Migraine Headache Prophylaxis

Aka: Migraine Headache Prophylaxis, Migraine Prophylaxis

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II. Epidemiology

  1. Of the 38% of episodic Migraine patients in whom prophylaxis is indicated, less than half are taking prophylaxis

III. Indications: Frequent Migraine Headaches

  1. Headache frequency
    1. Headaches per month: >=4 (or >=2 severe Headaches) OR
    2. Headache days per month: 8 or more
    3. Consider in any patient desiring Migraine Prophylaxis to reduce Headache frequency
  2. Headache duration
    1. Prolonged Headaches >2 days with Disability
  3. Headache response to Migraine Abortive Treatment
    1. Debilitating Headache despite acute Migraine abortive agents
    2. Intolerance or contraindications to acute Migraine abortive agents
    3. Analgesic Overuse Headaches or overuse of acute Migraine abortive agents
      1. Triptans, ergots, opiods or combination Analgesics >10 days/month OR
      2. Non-Opioid Analgesics, NSAIDS or Tylenol >15 days/month
  4. Other indications
    1. Complicated Migraine Headache subtypes (prominent neurologic findings)

IV. Protocol

  1. See Migraine Headache Management
  2. See Headache Self-Help Measure
  3. See Migraine Headache Triggers
  4. Approach
    1. Effective prophylaxis reduces Headache frequency or severity by 50%
    2. Keep Headache diary
    3. Start prophylaxis at low dose and gradually increase
    4. For each step, titrate dose every 2-4 weeks until effective over a 2-6 month period
    5. Consider tapering to lowest effective dose at 6-12 months
  5. At each step assess prophylactic agent with a validated symptom score
    1. Migraine Disability Assessment
    2. Headache Impact Test
    3. Migraine Physical Function Impact Diary
  6. Step 1: Select a first-line agent
    1. Beta Blocker (Propranolol, Metoprolol or Timolol)
    2. Divalproex (Depakote)
    3. Topiramate (Topamax)
    4. If Menstrual Migraines, Frovatriptan 2.5 mg twice daily for 5-7 days starting 0-2 days before Menses
  7. Step 2: Select a different first-line agent if not effective despite maximal tolerated dose
  8. Step 3: Consider a Calcitonin Gene-Related Peptide Blocker (CGRP Antagonist, see below)
  9. Step 4: Consider combining 2 first-line agents
  10. Step 5: Consider a second line agent
    1. Amitriptyline (Elavil)
    2. Venlafaxine (Effexor)
    3. Other Beta Blockers (Atenolol, Nadolol)
    4. If Menstrual Migraines, Zolmitriptan 2.5 mg three times daily for 5-7 days starting 0-2 days before Menses

V. Medications: Most Effective Agents for Migraine Prophylaxis

  1. Propranolol LA or Metoprolol XL: Level A Evidence
    1. Metoprolol and Timolol have similar efficacy to Propranolol in Migraine Prophylaxis (Level A evidence)
    2. Beta Blockers are a first choice unless contraindicated (e.g. baseline Sinus Bradycardia, athlete, Asthma)
    3. Propranolol LA 80 mg orally daily
      1. Gradually increase over 2-3 weeks until effective dose (typically 80 mg twice daily or 160 mg daily)
      2. Maximum: 240 to 320 mg orally daily
      3. May substitute with generic Propranolol non-XL
        1. Split daily dose into 3-4 divided doses
    4. Metoprolol XL
      1. Start 25-50 mg at bedtime nightly
      2. Next increase by 25 mg weekly up to 50-100 mg daily
  2. Amitriptyline (Elavil), Nortriptyline (Pamelor) or Venlafaxine: Level B Evidence
    1. Effective, but considered a second-line agent due to more adverse effects (esp. tricyclics)
    2. Consider in patients with comorbid Tension Headaches
    3. Tricyclics: Amitriptyline (Elavil), Nortriptyline (Pamelor)
      1. Start: 10 mg orally at bedtime
      2. Increase by 10 mg each week until at least 30 mg, and preferably 50-100 mg at bedtime
    4. SNRI: Venlafaxine (Effexor) XR
      1. Start XR 37.5 mg daily, and may titrate every 1-2 weeks to typical effective dose 150 mg/day
      2. Similar efficacy in Migraine Prophylaxis to Tricyclic Antidepressants
  3. Valproic Acid and derivatives: Level A Evidence
    1. Teratogenic (avoid in women at risk for pregnancy)
    2. See description for adverse effects and monitoring
    3. Depakote Extended Release (ER)
      1. Start 500 mg orally daily
      2. Increase after 1 week to 500 mg orally twice daily
      3. May increase in 250 mg increments if adverse effects
      4. Preferred Valproate form for Migraine Prophylaxis
    4. Other preparations
      1. DivalproexSodium (Depakote) 250-500 mg orally twice daily
      2. Valproic Acid (Depakene) 250-500 mg twice daily
  4. Topiramate (Topamax): Level A Evidence
    1. Teratogenic (avoid in women at risk for pregnancy)
    2. May blunt cognitive function and cause weight loss
    3. Dosing
      1. Bedtime dosing
        1. Start: 12.5 to 25 mg orally at bedtime
        2. Increase by 12.5 to 25 mg each week, until at 100 mg at bedtime
      2. Alternative twice daily dosing
        1. Start: 12.5 to 25 mg orally at bedtime for 1 week
        2. Next: 25 mg orally twice daily for 1 week
        3. Next: 25 mg orally in AM and 50 mg orally in PM for 1 week
        4. Next: 50 mg orally twice daily
    4. Efficacy
      1. Effective prophylaxis at 100-200 mg per day
      2. Silberstein (2004) Arch Neurol 61:490-5 [PubMed]
      3. Brandes (2004) JAMA 291:965-73 [PubMed]

VI. Medications: Calcitonin Gene-Related Peptide Blocker (CGRP Antagonist)

  1. General
    1. Biologic Agents released in 2018 to block the CGRP vasodilator
    2. Expensive ($6900/year)
  2. Indications
    1. Indicated in Migraines refractory to at least two first-line Migraine Prophylaxis agents
    2. Indications to continue agent after 3-6 months
      1. Headache days per month reduced by at least 50% OR
      2. Significant improvement on validated Migraine Headache survey (see above)
  3. Preparations
    1. Erenumab (Aimovig)
      1. Autoinjector once monthly
      2. Start 70 mg, and may increase as needed to 140 mg
    2. Fremanezumab (Ajovy)
      1. May give 225 mg prefilled syringe dose once monthly OR
      2. Give 675 mg (3 injections from prefilled syringes) once every 3 months
    3. Galcanezumab (Emgality)
      1. Once monthly injection via pen
      2. Load 240 mg once, then 120 mg monthly
    4. Rimegepant (Nurtec)
      1. Take 75 mg every other day
  4. Efficacy
    1. Reduces migraine Incidence by 2 fewer Migraine days/month
  5. References
    1. (2018) Presc Lett 25(12): 70

VII. Medications: Comorbidity Directed

  1. Neck Pain, Neuralgia, scalp Allodynia
    1. Gabapentin
  2. Frequent or prominent aura, or aura with Hemiplegia or autonomic symptoms
    1. Verapamil
  3. Post-Traumatic Headache
    1. Topiramate
    2. Amitriptyline
    3. Gabapentin
  4. Anxiety or hyperadrenergic state
    1. Beta Blocker (e.g. Propranolol, Metoprolol)
  5. Overweight or Obesity
    1. Topiramate
  6. Dizziness
    1. Verapamil
    2. Tricyclic Antidepressants (Amitriptyline, Nortriptyline)
    3. Topiramate
    4. Venlafaxine (Effexor)
  7. Seizure Disorder
    1. Topiramate
    2. Divalproex (Depakote)
  8. Hypertension
    1. Beta Blocker (e.g. Metoprolol)
  9. Mental Health Conditions
    1. Venlafaxine (Effexor) for Major Depression or anxiety
    2. Divalproex (Depakote) for Bipolar Disorder
    3. Tricyclic Antidepressants (Amitriptyline, Nortriptyline) for Major Depression or Insomnia

VIII. Medications: Antihypertensives

  1. Most effective agents - All are Beta Blockers (Level A evidence)
    1. Propranolol (Inderal)
      1. Start at 80 mg and titrate to effect up to 320 mg orally daily
      2. Use long acting (LA) once daily or divide two to three times daily with short acting
    2. Timolol
      1. Start at 10-15 mg orally once daily
      2. Increase to 20-30 mg orally daily or divided twice daily
    3. Metoprolol (Toprol XL, Lopressor)
      1. Start at 25-50 mg orally daily (succinate) or divided twice daily (tartrate)
      2. Titrate dose to effect up to 200 mg/day
  2. Probably effective (Level B evidence)
    1. Atenolol start 25 mg at bedtime
      1. May increase after 1 week to 50 mg at bedtime
      2. Consider divided dosing 50 mg twice daily or 100 mg once daily
    2. Nadolol
      1. Start 40 mg orally daily
      2. Increase by 40 mg weekly to 120 mg typical dose (up to 160 mg daily)
    3. Candesartan
      1. Start 4-8 mg once daily
      2. Titrate to most effective dose 8-16 mg once daily
  3. Possibly effective (Level C)
    1. Lisinopril
      1. Migraine without Aura associated with high ACE Level
      2. Schrader (2001) BMJ 322:19-23 [PubMed]
    2. Nebivolol (Bystolic)
    3. Clonidine
    4. Guanfacine
  4. Inadequate evidence
    1. Bisoprolol (Zebeta)
    2. Acetazolamide (Diamox)
    3. Calcium Channel Blockers
      1. Verapamil
      2. Nicardipine
      3. Nifedipine
      4. Nimodipine
  5. Ineffective (avoid)
    1. Acebutolol (Sectral)
    2. Telmisartan (Micardis)

IX. Medications: Nonsteroidal Antiinflammatory Drugs (NSAIDS)

  1. Risk of Analgesic Overuse Headache
  2. Probably effective (Level B)
    1. Naproxen
    2. NaproxenSodium (Anaprox) 550 mg twice daily
    3. Fenoprofen
    4. Ketoprofen
    5. Ibuprofen
  3. Possibly effective (Level C)
    1. Flurbiprofen
    2. Mefenamic Acid
  4. Unknown Efficacy
    1. Aspirin
    2. Indomethacin
  5. Ineffective
    1. Nabumetone (Relafen)

X. Medications: Antidepressants

  1. Probably effective (Level B evidence)
    1. Amitriptyline (Elavil) 30 to 150 mg orally daily
    2. Venlafaxine (Effexor)
  2. Inadequate evidence
    1. Fluvoxamine
    2. Protriptyline
    3. Fluoxetine (Prozac) 20-40 mg orally daily
      1. Headache worsens in 30% of cases
      2. Steiner (1998) Cephalalgia 18:283-6 [PubMed]
  3. Ineffective agents (avoid)
    1. Clomipramine (Anafranil)

XI. Medications: Anticonvulsants

  1. Most effective agents (Level A Evidence)
    1. Valproic Acid (Depakote) 250 to 750 mg orally twice daily
    2. Topiramate (Topamax)
  2. Possibly effective (Level C evidence)
    1. Carbamazepine
  3. Inadequate evidence
    1. Gabapentin
  4. Ineffective (avoid)
    1. Lamotrigine (Lamictal)
    2. Oxcarbazepine (Trileptal)

XII. Medications: Complementary Therapy, Non-Pharmacologic and Vitamin Supplementation

  1. Probably effective (Level B)
    1. Relaxation Training, Biofeedback, Cognitive Behavioral Therapy
      1. However, high quality evidence is lacking
    2. Tanacetum parthenium (Feverfew)
      1. Dose: 50 to 75 mg orally daily to twice daily
      2. Avoid in pregnancy (risk of contractions)
    3. Vitamin B2 (Riboflavin)
      1. Dose: 400 mg orally daily
      2. Schoenen (1998) Neurology 50:466-70 [PubMed]
    4. Acupuncture
      1. Appears as effective as standard Migraine Prophylaxis medications
      2. See Acupuncture for additional studies
      3. Da Silva (2015) Headache 55(3): 470-3 [PubMed]
  2. Possibly effective (Level C)
    1. Coenzyme Q10 100 mg orally 3-4 times daily
      1. Reduces Migraines by a third
      2. Sandor (2005) Neurology 64:713-5 [PubMed]
    2. Magnesium Oxide 300 mg daily or Magnesium Dicitrate 600 mg daily
      1. May also assist with Migraine medication-induced Constipation
      2. May reduce severity and duration of Migraines
      3. Wang (2004) Headache 43(6):601-10 [PubMed]
  3. Avoid due to toxicity
    1. Petasites hybridus (Butterbur)
      1. NOT Recommended due to contamination with pyrrolizidine alkaloids (carcinogenic and hepatotoxic)
      2. Best evidence of efficacy (Level A), but avoid due to toxicity
      3. Dose Petadolex 50-75 mg orally twice daily
      4. May reduce Migraine frequency by 50%
      5. GI intolerance is common (and hepatotoxicity risk)
      6. Lipton (2004) Neurology 63:2240-4 [PubMed]

XIII. Medications: Miscellaneous

  1. Probably effective (Level B)
    1. N-alpha-methyl Histamine
      1. Dose 1-10 ng twice weekly SQ Injection
      2. Millan-Guerrero (2006) Can J Neurol 33: 195-99 [PubMed]
    2. Botulinum Toxin A injections
      1. Third-line option after 2-3 failed prophylactic agents
      2. Indicated in chronic Migraines but not episodic Migraines
      3. Injection sites
        1. Occiput (Occipitalis Muscle)
        2. Posterior Neck (Cervical paraspinal, trapezius Muscle)
        3. Parietal, supraauricular (Temporalis Muscle)
        4. Frontal forehead (Corrugator, Procerus, Frontalis Muscles)
      4. FDA approved for chronic Migraines since 2010
      5. Best effect after 3 cycles of injection
      6. Silberstein (2014) J Neurol Neurosurg Psychiatry [PubMed]
  2. Possibly effective (Level C)
    1. Cyproheptadine (Periactin) 4-16 mg orally daily
      1. Serotonin Agonist
  3. Inadequate evidence
    1. Lithium Carbonate (Lithobid) 300 mg PO bid-tid
    2. Anticoagulants and antiplatelet agents
      1. Cyclandilate
      2. Coumadin
      3. Picotamide
      4. Acenocoumarol
  4. Ineffective (avoid)
    1. Clonazepam
    2. Montelukast

XIV. References

  1. Robertson (2017) Migraine Headache Prevention, Mayo Clinical Reviews, Rochester, MN
  2. Jackson (1998) CMEA Internal Medicine Lecture, San Diego
  3. Ha (2019) Am Fam Physician 99(1): 17-24 [PubMed]
  4. Holland (2012) Neurology 78(17):1346-53 [PubMed]
  5. Jackson (2015) PLoS One 10(7): e0130733 [PubMed]
  6. Modi (2006) Am Fam Physician 73:72-80 [PubMed]
  7. Moore (1997) Am Fam Physician 56(8):2039-48 [PubMed]
  8. Moreland (2025) Am Fam Physician 111(5): 443-50 [PubMed]
  9. Mulleners (2015) Cephalgia 35(1): 51-62 [PubMed]
  10. Noble (1997) Am Fam Physician 56(9):2279-86 [PubMed]
  11. Parsekyan (2000) West J Med 173:341-5 [PubMed]
  12. Polizzotto (2002) J Fam Pract 51(2):161-7 [PubMed]
  13. Rollo (2023) Curr Neuropharmacol 21(8): 1767-85 [PubMed]
  14. Silberstein (2012) Neurology 78: 1337-45 [PubMed]

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