What are alternative oral medications for a patient with an acute migraine attack who has not responded to Tylenol (acetaminophen) and Motrin (ibuprofen), and for whom triptans are contraindicated?

Alternative Oral Medications for Acute Migraine When Triptans Are Contraindicated

When triptans are contraindicated, use gepants (ubrogepant 50-100 mg or rimegepant) as your primary oral alternative for moderate to severe migraine, or lasmiditan 50-200 mg if gepants are unavailable or ineffective. 1, 2

First-Line Alternative: CGRP Antagonists (Gepants)

Gepants represent the strongest evidence-based alternative when triptans cannot be used. 1, 2

• Ubrogepant (Ubrelvy) 50-100 mg is FDA-approved for acute migraine treatment and achieved pain freedom in 19-22% of patients at 2 hours (versus 12-14% with placebo), with most bothersome symptom freedom in 38-39% (versus 27-28% with placebo) 3
• Ubrogepant has no vasoconstriction, making it safe in patients with cardiovascular disease, uncontrolled hypertension, or cerebrovascular disease—the exact populations where triptans are contraindicated 2, 4
• A second dose can be taken 2 hours after the first if needed, but avoid a second dose within 24 hours if taking moderate CYP3A4 inhibitors (verapamil, cyclosporine, ciprofloxacin, fluconazole, fluvoxamine) 3
• Contraindication: Do not use with strong CYP3A4 inhibitors (ketoconazole, clarithromycin, itraconazole) 3
• Rimegepant and zavegepant are alternative gepants with similar efficacy profiles 2, 5

Second-Line Alternative: Ditans (Lasmiditan)

Lasmiditan (Reyvow) 50-200 mg is a 5-HT1F receptor agonist without vasoconstrictor activity, making it safe in cardiovascular disease. 1, 4, 6

• Lasmiditan showed dose-dependent efficacy with headache response rates at 2 hours of 56% (50 mg), 67% (100 mg), 66% (200 mg), and 67% (400 mg) versus 38% with placebo 6
• Critical safety warning: Patients must not drive or operate machinery for at least 8 hours after taking lasmiditan due to CNS effects (dizziness, vertigo, somnolence, fatigue) 1, 6, 7
• CNS adverse events are dose-dependent: severe adverse events occurred in 20% (50 mg), 28% (100 mg), 39% (200 mg), and 44% (400 mg) versus 6% with placebo 6
• Consider lasmiditan when gepants fail or are unavailable, particularly in patients who can tolerate sedation and do not need to drive 1, 8

Third-Line Alternative: Intranasal Dihydroergotamine (DHE)

DHE nasal spray has good evidence for efficacy and safety as monotherapy for acute migraine. 2, 5

• DHE is an option when oral gepants and ditans are ineffective or unavailable 2
• Important contraindication: DHE is contraindicated in the same cardiovascular conditions as triptans (ischemic heart disease, uncontrolled hypertension, cerebrovascular disease), so verify why triptans are contraindicated before using DHE 2

Adjunctive Antiemetics for Synergistic Analgesia

Prokinetic antiemetics provide independent analgesic benefit beyond treating nausea. 1, 2

• Metoclopramide 10 mg PO provides synergistic analgesia through central dopamine receptor antagonism and should be given 20-30 minutes before other acute medications 2
• Prochlorperazine 25 mg PO is an alternative antiemetic with comparable efficacy to metoclopramide 2
• These agents work as adjuncts to enhance absorption and provide additional pain relief, not just for nausea 2

Critical Frequency Limitation

Limit all acute migraine medications to no more than 2 days per week (10 days per month) to prevent medication-overuse headache. 1, 2, 5

• If the patient requires acute treatment more than twice weekly, immediately initiate preventive therapy rather than increasing acute medication frequency 1, 2
• Medication-overuse headache creates a vicious cycle of increasing headache frequency leading to daily headaches 2, 5

Medications to Absolutely Avoid

Never use opioids or butalbital-containing compounds for acute migraine treatment. 1, 2, 5

• Opioids have questionable efficacy, lead to dependency, cause rebound headaches, and result in loss of efficacy over time 1, 2
• Oral ergot alkaloids are poorly effective and potentially toxic 1

Treatment Algorithm When Triptans Are Contraindicated

1. First attempt: Ubrogepant 50-100 mg (or rimegepant/zavegepant) 2, 3
2. If gepants fail after 2-3 attacks: Switch to lasmiditan 50-200 mg (if patient can avoid driving for 8 hours) 1, 6
3. Add metoclopramide 10 mg 20-30 minutes before either gepant or ditan for synergistic analgesia 2
4. If all oral options fail: Consider intranasal DHE (only if cardiovascular contraindications don't apply) 2
5. If needing treatment >2 days/week: Initiate preventive therapy immediately (propranolol, topiramate, or CGRP monoclonal antibodies) 1, 2