What is the first‑line preventive medication regimen for a patient with frequent migraines (≥4 headache days per month) who wants to reduce attack frequency?

First-Line Preventive Medication for Frequent Migraines

Beta-blockers without intrinsic sympathomimetic activity (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 headache days per month. 1

Indications for Preventive Therapy

• Preventive treatment should be considered when migraine continues to impair quality of life despite optimized acute therapy, particularly in patients adversely affected on ≥2 days per month. 1
• Additional indications include overuse of acute medication (using abortive medications more than twice weekly), severe or prolonged attacks, and contraindications to acute treatments. 1, 2
• The goal is to reduce attack frequency by ≥50%, decrease severity, and restore responsiveness to acute treatments. 1

First-Line Preventive Medications

Beta-Blockers

• Propranolol 80–240 mg/day is the most established first-line agent with strong randomized controlled trial evidence and FDA approval for migraine prevention. 1, 2
• Alternative beta-blockers include metoprolol, atenolol, and bisoprolol, all with proven efficacy but without intrinsic sympathomimetic activity. 1, 2
• Timolol 20–30 mg/day also has strong evidence for efficacy. 1, 2
• Beta-blockers are particularly useful for patients with comorbid hypertension or anxiety. 2

Topiramate

• Topiramate 50–100 mg/day (typically 50 mg twice daily) is a first-line agent with robust evidence for both episodic and chronic migraine prevention. 1, 2
• Topiramate is the preferred first-line choice for patients with obesity because it promotes weight loss as an additional therapeutic benefit. 2
• Common adverse effects include paresthesias, cognitive slowing, and kidney stones, which may limit tolerability. 1

Candesartan

• Candesartan is a first-line angiotensin-receptor blocker particularly useful for patients with comorbid hypertension. 1, 2
• It offers an alternative for patients who cannot tolerate beta-blockers or topiramate. 1, 2

Second-Line Preventive Medications

Flunarizine

• Flunarizine 5–10 mg once daily (typically at night) is an effective second-line calcium channel blocker where available, with efficacy comparable to propranolol and topiramate. 1, 2
• Common adverse effects include sedation, weight gain, and risk of depression or extrapyramidal symptoms, particularly in elderly patients. 2
• It is contraindicated in patients with active Parkinsonism or current depression. 2

Amitriptyline

• Amitriptyline 30–150 mg/day is a second-line tricyclic antidepressant particularly effective for patients with comorbid depression, anxiety, sleep disturbances, or mixed migraine and tension-type headache. 1, 2
• Evidence for chronic migraine prophylaxis is limited compared to episodic migraine. 2

Sodium Valproate/Divalproex

• Sodium valproate 800–1500 mg/day or divalproex sodium 500–1500 mg/day are second-line options with proven efficacy. 1, 2
• These agents are strictly contraindicated in women of childbearing potential due to teratogenic risk. 1, 2
• Common adverse effects include weight gain, hair loss, tremor, and hepatotoxicity. 2

Third-Line Preventive Medications: CGRP Monoclonal Antibodies

• Erenumab, fremanezumab, galcanezumab, or eptinezumab should be considered when 2–3 oral preventive medications have failed or are contraindicated. 1, 2
• These are administered as monthly subcutaneous injections (or quarterly for some formulations). 1, 2
• Efficacy should be assessed only after 3–6 months of treatment, as response may be delayed. 1, 2
• In Europe, regulatory restrictions limit their use to patients in whom other preventive drugs have failed or are contraindicated. 1

Implementation Strategy

Dosing and Titration

• Start with a low dose and titrate slowly until clinical benefits are achieved or side effects limit further increases. 2
• For propranolol, the typical effective dose is 160 mg once daily, with some patients requiring up to 240 mg daily; doses below 160 mg are generally sub-therapeutic. 2
• For topiramate, begin at 25 mg daily and increase by 25 mg weekly to reach the target dose of 50–100 mg/day. 2

Duration of Trial

• An adequate trial requires 2–3 months at the target dose before assessing efficacy for oral preventive medications. 1, 2
• For CGRP monoclonal antibodies, efficacy should be assessed after 3–6 months. 1, 2
• For onabotulinumtoxinA (used only for chronic migraine, not episodic), efficacy should be assessed after 6–9 months. 1

Monitoring and Follow-Up

• Patients should maintain a headache diary to track attack frequency, severity, duration, disability, and treatment response. 2
• A useful measure of success is calculating the percentage reduction in monthly migraine days or monthly headache days of moderate-to-severe intensity. 1
• If a therapeutic dose is ineffective after 2–3 months, switch to an alternative preventive medication from a different drug class. 1

Duration of Therapy

• When treatment has been successful for 6–12 months, consider pausing preventive therapy to determine whether it can be discontinued. 1, 2
• The purpose of pausing is to minimize unnecessary drug exposure and allow some patients to manage their migraine with acute medications only. 1
• Failure of one preventive treatment does not predict failure of other drug classes, except when failure is due to poor adherence. 1

Non-Pharmacological Adjuncts

• Neuromodulatory devices, biobehavioral therapy (relaxation training, biofeedback, cognitive behavioral therapy), and acupuncture have supporting evidence and can be used as adjuncts to medication or as stand-alone treatments when medications are contraindicated. 1, 2
• Limited to no evidence exists for physical therapy, spinal manipulation, and dietary approaches. 1
• Complementary treatments such as riboflavin, magnesium, and melatonin have limited evidence and are not routinely recommended. 1

Critical Pitfalls to Avoid

• Do not maintain sub-therapeutic doses (e.g., propranolol <160 mg or amitriptyline <30 mg) indefinitely; doses must be optimized before declaring treatment failure. 2
• Do not discontinue preventive therapy prematurely; an adequate trial requires 2–3 months at the target dose. 1, 2
• Do not allow patients to use acute medications more than 2 days per week, as this creates medication-overuse headache and undermines preventive therapy. 1, 2
• Screen for medication-overuse headache (using acute medications ≥10 days/month for triptans or ≥15 days/month for NSAIDs) before starting preventive therapy, as overuse can interfere with preventive treatment efficacy. 2
• Address comorbidities when selecting preventive medications: avoid valproate in women of childbearing potential, choose topiramate for obesity, choose amitriptyline for depression/anxiety, and choose beta-blockers or candesartan for hypertension. 1, 2
• Do not initiate multiple new preventive agents simultaneously; use sequential monotherapy to identify efficacy and adverse-effect profiles. 2

Treatment Algorithm

1. First-line choice:

   • Propranolol 80–240 mg/day (or alternative beta-blocker) for most patients 1, 2
   • Topiramate 50–100 mg/day for patients with obesity 2
   • Candesartan for patients with comorbid hypertension 1, 2

2. If first-line fails or is not tolerated after 2–3 months:

   • Flunarizine 5–10 mg/day (where available) 1, 2
   • Amitriptyline 30–150 mg/day for comorbid depression, anxiety, or sleep disturbances 1, 2
   • Valproate/divalproex (only in men or women not of childbearing potential) 1, 2

3. If 2–3 oral preventives fail:

   • CGRP monoclonal antibodies (erenumab, fremanezumab, galcanezumab, or eptinezumab) 1, 2

4. Throughout treatment:

   • Limit acute medication use to ≤2 days per week 1, 2
   • Maintain headache diary 2
   • Reassess efficacy after appropriate trial duration 1, 2