What are the recommended treatments for prophylaxis of chronic migraine headaches?

Prophylaxis of Chronic Migraine Headache

For chronic migraine prophylaxis, topiramate 100 mg/day is the recommended first-line treatment, with onabotulinumtoxinA (Botox) as the FDA-approved second-line option when first-line agents fail or are not tolerated. 1

Defining Chronic Migraine and Indications for Prophylaxis

Chronic migraine is defined as 15 or more headache days per month, each lasting at least 4 hours, with headaches on 8 or more days having migraine features, persisting for more than 3 months. 2

Prophylactic treatment should be initiated when patients experience: 2

• Two or more attacks per month producing disability lasting 3 or more days
• Contraindication to or failure of acute treatments
• Use of abortive medication more than twice per week
• Presence of uncommon migraine conditions (hemiplegic migraine, prolonged aura, migrainous infarction)

First-Line Prophylactic Treatment: Topiramate

Topiramate is the only agent with proven efficacy in randomized, placebo-controlled trials specifically for chronic migraine. 2 This distinguishes it from other commonly used agents like propranolol, amitriptyline, and valproate, which have evidence primarily for episodic migraine. 2

Dosing and Titration

• Start at 25 mg daily and increase by 25-50 mg weekly to a target dose of 100 mg/day 3, 4
• The 100 mg/day dose is optimal; no additional efficacy is seen at 200 mg/day 5
• Allow 2-3 months for full therapeutic effect before assessing efficacy 2, 1

Expected Outcomes

Topiramate reduces monthly migraine days by approximately 3.5 days compared to placebo, even in patients with medication overuse. 3 The 50% responder rate (patients achieving at least 50% reduction in migraine days) is significantly higher than placebo, with an absolute risk difference of 168 more responders per 1,000 patients treated. 6

Specific Patient Populations

Topiramate is particularly beneficial for patients with obesity, as it is associated with weight loss rather than weight gain. 1, 5 This makes it preferable to amitriptyline or valproate in overweight patients.

Common Adverse Effects

The most frequent side effects include paresthesias (53%), nausea (9%), dizziness, fatigue, decreased appetite, and cognitive disturbances ("disturbance in attention"). 5, 3 Approximately 80 more patients per 1,000 will discontinue topiramate due to adverse events compared to placebo. 6

Second-Line Treatment: OnabotulinumtoxinA (Botox)

OnabotulinumtoxinA is the only FDA-approved therapy specifically for chronic migraine prophylaxis and should be considered when topiramate fails, is not tolerated, or is contraindicated. 2, 7, 8

Eligibility and Administration

• Indicated for adults with chronic migraine (≥15 headache days per month, each lasting ≥4 hours) 7, 8
• NOT indicated for episodic migraine (<15 headache days per month) 7
• Requires specialist administration following the Phase III PREEMPT protocol 2
• Patients need at least 2-3 treatment cycles (administered every 12 weeks) before being classified as non-responders 7

Efficacy

OnabotulinumtoxinA reduces headache days, migraine episodes, total cumulative headache hours, headache severity, and improves health-related quality of life scores. 2, 7

Critical Safety Warnings

The FDA label includes a black box warning for spread of toxin effects causing botulism-like symptoms, including: 8

• Problems swallowing, speaking, or breathing (can occur hours to weeks after injection)
• Loss of strength and muscle weakness
• Double vision, blurred vision, drooping eyelids
• Hoarseness or voice changes
• Difficulty speaking clearly
• Loss of bladder control
• Trouble breathing or swallowing

Patients with pre-existing breathing or swallowing problems are at highest risk and may require feeding tubes or respiratory support. 8 Death can occur as a complication of severe swallowing or breathing problems. 8

Alternative First-Line Agents (Based on Episodic Migraine Evidence)

While the following agents are recommended for migraine prophylaxis generally, they lack robust randomized controlled trial data specifically for chronic migraine: 1

• Propranolol 80-240 mg/day 2
• Timolol 20-30 mg/day 2
• Amitriptyline 30-150 mg/day 2
• Divalproex sodium 500-1500 mg/day or sodium valproate 800-1500 mg/day 2

These agents may be considered when topiramate is contraindicated or not tolerated, particularly when comorbidities favor specific agents (e.g., amitriptyline for depression or sleep disturbances). 1

Third-Line Options: CGRP Monoclonal Antibodies

CGRP monoclonal antibodies (erenumab, fremanezumab, galcanezumab) are proven beneficial for patients in whom at least two other preventive medications have failed. 1 These represent third-line therapy after topiramate and onabotulinumtoxinA.

Critical Management Considerations

Medication Overuse Headache (MOH)

Approximately 73-78% of chronic migraine patients have medication overuse, which must be identified and addressed. 2, 3 MOH can mimic or worsen chronic migraine symptoms. 1 Management requires:

• Patient education about the risk of MOH 1
• Abrupt withdrawal of overused medications (except opioids, which require tapering) 1
• Limiting acute medication use to prevent recurrence 1

Acute Treatment During Prophylaxis

All chronic migraine patients need an appropriate acute treatment plan alongside prophylaxis: 2

• First-line: NSAIDs (aspirin, ibuprofen, naproxen sodium) 2
• Second-line: Triptans (most effective when taken early while headache is mild) 2, 1
• Strict limits on frequency of acute medication use to prevent MOH 1

Comorbidity Management

Chronic migraine commonly coexists with anxiety, depression, sleep disturbances, chronic pain, and obesity. 1 Addressing these comorbidities can improve migraine treatment outcomes. 1 Obesity is a specific risk factor for transformation from episodic to chronic migraine. 1

Treatment Algorithm

1. Confirm diagnosis: 15+ headache days/month for >3 months, with migraine features on 8+ days 2, 1

2. Rule out medication overuse headache: Address if present before initiating prophylaxis 1

3. Initiate topiramate: Start 25 mg daily, titrate by 25-50 mg weekly to 100 mg/day target 1, 3

4. Evaluate response: Allow 2-3 months before assessing efficacy 2, 1

5. If topiramate fails or not tolerated: Consider onabotulinumtoxinA (requires specialist referral) 7, 1

6. If two agents fail: Consider CGRP monoclonal antibodies 1

7. Provide acute treatment plan: NSAIDs or triptans with clear frequency limits 1

8. Address comorbidities: Treat obesity, depression, sleep disorders, anxiety as indicated 1

Common Pitfalls to Avoid

• Do not use acetaminophen alone for acute migraine treatment—there is no evidence for efficacy 2
• Do not prescribe Botox for episodic migraine (<15 headache days/month)—it is not indicated 7
• Do not classify patients as Botox non-responders before completing at least 2-3 treatment cycles 7
• Do not overlook medication overuse headache—it affects most chronic migraine patients and must be addressed 2, 1, 3
• Do not increase topiramate beyond 100 mg/day expecting better efficacy—no additional benefit is seen 5
• Do not forget to counsel patients about cognitive side effects of topiramate, particularly "brain fog" 3