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What are the best prophylactic drugs for migraine?

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BETA-BLOCKERS without intrinsic sympathomimetic activity, amitriptyline, divalproex sodium/sodium valproate, and topiramate are the most effective drugs for preventing episodic migraine (strength of recommendation: A, multiple, well-designed, randomized controlled trials [RCTs]).

Evidence summary

Many medications have been evaluated for migraine prophylaxis. However, very few head-to-head trials of more than 2 drugs have been published, and no recent meta-analyses of available drug classes have been performed. The most commonly evaluated outcome is a 50% reduction in headache frequency.

Propranolol and timolol offer consistent prevention

Propranolol and timolol have consistently demonstrated efficacy for preventing episodic migraine. In a 1991 meta-analysis, propranolol resulted in a 44% reduction in the headache index—a composite score that takes into account both intensity and duration—compared with a 14% reduction for placebo.1

Less evidence supports other beta-blockers

Atenolol, metoprolol, and nadolol have demonstrated a moderate effect, but less evidence exists to support their use.2 A recent trial comparing metoprolol and nebivolol demonstrated a positive response—defined as a 50% reduction in headache frequency—to each drug at 14 weeks (57% of metoprolol-treated and 50% of nebivolol-treated patients), but noted that nebivolol was better tolerated.3

Beta-blockers with intrinsic sympathomimetic activity (acebutolol, alprenolol, oxprenolol, pindolol) appear to be ineffective for migraine prevention.4

Amitriptyline works better than propranolol for some migraines

Amitriptyline is the most often studied antidepressant and the only one with consistent support for efficacy in preventing migraine. A 1981 trial found amitriptyline to be more effective than propranolol in mixed migraine-tension-type headache, whereas propranolol was more effective for migraine alone.5

Some support for fluoxetine, none for similar drugs

Limited evidence exists for the use of fluoxetine, 20 mg daily. A small 1999 study of patients with migraine without aura found a 57% reduction in total pain index—a value based on pain intensity and hours of headache per month—with fluoxetine compared with an insignificant 31% reduction with placebo.6

No evidence from controlled trials supports the use of fluvoxamine, paroxetine, sertraline, phenelzine, venlafaxine, mirtazapine, trazodone, or bupropion.4

Divalproex sodium, sodium valproate are effective

Divalproex sodium and sodium valproate show strong, consistent evidence of efficacy; they may be particularly useful for patients with prolonged or atypical migraine aura.4 Initial studies of delayed-release divalproex at doses ranging from 500 to 1500 mg daily found that 44% of divalproex-treated patients reported a 50% reduction in migraine frequency, compared with 21% in the placebo group (number needed to treat [NNT]=4).7

A more recent study of the extended-release form of divalproex sodium demonstrated a 4-week reduction in headache rate to 1.2 from a baseline of 4.4, compared with a decrease of 0.6 for placebo (95% confidence interval [CI] of treatment difference, 0.2-1.2).8

Recommended drugs for migraine prophylaxis13

Propranolol80-240 mg/dMay cause fatigue. When used in combination with rizatriptan, give a lower dose of rizatriptan.
Timolol20-30 mg/dAs with propranolol, may cause fatigue.
Avoid β-blockers in patients with asthma or Raynaud’s disease.
Amitriptyline25-150 mg/dDrowsiness, weight gain, and significant anticholinergic adverse events are common.
Divalproex sodium;
Sodium valproate
500-1500 mg/d;
800-1500 mg/d
Side effects include nausea, drowsiness, weight gain, hair loss, and tremor. Hepatotoxicity, pancreatitis, and hyperammonemia have been reported rarely. Pregnancy category D.
Topiramate100-200 mg/dParesthesia is the most common adverse event; fatigue, nausea, anorexia, and cognitive symptoms are less common.
Carbonic anhydrase inhibition may cause metabolic acidosis.
Acute myopia and angle closure glaucoma are rare events.

Topiramate may decrease frequency as much as propranolol

Topiramate has significantly reduced the mean frequency of episodic migraine at doses of 100 to 200 mg daily and also improved secondary end points, including number of migraine days per month, use of acute medication, and daily activity.9 One study found that topiramate 100 mg daily had comparable efficacy to propranolol 160 mg daily; both drugs decreased monthly migraine frequency to 1.6 from a baseline of 4.9 with topiramate and 5.1 with propranolol (95% CI for the pair-wise difference of topiramate minus propranolol,-0.58 to 0.60).10


Evidence-based answers from the Family Physicians Inquiries Network

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