Migraine Prophylaxis

Article Author:
Anil Kumar
Article Editor:
Renu Kadian
1/19/2019 5:41:05 PM
PubMed Link:
Migraine Prophylaxis


Recurrent migraines can be functionally disabling and can impair quality of life.

After treatment of acute migraines, all migraine patients should be evaluated for preventive therapy. The purpose of preventive therapy is to decrease the frequency, severity, and duration of migraine attacks. Furthermore, preventative therapy can increase responsiveness to acute migraine therapy and improve quality of life.

Prophylactic treatment is not curative, and most patients will still need abortive medications for an acute migraine. Before starting prophylactic medications, it is imperative to evaluate if patients are using proper and adequate abortive therapies. Overuse of abortive medications can cause rebound headaches.

Migraine attacks are associated with neuronal activation, which is thought to be due to cortical spreading activation (CSD) or a brainstem generator. Preventive medications inhibit CSD through a variety of mechanisms, for example, blocking calcium and sodium channels, blocking of gap junctions, and inhibiting matrix metalloproteinases.

  • Beta blockers block noradrenergic receptors, reduce synthesis and release of norepinephrine, inhibit central beta-adrenergic receptors, and reduce overall adrenergic tone.
  • Topamax blocks calcium and sodium channels. It also inhibits excitatory glutamatergic receptors and increases GABA inhibitory activity.
  • Valproate acts by decreasing neurogenic inflammation via GABA-A receptors.
  • Tricyclic antidepressants decrease neuronal excitatory tone by inhibiting norepinephrine and 5HT high-affinity uptake and downregulating beta-adrenergic receptors. They also upregulate GABA-B receptors.
  • Calcium-channel blockers inhibit calcium influx, inhibit 5HT release and reduce the release of glutamate, leading to inhibition of CSD.
  • Gabapentin acts by blocking voltage-gated calcium channels. It increases GABA synthesis, which in turn increases 5HT concentration, leading to inhibitory actions.

It is important to determine the frequency, duration, and severity of headaches, and any triggers that may precipitate the headaches.

All patients with migraine headaches should maintain a headache diary to determine the frequency, severity, and duration of headaches. It also helps identify any triggers that can cause a migraine headache. Some common triggers include environmental factors such as noise, odor, among others, medications (like OCP, HRT, H2 blockers), food (cheese, wine, chocolate), and behavioral factors such as sleep deficit or excessive sleep. If triggers can be identified and modified, preventive drug therapy may not be needed.


The function of prophylactic therapy for a migraine is to avoid the following:

  • Disabling headache, causing significant disability more than 2 days a month
  • Contraindication, significant adverse side effects or refractoriness to acute abortive therapy
  • Use of abortive medications more than 2 times per week.
  • Atypical  migraine presentations  like a migraine with prolonged aura, hemiplegic migraine
  • Patient preference

Approximately 28 million Americans older than the age of 12 suffer from migraine headaches. Around 18% of women and 6% of men in the United States suffer from migraine headaches. Around 38% of those with a migraine headache need to be on preventive therapy; whereas, only 3% to 13% of migraine sufferers use preventative therapy.

Issues of Concern

Pharmacological Therapy for Migraine Prophylaxis

Various medications are available for migraine prophylaxis and prevention. Choosing the right agent is important. The efficacy, side effects, contraindications, cost, and compliance should be considered when deciding the right agent. It is also very important to consider comorbid medical conditions and drug interactions. Efficacy of treatment can be assessed only after a 2 to 3-month trial; a full trial may take up to 6 months. Always start at a low dose and titrate up slowly. Monotherapy is preferred as there are no significant benefits of using more than one drug unless indicated for other comorbid condition. Patients should be re-evaluated, and medications preferably discontinued after 1 year, even if the patient shows improvement in symptoms. Successful therapy is defined as a reduction of migraine attacks by at least 50%.

Beta Blockers

Propranolol is the most common and one of the most effective first-line medications used for migraine prophylaxis. Starting dose is 40 mg to 160 mg and can go up to 320 mg daily. It may take up to 12 weeks at an adequate dose for therapeutic benefits to become apparent.

Other beta blockers that can be used are timolol, atenolol, and metoprolol. They should be considered in patients with the underlying cardiovascular disease. Common side effects of this group of medications are fatigue, nausea, dizziness, decreased exercise tolerance, and depression. Contraindications include severe asthma, peripheral vascular disease, severe bradycardia, and heart blocks.


Depakote and sodium valproate are 2 anticonvulsant drugs that are used for migraine prophylaxis. They are amongst the first-line agents used for migraine prevention. They are particularly useful for prolonged and atypical migraine. The dose used is 400 to 1000 mg daily. Common side effects include nausea, drowsiness, hair loss, tremors, and hyperammonemia. They are contraindicated in patients with severe liver disease and pancreatitis. Sodium valproate cannot be used in pregnancy because of teratogenicity.

Topamax is another drug used as a first-line treatment option for migraine prophylaxis. Topamax has comparable efficacy to propranolol for preventing migraine headaches. It should be started at a low dose with 25 mg daily and slowly titrated up to 100 mg twice daily. Patients should continue treatment for at least 2 to 3 months before the treatment efficacy is evaluated. Common side effects include memory and concentration problems, paresthesia, fatigue, nausea, and anorexia. Topamax can cause metabolic acidosis and also precipitate kidney stones, acute myopia, and angle closure glaucoma.

Gabapentin has little efficacy for migraine prevention. The recommended dose is 1200 to 2400 mg per day. Common side effects include somnolence and dizziness.


Amitriptyline is shown to have some benefit in migraine prevention. It may be more effective than propranolol in mixed migraine-tension type of a headache. Response to treatment can be seen in up to 4 weeks and is more rapid than with beta blockers. The dose used is 20 to 75 mg daily.

Another antidepressant that is probably effective in migraine prevention is venlafaxine. It is probably as effective as amitriptyline. The dose used is 150 mg daily. Fluoxetine has also been used for migraine prophylaxis. Common side effects include weight gain, drowsiness, dry mouth, and urinary retention. Contraindicated in concurrent use with monoamine oxidase inhibitors (MAOIs).

Calcium-Channel Blockers

Verapamil has shown weak efficacy for preventing migraines. It is used as one of the second-line pharmacological options for migraine prophylaxis.

Flunarizine is a nonspecific CCB that has shown evidence of some efficacy. It is not available in the United States.

Angiotensin Blockers: ACEIs/ARBs

Lisinopril and candesartan are 2 medications in this group that have some shown some, although weak, efficacy for migraine prevention.


They are used for prevention of a menstrual migraine. Start treatment a few days before the anticipated start of the menstrual cycle and continue for first few days.


Zolmitriptan, frovatriptan, and naratriptan have shown benefits in the short-term prevention of menstrual-related migraines. They are started several days before the expected onset and continued for 5 to 6 days.


Some other medications that have some but little efficacy for migraine prevention include Magnesium, Vitamin B2, Coenzyme Q10, Hormone treatment, Botulinum toxin.

Benefits of Botulinum toxin A have not been statistically proven for treatment of an episodic migraine headache; however, it is proven to be effective for treatment of chronic headaches.

Methysergide and phenelzine are used as last resorts for severe and refractory cases. Use for more than 6 months can cause cardiac and retroperitoneal fibrosis.

Alternative Therapies

Butterbur and feverfew are 2 herbal medications available for use for migraine prophylaxis. Studies have failed to prove any substantial benefit with feverfew. Butterbur extract made from underground parts of the plant has been endorsed by American Academy of Neurology and the American Headache Society, to reduce the frequency of migraines.

Non-Pharmacological Therapies

Identifying and modifying the trigger if possible. It is important to maintain headache diaries to identify triggers and follow response when triggers modified.

Therapies that can help prevent migraines include relaxation, acupuncture, massage, cognitive behavior therapy, and biofeedback techniques.

The FDA approved a transcutaneous electrical nerve stimulation (TENS) device in March 2014 for use in migraine prevention. More studies are needed to determine its long-term efficacy.

2012 AHS/AAN Guidelines for Migraine Prevention in Adults

Medications are divided into 3 groups:

Level A (medications that have proven effectiveness and should be offered to patients who require migraine prophylaxis): Sodium valproate, valproic acid, propranolol, timolol, topiramate, butterbur.

Level B (medications that are probably effective and should be considered for migraine prevention): Amitriptyline, feverfew, naproxen, fenoprofen, ketoprofen, ibuprofen, magnesium, atenolol, venlafaxine, riboflavin, histamine.

Level C (medications with possible effectiveness and may be considered for migraine prevention): Candesartan, carbamazepine, lisinopril, pindolol, nebivolol, clonidine, cyproheptadine, coenzyme Q10.

Migraine Prophylaxis in Children

Propranolol is the most effective medication available to prevent a migraine headache in children. It should be used with caution in patients with asthma, reactive airway disease, diabetes, and depression.

Cyproheptadine is an antihistamine and serotonin antagonist; it can be used for migraine prevention in children. Weight gain and anticholinergic side effects can occur with its use.

Other medications that may have little benefit include amitriptyline, topiramate, and sodium valproate.

Migraine Prophylaxis in Pregnancy

It is very important to maintain a cautious approach. Risks and benefits should be discussed with the patient in detail. Labetalol at a dose of 150 mg twice per day has shown some benefit in pregnant women. Propranolol, topiramate, amitriptyline, fluoxetine, and gabapentin are pregnancy category C drugs. Valproic acid is teratogenic and contraindicated, and use of lisinopril and Candesartan is not recommended for pregnant women.

Clinical Significance

Recurrent migraines are often functionally disabling and can impair quality of life. Prophylactic therapy may decrease the frequency, severity, and duration of migraine attacks, increase responsiveness to acute migraine therapy, and improve quality of life.


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