Migraine Treatment and Prevention

CLINICAL ACTIONS:

Migraine is a complex neurologic event encompassing moderate to severe headache as well as systemic and neurologic symptoms.  Treatment is aimed at both amelioration of symptoms as well as prevention of attacks.  Dosage below is based on the Lancet (2018) review and International Headache Society (IHS) guidelines but may vary based on a patient’s medical and clinical circumstances.

ACUTE TREATMENT

General principles to manage acute migraine include

• Treat early (ideally within the first 20 mintutes of onset) while pain is mild
• Consider non-oral routes of administration for patients with nausea/vomiting or rapid pain peak (≤30 min)
  • Nasal spray
  • Injection
  • Suppository
  • Combination approach using medications with different mechanisms of action for those who do not obtain quick relief or relapse within 24 – 48 hours
  • Educate patients regarding potential for medication-overuse
  • Minimize use of ‘simple’ analgesics to <15 days per month and triptans, ergots, or combination analgesics to less than 10 days per month (see below for specific meds)

Simple analgesics – Effective for Mild Pain

• NSAIDS
  • Aspirin 975 – 1000 mg
  • Ibuprofen 400 mg
  • Naproxen 500 – 550 mg (up to 825 mg)
  • Diclofenac potassium 50 mg
  • Indomethacin suppositories 50 mg
    • May be cut into 1/2 or 1/3
• Acetaminophen
  • Acetaminophen (Paracetamol) 1000 mg
  • May be combined with NSAIDs and caffeine

Triptans – First Line for Moderate/Severe Pain

• Selective Serotonin 5-HT Receptor Agonists
• Contraindications due to vasoconstriction
  • History of symptomatic peripheral, coronary, and cerebrovascular disease and severe hypertension
• Pregnancy
  • May be associated with pregnancy-related vascular events, but data currently (mostly based on sumatriptan) has not demonstrated an association with birth defects
  • Usually begin with acetaminophen, then aspirin/NSAIDs and use triptans as 3^rd line therapy when indicated
• Triptans have an overall favorable safety profile when not contraindicated and available without subscription in some European countries
• Typical doses and routes
  • Sumatriptan
    • 6 mg subcutaneous
    • 20 mg intranasal
    • 50 mg oral
    • 100 mg oral
  • Zolmitriptan 5 mg intranasal/2.5 mg oral
  • Almotriptan 12.5 mg oral
  • Eletriptan 20-40 mg oral
  • Frovatriptan 2.5 mg oral
  • Naratriptan 2.5 mg oral
• Patients may respond differently to different triptans and patient preference will also play a role (e.g. patients tend to prefer oral medications)
• Lasmitidan (Reyvow) highly selective 5-HT1f antagonist, is similar to triptans with a favorable adverse event profile  

Dihydroergotamine

• Used when triptans are not well tolerated or patient not responding
• Alpha-adrenergic blocker and arterial vasoconstrictor
  • 1 mg nasal spray, subcutaneous or IM
• Contraindications include
  • Pregnant or nursing
  • Cardiac or circulatory disease (similar to triptans)
• Additional contraindications due to life-threatening peripheral ischemia due to coadministration of dihydroergotamine with CYP 3A4 inhibitors
  • Anti-HIV medications (protease inhibitors)
  • Macrolide antibiotic such as clarithromycin or erythromycin

Opiods/Butalbital Containing Analgesics

• Best to avoid due to high incidence adverse events, habituation, addiction, and medication overuse headache with as little as 3 butalbital exposures per month

Note: The FDA has approved medications for treatment of migraine with and without aura, based on new classes of drugs (see ‘Primary Sources – Learn More’ below) 

• Lasmiditan (Reyvow): A new class of serotonin (5-HT)1f receptor agonists
• Ubrogepant (Ubrelvy: An oral calcitonin gene–related peptide receptor antagonist
• Rimegepant (Nurtec ODT): An oral calcitonin gene-related peptide receptor antagonist 

PREVENTATIVE TREATMENT

• Consider preventative treatment
  • When ≥ 8 headache days/month or ≥4 migraines/month
  • For patients with chronic migraine

Beta Blockers

• Atenolol (B level evidence): 50 to 200 mg once a day
• Metoprolol (A level evidence): 50 to 200 mg once a day for long-acting formulation
• Nadolol (B level evidence): 20 to 160 mg once a day
• Propranolol (A level evidence): 40 to 240 mg once a day for long-acting formulation
• Timolol (A level evidence): 20 to 60 mg once a day 

Antidepressants

• Amitriptyline (B level evidence): 10 to 50 mg before bed
• Nortriptyline (no studies available): 10 to150 mg before bed
• Venlafaxine (B level evidence): 75 to 225 mg once a day for long-acting formulation

Calcium-Channel Blockers and Anticonvulsants

• Verapamil (U level evidence): 120 to 960 mg in divided doses for long-acting formulation
• Flunarizine (A level evidence): 5 to 10 mg once a day
• Gabapentin (U level evidence): 600 to 3600 mg in two–three divided doses
• Topiramate (A level evidence): 50 to 200 mg twice a day or before bed
  • Pregnancy Risk: FDA category D due to strong association with birth defects
• Valproic acid–divalproex (A level evidence): 500 – 2000 mg once a day or in two divided doses
  • Pregnancy Risk: FDA category D due to strong association with birth defects

Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers

• Lisinopril (C level evidence): 10 to 40 mg once a day
• Candesartan (C level evidence): 16 to 32 mg once a day
  • Pregnancy Risk: FDA category D due to strong association with birth defects
• Cyproheptadine (C level evidence): 4 to 16 mg before bed
• Ibuprofen (B level evidence): 200 mg twice a day
• Fenoprofen (B level evidence): 200 to 600 mg twice a day
• Ketoprofen (B level evidence): 50 mg three times a day
• Naproxen (B level evidence): 500 to 1100 mg once a day
• Naproxen sodium (B level evidence): 550 mg twice a day

Calcitonin Gene-Related Peptide (CGRP-R) ModulatorsBlockers. A relatively new class of migraine therapies that are highly efficacious

• Galcanezumab (Emgality): 240mg once as loading dose, then 120mg once monthly subcutaneously (self-administered) 
• Fremanezumab (Ajovy): 225mg once monthly subcutaneously (self-administered) 
• Rimegepant (Nurtec ODT): 75 mg orally taken once every other day (dissolving tablet) 
• Atogepant (Qulipta): 10, 30, or 60mg orally taken once every day 
• Eptinezumab (Vyepti): 100mg IV administered every 3 months. Some patients may benefit from 300mg IV administered every 3 months 
• Erenumab (First FDA-approved CGRP-R blocker for migraine prevention): 70mg once monthly subcutaneously (self-administered)
  • Some patients may benefit from a dosage of 140mg once monthly administered once monthly as two consecutive injections of 70mg each

Miscellaneous agents

• Acupuncture (minimum of 6 sessions prior to realized therapeutic effect) 
• Dry needling 
• Feverfew (B level evidence): 50 to 82 mg once a day
• Riboflavin (B level evidence): 400 mg once a day or 200 mg twice a day
• Ubidecarenone (coenzyme Q10) C 300 mg once a day
• Magnesium citrate (B level evidence): 400 to 600 mg once a day
• OnabotulinumtoxinA also called botulinum toxin type A (A level evidence): 155 to 195 mg once every 12 weeks (for chronic migraine)
  • FDA approved for chronic, not episodic migraine

Notes: (Canadian Headache Society Guidelines)

• Level A: drug has been established as effective | Level B: drug is probably effective | Level C: drug is possibly effective (requires at least one class 2 study or two consistent class 3 studies) | Level U: data are inadequate or conflicting, treatment is unproven

SYNOPSIS:

Treatment of migraines is intended to reduce the acute symptoms as well as prevent future events.  A multitude of medical therapies are available to this end. When starting therapy begin with the lowest dose and escalate slowly. A 2-3 month trial is necessary to determine efficacy.  6 months may be needed to achieve maximal result.

KEY POINTS:

• Patient using oral sumatriptan but headache not resolved within 2 hours or returns after transient improvement
  • Second dose may be administered at least 2 hours after the first dose
  • Maximum daily dose is 200 mg in a 24-hour period
• Discuss family planning with all women of childbearing age; review adverse effects on pregnancy prior to initiating treatment
• Emerging treatments include:
  • Neuromodulation devices
  • External trigeminal nerve stimulation
  • Noninvasive vagus nerve stimulation

Learn More – Primary Sources

Lancet: Migraine

Headache Classification Committee of the International Headache Society (IHS) The International Classification of Headache Disorders, 3rd edition (2018).

Mother To Baby: Sumatriptan Fact Sheet

FDA HIGHLIGHTS OF PRESCRIBING INFORMATION: UBRELVY (ubrogepant)

AAFP: Approach to Acute Headache in Adults

BMJ: Management of chronic migraine