candesartan are the recommended first-line preventive medications for patients with ≥4 migraine days per month. 1

Indications for Preventive Therapy

• Preventive treatment should be considered in patients adversely affected by migraine on ≥2 days per month despite optimized acute treatment. 1
• Additional indications include: disability lasting ≥3 days per month, use of acute medications more than twice weekly (to prevent medication-overuse headache), contraindications to acute treatments, or uncommon migraine conditions such as hemiplegic migraine or prolonged aura. 2, 3
• Patients requiring acute medication more than 2 days per week are at high risk for medication-overuse headache and should transition immediately to preventive therapy. 2

First-Line Medication Selection Algorithm

Beta-Blockers (Preferred for Most Patients)

• Propranolol 80–240 mg/day is FDA-approved and has the strongest evidence base among all preventive medications, with the most thorough evaluation in randomized controlled trials. 1, 3, 4
• Alternative beta-blockers include metoprolol, atenolol, or bisoprolol, all supported by moderate-quality evidence. 1, 3
• Timolol 20–30 mg/day also has strong RCT evidence and FDA approval. 3
• Beta-blockers are particularly appropriate for patients with comorbid hypertension or anxiety. 3
• Contraindications: asthma, severe bradycardia, heart block, or peripheral vascular disease. 3

Topiramate 50–100 mg/day

• Topiramate is FDA-approved and represents a first-line option with robust evidence for both episodic and chronic migraine. 1, 3, 5
• Topiramate is the preferred first-line agent for patients with obesity because it promotes weight loss as a beneficial side effect. 3
• The standard target dose is 50 mg twice daily (100 mg/day total); doses of 200 mg/day do not provide additional efficacy but increase adverse effects. 4
• Common adverse effects include paresthesias, cognitive slowing, language difficulties, and gastrointestinal disturbances—these are frequent and may limit tolerability. 4
• Strict contraindication in pregnancy due to teratogenic risk (cleft palate, developmental delays). 3

Candesartan

• Candesartan is a first-line agent particularly useful for patients with comorbid hypertension. 1, 3
• It has good evidence for efficacy with a favorable side-effect profile compared to other first-line agents. 5

Initiation and Titration Strategy

Start Low, Go Slow

• All preventive medications should be started at a low dose and titrated slowly until therapeutic benefit is achieved or side effects preclude further increases. 3, 5
• An adequate trial period of 2–3 months is required before determining efficacy; premature discontinuation is a common pitfall. 3, 6

Propranolol Titration

• Start at 40 mg twice daily and increase by 40 mg every 1–2 weeks as tolerated. 3
• Target dose: 80–240 mg/day divided into two or three doses. 3
• Monitor blood pressure and heart rate at each titration step. 3

Topiramate Titration

• Start at 25 mg once daily at bedtime to minimize cognitive side effects. 5, 6
• Increase by 25 mg weekly until reaching 50 mg twice daily (100 mg/day). 5, 6
• Slower titration (every 2 weeks) may improve tolerability in patients sensitive to side effects. 5

Candesartan Dosing

• Start at 8 mg once daily and increase to 16 mg once daily after 2 weeks if tolerated. 5

Second-Line Medications (When First-Line Fails or Is Contraindicated)

• Flunarizine 5–10 mg/day (where available) is an effective second-line option with efficacy comparable to propranolol. 1, 7
• Amitriptyline 30–150 mg/day is preferred for patients with comorbid depression, anxiety, insomnia, or mixed migraine/tension-type headache. 1, 3, 8
• Sodium valproate 800–1500 mg/day is effective but strictly contraindicated in women of childbearing potential due to severe teratogenic risk. 1, 3

Third-Line: CGRP Monoclonal Antibodies

• Erenumab, fremanezumab, galcanezumab, or eptinezumab should be considered only after failure of 2–3 oral preventive medications. 1, 3
• These agents require 3–6 months to assess efficacy (longer than oral agents). 3
• Significantly higher cost ($5,000–$6,000 annually) limits first-line use. 3

Monitoring and Follow-Up

• Headache diaries (paper or smartphone-based) are essential to track attack frequency, severity, duration, disability, and treatment response. 2, 3
• Schedule follow-up at 4–6 weeks after initiation to assess tolerability and titrate dose. 3
• Reassess efficacy at 2–3 months (or 3–6 months for CGRP antibodies). 3
• Success is defined as ≥50% reduction in monthly migraine days; this threshold justifies continuing therapy. 3

Critical Pitfalls to Avoid

• Inadequate trial duration: Discontinuing preventive therapy before 2–3 months prevents accurate assessment of efficacy. 3, 6
• Starting at too high a dose: This leads to poor tolerability and premature discontinuation; always start low and titrate slowly. 3, 5
• Failing to address medication-overuse headache: Acute medications used ≥10 days/month (triptans) or ≥15 days/month (NSAIDs) interfere with preventive therapy and must be limited to ≤2 days/week. 2, 3
• Ignoring comorbidities: Valproate in women of childbearing potential, beta-blockers in asthma, and topiramate in pregnancy are absolute contraindications. 3
• Using amitriptyline as first-line for chronic migraine: Amitriptyline lacks robust RCT evidence for chronic migraine; topiramate is the evidence-based first choice. 3

Non-Pharmacological Adjuncts

• Neuromodulatory devices, biobehavioral therapy (cognitive-behavioral therapy, biofeedback, relaxation training), and acupuncture can be used as adjuncts to medication or as stand-alone treatments when medications are contraindicated. 1, 3, 6
• Trigger identification and modification (sleep hygiene, regular meals, hydration, stress management) should be addressed in all patients. 3, 6

Duration of Preventive Therapy

• After 6–12 months of successful therapy (≥50% reduction in migraine days), consider a trial of tapering or discontinuation to determine if preventive therapy can be stopped. 2, 3
• Many patients will require long-term preventive therapy; relapse after discontinuation is common. 3