Evidence-based answers from the Family Physicians Inquiries Network Jonathon M. Firnhaber, MD Brody School of Medicine at East Carolina University, What are the best prophylactic Greenville, NC Katherine Rickett, drugs for migraine? MSLS, MSEd Laupus Health Sciences Library, East Carolina University, Greenville, NC EVIDENCE-BASED ANSWER Beta-blockers with in- trinsic sympathomimetic Beta-blockers without intrinsic sympathomimetic activity (acebutolol, alpre- A activity, amitriptyline, divalproex sodium/sodium nolol, oxprenolol, pindo- valproate, and topiramate are the most eff ective drugs for lol) appear to be ineff ective preventing episodic migraine (strength of recommendation: for migraine prevention.4 A, multiple, well-designed, randomized controlled trials Propranolol [RCTs]). Amitriptyline works and timolol have better than propranolol consistently for some migraines demonstrated Evidence summary Amitriptyline is the most often studied anti- effi cacy for Many medications have been evaluated for depressant and the only one with consistent preventing migraine prophylaxis. However, very few head- support for effi cacy in preventing migraine. A episodic to-head trials of more than 2 drugs have been 1981 trial found amitriptyline to be more ef- migraine. published, and no recent meta-analyses of fective than propranolol in mixed migraine- available drug classes have been performed. tension-type headache, whereas propranolol Th e most commonly evaluated outcome is a was more eff ective for migraine alone.5 50% reduction in headache frequency. Some support for fl uoxetine, Propranolol and timolol none for similar drugs offer consistent prevention Limited evidence exists for the use of fl uox- Propranolol and timolol have consistently etine, 20 mg daily. A small 1999 study of pa- demonstrated effi cacy for preventing episodic tients with migraine without aura found a 57% migraine. In a 1991 meta-analysis, proprano- reduction in total pain index—a value based lol resulted in a 44% reduction in the head- on pain intensity and hours of headache per ache index—a composite score that takes into month—with fl uoxetine compared with an in- account both intensity and duration—com- signifi cant 31% reduction with placebo.6 pared with a 14% reduction for placebo.1 No evidence from controlled trials sup- ports the use of fl uvoxamine, paroxetine, ser- Less evidence supports traline, phenelzine, venlafaxine, mirtazapine, other beta-blockers trazodone, or bupropion.4 Atenolol, metoprolol, and nadolol have dem- onstrated a moderate eff ect, but less evidence Divalproex sodium, exists to support their use.2 A recent trial sodium valproate are effective comparing metoprolol and nebivolol demon- Divalproex sodium and sodium valproate strated a positive response—defi ned as a 50% show strong, consistent evidence of effi cacy; reduction in headache frequency—to each they may be particularly useful for patients drug at 14 weeks (57% of metoprolol-treated with prolonged or atypical migraine aura.4 and 50% of nebivolol-treated patients), but Initial studies of delayed-release divalproex at 3 noted that nebivolol was better tolerated. doses ranging from 500 to 1500 mg daily found 608 THE JOURNAL OF FAMILY PRACTICE | NOVEMBER 2009 | VOL 58, NO 11 608_JFP1109 608 10/19/09 11:46:01 AM TABLE Recommended drugs for migraine prophylaxis13 Drug Dose Comments Propranolol 80-240 mg/d May cause fatigue. When used in combination with rizatriptan, give a lower dose of rizatriptan. Timolol 20-30 mg/d As with propranolol, may cause fatigue. Avoid β-blockers in patients with asthma or Raynaud’s disease. Amitriptyline 25-150 mg/d Drowsiness, weight gain, and signifi cant anticholinergic adverse events are common. Divalproex sodium; 500-1500 Side effects include nausea, drowsiness, weight gain, hair loss, mg/d; and tremor. Hepatotoxicity, pancreatitis, and hyperammonemia Sodium valproate 800-1500 have been reported rarely. Pregnancy category D. mg/d Topiramate 100-200 mg/d Paresthesia 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. Amitriptyline is more effective than propranolol for mixed that 44% of divalproex-treated patients re- drugs for migraine prophylaxis found that migraine- ported a 50% reduction in migraine frequen- anticonvulsants, as a class, reduce migraine tension-type cy, compared with 21% in the placebo group frequency by about 1.3 attacks per 28 days headache, (number needed to treat [NNT]=4).7 when compared with placebo (based on whereas A more recent study of the extended- 10 trials [N=902]). When analyzing data on propranolol release form of divalproex sodium demon- relative frequency of migraines, data from 13 works better strated a 4-week reduction in headache rate trials (N=1773) were combined and showed for migraine to 1.2 from a baseline of 4.4, compared with that anticonvulsants more than doubled the alone. a decrease of 0.6 for placebo (95% confi dence number of patients with a 50% or greater de- interval [CI] of treatment diff erence, 0.2-1.2).8 crease in migraine frequency relative to pla- cebo (relative risk=2.25; 95% CI, 1.79-2.84; Topiramate may decrease frequency NNT=3.9; 95% CI, 3.4-4.7).11 as much as propranolol Topiramate has signifi cantly reduced the mean Other drugs to keep on your radar frequency of episodic migraine at doses of 100 Agents available in the United States that have to 200 mg daily and also improved second- at least limited evidence supporting their use ary end points, including number of migraine to prevent episodic migraine include gaba- days per month, use of acute medication, and pentin, lisinopril, candesartan, memantine, daily activity.9 One study found that topiramate ribofl avin, magnesium, feverfew, coenzyme 100 mg daily had comparable effi cacy to pro- Q10, butterbur, and melatonin. pranolol 160 mg daily; both drugs decreased Drugs so far proved ineff ective in pre- monthly migraine frequency to 1.6 from a base- venting episodic migraine include clonidine, line of 4.9 with topiramate and 5.1 with pro- carbamazepine, clonazepam, vigabatrin, ox- pranolol (95% CI for the pair-wise diff erence of carbazepine, zonisamide, lamotrigine, nife- topiramate minus propranolol, −0.58 to 0.60).10 dipine, and acetazolamide. Botulinum toxin type A given by intramuscular injection in the Anticonvulsants also reduce head and neck region has demonstrated limit- migraine frequency ed effi cacy in chronic headache disorders, but A 2004 Cochrane review of anticonvulsant doesn’t prevent episodic migraine.12 CONTINUED JFPONLINE.COM VOL 58, NO 11 | NOVEMBER 2009 | THE JOURNAL OF FAMILY PRACTICE 609 609_JFP1109 609 10/19/09 11:46:05 AM Recommendations Th e 2000 guidelines of the American Association of Neurology address Group 1 (fi rst-line) drugs and Group 2 drugs: ❚ Group 1 drugs (medium to high effi - cacy, good strength of evidence, and a range of severity [mild to moderate] and frequency [infrequent to frequent] of side eff ects) include amitriptyline, divalproex sodium, proprano- lol, and timolol. ❚ Group 2 drugs (lower effi cacy than Group 1, or limited strength of evidence, and SEE THE BEST THAT CLEVELAND HAS TO OFFER. mild to moderate side eff ects) include aspirin (but not combination products), atenolol, feno- Family Medicine profen, feverfew, fl urbiprofen, fl uoxetine, ga- bapentin, guanfacine, ketoprofen, magnesium, The Department of Family Medicine at the Cleveland Clinic is mefenamic acid, metoprolol, nadolol, naprox- seeking board certified/eligible Family Medicine Physicians for 13 outpatient positions in our Family Health Centers located en, nimodipine, verapamil, and vitamin B2. throughout the Cleveland area. The positions include the Topiramate was still under study when the opportunity to teach medical students from the Cleveland Clinic Lerner College of Medicine, precept Family Medicine Residents and guidelines were released and wasn’t approved to participate in practice based research. by the US Food and Drug Administration for Cleveland Clinic is an equal opportunity employer and is committed migraine prophylaxis until 2004. Th e 2000 to increasing the diversity of its faculty. It welcomes nominations of and applications from women and members of minority groups, as guidelines are undergoing revision. well as others who would bring additional dimensions to its research, teaching, and clinical missions. Cleveland Clinic is a smoke/drug free work environment. Interested candidates should forward a current copy of their CV in WORD format to the attention of: JoeVitale, Senior Director, References Office of Physician Recruitment, Professional Staff Affairs; 1. Holroyd KA, Penzien DB, Cordingley GE. Propranolol in the [email protected] or apply online at www.ccf.org management of recurrent migraine: a meta-analytic review. Headache. 1991;31:333-340. 2. Silberstein SD, Goadsby PJ. Migraine: preventive treatment. Cephalalgia. 2002;22:491-512. 3. Schellenberg R, Lichtenthal A, Wöhling H, et al. Nebivolol and metoprolol for treating migraine: an advance on -blocker treat- ment? Headache. 2008;48:118-125. ADVERTISERS AND PRODUCTS 4. Snow V, Weiss K, Wall EM, et al. Pharmacologic management of acute attacks of migraine and prevention of migraine headache. Ann Intern Med. 2002;137:840-849. CVD/HIV Conference ............................................................. 601 5. Mathew NT. Prophylaxis of migraine and mixed headache: a ran- domized