What are the treatment options for intractable migraines?

Treatment of Intractable Migraine

For intractable migraine, initiate preventive therapy immediately while optimizing acute treatment, as relying solely on escalating acute medication use creates a vicious cycle of medication-overuse headache that worsens the condition. 1, 2

Defining Intractable Migraine

Intractable migraine typically refers to patients experiencing:

• Two or more attacks per month producing disability for 3+ days 1
• Use of acute medications more than twice weekly 1, 2
• Failure of multiple acute treatments despite optimization 1
• Progressive worsening despite standard therapy 2

Critical First Step: Rule Out Medication-Overuse Headache

Before escalating therapy, assess for medication-overuse headache (MOH), which occurs when acute medications are used ≥10 days/month for triptans or ≥15 days/month for NSAIDs. 1, 2 MOH paradoxically increases headache frequency and can present as daily headaches or marked increase in migraine frequency. 3 This is a common pitfall—patients often increase acute medication frequency in response to worsening headaches, which perpetuates the problem. 2

Acute Treatment Optimization for Severe Attacks

First-Line Combination Therapy

Use combination therapy with a triptan plus NSAID, as this provides superior efficacy compared to either agent alone. 1, 2

• Sumatriptan 50-100 mg PLUS naproxen sodium 500 mg provides 130 more patients per 1000 achieving sustained pain relief at 48 hours compared to monotherapy 2
• Take medication early in the attack while pain is still mild for maximum effectiveness 1, 2
• This combination addresses the 40% of patients who experience symptom recurrence within 48 hours 2

Route Selection Based on Severity

For patients with rapid progression to peak intensity or significant nausea/vomiting:

• Subcutaneous sumatriptan 6 mg provides the highest efficacy (59% complete pain relief by 2 hours) with onset within 15 minutes 1, 2
• Intranasal sumatriptan 5-20 mg offers faster absorption than oral formulations 2

Emergency Department/Urgent Care Protocol

The most effective IV combination is metoclopramide 10 mg IV plus ketorolac 30 mg IV, providing both direct analgesic effects and rapid pain relief. 2

• Metoclopramide provides independent analgesic benefit through central dopamine receptor antagonism, not just antiemetic effects 2
• Ketorolac has rapid onset with 6-hour duration and minimal rebound headache risk 2
• Alternative: Prochlorperazine 10 mg IV has comparable efficacy to metoclopramide with a favorable side effect profile 2
• Avoid opioids and butalbital-containing compounds, as these lead to dependency, rebound headaches, and eventual loss of efficacy 1, 2

Preventive Therapy: The Cornerstone of Intractable Migraine Management

Preventive therapy is mandatory for intractable migraine and should be initiated immediately, not after further acute treatment failures. 1, 2 The goal is to reduce attack frequency by ≥50%, restore responsiveness to acute treatments, and prevent progression to chronic migraine. 1

First-Line Preventive Medications

Beta-blockers without intrinsic sympathomimetic activity:

• Propranolol 80-240 mg/day 1
• Metoprolol, atenolol, or bisoprolol 1
• Timolol 20-30 mg/day 1
• Common adverse effects (dizziness, fatigue, depression) are generally well-tolerated 1

Topiramate 64: Start low and titrate slowly; allow 2-3 months for full therapeutic effect 1

Candesartan: Effective first-line option 1

Second-Line Preventive Medications

• Amitriptyline 30-150 mg/day: Particularly useful for patients with mixed migraine and tension-type headache 1
• Flunarizine: Effective second-line option 1
• Sodium valproate 800-1,500 mg/day or divalproex sodium 500-1,500 mg/day: Strictly contraindicated in women of childbearing potential due to teratogenic risk 1

Third-Line Preventive Medications: CGRP Monoclonal Antibodies

Consider CGRP monoclonal antibodies (erenumab, fremanezumab, galcanezumab, eptinezumab) when oral preventives have failed or are contraindicated. 1

• These work faster than oral agents and don't require titration 4
• Efficacy should be assessed after 3-6 months (compared to 2-3 months for oral agents) 1
• In Europe, regulatory restrictions limit use to patients who have failed other preventive drugs 1

Critical Timing Expectations

Set realistic expectations about preventive therapy onset:

• Oral preventive medications: 2-3 months for efficacy assessment 1
• CGRP monoclonal antibodies: 3-6 months 1
• OnabotulinumtoxinA: 6-9 months 1

Failure of one preventive class does not predict failure of others (except when due to poor adherence). 1 If a therapeutic dose is ineffective after the appropriate trial duration, switch to an alternative medication class. 1

Algorithm for Failed Triptan Response

When a patient's current triptan stops working:

1. First, try a different triptan, as failure of one does not predict failure of others 2
2. Ensure early administration while headache is still mild 2
3. Add combination therapy with fast-acting NSAID (naproxen 500 mg) 2
4. Consider route change to subcutaneous or intranasal if oral fails 2
5. If all triptans fail after adequate trials, escalate to third-line agents like ditans (lasmiditan) or gepants (rimegepant, ubrogepant, zavegepant) 1, 2

Non-Pharmacological Adjuncts

Consider neuromodulatory devices, biobehavioral therapy, and acupuncture as adjuncts or stand-alone treatments when medications are contraindicated. 1

• Evidence supports non-invasive neuromodulatory devices 1
• Biobehavioral therapy (relaxation training, thermal biofeedback, cognitive-behavioral therapy) has demonstrated efficacy 1
• Acupuncture may be beneficial, though not superior to sham acupuncture in controlled trials 1
• Little to no evidence exists for physical therapy, spinal manipulation, or dietary approaches 1

Medication Frequency Limits to Prevent MOH

Strictly limit all acute migraine medications to no more than 2 days per week:

• NSAIDs: ≥15 days/month triggers MOH 1
• Triptans: ≥10 days/month triggers MOH 1
• Combination analgesics, ergots, opioids: ≥10 days/month 3

If patients require acute treatment more than twice weekly, this is an absolute indication for preventive therapy. 1, 2

Special Considerations for Women of Childbearing Potential

Discuss adverse effects of pharmacologic treatments during pregnancy and lactation before initiating therapy. 1

• Valproate is strictly contraindicated due to teratogenic risk 1
• Topiramate also carries teratogenic potential 5
• Triptans have varying safety profiles in pregnancy; discuss risks and benefits 1

When to Pause Preventive Therapy

After 6-12 months of successful preventive treatment, consider pausing to determine if therapy can be stopped. 1 This minimizes unnecessary drug exposure and allows some patients to manage with acute medications only. 1 Calculate the percentage reduction in monthly migraine days to quantify success—a pragmatic, case-by-case approach is needed. 1

Treatments to Avoid

Never use opioids or butalbital-containing compounds for routine migraine treatment, as they lead to medication-overuse headache, dependency, and loss of efficacy. 1, 2 Reserve opioids only for rare rescue situations when all other evidence-based treatments have failed, contraindications exist, sedation is acceptable, and abuse risk has been addressed. 1, 2