A patient on amitriptyline 50 mg daily and propranolol 80 mg daily still experiences >6 migraine attacks per month; what should be done next?

Escalate Preventive Therapy Immediately

This patient has failed adequate trials of two first-line preventive medications (propranolol 80 mg and amitriptyline 50 mg) while experiencing >6 migraine episodes per month, which mandates escalation to a more effective preventive regimen rather than continuing subtherapeutic doses of current medications. 1

Immediate Action: Optimize Current Preventive Doses Before Adding New Agents

Increase propranolol to 160-240 mg daily (current dose of 80 mg is at the lower end of the therapeutic range), as the usual effective dose for migraine prophylaxis is 160 mg once daily, with some patients requiring up to 240 mg daily. 2, 3

Increase amitriptyline to 75-100 mg daily (current dose of 50 mg is mid-range), as the most efficacious dosages in clinical trials ranged from 30-150 mg/day, with higher doses within this range often needed for adequate response. 2

• Allow an adequate trial period of 2-3 months at the optimized doses before determining efficacy, as clinical benefits may not become apparent for this duration. 2
• The patient should keep a headache diary to track attack frequency, severity, duration, and disability to objectively assess treatment response. 1

If Optimization Fails: Add Topiramate as Third-Line Agent

If the patient continues to experience >6 migraine days per month after 2-3 months at optimized doses of propranolol and amitriptyline, add topiramate 50-100 mg daily (typically 50 mg twice daily), which has the strongest evidence for chronic migraine prevention among oral agents. 1

• Topiramate is the only oral preventive with robust RCT evidence specifically for chronic migraine (≥15 headache days per month). 1
• Start topiramate at a low dose (25 mg daily) and titrate slowly by 25 mg weekly to minimize side effects, particularly cognitive slowing and paresthesias. 1

Alternative Third-Line Option: Valproate/Divalproex

Divalproex sodium 500-1500 mg/day or sodium valproate 800-1500 mg/day can be considered if topiramate is not tolerated, as these agents have good evidence for efficacy and may be particularly effective in patients with prolonged or atypical migraine aura. 2

• Valproate is strictly contraindicated in women of childbearing potential due to teratogenic effects (neural tube defects), requiring mandatory contraception counseling or alternative agent selection. 1
• Common adverse effects include weight gain, hair loss, tremor, and teratogenic potential. 2

Consider CGRP Monoclonal Antibodies After Failure of 2-3 Oral Preventives

If the patient fails adequate trials of propranolol, amitriptyline, and topiramate (or valproate), escalate to CGRP monoclonal antibodies (erenumab, fremanezumab, galcanezumab, or eptinezumab), which should be considered when other preventive treatments have failed or are contraindicated. 1

• CGRP monoclonal antibodies are administered monthly via subcutaneous injection and require 3-6 months for efficacy assessment. 1
• These agents are significantly more expensive than oral agents, with annualized costs of $5,000-$6,000. 1

Critical Medication-Overuse Headache Assessment

Rule out medication-overuse headache (MOH) immediately, as using acute medications ≥10 days/month for triptans or ≥15 days/month for NSAIDs can paradoxically increase headache frequency and interfere with preventive treatment. 1

• If MOH is present, abrupt cessation of overused acute medications is required, with the understanding that headache intensity may temporarily worsen for 2-10 days during withdrawal. 1
• Strictly limit all acute migraine medications to ≤2 days per week (≤10 days per month) to prevent MOH recurrence. 1

Address Modifiable Risk Factors

Systematically evaluate and manage obesity, excessive caffeine intake, obstructive sleep apnea, psychiatric comorbidities (depression, anxiety), and stress, as these factors perpetuate chronic migraine and reduce treatment responsiveness. 1

• Weight loss can reduce migraine frequency in patients with obesity. 1
• Screen and treat obstructive sleep apnea, which can increase migraine frequency. 1
• Stress management through behavioral interventions (cognitive behavioral therapy, biofeedback, relaxation training) can reduce reliance on acute medications. 1

Common Pitfalls to Avoid

Do not continue subtherapeutic doses of preventive medications indefinitely—the patient is currently on propranolol 80 mg (minimum effective dose) and amitriptyline 50 mg (mid-range dose), both of which should be optimized before declaring treatment failure. 2, 3

Do not allow the patient to increase frequency of acute medication use in response to treatment failure, as this creates a vicious cycle of MOH; instead, transition to optimized preventive therapy while strictly limiting acute treatment to ≤2 days per week. 1

Do not start multiple new preventive medications simultaneously, as this makes it impossible to determine which agent is effective or responsible for adverse effects; use sequential monotherapy or add one agent at a time. 2

Do not abandon preventive therapy prematurely—an adequate trial requires 2-3 months at the target dose for oral agents, and efficacy should be assessed only after this period. 2, 1