What are the medications used to treat chronic migraine?

Medications for Chronic Migraine

For chronic migraine (≥15 headache days per month), topiramate is the first-line preventive medication, followed by onabotulinumtoxinA if topiramate fails, and then CGRP monoclonal antibodies as third-line therapy after failure of at least two other preventive medications. 1, 2

Critical Diagnostic Prerequisite

• Rule out medication overuse headache (MOH) before initiating any preventive therapy, as MOH frequently mimics chronic migraine and will prevent response to preventive medications 1, 2
• MOH occurs when acute medications are used ≥10 days per month and requires withdrawal of overused medications before starting preventive treatment 3, 2

Acute Treatment Medications (Limited Use)

Acute medications must be strictly limited to no more than twice weekly to prevent medication overuse headache 1, 2

First-Line Acute Treatment

• NSAIDs: aspirin, ibuprofen, naproxen sodium, or diclofenac potassium 1, 2
• Combination agent: acetaminophen plus aspirin plus caffeine 1
• Antiemetics: domperidone or metoclopramide when nausea/vomiting is present 1, 2

Second-Line Acute Treatment (When NSAIDs Fail)

• Triptans: naratriptan, rizatriptan, zolmitriptan, or sumatriptan (oral or subcutaneous) 1, 4, 5
• DHE nasal spray 1
• Lasmiditan (selective 5HT1F receptor agonist) 6
• CGRP receptor antagonists (gepants) 6

Medications to Avoid

• Ergot alkaloids, opioids, and barbiturates should be avoided due to questionable efficacy and high risk of dependency and medication overuse headache 2

Preventive Medications: Algorithmic Approach

First-Line Preventive Medications

Topiramate is the drug of first choice due to proven efficacy in chronic migraine and much lower cost compared to biologics 1, 2

• Topiramate: 100 mg/day (titrate gradually from low dose) 1, 2, 7
  • Particularly beneficial in obese patients due to weight loss effect 1, 3
  • May take 2-3 months to see clinical benefit 1

Alternative first-line options (though evidence is stronger for episodic migraine than chronic migraine):

• Beta-blockers: propranolol (80-240 mg/day), timolol (20-30 mg/day), atenolol, bisoprolol, or metoprolol 1, 8, 7
  • Note: Propranolol increases rizatriptan levels by 70%, requiring dose adjustment 5
• Candesartan 1, 7, 9

Second-Line Preventive Medications

If topiramate fails or is not tolerated:

• Amitriptyline: 30-150 mg/day 1, 7, 10, 9
  • Particularly beneficial for patients with depression or sleep disturbances 1
• Flunarizine: 10 mg/day (where available) 1
  • Adverse events include sedation, weight gain, depression, and extrapyramidal symptoms in elderly 1
• Divalproex sodium/sodium valproate: 500-1500 mg/day or 800-1500 mg/day 1, 7, 11, 10
  • Strictly contraindicated in women of childbearing potential 1

Third-Line Preventive Medications

OnabotulinumtoxinA is indicated after topiramate and at least one other preventive medication have failed 1, 2, 7

• Efficacy should be assessed only after 6-9 months 1
• FDA-approved specifically for chronic migraine prevention 7, 9

CGRP monoclonal antibodies are reserved for patients who have failed at least two or three other preventive medications due to regulatory restrictions and high cost 1, 2

• Erenumab, fremanezumab, and galcanezumab have proven benefit in patients who failed multiple preventive medications 1, 9, 6
• Eptinezumab is also available 1
• Efficacy should be assessed only after 3-6 months 1

Medications with Limited Evidence for Chronic Migraine

No robust data from randomized controlled trials support the use of beta-blockers, candesartan, or amitriptyline specifically for chronic migraine, although they are commonly used in clinical practice 1

Non-Pharmacological Preventive Therapies

These can be used as adjuncts or stand-alone treatments when medications are contraindicated:

• Cognitive-behavioral therapy (CBT) 1, 2, 9
• Biofeedback 1, 2, 9
• Relaxation training 1, 2, 9
• Regular exercise: 40 minutes three times weekly (as effective as topiramate) 3, 2
• Neuromodulatory devices 1, 2
• Acupuncture 1

Nutraceuticals with Fair Evidence

• Magnesium citrate 1, 9
• Riboflavin 1, 9
• Coenzyme Q10 9
• Feverfew 1

Critical Management Principles

• Start preventive medications at low doses and titrate slowly until clinical benefits are achieved or limited by adverse events 1
• Allow adequate trial period: 2-3 months for oral medications, 3-6 months for CGRP antibodies, 6-9 months for onabotulinumtoxinA 1
• Avoid interfering medications such as overused acute medications during preventive treatment 1
• Consider pausing preventive therapy after 6-12 months of stability to determine if treatment can be stopped 1
• Address comorbidities (depression, anxiety, sleep disorders, obesity, chronic pain) as their management directly improves migraine outcomes 1, 3, 2

Common Pitfalls to Avoid

• Do not initiate preventive therapy without first ruling out and treating MOH 2
• Do not allow unlimited acute medication use - strict limitation to twice weekly prevents progression 2
• Do not abandon treatment prematurely - efficacy may take 2-3 months to manifest 1
• Do not use valproate in women of childbearing potential 1

When to Refer to Specialist

• Confirmed chronic migraine diagnosis 2
• Failure of multiple preventive medications 2
• Consideration of onabotulinumtoxinA or CGRP antibodies 2
• Diagnostic uncertainty 2