In an adult (≥18 years) with episodic migraine (≥4 migraine days/month) or chronic migraine (≥15 headache days/month, ≥8 migraine days) who has already failed at least two approved preventive agents, what other prophylactic options are available?

Migraine Prophylaxis Options After Multiple Treatment Failures

For adults with episodic or chronic migraine who have failed at least two approved preventive agents, CGRP monoclonal antibodies (erenumab, fremanezumab, galcanezumab) represent the strongest evidence-based next step, with onabotulinumtoxinA reserved specifically for chronic migraine (≥15 headache days/month). 1, 2

First-Line Options After Standard Preventive Failures

CGRP Monoclonal Antibodies (Strongest Recommendation)

• Erenumab, fremanezumab, or galcanezumab carry strong recommendations for both episodic and chronic migraine prevention and should be prioritized after failure of conventional oral preventives 1
• These agents demonstrated superior efficacy in head-to-head comparisons, with fremanezumab reducing migraine days by -3.7 days (monthly dosing) and -3.4 days (quarterly dosing) versus -2.2 days with placebo over 3 months 3
• Erenumab showed -3.2 days reduction (70mg) and -3.7 days (140mg) versus -1.8 days with placebo, with 50% responder rates of 43.3% and 50.0% respectively versus 26.6% for placebo 4
• Eptinezumab (intravenous) receives a weak recommendation due to lower quality evidence, despite being effective 1

OnabotulinumtoxinA for Chronic Migraine Only

• OnabotulinumtoxinA is FDA-approved exclusively for chronic migraine prophylaxis (≥15 headache days/month with ≥8 migraine days) and should NOT be used for episodic migraine 1, 2
• The FDA-approved dose is 155 units subcutaneously every 12 weeks, administered using the PREEMPT protocol 1, 2
• Demonstrated reduction of -8.4 headache days versus -6.6 days with placebo at 24 weeks in the PREEMPT trials 1, 2
• Requires documentation of failure of 2-3 oral preventives from different medication classes before initiation 2

Second-Tier Oral Preventive Options

Angiotensin Receptor Blockers

• Candesartan or telmisartan carry strong recommendations for episodic migraine prevention 1
• These represent excellent alternatives when CGRP antagonists are not accessible or contraindicated 1

Oral CGRP Antagonists (Gepants)

• Atogepant receives a weak recommendation for episodic migraine prevention 1
• Rimegepant has insufficient evidence for preventive use (though effective for acute treatment) 1

Anticonvulsants

• Topiramate receives weak recommendations for both episodic and chronic migraine, with established efficacy in randomized controlled trials 1
• Valproate has weak recommendation for episodic migraine only 1
• Gabapentin receives a weak recommendation AGAINST use due to insufficient efficacy data 1

Other Agents with Weak Supporting Evidence

• Lisinopril (ACE inhibitor) for episodic migraine 1
• Propranolol (beta-blocker) for migraine prevention 1
• Memantine for episodic migraine 1
• Oral magnesium for migraine prevention 1

Critical Management Considerations

Medication Overuse Assessment

• Before initiating any new preventive therapy, assess for medication overuse headache (MOH), defined as triptans, ergotamines, or combination analgesics used >10 days/month 2, 5
• MOH can prevent response to any preventive therapy and must be addressed first 5
• Withdrawal from overused medications should ideally occur before starting new preventives, though onabotulinumtoxinA can be initiated concurrently if withdrawal is not feasible 2

Treatment Duration and Failure Definition

• Each preventive medication trial requires at least 60 days at therapeutic doses to assess efficacy 2
• Document medication name, dose, start/stop dates, and specific reason for discontinuation 2
• For onabotulinumtoxinA, allow 2-3 treatment cycles (6-9 months) to assess full efficacy 5

Modifiable Risk Factors

• Address obesity, caffeine overuse, obstructive sleep apnea, psychiatric comorbidities, and stress as these contribute to migraine chronification 1
• Behavioral interventions should complement pharmacologic therapy 1

Treatment Algorithm Priority

1. Rule out medication overuse headache first 2, 5
2. For chronic migraine (≥15 headache days/month): CGRP monoclonal antibodies (erenumab, fremanezumab, galcanezumab) OR onabotulinumtoxinA 1, 2
3. For episodic migraine: CGRP monoclonal antibodies OR candesartan/telmisartan 1
4. If CGRP antagonists fail or are contraindicated: Consider topiramate, atogepant, or other second-tier agents 1
5. For complex cases with multiple treatment failures: Refer to headache specialist for comprehensive evaluation and consideration of combination therapies 5

Common Pitfalls to Avoid

• Do not use onabotulinumtoxinA for episodic migraine - it carries a weak recommendation AGAINST this indication 1
• Do not continue ineffective preventive regimens - this impairs quality of life and exposes patients to unnecessary adverse events without benefit 5
• Do not overlook medication overuse - this is present in up to 73% of chronic migraine patients and prevents treatment response 1, 5
• Do not use gabapentin - evidence specifically recommends against its use for episodic migraine prevention 1