What are the first‑line preventive treatment options for an adult patient with recurrent migraine attacks?

First-Line Preventive Treatment for Recurrent Migraine Attacks

Propranolol 80–240 mg/day, timolol 20–30 mg/day, or topiramate 50–100 mg/day are the established first-line preventive medications for migraine, with CGRP-targeting monoclonal antibodies (erenumab, fremanezumab, galcanezumab) now also considered first-line options based on superior efficacy and tolerability data. 1, 2, 3

Indications for Starting Preventive Therapy

Initiate preventive treatment when any of the following criteria are met:

• ≥2 migraine attacks per month causing disability lasting ≥3 days 1, 2
• Acute medication use >2 days per week (≥10 days/month for triptans or ≥15 days/month for NSAIDs), which creates risk for medication-overuse headache 1, 2
• Failure of or contraindication to acute treatments 1, 2
• Uncommon migraine conditions including hemiplegic migraine, migraine with prolonged aura, or migrainous infarction 1, 2
• Patient preference for preventive approach over frequent acute treatment 1, 2

First-Line Preventive Medications: Evidence-Based Algorithm

Beta-Blockers (Strongest Traditional Evidence)

Propranolol 80–240 mg/day has the most robust evidence among traditional preventives, with consistent efficacy demonstrated across multiple randomized controlled trials and FDA approval for migraine prevention 1, 2, 4

• Typical effective dose is 160 mg once daily; doses below 160 mg are generally sub-therapeutic 2, 4
• Maximum dose is 240 mg/day 1, 2
• Preferred for patients with comorbid hypertension or anxiety 2, 4

Alternative beta-blockers with proven efficacy include:

• Timolol 20–30 mg/day 1, 2
• Metoprolol, atenolol, nadolol, or bisoprolol 1, 2, 4

Contraindications: Asthma, heart block, severe peripheral vascular disease 1

Topiramate (Strongest Evidence for Chronic Migraine)

Topiramate 50–100 mg/day (typically 50 mg twice daily) is the only oral preventive with robust RCT evidence specifically for chronic migraine 2, 4

• Start 25 mg daily, increase by 25 mg weekly to target dose 4
• Preferred first-line choice for patients with obesity because it promotes weight loss 2, 4, 5
• Common adverse effects: paresthesias, cognitive slowing, kidney stones 2, 4

CGRP-Targeting Monoclonal Antibodies (Highest Efficacy & Tolerability)

The American Headache Society now considers CGRP-targeting therapies as first-line options without requiring prior failure of other preventives 3

Erenumab, fremanezumab, galcanezumab, or eptinezumab administered as monthly subcutaneous injections 2, 6, 7, 8, 3

• Superior efficacy and tolerability compared to traditional preventives, with evidence "vastly exceeding that for any other preventive treatment approach" 3
• Serious adverse events are rare 3
• Efficacy assessed after 3–6 months of treatment 2, 4
• Primary limitation: Cost ($5,000–$6,000 annually) and insurance restrictions often require failure of 2–3 oral preventives first 2, 4

Fremanezumab dosing options: 225 mg monthly OR 675 mg every 3 months (three consecutive 225 mg injections) 6

Contraindication: Serious hypersensitivity to the specific monoclonal antibody or excipients 6

Candesartan (ARB Alternative)

Candesartan is a first-line angiotensin-receptor blocker with strong evidence for episodic migraine prevention 2, 4

• Preferred for patients with comorbid hypertension 2, 4
• Alternative when beta-blockers or topiramate are contraindicated 2, 4

Second-Line Preventive Options

Amitriptyline 30–150 mg/day

• Preferred for patients with comorbid depression, anxiety, sleep disturbance, or mixed migraine/tension-type headache 1, 2, 4, 9, 5
• Evidence for chronic migraine prophylaxis is limited compared to episodic migraine 2, 4
• Sedating properties provide dual benefit for sleep improvement 2

Divalproex/Valproate

• Divalproex sodium 500–1500 mg/day or sodium valproate 800–1500 mg/day 1, 2, 10, 9
• Strictly contraindicated in women of childbearing potential due to teratogenic risk 1, 2, 4, 5
• Adverse effects: weight gain, hair loss, tremor 1, 2

Flunarizine 5–10 mg once daily

• Efficacy comparable to propranolol and topiramate 2, 4
• Typically dosed at night to minimize daytime sedation 2
• Contraindicated in active Parkinsonism or current depression 2, 4
• Adverse effects: sedation, weight gain, extrapyramidal symptoms (especially in elderly) 2, 4

Practical Implementation Strategy

Dosing and Titration

• Start all oral preventives at low doses and titrate slowly until clinical benefit is achieved or side effects limit further increase 2, 4, 10
• Adequate trial duration: 2–3 months at target dose before assessing efficacy 1, 2, 4, 10, 9
• For CGRP monoclonal antibodies: assess after 3–6 months 2, 4
• For onabotulinumtoxinA (chronic migraine only): assess after 6–9 months 2

Monitoring and Outcome Measures

• Headache diary documenting attack frequency, severity, duration, disability, and acute medication use 2, 4
• Success defined as ≥50% reduction in monthly migraine days 2, 4
• If target dose is ineffective after 2–3 months, switch to alternative preventive from different drug class 4
• After 6–12 months of sustained success, consider trial pause to assess need for continued prophylaxis 2, 4

Critical Pitfalls to Avoid

• Do not maintain sub-therapeutic doses indefinitely (e.g., propranolol <160 mg or amitriptyline <30 mg); optimize dose before declaring treatment failure 2, 4
• Do not discontinue preventive therapy prematurely; 2–3 months at target dose is required 2, 4, 10
• Screen for medication-overuse headache (acute use ≥10 days/month for triptans or ≥15 days/month for NSAIDs) before initiating preventive therapy 2, 4
• Limit acute medications to ≤2 days per week to prevent medication-overuse headache 1, 2, 4
• Initiate only one new preventive agent at a time; use sequential monotherapy to identify efficacy and tolerability 2, 4
• Tailor preventive choice to comorbidities: avoid valproate in women of childbearing potential; select topiramate for obesity; choose amitriptyline for depression/anxiety; prefer beta-blockers or candesartan for hypertension 2, 4

Adjunctive Non-Pharmacological Options

• Cognitive behavioral therapy, biofeedback, relaxation training have supporting evidence as adjuncts or stand-alone options when medications are contraindicated 2, 4, 5
• Neuromodulatory devices can be considered as adjuncts 2, 4
• Acupuncture has limited evidence (not superior to sham in controlled trials) 2
• Trigger identification and management: sleep hygiene, regular meals, hydration, stress management, limiting caffeine and alcohol 2, 5
• Physical therapy, spinal manipulation, and dietary approaches have limited to no evidence 2, 4