What are the treatment options for intractable migraines?

Treatment of Intractable Migraine

For intractable migraine that has failed standard oral therapies, use combination therapy with a triptan plus an NSAID or acetaminophen as first-line treatment, administered via nonoral routes (subcutaneous, intranasal, or intravenous) when nausea/vomiting is present, and explicitly avoid opioids and butalbital-containing compounds. 1

Initial Approach to Intractable Migraine

When a patient presents with intractable migraine (defined as severe migraine not responding to usual acute treatments), the treatment algorithm should proceed as follows:

First-Line: Combination Therapy via Nonoral Routes

• Administer a triptan combined with an NSAID or acetaminophen when oral medications have failed, as combination therapy improves efficacy over monotherapy 1
• Use nonoral administration routes (subcutaneous sumatriptan, intranasal formulations, or IV medications) when nausea or vomiting are significant components of the attack 1
• Subcutaneous sumatriptan achieves peak concentrations of 71 ng/mL (range 49-110 ng/mL) compared to only 51 ng/mL with oral 100mg dosing, providing faster and more reliable absorption 2
• Add an antiemetic (metoclopramide or prochlorperazine) to address nausea and improve medication absorption 1, 3

Second-Line: Dihydroergotamine (DHE)

• Intranasal or injectable DHE has good evidence for efficacy and safety in intractable migraine 1
• DHE may be particularly useful when triptans have failed or are contraindicated 1
• Note that DHE has lower likelihood of freedom from nausea/vomiting compared to triptans (200 more events per 1000 for nausea, 40 more for vomiting) 1

Third-Line: Newer Agents

• Consider lasmiditan (ditan) or CGRP antagonists (gepants) for patients who have failed or have contraindications to triptans 1, 3, 4
• These agents do not cause vasospasm and can be used in patients with cardiovascular risk factors, which affects more than 20% of adults with migraine 4
• However, gepants may have lower likelihood of pain freedom at 2 hours compared to triptan-NSAID combinations (low-certainty evidence) 1

Critical Medications to Avoid

Explicitly do not use opioids or butalbital-containing compounds for intractable migraine treatment, as these increase risk of medication overuse headache, dependency, and have limited efficacy evidence 1, 3

• The 2025 American College of Physicians guideline provides a strong recommendation against opioids and butalbital 1
• While butorphanol nasal spray has evidence for efficacy, opioid treatment should only be considered if other medications cannot be used, abuse risk has been addressed, and sedation is not a concern 1

Addressing Medication Overuse

A critical pitfall in intractable migraine is unrecognized medication overuse headache:

• Limit acute treatment to no more than 2 days per week to prevent medication overuse headache 1, 3
• Medication overuse headache is defined as headache occurring ≥15 days/month for ≥3 months due to overuse of acute medications 1
• The threshold varies by medication: ≥15 days/month for NSAIDs, ≥10 days/month for triptans 1
• If medication overuse is suspected, detoxification with withdrawal of overused drugs may be necessary before other treatments will be effective 2

Rescue Therapy Considerations

For truly refractory cases in emergency or inpatient settings:

• IV formulations of NSAIDs (lysine acetylsalicylate), propacetamol, or nefopam may be used 5
• Corticosteroids are used in some settings for status migrainosus, though evidence is limited 5
• A "rescue medication" for home use (noting the guideline's cautious language about compounds containing butalbital) may be considered only when all other treatments have failed 1

Transition to Prevention

When acute treatments repeatedly fail, preventive therapy is mandatory:

• Preventive treatment is indicated when migraine significantly interferes with daily routine despite acute treatment, or when acute medications are used more than twice weekly 1, 6
• First-line preventive options include topiramate, valproic acid, propranolol (80-240 mg/day), timolol (20-30 mg/day), or amitriptyline (30-150 mg/day) 1, 3
• For chronic migraine specifically, topiramate is first-line due to lower cost 3
• OnabotulinumtoxinA and CGRP monoclonal antibodies should be considered for patients who have failed multiple preventive medications 3

Important Safety Considerations

Cardiovascular Screening

• Triptans are contraindicated in patients with coronary artery disease, Prinzmetal's angina, uncontrolled hypertension, history of stroke/TIA, or Wolff-Parkinson-White syndrome 2
• Perform cardiac evaluation if chest/throat/neck/jaw pain occurs after triptan use in high-risk patients 2
• Significant blood pressure elevation, including hypertensive crisis, has been reported with triptans 2

Serotonin Syndrome Risk

• Monitor for serotonin syndrome when combining triptans with SSRIs, SNRIs, TCAs, or MAO inhibitors 2
• Symptoms include mental status changes, autonomic instability, neuromuscular aberrations, and GI symptoms, typically occurring within minutes to hours 2

Pregnancy and Lactation

• Discuss adverse effects of pharmacologic treatments during pregnancy and lactation with patients of childbearing potential 1
• Treatment decisions must weigh maternal disability against fetal/neonatal risks 1

Timing and Dosing Strategy

• Counsel patients to begin treatment as soon as possible after migraine onset, ideally while pain is still mild, as this improves triptan efficacy 1, 3
• Use maximum allowed doses rather than subtherapeutic dosing, which is a common cause of treatment failure 5
• Consider switching within and between medication classes if initial trials are inadequate 4

Addressing Comorbidities

• Identify and treat comorbid conditions including depression, sleep disturbances, obesity, and cardiovascular risk factors, as these may perpetuate intractable migraine 3
• Medications like amitriptyline and topiramate can address both migraine prevention and certain comorbidities 3