What is the best treatment approach for a patient with a history of frequent or severe migraines, considering preventive medications and potential cardiovascular disease risk?

Migraine Prevention: Evidence-Based Treatment Approach

When to Initiate Preventive Therapy

Preventive therapy should be started immediately if you experience ≥2 migraine attacks per month with disability lasting ≥3 days, or if you use acute medications more than 2 days per week. 1

Additional indications include:

• Contraindication to or failure of acute treatments 1
• Uncommon migraine conditions (hemiplegic migraine, prolonged aura, migrainous infarction) 1
• Patient preference for prevention over frequent acute treatment 1

First-Line Preventive Medications

Start with propranolol 80-240 mg/day, timolol 20-30 mg/day, topiramate 50-100 mg/day, or candesartan as your first-line agent. 1

Beta-Blockers (Strongest Evidence)

• Propranolol 80-240 mg/day is FDA-approved with the strongest evidence for efficacy 1
• Timolol 20-30 mg/day has equally strong evidence 1
• Alternative beta-blockers include metoprolol, atenolol, bisoprolol, or nadolol 1
• Avoid in patients with asthma, heart block, or depression 1

Topiramate

• Dose: 100 mg/day (typically 50 mg twice daily) 1
• Particularly useful for patients with obesity due to associated weight loss 1
• Start low (25 mg daily) and titrate slowly over 4-6 weeks to minimize side effects 1

Candesartan

• First-line agent, especially useful for patients with comorbid hypertension 1
• Strong recommendation from VA/DoD guidelines 2

Second-Line Preventive Medications

If first-line agents fail or are not tolerated, use amitriptyline 30-150 mg/day or divalproex sodium 500-1500 mg/day. 1

Amitriptyline

• Optimal choice for patients with comorbid depression, anxiety, or mixed migraine/tension-type headache 1
• Start at 10-25 mg at bedtime and titrate slowly 1
• Common side effects: dry mouth, sedation, weight gain 1

Valproate/Divalproex

• Sodium valproate 800-1500 mg/day or divalproex sodium 500-1500 mg/day 1
• STRICTLY CONTRAINDICATED in women of childbearing potential due to teratogenic effects 1, 2
• Effective but requires monitoring for hepatotoxicity and thrombocytopenia 1

Flunarizine (Where Available)

• Dose: 5-10 mg once daily at night 1
• Efficacy comparable to propranolol and topiramate 1
• Contraindicated in active Parkinsonism, history of extrapyramidal disorders, or current depression 1
• Avoid in elderly due to increased risk of extrapyramidal symptoms and depression 1

Third-Line: CGRP Monoclonal Antibodies

Consider erenumab, fremanezumab, or galcanezumab when 2-3 oral preventive medications have failed or are contraindicated. 1

• Administered monthly via subcutaneous injection 1
• Efficacy assessment requires 3-6 months (not 2-3 months like oral agents) 1
• Strong recommendation from VA/DoD guidelines for both episodic and chronic migraine 2
• Significantly more expensive: $5,000-$6,000 annually 1
• Eptinezumab (IV) has weaker evidence 1

Implementation Strategy

Start with a low dose and titrate slowly until clinical benefits are achieved or side effects limit further increases. 1

Trial Period

• Allow 2-3 months for oral preventive medications before determining efficacy 1
• Allow 3-6 months for CGRP monoclonal antibodies 1
• Use headache diaries to track attack frequency, severity, duration, disability, and treatment response 1

Success Metrics

• Goal: ≥50% reduction in monthly migraine days 1
• Improved quality of life and reduced headache-related distress 3

Duration of Therapy

• Continue successful preventive therapy for 6-12 months 1
• After stability, consider tapering or discontinuing to determine if treatment can be stopped 1

Critical Cardiovascular Considerations

For patients with cardiovascular disease risk factors or established CAD, avoid triptans for acute treatment and choose preventive agents carefully. 4

Cardiovascular Risk Assessment

• Beta-blockers are ideal for patients with hypertension or CAD as they treat both conditions 1
• Candesartan is preferred for patients with hypertension 1
• Avoid triptans in patients with uncontrolled hypertension, ischemic heart disease, or vasospastic CAD 4

For Acute Treatment in CAD Patients

• Use NSAIDs (naproxen 500-825 mg, ibuprofen 400-800 mg) as first-line 5
• CGRP antagonists (gepants: rimegepant, ubrogepant, zavegepant) have no vasoconstriction and are safe alternatives when triptans are contraindicated 5
• Lasmiditan (ditan) is a 5-HT1F agonist without vasoconstrictor activity, safe for cardiovascular disease 5

Common Pitfalls to Avoid

Do not fail to recognize medication overuse headache before starting preventive therapy. 1

• Medication overuse headache occurs with acute medication use ≥10 days/month for triptans or ≥15 days/month for NSAIDs 1
• Overuse interferes with preventive treatment effectiveness 1
• Limit all acute medications to ≤2 days per week 5, 1

Do not start with too high a dose, leading to poor tolerability and discontinuation. 1

Do not give inadequate trial duration (less than 2-3 months for oral agents). 1

Do not prescribe valproate to women of childbearing potential. 1, 2

Do not use opioids or butalbital for acute migraine treatment. 5

Non-Pharmacological Adjuncts

Consider cognitive behavioral therapy, biofeedback, and relaxation training alongside medication. 1

• Neuromodulatory devices can be used as adjuncts or stand-alone treatments when medications are contraindicated 1
• Acupuncture may be beneficial, though not superior to sham acupuncture in controlled trials 1
• Identify and modify triggers: sleep hygiene, regular meals, hydration, stress management 1

Specific Algorithm for Treatment Selection

1. If patient has hypertension or CAD: Start with beta-blocker (propranolol/timolol) or candesartan 1

2. If patient has obesity: Start with topiramate 1

3. If patient has depression/anxiety or mixed headache types: Start with amitriptyline 1

4. If patient is a woman of childbearing potential: Avoid valproate; choose beta-blocker, topiramate, or candesartan 1

5. If 2-3 oral agents fail: Escalate to CGRP monoclonal antibodies 1

6. If patient has frequent acute medication use (>2 days/week): Address medication overuse headache first, then initiate preventive therapy 1