What is the optimal prophylactic and acute treatment for a 26‑year‑old woman with migraine refractory to propranolol and topiramate, intolerant to flunarizine because of drowsiness, and with inadequate relief from naproxen?

Optimal Management for Refractory Migraine in a 26-Year-Old Woman

For prophylaxis, initiate amitriptyline 10-25 mg at bedtime, titrating to 30-150 mg/day over weeks to months, as this is the evidence-based second-line agent after failure of propranolol and topiramate, with particular benefit when comorbid sleep disturbance or mixed tension-type features exist. 1, 2

Prophylactic Treatment Strategy

Why Amitriptyline is the Next Step

• Amitriptyline is the only tricyclic antidepressant with consistent evidence from controlled trials demonstrating efficacy for migraine prevention, reducing headache frequency by more than 50% in approximately 72% of patients. 2
• After failure of first-line agents (propranolol and topiramate), amitriptyline represents the logical second-line choice with strong evidence for episodic migraine prophylaxis. 1, 2
• Flunarizine, while effective, has already been tried and caused intolerable drowsiness in this patient, eliminating it as an option despite its proven efficacy comparable to propranolol and topiramate. 1

Dosing and Implementation

• Start with 10-25 mg at bedtime to minimize side effects, particularly drowsiness and anticholinergic symptoms (dry mouth, constipation). 2
• Titrate slowly by 10-25 mg increments every 1-2 weeks to a target therapeutic range of 30-150 mg/day as tolerated. 1, 2
• Allow a full 2-3 month trial at the therapeutic dose before declaring treatment failure, as clinical benefits may not become apparent until this period has elapsed. 1, 2
• Taking the medication at bedtime leverages its sedating properties to improve sleep while minimizing daytime drowsiness. 2

Monitoring and Follow-Up

• Track attack frequency, severity, duration, and disability using headache diaries to objectively assess response. 1
• Assess for common side effects at follow-up visits: weight gain, drowsiness, dry mouth, and constipation. 2
• Educate the patient to limit acute medication use to ≤2 days per week to prevent medication overuse headache, which can interfere with preventive treatment effectiveness. 1, 2

Acute Treatment Optimization

Why Naproxen is Inadequate

• The patient reports naproxen "takes too long to relieve headache," suggesting either inadequate dosing, delayed administration, or need for a more rapidly acting agent. 1

Recommended Acute Treatment Strategy

• Switch to a triptan for acute migraine attacks, as triptans are highly effective for headache relief and associated symptoms (nausea, photophobia, phonophobia) with faster onset than NSAIDs. 3
• Administer the triptan early in the attack (within the first hour of headache onset) to maximize efficacy and prevent progression. 1
• Consider adding an antiemetic (metoclopramide 10 mg or domperidone 10 mg) 15-20 minutes before triptan administration to enhance absorption and address nausea. 4
• For very severe attacks, subcutaneous sumatriptan 6 mg provides the most rapid and complete relief among all acute migraine treatments. 4

Critical Pitfall to Avoid

• Limit acute medication use to ≤2 days per week (or ≤10 days per month for triptans) to prevent medication overuse headache, which worsens migraine frequency and interferes with preventive therapy. 1, 2

Third-Line Options if Amitriptyline Fails

CGRP Monoclonal Antibodies

• If amitriptyline fails after a 2-3 month adequate trial, escalate to CGRP monoclonal antibodies (erenumab, fremanezumab, or galcanezumab) administered monthly via subcutaneous injection. 1
• These agents have strong evidence for prevention of episodic or chronic migraine and are recommended after failure of 2-3 oral preventive medications. 1
• Allow 3-6 months to assess efficacy with CGRP monoclonal antibodies, as response may be delayed compared to oral agents. 1
• The primary limitation is cost, with annualized expenses of $5,000-$6,000 compared to generic oral agents. 1

Alternative Oral Agents

• Candesartan (angiotensin-receptor blocker) is a first-line agent with strong evidence, particularly useful if hypertension coexists. 1, 5
• Alternative beta-blockers (atenolol, bisoprolol, or metoprolol) may be tried if propranolol failed due to side effects rather than lack of efficacy. 1

Special Considerations for This Patient

Age and Reproductive Potential

• Avoid valproate/divalproex sodium entirely in this 26-year-old woman of childbearing potential due to teratogenic risk, even with contraception. 1, 4

Addressing Comorbidities

• If depression, anxiety, or sleep disturbances are present, amitriptyline provides dual benefit by treating both migraine and mood/sleep disorders simultaneously. 1, 2
• If obesity is present, consider topiramate re-trial at optimized dosing (100 mg/day, typically 50 mg twice daily) as it promotes weight loss, though this patient has already failed topiramate. 1

Common Pitfalls to Avoid

• Do not maintain sub-therapeutic doses of preventive medications indefinitely; amitriptyline requires 30-150 mg/day for efficacy, not the 10-25 mg starting dose. 1
• Do not discontinue amitriptyline prematurely; many clinicians stop treatment before the required 2-3 month trial period needed to assess true efficacy. 2
• Do not use ergotamine during preventive treatment with amitriptyline, as it can diminish effectiveness. 2
• Do not initiate multiple new preventive agents simultaneously; sequential monotherapy allows identification of efficacy and adverse-effect profiles. 1