This post is part of a series on migraine pharmacology. Part 1 updates some concepts on pathophysiology and clinical features of the disease, while part 3 will discuss aspects on drug therapy of acute episodes.
Prophylactic drugs overview
The image below reviews the different drug classes used in migraine prophylaxis and acute treatment.
Beta-adrenergic blockers
Propanolol (Inderal, Avlocardyl and others) is the most widely used beta-blocker for migraine prevention, several mechanisms of action are responsible for its effectiveness as a preventive medication:
- It inhibits norepinephrine release through alpha-2 agonism, thus reducing central catecholaminergic activity.
- It antagonizes 5-HT1A and 5-HT2Breceptors, reducing neuronal excitability.
- It inhibits nitric oxide production by blocking inducible nitric oxide synthase, through alpha2-agonist action. Nitric oxide is believed to be the common final pathway for vasodilation in migraine.
- It inhibits excitatory glutamate receptors, decreasing neuronal activity.
- It has membrane-stabilizing properties.
Propanolol is a first line agent for migraine prevention.
Prescribers should keep in mind beta blockers adverse effects and contraindications.
Propanolol dosage for migraine prophylaxis is 80 to 240 mg per day, in three or four divided doses. The usual dose is around 160 mg/d.
Timolol (Betimol)is the other beta-blocker that has been approved by the FDA for the prevention of this clinical condition. The recommended Timolol dose for migraine prophylaxis is 10 to 15 mg twice per day.
All drugs from this class can produce central nervous system adverse effects, such as fatigue, sleep disorders, and depression. Another common side effect is decreased exercise tolerance. Less common are orthostatic hypotension, significant bradycardia, and impotence.
Contraindications to the use of nonselective beta blockers include: congestive heart failure, asthma, and insulin-dependent diabetes.
Calcium channel blockers
Clinical trials have shown that Flunarizine (Sibelium) is an effective prophylactic medication for reducing the frequency of migraine episodes. This drug is not available in the US, its use is common in some European countries and in South America.
Flunarizine is the only calcium channel blocker shown to be effective as prophylactic drug.
Some studies show that flunarizine is as effective as propanolol in reducing severity and frequency of the attacks.
The recommended flunarizine dose in this setting is of 10 mg/d. The most important adverse effect of flunarizine use is weight gain, which limits patient compliance, specially in women.
Evidence does not support the use of other calcium channel blockers. Nimodipine failed to demonstrate any effects in clinical trials, while there is no convincing evidence of the effect of verapamil.
Tricyclic antidepressants
The use of antidepressants for the prevention of migraine episodes has not been approved by the U.S. Food and Drug Administration. However, its off-label use is common and has proved to be effective in the case of amitryptilne.
Amitriptyline (Elavil, Tryptanol and others )is a first-line agent for migraine prophylaxis and is the only TCA with consistent evidence supporting its effectiveness for this use. The dose range for amitriptyline in migraine prevention is 25 to 100 mg.
Side effects are related to TCAs blockade of cholinergic and histamine receptors (read more). These include dry mouth, tachycardia, constipation, dizziness, mental confusion, blurred vision, and urinary retention.
Other classes of antidepressants have been considered for migraine prophylaxis, such as SSRI and MAO inhibitors. There is poor evidence for SSRIs use and there are no conclusive randomized controlled trials about the use of MAO inhibitors.
Anticonvulsants
A 2005 Cochrane review supports the use of antiepileptic drugs to reduce headache frequency in patients with migraine. According to that review, valproic acid and divalproex have the strongest evidence to support their use for this indication.
Valproate may raise inhibitory tone in the hyper-excitable migraine brain via GABA. The usual effective dose of divalproex sodium is 500 to 1000 mg/d of the extended release formulation.
Valproic acid (Depakene) and derivatives should not be used in patients who are pregnant.
Since valproate is a severe teratogenic drug, it should not be used as a first line preventive medication in women of child-bearing age.
Topiramate (Topamax) has a variety of actions that may prevent migraine, including increasing inhibitory GABA activity, blocking calcium channels, and inhibiting carbonic anhydrase.
Topiramate is well tolerated when started at a low dose, usually 15 or 25 mg, and increased weekly up to 100 mg, which is the recommended dose. Topiramate is associated with weight loss in around 4% of treated patients.
Gabapentin (Neurontin) recommended dose is between 900 and 3600 mg qd. Just as pregabalin, it acts by modulating glutamate and GABA function, as well as regulating intracellular calcium influx. Among the most common adverse effects are dizziness and sedation.
Clinical guidelines for migraine prophylaxis
Evidence-based guidelines for migraine headache in the primary care setting: pharmacological management for prevention of migraine. American Academy of Neurology. Download PDF
Pharmacologic management of acute attacks of migraine and prevention of migraine headache. Ann Intern Med 2002;137:840-9. Download PDF
Your opinion and experience matters
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References
Chronicle E, Mulleners W. Anticonvulsant drugs for migraine prophylaxis. Cochrane Database Syst Rev 2004;(4):CD003226.
Modi, S, , Lowder, D.Medications for Migraine Prophylaxis. Am Fam Physician. 2006;73:72-8, 79-80.
Fauci, Anthony S., Braunwald, Eugene, Kasper,Dennis L. “Harrison’s Principles of Internal Medicine”, 17 edition. Mc Graw Hill: 2008.
Diener HC, Matias-Guiu J. Efficacy and tolerability in migraine prophylaxis of flunarizine in reduced doses: a comparison with propranolol 160 mg daily. Cephalalgia. 2002 Apr;22(3):209-21.
Bordini CA, Arruda MA. Propranolol vs flunarizine vs flunarizine plus propranolol in migraine without aura prophylaxis. A double-blind trial. Arq Neuropsiquiatr. 1997 Sep;55(3B):536-41