What are the next steps for treating migraines in patients who have not responded to Triptans (serotonin receptor agonists)?

Treatment for Migraines When Triptans Fail

If triptans are not working, try a different triptan first—25-81% of sumatriptan non-responders achieve pain relief with an alternative triptan—and if all triptans fail after adequate trials, escalate to CGRP antagonists (gepants) like ubrogepant or rimegepant. 1

Immediate First Step: Switch to a Different Triptan

• Failure of one triptan does not predict failure of others, making triptan switching the most evidence-based initial strategy 1, 2, 3
• Rizatriptan 10 mg reaches peak concentration fastest among oral triptans (60-90 minutes) and may work when other triptans fail 1
• Eletriptan 40 mg or zolmitriptan 2.5-5 mg are reportedly more effective with fewer adverse reactions than sumatriptan 1
• Naratriptan has the longest half-life, which may decrease recurrent headaches 1
• Try each alternative triptan for 2-3 headache episodes before abandoning it, as individual response varies significantly 1

Consider Route of Administration Change

If oral triptans consistently fail, the problem may be absorption rather than the medication itself:

• Subcutaneous sumatriptan 6 mg provides the highest efficacy (59% complete pain relief at 2 hours) with onset within 15 minutes, particularly effective for rapid progression to peak intensity or significant nausea/vomiting 1
• Intranasal sumatriptan 5-20 mg bypasses gastric absorption issues, offering an alternative route for patients with oral triptan failure 1
• Rizatriptan as absorbable wafer offers non-oral administration without injection 1

Optimize with Combination Therapy

Combining a triptan with a fast-acting NSAID provides superior efficacy compared to either agent alone:

• Sumatriptan 50-100 mg PLUS naproxen sodium 500 mg results in 130 more patients per 1000 achieving sustained pain relief at 48 hours 1
• This combination addresses the 40% of patients who experience symptom recurrence within 48 hours after apparently successful triptan treatment 4
• Both medications must be taken together early in the attack while headache is still mild for maximum effectiveness 4

Add Antiemetic for Synergistic Analgesia

Beyond treating nausea, antiemetics provide direct analgesic benefit:

• Metoclopramide 10 mg (oral or IV) given 20-30 minutes before or with the triptan provides synergistic analgesia through central dopamine receptor antagonism 1
• Prochlorperazine 10 mg IV or 25 mg oral/suppository provides comparable efficacy to metoclopramide 1

Third-Line Options: CGRP Antagonists (Gepants)

If all triptans fail after adequate trials, escalate to gepants:

• Ubrogepant 50-100 mg or rimegepant are recommended as primary alternatives when triptans are ineffective or contraindicated 5, 1
• Gepants have no vasoconstriction, making them safe for patients with cardiovascular disease, uncontrolled hypertension, or cerebrovascular disease—common contraindications for triptans 1
• These represent the most recent evidence-based option for triptan-refractory migraine 5

Fourth-Line Option: Ditans

• Lasmiditan 50-200 mg is a 5-HT1F receptor agonist without vasoconstrictor activity, recommended when all other pharmacologic treatments fail 5, 1
• Patients cannot drive or operate machinery for at least 8 hours after taking lasmiditan due to CNS effects including dizziness, vertigo, somnolence, and fatigue 1

Alternative Parenteral Options for Severe Attacks

• Dihydroergotamine (DHE) intranasal or IV has good evidence for efficacy as monotherapy 5, 1
• IV metoclopramide 10 mg plus IV ketorolac 30 mg provides rapid pain relief for severe attacks requiring emergency department treatment 6

Critical Frequency Limitation to Prevent Medication-Overuse Headache

Strictly limit all acute migraine medications to no more than 2 days per week (10 days per month for triptans, 15 days per month for NSAIDs) to prevent medication-overuse headache, which paradoxically increases headache frequency and can lead to daily headaches 1, 4

When to Initiate Preventive Therapy

Immediately start preventive therapy if:

• Patient uses acute medications more than twice weekly 1, 4
• Patient has two or more attacks per month producing disability lasting 3+ days 1
• Quality of life remains impaired despite optimized acute therapy 1

First-line preventive options include propranolol 80-240 mg/day, topiramate, divalproex sodium, or amitriptyline 30-150 mg/day 4

Medications to Absolutely Avoid

Do not use opioids or butalbital for acute migraine treatment, as they have questionable efficacy, considerable adverse effects, risk of dependency, and lead to rebound headaches 5, 1, 4

Common Pitfalls to Avoid

• Do not abandon triptan therapy after a single failed attempt—individual response varies significantly between different triptans 1
• Do not allow patients to increase frequency of acute medication use in response to treatment failure—this creates a vicious cycle of medication-overuse headache 6
• Do not delay preventive therapy in patients requiring acute treatment more than twice weekly—transition to preventive therapy while optimizing acute treatment strategy 6
• Ensure patients take medication early in the attack while pain is still mild, as delayed administration significantly reduces efficacy 4