What is the next step in treating an adult patient with a history of migraines who has not responded to sumatriptan (Imitrex)?

When Sumatriptan Fails: Next Steps in Migraine Treatment

Try a different triptan first, as failure of one triptan does not predict failure of others—if all triptans fail after adequate trials (no response in at least 3 consecutive attacks), escalate to third-line agents like gepants (ubrogepant or rimegepant) or ditans (lasmiditan). 1, 2

Immediate Action: Try Alternative Triptans

• Switch to a different triptan formulation or route before abandoning the triptan class entirely, as individual response varies significantly between different triptans 1
• Consider subcutaneous sumatriptan 6 mg if oral sumatriptan failed, particularly for patients who rapidly reach peak headache intensity or experience early vomiting—this route provides the highest efficacy (59% pain-free at 2 hours) with onset within 15 minutes 1, 2, 3
• Alternative oral triptans to trial include rizatriptan, zolmitriptan, or naratriptan, each taken early when pain is still mild 1

Optimize Current Triptan Strategy

Before declaring triptan failure, ensure proper usage:

• Take the triptan early when headache is still mild, not during aura phase or after pain becomes severe—early treatment significantly improves efficacy 1, 2
• Add fast-acting NSAIDs (naproxen sodium 500 mg, ibuprofen lysine, or diclofenac potassium) simultaneously with the triptan to prevent the 40% relapse rate within 48 hours 1, 2
• Verify the patient is not taking triptans more than 2 days per week, as this causes medication-overuse headache and paradoxically reduces triptan effectiveness 1, 2

Third-Line Medications After All Triptans Fail

If all available triptans fail after adequate trials (no response in ≥3 consecutive attacks) or are contraindicated:

CGRP Antagonists (Gepants) - Preferred Third-Line Option

• Ubrogepant 50-100 mg or rimegepant are the preferred alternatives when triptans fail, with no vasoconstriction making them safe for patients with cardiovascular disease 1, 2
• These agents work through a different mechanism than triptans and can be effective even when all triptans have failed 1, 2

Ditans (Lasmiditan) - Alternative Third-Line Option

• Lasmiditan 50-200 mg is a 5-HT1F receptor agonist without vasoconstrictor activity, comparable in efficacy to triptans 1, 2
• Critical warning: Patients must not drive or operate machinery for at least 8 hours after taking lasmiditan due to CNS effects (dizziness, vertigo, somnolence) 2

Rule Out Medication-Overuse Headache

Before escalating therapy, assess medication frequency:

• If the patient uses acute medications (any triptan, NSAID, or combination) ≥10 days per month for triptans or ≥15 days per month for NSAIDs, medication-overuse headache is likely causing treatment failure 1, 2
• This creates a vicious cycle where increasing medication use paradoxically worsens headache frequency and reduces treatment responsiveness 1, 2

Initiate Preventive Therapy

If headaches occur ≥2 times per week or produce disability ≥3 days per month, preventive therapy is mandatory:

First-Line Preventive Medications

• Propranolol 80-240 mg/day or timolol 20-30 mg/day (beta-blockers without intrinsic sympathomimetic activity) 1, 2
• Amitriptyline 30-150 mg/day (particularly effective for mixed migraine and tension-type headache) 1, 2
• Divalproex sodium 500-1500 mg/day or sodium valproate 800-1500 mg/day 1

Timeline for Preventive Efficacy

• Allow 2-3 months for oral preventives, 3-6 months for CGRP monoclonal antibodies, and 6-9 months for onabotulinumtoxinA before declaring failure 2
• Preventive therapy reduces attack frequency by ≥50% and restores responsiveness to acute treatments 2

Critical Pitfall to Avoid

Never allow patients to increase frequency of acute medication use in response to treatment failure—this creates medication-overuse headache and worsens the underlying condition. Instead, transition to preventive therapy while optimizing the acute treatment strategy with alternative agents. 1, 2