What are the recommended preventive treatment options for an adult migraine patient without known contraindications?

Prophylaxis of Migraine

For an adult migraine patient without contraindications, initiate preventive therapy with propranolol 80–240 mg/day, timolol 20–30 mg/day, topiramate 50–100 mg/day, or candesartan as first-line agents, based on the strongest evidence from multiple randomized controlled trials and FDA approval. 1

Indications for Starting Preventive Therapy

You should initiate preventive treatment when any of the following criteria are met:

• ≥2 migraine attacks per month causing disability lasting ≥3 days 1
• 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
• Failure of or contraindications to acute treatments 1, 2
• Uncommon migraine subtypes such as hemiplegic migraine, prolonged aura, or migrainous infarction 1
• Patient preference for preventive over frequent acute treatment 1, 2

First-Line Preventive Medications

Beta-Blockers (Strongest Traditional Evidence)

• Propranolol 80–240 mg/day carries the most robust evidence among traditional preventives, with FDA approval and multiple randomized controlled trials demonstrating efficacy 1, 3
• The maximum dose is 240 mg/day; doses below 160 mg/day are generally sub-therapeutic and should be titrated upward 1
• Timolol 20–30 mg/day also has strong evidence for migraine prevention 1
• Alternative beta-blockers with demonstrated efficacy include metoprolol, atenolol, nadolol, and bisoprolol 1, 3
• 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 1
• Preferred in patients with obesity because it promotes weight loss 1
• Common adverse effects include cognitive inefficiency, paresthesia, fatigue, and weight loss 1

Candesartan (First-Line for Hypertensive Patients)

• Candesartan is particularly useful for patients with comorbid hypertension 1
• Strong evidence supports its use as a first-line agent 1

Second-Line Preventive Medications

Amitriptyline

• Amitriptyline 30–150 mg/day is preferred for patients with comorbid depression, anxiety, sleep disturbance, or mixed migraine/tension-type headache 1, 4
• Lacks robust RCT evidence specifically for chronic migraine; efficacy is mainly demonstrated in episodic migraine 1
• Higher doses within the 30–150 mg range are often needed for adequate response 1

Valproate/Divalproex (With Critical Safety Caveat)

• Divalproex sodium 500–1500 mg/day or sodium valproate 800–1500 mg/day are effective 1, 4
• Strictly contraindicated in women of childbearing potential due to teratogenic risk 1, 2
• Common adverse effects include weight gain, hair loss, and tremor 1

Third-Line: CGRP Monoclonal Antibodies

• Erenumab, fremanezumab, galcanezumab, or eptinezumab should be considered when 2–3 oral preventives have failed or are contraindicated 1, 3
• Administered monthly via subcutaneous injection (or quarterly for eptinezumab IV) 1
• Efficacy assessment requires 3–6 months of treatment 1
• Significantly more expensive than oral agents, with annualized cost of $5,000–$6,000 1

Implementation Strategy

Dosing Principles

• Start low and titrate slowly until clinical benefit is achieved or side effects limit further increases 1, 2
• An adequate therapeutic trial requires 2–3 months at the target dose before judging efficacy 1, 5
• Do not maintain sub-therapeutic doses (e.g., propranolol <160 mg or amitriptyline <30 mg) indefinitely 1

Monitoring and Follow-Up

• Use headache diaries to track attack frequency, severity, duration, disability, treatment response, and adverse effects 1
• Assess treatment response at 2–3 months after starting or modifying therapy 1
• Consider pausing preventive treatment after 6–12 months of successful therapy to determine if it can be discontinued 1
• A useful measure of success is calculating the percentage reduction in monthly migraine days 1

Non-Pharmacological Adjuncts

• Cognitive behavioral therapy, biofeedback, and relaxation training should be offered alongside medication as effective adjuncts 1
• Neuromodulatory devices can be considered as adjuncts or stand-alone treatments when medications are contraindicated 1
• Acupuncture has some supporting evidence, though not superior to sham acupuncture 1, 3
• Identify and modify triggers: sleep hygiene, regular meals, hydration, stress management 1

Critical Pitfalls to Avoid

• Do not fail to recognize medication-overuse headache from frequent use of acute medications (≥10 days/month for triptans or ≥15 days/month for NSAIDs) 1
• Do not conduct inadequate duration of preventive trial (less than 2–3 months at target dose) 1
• Do not start with too high a dose, leading to poor tolerability and discontinuation 1
• Do not prescribe valproate to women of childbearing potential without addressing contraception or choosing an alternative 1
• Do not initiate multiple new preventive agents simultaneously; use sequential monotherapy 1

Choosing the Agent Based on Comorbidities

• Obesity present → initiate topiramate as first-line 1
• Depression, anxiety, or sleep disturbance present → initiate amitriptyline as first-line 1
• Hypertension present → initiate propranolol, metoprolol, or candesartan as first-line 1
• No significant comorbidities → initiate propranolol or topiramate, given their stronger evidence base 1

Medications to Avoid

• Opioids and butalbital-containing compounds should be avoided due to questionable efficacy, high risk of dependency, rebound headaches, and medication-overuse headache 1, 6
• Oral ergot alkaloids should be avoided due to questionable efficacy with considerable adverse effects 1