What are the recommended drugs and dosages for migraine prophylaxis in patients with frequent or severe migraines, considering comorbidities such as depression, anxiety, asthma, and cardiovascular conditions?

Migraine Prophylaxis: Drugs, Dosages, and Titration

First-Line Preventive Medications

Beta-blockers are the most established first-line agents, with propranolol 80-240 mg/day showing the strongest evidence for efficacy. 1, 2

Propranolol

• Starting dose: 80 mg once daily (extended-release formulation) 2
• Titration: Increase to 120 mg once daily after 3-7 days if needed, then to 160 mg once daily 2
• Target dose: 120-160 mg once daily for most patients 2
• Maximum dose: 240 mg/day (some patients may require up to 640 mg/day for hypertension, though this is rarely needed for migraine) 2
• Trial duration: Allow 4-6 weeks at maximum tolerated dose before determining efficacy 2
• Particularly useful for: Patients with comorbid hypertension or anxiety 1

Topiramate

• Starting dose: 25 mg once daily at bedtime 3, 4
• Titration: Increase by 25 mg weekly 4, 5
• Target dose: 100 mg/day (50 mg twice daily) is the recommended dose for most patients 1, 3
• Alternative low-dose strategy: 25% of patients respond to 50 mg/day, which offers better tolerability 6
• Trial duration: 6-8 weeks at target dose before assessing efficacy 6
• Particularly useful for: Patients with comorbid obesity (causes weight loss) 1
• Common adverse effects: Paresthesias (35-51%), cognitive effects (11%), fatigue, nausea 3, 5
• Discontinuation rate: 28% due to adverse events, most commonly cognitive effects 4, 5

Candesartan

• Recommended as first-line agent, particularly for patients with comorbid hypertension 1, 7
• Dosing details not specified in guidelines, but typically 16-32 mg once daily based on general practice 1

Second-Line Preventive Medications

Amitriptyline

• Dose range: 30-150 mg/day at bedtime 1
• Starting dose: Begin with 10-25 mg at bedtime, titrate slowly 1
• Particularly useful for: Patients with comorbid depression, anxiety, or mixed migraine and tension-type headache 1

Valproate/Divalproex Sodium

• Valproate dose: 800-1500 mg/day 1, 7
• Divalproex sodium dose: 500-1500 mg/day 1, 7
• Absolute contraindication: Women of childbearing potential due to severe teratogenic effects 1, 7

Flunarizine (where available)

• Starting dose: 5-10 mg once daily at night 1
• Standard dose: 10 mg once daily is most commonly used 1
• Alternative dose: 5 mg once daily for patients concerned about side effects 1
• Trial duration: 2-3 months before assessing efficacy 1
• Contraindications: Active Parkinsonism, history of extrapyramidal disorders, current depression 1
• Avoid in elderly: Increased risk of extrapyramidal symptoms and depression 1

Third-Line: CGRP Monoclonal Antibodies

CGRP monoclonal antibodies should be considered when patients have failed 2-3 oral preventive medications. 1

Available Agents

• Erenumab, fremanezumab, galcanezumab: Monthly subcutaneous injection 1, 7
• Eptinezumab: Intravenous administration 7
• Trial duration: Efficacy assessment requires 3-6 months (longer than oral agents) 1
• Cost consideration: $5,000-$6,000 annually, significantly more expensive than oral agents 1

Implementation Strategy

Starting Preventive Therapy

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

• Adequate trial period: 2-3 months for oral agents before determining efficacy 1
• For CGRP antibodies: 3-6 months required 1
• Monitoring: Use headache diaries to track attack frequency, severity, duration, disability, and treatment response 1

Discontinuation Strategy

• After 6-12 months of successful therapy, consider pausing preventive treatment to determine if it can be discontinued 1
• Success measure: Calculate percentage reduction in monthly migraine days 1
• Taper gradually over several weeks when discontinuing, especially for beta-blockers and topiramate 2

Critical Pitfalls to Avoid

Medication Overuse Headache

Rule out medication overuse headache before starting preventive therapy: defined as using acute medications ≥10 days/month for triptans or ≥15 days/month for NSAIDs. 1

Common Errors

• Inadequate trial duration: Less than 2-3 months is insufficient 1
• Starting dose too high: Leads to poor tolerability and discontinuation 1
• Failing to address comorbidities: Avoid valproate in women of childbearing potential, use propranolol for comorbid anxiety, use amitriptyline for comorbid depression 1
• Not limiting acute medication use: Frequent acute medication use interferes with preventive treatment 1

Indications for Preventive Therapy

Preventive therapy should be considered for patients with ≥2 migraine attacks per month with disability lasting ≥3 days per month. 1

Additional indications include:

• Using abortive medication more than twice per week 1
• Contraindications to or failure of acute treatments 1
• Uncommon migraine conditions (hemiplegic migraine, migraine with prolonged aura, migrainous infarction) 1

Non-Pharmacological Adjuncts

Consider neuromodulatory devices, cognitive behavioral therapy, biofeedback, and relaxation training as adjuncts to medication or as stand-alone treatments when medications are contraindicated. 1

• Acupuncture may be considered, though not superior to sham acupuncture in controlled trials 1
• Identify and modify triggers: sleep hygiene, regular meals, hydration, stress management 1