What are the next steps for treating a migraine that is not relieved by acetaminophen (Tylenol), cyclobenzaprine (Flexeril), ketorolac (Toradol), sumatriptan (Sumatriptan), or butalbital/acetaminophen/caffeine (Fioricet)?

Refractory Migraine: Next-Line Treatment Options

For a migraine unresponsive to acetaminophen, cyclobenzaprine, ketorolac, sumatriptan, and butalbital/acetaminophen/caffeine, administer IV metoclopramide 10 mg plus IV prochlorperazine 10 mg as your next-line therapy, and immediately initiate preventive therapy to break the cycle of treatment-resistant attacks. 1

Immediate Acute Management

IV Combination Therapy

• Administer metoclopramide 10 mg IV plus prochlorperazine 10 mg IV together as both provide independent analgesic effects through central dopamine receptor antagonism, not just antiemetic properties 1
• This combination addresses the refractory nature of the attack through dual dopamine antagonism with complementary mechanisms 1
• Prochlorperazine has demonstrated efficacy comparable to metoclopramide with a favorable side effect profile (21% adverse events vs 50% with chlorpromazine) 1

Alternative IV Options if Dopamine Antagonists Fail

• Dihydroergotamine (DHE) IV or intranasal has good evidence for efficacy as monotherapy for acute migraine attacks 1
• Consider subcutaneous sumatriptan 6 mg if oral sumatriptan failed—the subcutaneous route achieves 59% complete pain relief by 2 hours with onset within 15 minutes, significantly superior to oral formulations 1

Critical Pitfall: Rule Out Medication-Overuse Headache

• Before escalating therapy further, assess medication frequency—if this patient uses acute medications more than 2 days per week, medication-overuse headache (MOH) is likely driving treatment resistance 1
• MOH creates a vicious cycle where increasing medication use paradoxically worsens headache frequency and reduces treatment responsiveness 1

Mandatory Transition to Preventive Therapy

Indications Present in This Case

• This patient meets criteria for preventive therapy: failure of multiple acute treatments indicates either severe migraine disease or MOH, both requiring prevention 1
• Preventive therapy reduces attack frequency by ≥50% and restores responsiveness to acute treatments 1

First-Line Preventive Options

• Propranolol 80-240 mg/day is the first-line preventive medication with the strongest evidence base 2, 1
• Topiramate 50-100 mg daily is equally effective as first-line prevention 2
• Amitriptyline 10-100 mg at night is particularly useful if the patient has mixed migraine and tension-type features 2

Timeline for Preventive Efficacy

• Oral preventive agents require 2-3 months for full efficacy assessment 1
• CGRP monoclonal antibodies (erenumab 70-140 mg subcutaneous monthly, fremanezumab 225 mg monthly) require 3-6 months for efficacy assessment and should be considered if oral preventives fail 2, 1
• OnabotulinumtoxinA (155-195 units to 31-39 sites every 12 weeks) requires 6-9 months for efficacy assessment and represents third-line prevention 2

Future Acute Treatment Strategy

Optimize Acute Medication Approach

• Switch to combination therapy: sumatriptan 50-100 mg PLUS naproxen sodium 500 mg taken together at migraine onset while pain is still mild 1
• This combination is superior to either agent alone, with 130 more patients per 1000 achieving sustained pain relief at 48 hours 1
• Failure of one triptan does not predict failure of others—consider trying rizatriptan, eletriptan, or zolmitriptan if sumatriptan continues to fail 1

Strict Frequency Limitation

• Limit ALL acute migraine medications to no more than 2 days per week to prevent MOH 1
• This includes NSAIDs (≥15 days/month triggers MOH) and triptans (≥10 days/month triggers MOH) 1

Alternative Acute Options if Standard Therapies Contraindicated

Newer CGRP Antagonists (Gepants)

• Rimegepant, ubrogepant, or zavegepant are alternatives when triptans are contraindicated or ineffective 1
• These do not cause vasoconstriction and are safe in patients with cardiovascular disease 1

What NOT to Do

Avoid Escalating to Opioids

• Do not prescribe hydromorphone, oxycodone, or other opioids—these should be reserved only when all other options are contraindicated, sedation is acceptable, and abuse risk has been addressed 1
• Opioids lead to dependency, rebound headaches, and eventual loss of efficacy 1
• Butalbital-containing compounds (Fioricet) similarly cause MOH and should be discontinued 1

Avoid Cyclobenzaprine

• Cyclobenzaprine (Flexeril) has no evidence for migraine treatment and should not have been prescribed—it is a muscle relaxant without antimigraine properties 1