In a patient with chronic migraine requiring daily preventive therapy, which prophylactic medication(s) are first‑line?

Chronic Migraine: Daily Prophylaxis Recommendations

First-Line Prophylactic Medications

For chronic migraine requiring daily preventive therapy, beta-blockers (propranolol 80–240 mg/day, metoprolol, atenolol, or bisoprolol), topiramate 50–100 mg/day, or candesartan are the recommended first-line options. 1

• Propranolol 80–240 mg/day carries the strongest evidence among traditional preventives, with FDA approval and multiple randomized controlled trials demonstrating efficacy; doses below 160 mg/day are generally sub-therapeutic. 1, 2, 3

• Topiramate 50–100 mg/day (typically 50 mg twice daily) is the only oral preventive with robust RCT evidence specifically for chronic migraine and should be prioritized when obesity is present due to associated weight loss. 1, 2, 4

• Candesartan is particularly useful when hypertension coexists. 1, 2

• All first-line agents require an adequate trial of 2–3 months at target dose before judging efficacy; patients should be counseled that immediate benefits are rarely observed. 1, 2

Second-Line Prophylactic Medications

• Amitriptyline 30–150 mg/day is preferred when comorbid depression, anxiety, sleep disturbances, or mixed migraine/tension-type headache are present, though it lacks robust RCT evidence specifically for chronic migraine. 1, 2, 5

• Flunarizine 5–10 mg once daily (where available) is effective as a second-line agent but should be avoided in patients with Parkinsonism or depression. 1, 2

• Sodium valproate 800–1500 mg/day or divalproex sodium 500–1500 mg/day are effective but strictly contraindicated in women of childbearing potential due to teratogenic risk. 1, 2, 6, 5

Third-Line Options for Refractory Chronic Migraine

• CGRP monoclonal antibodies (erenumab, fremanezumab, galcanezumab, eptinezumab) should be considered when two or more oral preventives have failed or are contraindicated; efficacy requires assessment after 3–6 months. 1, 2

• OnabotulinumtoxinA 155–195 units to 31–39 sites every 12 weeks is the only FDA-approved therapy specifically for chronic migraine prophylaxis and should be used when three oral preventives have failed. 7, 4

Critical Medication-Overuse Prevention

• All acute migraine medications must be limited to ≤ 2 days per week (≤ 10 days per month) to prevent medication-overuse headache, which paradoxically increases headache frequency and can sustain chronic migraine. 1, 7, 2

• If medication-overuse headache is present (acute medications used ≥10 days/month for triptans or ≥15 days/month for NSAIDs), abrupt cessation of overused medications is required before preventive therapy can be fully effective; withdrawal headache may worsen for 2–10 days. 7

Treatment Algorithm

1. Initiate first-line agent (propranolol 80–240 mg/day, topiramate 50–100 mg/day, or candesartan) based on comorbidities: choose topiramate if obesity is present, propranolol if hypertension or no specific comorbidity exists. 1, 2

2. Titrate slowly from low starting doses to target therapeutic dose over several weeks to minimize adverse effects. 1, 2

3. Assess efficacy after 2–3 months at target dose; if ineffective, switch to an alternative first-line agent (failure of one class does not predict failure of others). 1, 2

4. Escalate to second-line agents (amitriptyline, flunarizine, or valproate in appropriate patients) if all first-line options fail. 1, 2

5. Consider third-line therapy (CGRP monoclonal antibodies or onabotulinumtoxinA) after failure of two oral preventives. 1, 7, 2

6. Reassess after 6–12 months of successful control to determine if preventive therapy can be paused. 1, 2

Common Pitfalls to Avoid

• Do not maintain sub-therapeutic doses (e.g., propranolol <160 mg/day) indefinitely; optimize dosing before declaring treatment failure. 2

• Do not abandon treatment prematurely; efficacy requires 2–3 months at target dose for oral agents. 1, 2

• Do not allow continued overuse of acute medications; this creates a vicious cycle that prevents preventive therapy from working. 7

• Avoid opioids and butalbital-containing compounds for acute treatment, as they provide questionable efficacy, cause dependency, and worsen long-term outcomes. 1, 7

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, 2

• Limited evidence exists for physical therapy, spinal manipulation, and dietary approaches. 1