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New Guidelines on Treating Migraine Press Kit

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New Guidelines on Treating Migraine …

New Guidelines on Treating Migraine
Press Kit

64th AAN Annual Meeting
New Orleans Ernest N. Morial Convention Center

April 21–28, 2012

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  • 1. NewGuidelines onTreating MigrainePress Kit64thAANAnnualMeetingNew OrleansErnest N. MorialConvention CenterApril 21–28, 2012
  • 2. EMBARGOED FOR RELEASE UNTIL 4 P.M. ET, MONDAY, APRIL 23, 2012Media Contacts:Rachel Seroka, rseroka@aan.com, (651) 695-2738Angela Babb, APR, ababb@aan.com, (651) 695-2789AAN Press Room (April 22–27): (504) 670-4511New Guidelines: Treatments Can Help Prevent MigraineNEW ORLEANS – Research shows that many treatments can help prevent migraine in certain people,yet few people with migraine who are candidates for these preventive treatments actually use them,according to new guidelines issued by the American Academy of Neurology. The guidelines, which wereco-developed with the American Headache Society, will be announced at the American Academy ofNeurology’s 64th Annual Meeting in New Orleans and published in the April 24, 2012, print issue ofNeurology®, the medical journal of the American Academy of Neurology.“Studies show that migraine is underrecognized and undertreated,” said guideline author Stephen D.Silberstein, MD, FACP, FAHS, of Jefferson Headache Center at Thomas Jefferson University inPhiladelphia and a Fellow of the American Academy of Neurology. “About 38 percent of people whosuffer from migraine could benefit from preventive treatments, but only less than a third of these peoplecurrently use them.”Unlike acute treatments, which are used to relieve the pain and associated symptoms of a migraine attackwhen it occurs, preventive treatments usually are taken every day to prevent attacks from occurring asoften and to lessen their severity and duration when they do occur.“Some studies show that migraine attacks can be reduced by more than half with preventive treatments,”Silberstein said.The guidelines, which reviewed all available evidence on migraine prevention, found that amongprescription drugs, the seizure drugs divalproex sodium, sodium valproate and topiramate, along with thebeta-blockers metoprolol, propranolol and timolol, are effective for migraine prevention and should beoffered to people with migraine to reduce the frequency and severity of attacks. The seizure druglamotrigine was found to be ineffective in preventing migraine.The guidelines also reviewed over-the-counter treatments and complementary treatments. The guidelinefound that the herbal preparation Petasites, also known as butterbur, is effective in preventing migraine.Other treatments that were found to be probably effective are the nonsteroidal anti-inflammatory drugsfenoprofen, ibuprofen, ketoprofen, naproxen and naproxen sodium, subcutaneous histamine andcomplementary treatments magnesium, MIG-99 (feverfew) and riboflavin.Silberstein noted that while people do not need a prescription from a physician for these over-the-counterand complementary treatments, they should still see their doctor regularly for follow-up. “Migraines canget better or worse over time, and people should discuss these changes in the pattern of attacks with theirdoctors and see whether they need to adjust their dose or even stop their medication or switch to adifferent medication,” said Silberstein. “In addition, people need to keep in mind that all drugs, includingover-the-counter drugs and complementary treatments, can have side effects or interact with othermedications, which should be monitored.”-more-
  • 3. Learn more about the guideline’s recommendations at http://www.aan.com/guidelines.The American Academy of Neurology, an association of more than 25,000 neurologists and neuroscienceprofessionals, is dedicated to promoting the highest quality patient-centered neurologic care. Aneurologist is a doctor with specialized training in diagnosing, treating and managing disorders of thebrain and nervous system such as stroke, Alzheimer’s disease, epilepsy, Parkinson’s disease and multiplesclerosis.The American Headache Society®(AHS) is a professional society of health care providers dedicated tothe study and treatment of headache and face pain. The Societys objectives are to promote the exchangeof information and ideas concerning the causes and treatments of headache and related painful disorders.Educating physicians, health professionals and the public and encouraging scientific research are theprimary functions of this organization. AHS activities include an annual scientific meeting,a comprehensive headache symposium, regional symposia for neurologists and family practicephysicians, publication of the journal Headache and sponsorship of the AHS Committee for HeadacheEducation (ACHE). www.americanheadachesociety.orgFor more information about the American Academy of Neurology, visit http://www.aan.com or find us onFacebook, Twitter, Google+ and YouTube.Editor’s Note on Press Conference:Dr. Silberstein will be available for media questions during a press conference at 11:00 a.m. ET/10:00a.m. CT, on Monday, April 23, 2012, in Room 222 of the New Orleans Ernest N. Morial ConventionCenter in New Orleans. Please contact Rachel Seroka, rseroka@aan.com, to receive conference callinformation for those reporters covering the press conference off-site.Dr. Silberstein is also available for advance media interviews. Please contact Rachel Seroka,rseroka@aan.com, to schedule an advance interview.To access more than 2,300 non-late-breaking abstracts to be presented at the 2012 Annual Meeting of theAmerican Academy of Neurology, visit http://www.aan.com/go/am12/science. Advance copies of allEmerging Science abstracts (formerly known as Late-Breaking Science abstracts) to be presented at theAnnual Meeting are available by contacting Rachel Seroka, rseroka@aan.com.
  • 4. Evidence-based guideline update: Pharmacologictreatment for episodic migraine preventionin adultsReport of the Quality Standards Subcommittee of the American Academy ofNeurology and the American Headache SocietyS.D. Silberstein, MD,FACPS. Holland, PhDF. Freitag, DOD.W. Dodick, MDC. Argoff, MDE. Ashman, MDABSTRACTObjective: To provide updated evidence-based recommendations for the preventive treatment ofmigraine headache. The clinical question addressed was: What pharmacologic therapies areproven effective for migraine prevention?Methods: The authors analyzed published studies from June 1999 to May 2009 using a struc-tured review process to classify the evidence relative to the efficacy of various medications avail-able in the United States for migraine prevention.Results and Recommendations: The author panel reviewed 284 abstracts, which ultimatelyyielded 29 Class I or Class II articles that are reviewed herein. Divalproex sodium, sodium val-proate, topiramate, metoprolol, propranolol, and timolol are effective for migraine prevention andshould be offered to patients with migraine to reduce migraine attack frequency and severity(Level A). Frovatriptan is effective for prevention of menstrual migraine (Level A). Lamotrigine isineffective for migraine prevention (Level A). Neurology®2012;78:1337–1345GLOSSARYAAN ϭ American Academy of Neurology; AE ϭ adverse event; CI ϭ confidence interval; ER ϭ extended-release; MAM ϭmenstrually associated migraine; PMP ϭ perimenstrual period; RCT ϭ randomized controlled trial.Epidemiologic studies suggest approximately 38%of migraineurs need preventive therapy, but only3%–13% currently use it.1In 2000, the AmericanAcademy of Neurology (AAN) published guide-lines for migraine prevention.2,3Since then, newclinical studies have been published on the efficacyand safety of migraine preventive therapies. Thisguideline seeks to assess this new evidence to an-swer the following clinical question: For patientswith migraine, which pharmacologic therapies areproven effective for prevention, as measured byreduced migraine attack frequency, reduced num-ber of migraine days, or reduced attack severity?This article addresses the safety and efficacy ofpharmacologic therapies for migraine prevention.Separate guidelines are available for botulinumtoxin.4The 2008 guideline included a Level B re-commendation that botulinum toxin was probablyineffective for treatment of episodic migraine. A newguideline is in development. An updated guidelineon nonsteroidal anti-inflammatory drugs5and com-plementary alternative treatments has been approvedfor publication as a companion to this guideline.5DESCRIPTION OF THE ANALYTIC PROCESSThe AAN and the American Headache Society partic-ipated in the development process. An author panel ofheadache and methodologic experts was assembled toreview the evidence. Computerized searches of theMEDLINE, PsycINFO, and CINAHL databases iden-tified new studies (published in English). The searchstrategy used the MeSH term “headache” (exploded)and a published search strategy for identifying ran-domized controlled trials (RCTs) published betweenJune 1999 and May 2007. Additional MEDLINEsearches revealed studies published through MaySee page 1346Supplemental data atwww.neurology.orgSupplemental DataPodcastCMEFrom Thomas Jefferson University (S.D.S.), Jefferson Headache Center, Philadelphia, PA; the Armstrong Atlantic State University (S.H.), Savannah,GA; Comprehensive Headache Center (F.F.), Baylor University Headache Medicine Center, Dallas, TX; Mayo Clinic (D.D.), Scottsdale, AZ; NewYork University School of Medicine (C.A.), Albany; and Elmendorf Air Force Base (E.A.), AK.Appendices e-1–e-5, reference e1, and tables e-1 and e-2 are available on the Neurology௡ Web site at www.neurology.org.Approved by the Quality Standards Subcommittee on February 19, 2011; by the Practice Committee on June 19, 2011; by the AHS Board ofDirectors on March 29, 2012; and by the AAN Board of Directors on January 27, 2012.Study funding: This guideline was developed with financial support from the American Academy of Neurology and the American Headache Society.None of the authors received reimbursement, honoraria, or stipends for their participation in development of this guideline.Go to Neurology.org for full disclosures. Disclosures deemed relevant by the authors, if any, are provided at the end of this article.Correspondence & reprintrequests to American Academy ofNeurology:guidelines@aan.comSPECIAL ARTICLECopyright © 2012 by AAN Enterprises, Inc. 1337
  • 5. 2009, which were reviewed and included as supple-mental articles.Studies of pharmacologic agents available in theUnited States were included in the analysis if theyrandomized adult patients with migraine to the agentunder study or a comparator drug (including placebo)and utilized masked outcome assessment. At least 2panelists independently reviewed each study and ratedit according to the AAN therapeutic classification of ev-idence scheme (appendix e-3 on the Neurology®Website at www.neurology.org). Differences in ratings wereresolved by author panel discussion.ANALYSIS OF EVIDENCE The original searchidentified 179 articles. A supplemental search(2007–2009) yielded 105 additional articles. Of thetotal 284 articles, 29 were classified as Class I or ClassII and are reviewed herein. Studies were excluded ifthey:• Assessed the efficacy of therapeutic agents forheadache other than episodic migraine in adults• Assessed acute migraine treatment, migraineaura treatment/prevention, or nonpharmaco-logic treatments (e.g., behavioral approaches)• Used quality of life measures, disability assess-ment, or nonstandardized outcomes as primaryefficacy endpoints• Tested the efficacy of drugs not available in theUnited StatesSince the 2000 guideline publication, the AANrevised its evidence classification criteria to in-clude study completion rates. Studies with com-pletion rates below 80% were downgraded; severalstudies in the original guideline have thus beendowngraded.We found no new Class I or II studies publishedfor acebutolol, atenolol, bisoprolol, carbamazepine,Table 1 Classification of migraine preventive therapies (available in the United States)Level A: Medicationswith establishedefficacy (>2 Class Itrials)Level B: Medicationsare probablyeffective (1 Class Ior 2 Class II studies)Level C: Medicationsare possiblyeffective (1 Class IIstudy)Level U: Inadequateor conflicting datato support or refutemedication useOther: Medications thatare established aspossibly or probablyineffectiveAntiepileptic drugs Antidepressants/SSRI/SSNRI/TCAACE inhibitorsLisinoprilCarbonic anhydraseinhibitorEstablished as noteffectiveDivalproex sodium Amitriptyline Angiotensin receptorblockersAcetazolamide Antiepileptic drugsSodium valproate Venlafaxine Candesartan Antithrombotics LamotrigineTopiramate ␤-Blockers ␣-Agonists Acenocoumarol Probably not effective␤-Blockers AtenololaClonidineaCoumadin ClomipramineaMetoprolol NadololaGuanfacineaPicotamide Possibly not effectivePropranolol Triptans (MRMb) Antiepileptic drugs AntidepressantsSSRI/SSNRIAcebutololaTimololaNaratriptanbCarbamazepineaFluvoxamineaClonazepamaTriptans (MRMb) Zolmitriptanb␤-Blockers Fluoxetine NabumetoneaFrovatriptanbNebivolol Antiepileptic drugs OxcarbazepinePindololaGabapentin TelmisartanAntihistamines TCAsCyproheptadine Protriptylinea␤-BlockersBisoprololaCaϩϩ blockersNicardipineaNifedipineaNimodipineVerapamilDirect vascularsmooth musclerelaxantsCyclandelateAbbreviations: ACE ϭ angiotensin-converting-enzyme; MRM ϭ menstrually related migraine; SSNRI ϭ selective serotonin–norepinephrine reuptake inhibitor; SSRI ϭ selective serotonin reuptake inhibitor; TCA ϭ tricyclic antidepressant.aClassification based on original guideline and new evidence not found for this report.bFor short-term prophylaxis of MRM.1338 Neurology 78 April 24, 2012
  • 6. clonazepam, clonidine, clomipramine, fluvoxamine,guanfacine, nabumetone, nadolol, nicardipine, ni-fedipine, or protriptyline. Recommendations forthese agents are based on the evidence reviewed inthe original guideline (see table 1). Currently, noClass I or Class II studies exist for anticoagulants(limited Class III and IV studies were identified; ta-ble 1 includes anticoagulants).Angiotensin receptor blockers and angiotensin-converting-enzyme inhibitors. In the 2000 guide-line, there were no studies testing the efficacy ofangiotensin receptor blockers or angiotensin-converting-enzyme (ACE) inhibitors for migraineprevention. Since that publication, 3 reports havebeen published.Candesartan. In a Class II crossover study (12-weektreatment separated by 4-week washout), the meannumber of headache days was 18.5 with placebo(26.3% reduction from baseline) vs 13.6 with cande-sartan (45.6% reduction from baseline; p ϭ 0.001).6Selected secondary endpoints also favored candesar-tan: headache hours (139 vs 95; p Ͻ 0.001), mi-graine days (12.6 vs 9.0; p Ͻ 0.001), migraine hours(92.2 vs 59.4; p Ͻ 0.001), and headache severity in-dex (293 vs 191; p Ͻ 0.001). No serious adverseevents (AEs) occurred. The most common AEs weredizziness (31%), “symptoms of the musculoskeletalsystem” (21%), and fatigue (14%); none occurredsignificantly more often than with placebo.Lisinopril. One Class II study reported significantreduction in all 3 primary endpoints with lisinoprilvs placebo (headache hours: 129 vs 162 [meanchange in hours 20, confidence interval (CI) 5–36];headache days: 19.7 vs 23.7 [20, CI 5–30]; migrainedays: 14.5 vs 18.5 [21, CI 9–34]).7AEs includedcough (26%; 10% discontinued treatment due tocough), dizziness (23%), and “tendency to faint”(10%). No serious AEs were reported.Telmisartan. In a single Class II placebo-controlled trial, telmisartan 80 mg did not show asignificant difference from placebo for reductionin migraine days (Ϫ1.65 vs Ϫ1.14).8Conclusions. Lisinopril and candesartan are possiblyeffective for migraine prevention (1 Class II studyeach). Telmisartan is possibly ineffective for reducingthe number of migraine days (1 negative Class IIstudy).Antiepileptic drugs. Divalproex. The original guidelinefound strong, consistent support (5 studies) for the effi-cacy of divalproex sodium and its corresponding com-pound, sodium valproate, for migraine prevention.Since the 2000 publication, 1 double-blind, ran-domized, Class I placebo-controlled 12-week trialshowed extended-release (ER) divalproex sodium500–1,000 mg/day had a mean reduction in 4-weekmigraine headache rate from 4.4/week (baseline) to3.2/week (Ϫ1.2 attacks/week) in the ER divalproex so-dium group and from 4.2/week to 3.6/week (Ϫ0.6attacks/week) in the placebo group (CI 0.2–1.2;p ϭ 0.006).9No significant differences were de-tected between groups in the number oftreatment-emergent AEs.Clinical context. In most headache trials, patientstaking divalproex sodium or sodium valproate re-ported no more AEs than those on placebo. How-ever, weight gain has been clinically observed withdivalproex sodium long-term use.9,10Treatment withthese agents requires careful follow-up and testingbecause of pancreatitis, liver failure, and teratogenic-ity risks.11Gabapentin. Since the 2000 publication, a Class IIIstudy12reported that a stable gabapentin dose (4-week titration phase to 2,400 mg/day; 8-week main-tenance phase) significantly reduced the medianmonthly migraine rate vs placebo on the basis of amodified intention-to-treat analysis.Lamotrigine. The original guideline reported a sin-gle Class I lamotrigine study13that failed to show asignificant effect for migraine prevention. A second,new Class I study comparing lamotrigine 50 mg/daywith placebo or topiramate 50 mg/day reported lam-otrigine was not more effective than placebo (forboth primary endpoints) and was less effective thantopiramate in reducing migraine frequency and in-tensity.14The primary outcome measure (responderrate: Ն50% monthly migraine frequency reduction)was 46% for lamotrigine vs 34% for placebo (p ϭ0.093, CI 0.02–0.26) and 63% for topiramate vs46% for lamotrigine (p ϭ 0.019, CI 0.03–0.31).Treatment-related AEs (rash, giddiness, sleepiness,and gastrointestinal intolerance) occurred in 10% ofpatients on lamotrigine.Oxcarbazepine. One Class II trial evaluated the effi-cacy of oxcarbazepine (1,200 mg/day) vs placebo.15There was no difference between oxcarbazepine(Ϫ1.30 [SE 0.282]) and placebo for mean change innumber of migraine attacks from baseline during thelast 28 days of the double-blind 15-week treatmentphase (Ϫ1.74 [SE 0.283]; p ϭ 0.2274).Topiramate. Four Class I studies14,16–18and 7 ClassII studies19–25report topiramate (50–200 mg/day) iseffective in migraine prevention.In a Class I placebo-controlled study (mean topi-ramate dose 125 mg/day [range 25–200 mg/day]),patients given topiramate experienced a significantlylower 28-day migraine frequency vs with placebo(3.31 Ϯ 1.7 vs 3.83 Ϯ 2.1; p ϭ 0.002).18In a secondplacebo-controlled Class I double-crossover study(reviewed above), topiramate was more effective thanNeurology 78 April 24, 2012 1339
  • 7. placebo and lamotrigine for primary efficacy mea-sures.14In the topiramate groups, 15% of patientsexperienced AEs, most commonly paresthesias,sleepiness, and gastrointestinal intolerance. The pla-cebo group reported gastrointestinal intolerance(3%) and anorexia (3%).Two additional Class I studies report topiramate isas effective as propranolol16or sodium valproate,17drugs previously established as effective for migraineprevention. In the first study, subjects given topiramate50 mg/day had reduced mean migraine frequency (epi-sodes/month) from baseline (6.07 Ϯ 1.89 to 1.83 Ϯ1.39; p Ͻ 0.001) at 8 weeks, decreased headache inten-sity VAS score from 7.1 Ϯ 1.45 to 3.67 Ϯ 2.1 (p Ͻ0.001), and decreased headache duration from 16.37 Ϯ7.26 hours to 6.23 Ϯ 5.22 hours (p Ͻ 0.001).16Sub-jects given topiramate reported paresthesias (23%),weight loss (16%), and somnolence (13%). In pa-tients treated with propranolol 80 mg/day, meanheadache frequency (episodes/month) decreasedfrom 5.83 Ϯ 1.98 to 2.2 Ϯ 1.67 (p Ͻ 0.001) at 8weeks, headache intensity VAS score decreased from6.43 Ϯ 1.6 to 4.13 Ϯ 1.94 (p Ͻ 0.001), and head-ache duration decreased from 15.10 Ϯ 6.84 hours to7.27 Ϯ 6.46 hours (p Ͻ 0.001). Although monthlyheadache frequency, intensity, and duration de-creased in both groups, the topiramate group re-ported significantly greater mean reduction(topiramate frequency decrease 4.23 Ϯ 1.2 vs pro-pranolol 3.63 Ϯ 0.96 [p ϭ 0.036; CI 0.39–1.16];topiramate intensity decrease 3.43 Ϯ 1.38 vs pro-pranolol 2.3 Ϯ 1.2 [p ϭ 0.001; CI 0.46–1.8]; topi-ramate duration decrease 10.1 Ϯ 4.3 vs propranolol7.83 Ϯ 4.5 [p ϭ 0.048; CI 0.17–4.6]).In a crossover Class I trial (2-month washout be-tween therapies) comparing topiramate 50 mg/daywith sodium valproate 400 mg/day, both groupsshowed improvement from baseline in headache fre-quency, intensity, and duration.17Average monthlymigraine frequency decreased by 1.8 times with so-dium valproate (baseline 5.4 Ϯ 2.5; posttreatment3.6 Ϯ 2.1; CI 1.0–2.6; p Ͻ 0.001), as comparedwith a 3-time reduction with topiramate (baseline5.4 Ϯ 2.0; posttreatment 2.4 Ϯ 2.4; CI 2.1–3.9; p Ͻ0.001). Headache intensity decreased by 3.7 with so-dium valproate (baseline 7.7 Ϯ 1.2; treatment 4.0 Ϯ2.1; CI 2.9–4.6; p Ͻ 0.001), as compared with areduction of 3.6 with topiramate (baseline 6.9 Ϯ 1.2,treatment phase 3.3 Ϯ 1.5; CI 2.9–4.3; p Ͻ 0.001).The average headache episode duration decreased by13.4 hours from baseline with sodium valproate(baseline 21.3 Ϯ 14.6; treatment 7.9 Ϯ 7.7; CI 7.5–19.3; p Ͻ 0.001) as compared with an 11.9-hourreduction with topiramate (baseline 17.3 Ϯ 8.4;treatment 5.4 Ϯ 6.4; CI 8.2–15.6; p Ͻ 0.001). Theoverall analysis of repeated-measures analysis of vari-ance demonstrated no differences in monthly head-ache frequency, intensity, or duration after the firstor second treatment rounds. Topiramate AEs wereweight loss (18.8%), paresthesias (9.4%), or both(25%). Sodium valproate AEs were weight gain(34.5%), hair loss (3.1%), and somnolence (3.1%).Results of 5 Class II studies support those of theClass I studies showing topiramate as effective formigraine prevention.19–25Four studies demonstratedsignificant improvement over placebo19,20,23,24; oneincluded an active comparator arm, suggestingequivalence of topiramate (100, 200 mg/day) andpropranolol (160 mg/day).20Two studies comparingtopiramate and amitriptyline (25–150 mg/day) re-ported no difference in efficacy for primary end-points; however, amitriptyline was associated with asignificant AE increase, and the amitriptyline-topiramate combination suggested improvement indepression scores vs monotherapy.21,22In one of thesestudies,21the most common AEs were similar to thosepreviously reported. One Class II placebo-controlled24-week pilot study failed to show a difference in effi-cacy between topiramate 200 mg and placebo.26Conclusions. Divalproex sodium and sodium val-proate are established as effective in migraine preven-tion (multiple Class I studies). Data are insufficientto determine the effectiveness of gabapentin (1 ClassIII study). Lamotrigine is established as ineffectivefor migraine prevention (2 Class I studies). Oxcarba-zepine is possibly ineffective for migraine prevention(1 Class II study). Topiramate is established as effec-tive for migraine prevention (4 Class I studies, multi-ple Class II studies; 1 negative Class II study).Topiramate is probably as effective for migraine pre-vention as propranolol (1 Class I study), sodium val-proate (1 Class I study), and amitriptyline (2 Class IIstudies).Antidepressants. Fluoxetine. In the original guideline,1 Class II study27showed fluoxetine (racemic) wassignificantly better than placebo for migraine preven-tion, but the results were not duplicated in a secondstudy.28Since the original guideline, a Class II study hasshown fluoxetine 20 mg/day was more effective thanplacebo in reducing total pain index scores (calcu-lated as [Dl ϫ 1] ϩ [D2 ϫ 2] ϩ [D3 ϫ 3], where D1,D2, and D3 represent headache hours calculated in amonth, with pain intensity shown by 1, 2, 3) at 6months.29After the 6 months, pain index scores for thefluoxetine group decreased from 135 (baseline) to 41.3(SD Ϯ 63.8; p ϭ 0.001). The placebo group pain indexwas 98 at baseline and 61.1 at 6 months (SD Ϯ 57.7;p ϭ 0.07); however, differences were noted betweentreatment groups for baseline measures.1340 Neurology 78 April 24, 2012
  • 8. Venlafaxine. In a Class I study, venlafaxine XR 150mg significantly reduced the number of headachedays (median reduction in days: venlafaxine 150 mgϪ4 days; venlafaxine 75 mg Ϫ2 days; placebo Ϫ1day; Kruskal-Wallis ϭ 10.306, df ϭ 2; p Ͻ 0.006).30All 3 groups showed decreased headache severity andduration from baseline; no differences were observedbetween treatment groups for these endpoints. Themost common AEs were nausea (41%), vomiting(27%), and drowsiness (27%). Fourteen percent of pa-tients receiving venlafaxine withdrew because of AEs.A Class II trial assessed the efficacy of venlafaxinevs amitriptyline; both were effective in reducing at-tack frequency (venlafaxine: baseline ϭ 4.15 [SD Ϯ2.24] vs 12 weeks ϭ 1.77 [SD Ϯ 1.39; p Ͻ 0.001];amitriptyline: baseline ϭ 3.27 [SD Ϯ 1.61] vs 12weeks 1.54 [SD Ϯ 1.54; p Ͻ 0.001]).31Patients tak-ing venlafaxine experienced nausea/vomiting (23%)and tachycardia (15%); 1 patient withdrew becauseof AEs. Patients taking amitriptyline reported hyper-somnolence (80%), dry mouth (69%), and concen-tration difficulties (54%).Tricyclic antidepressants. The original guideline con-cluded amitriptyline was established as effective for mi-graine prevention; that evidence has since beendowngraded to Class II (all 3 studies had Ͼ20% drop-out rates). Comparative studies of amitriptyline withtopiramate21,22and venlafaxine31(reviewed above) re-port similar efficacy at the doses tested.Conclusions. There is conflicting Class II evidencefor use of fluoxetine. Venlafaxine is probably effec-tive for migraine prevention (1 Class I study) and ispossibly as effective as amitriptyline in migraine pre-vention (1 Class II study). Amitriptyline is probablyeffective for migraine prevention (multiple Class IIstudies); it is probably as effective as topiramate (2Class II studies) and possibly as effective as venlafax-ine (1 Class II study) for migraine prevention.␤-Blockers. Metoprolol. The original guideline con-cluded metoprolol was probably effective in migraineprevention. We reclassified these studies as Class Iusing the revised AAN criteria.One new Class II study reported metoprolol (200mg/day) was more effective than aspirin (300 mg/day) in achieving 50% migraine frequency reduction(responder rate metoprolol ϭ 45.2%; aspirin ϭ29.6%; mean difference 15.65; CI 4.43–26.88).32Attack frequencies (attacks/month) at placebo run-inand week 20 are 3.36 to 2.37, respectively, for aspirinand 3.55 to 1.82, respectively, for metoprolol. Nosignificant AEs were reported.A small Class II study reported metoprolol (47.5–142.5 mg/day) had similar efficacy to nebivolol 5mg/day for migraine prevention (assessed by a de-crease in mean migraine attacks).33Propranolol. The original guideline concludedpropranolol was established as effective for migraineprevention.In a Class II study, propranolol (80 mg/day) wasmore effective than placebo and as effective as cypro-heptadine (4 mg/day) in reducing migraine fre-quency, duration, and attack severity.34Thedifference in attack frequency reduction was signifi-cant between treatments: propranolol Ϫ2.85 Ϯ 0.2(SEM) vs cyproheptadine Ϫ3.09 Ϯ 0.31 vs combi-nation 3.12 Ϯ 0.1 vs placebo Ϫ1.77 Ϯ 0.44 (all p Ͻ0.05 vs placebo). For attack frequency reduction,combination therapy was more effective than mono-therapy (p Ͻ 0.05). AEs were drowsiness, sleep dis-turbance, weight gain, fatigue, and dry mouth;percentages of patients affected were not reported.Conclusions. Metoprolol is established as effectivefor migraine prevention (2 Class I studies) and is pos-sibly as effective as nebivolol or aspirin for migraineprevention (1 Class II study each). Propranolol is estab-lished as effective for migraine prevention (multipleClass I studies) and is possibly as effective as cyprohep-tadine for migraine prevention (1 Class II study).Calcium-channel blockers. The original guidelineconcluded that verapamil and nimodipine were prob-ably effective for migraine prevention. The originalstudies on verapamil and nimodipine were found tohave conflicting Class III evidence on the basis of cur-rent classification criteria and were downgraded accord-ingly, yielding Level U recommendations.Conclusions. Data from older studies regarding vera-pamil and nimodipine are insufficient when currentAAN classification criteria are applied.Direct vascular smooth muscle relaxants. The originalguideline concluded cyclandelate was probably effec-tive for migraine prevention.Cyclandelate. Two new Class II studies reportedconflicting results. The first study showed cyclande-late to be no more effective than placebo in reducingmigraine days, attacks, or duration.35The secondstudy (smaller, underpowered; n ϭ 25) found cy-clandelate significantly reduced the number of mi-graine days and duration (assessed using a contingentnegative variation measure).36Conclusions. The efficacy of cyclandelate is unknown(conflicting Class II studies).Triptans. Since the original guideline, new Class Istudies have assessed the efficacy of frovatriptan,37,38naratriptan,39and zolmitriptan40for short-term pre-vention of menstrually associated migraine (MAM).Frovatriptan. Frovatriptan 2.5 mg BID/qd wasmore effective than placebo in reducing migraine fre-Neurology 78 April 24, 2012 1341
  • 9. quency.37The mean number of headache-free peri-menstrual periods (PMPs) per patient (primaryendpoint) was higher in the 2 frovatriptan groups(2.5 mg qd ϭ 0.69 [SD Ϯ 0.92; CI 1.14–2.73; p ϭ0.0091] vs 2.5 mg BID ϭ 0.92 [SD 1.03; CI 1.84–4.28; p Ͻ 0.0001] vs placebo ϭ 0.42 [SD Ϯ 0.78]),representing 64% (2.5 mg/day) and 119% (5 mg/day) increases in the mean number of headache-freePMPs per patient over placebo. A second Class Istudy38also reports the MAM headache incidenceduring the 6-day PMP was 67% for placebo, 52% forfrovatriptan 2.5 mg QD (p Ͻ 0.0001 vs placebo),and 41% for frovatriptan 2.5 mg BID (p Ͻ 0.0001vs placebo; p Ͻ 0.0001 vs QD regimen). The AEincidence and type for both regimens were similar tothose for placebo. The overall AE incidence for fro-vatriptan was 4.1% (2.5 mg BID) and 2.7% (2.5 mgqd) higher than during placebo treatment.Naratriptan. In a Class I study, 1 mg BID (givenfor 5 days, starting 2 days before menses onset) re-duced the number of perimenstrual migraine attacksand migraine days.39Patients treated withnaratriptan 1 mg experienced more headache-freePMPs than those on placebo (50% vs 25%, p ‫؍‬0.003). Naratriptan 1 mg reduced the number ofMAMs (2.0 vs 4.0, p Ͻ 0.05) and MAM days (4.2 vs7.0, p Ͻ 0.01) vs placebo. The AE incidence andseverity were similar to those of placebo; Ͻ10% ofpatients experienced dizziness, chest pain, or malaise.Zolmitriptan. One Class I study reported the effi-cacy of zolmitriptan 2.5 BID/TID vs placebo. Bothzolmitriptan regimens demonstrated superior effi-cacy vs placebo: the proportion of patients with aՆ50% MAM attack frequency reduction (zolmi-triptan 2.5 mg TID [58.6%], p ϭ 0.0007 vs placebo;zolmitriptan 2.5 mg BID [54.7%], p ϭ 0.002 vs pla-cebo; placebo 37.8%).40AEs were considered possi-bly treatment-related in 28 patients (33.3%) in thezolmitriptan 2.5 mg TID group, 29 (36.3%) in thezolmitriptan 2.5 mg BID group, and 18 (22.0%) inthe placebo group. The most common AEs were as-thenia, headache, dizziness, and nausea.Conclusions. Frovatriptan is established as effective forthe short-term prevention of MAMs (2 Class I studies).Zolmitriptan and naratriptan are probably effective forthe short-term prevention of MAMs (1 Class I studyeach). The utility of these agents in receiving a separateindication for pure menstrual migraine is currently be-ing deliberated by US regulatory authorities.Other agents. Since the original guideline, additionalstudies have been identified that assess the efficacy ofa carbonic anhydrase inhibitor and a neurokinin in-hibitor for migraine prevention.Carbonic anhydrase inhibitor. In a single Class IIstudy, acetazolamide 250 mg BID was no moreeffective than placebo in reducing migraine fre-quency, duration, and severity.e1This trial (n ϭ53) was stopped prematurely because of a highnumber of withdrawals (34%), primarily due toacetazolamide-associated AEs, including paresthe-sias and asthenia.Conclusions. The efficacy of acetazolamide is un-known at this time (1 Class II study terminated early).RECOMMENDATIONS Level A. The followingmedications are established as effective and should beoffered for migraine prevention:• Antiepileptic drugs (AEDs): divalproex so-dium, sodium valproate, topiramate• ␤-Blockers: metoprolol, propranolol, timolol• Triptans: frovatriptan for short-term MAMspreventionLevel B. The following medications are probablyeffective and should be considered for migraineprevention:• Antidepressants: amitriptyline, venlafaxine• ␤-Blockers: atenolol, nadolol• Triptans: naratriptan, zolmitriptan for short-term MAMs preventionLevel C. The following medications are possibly effec-tive and may be considered for migraine prevention:• ACE inhibitors: lisinopril• Angiotensin receptor blockers: candesartan• ␣-Agonists: clonidine, guanfacine• AEDs: carbamazepine• ␤-Blockers: nebivolol, pindololLevel U. Evidence is conflicting or inadequate to sup-port or refute the use of the following medicationsfor migraine prevention:• AEDs: gabapentin• Antidepressants• Selective serotonin reuptake inhibitor/selec-tive serotonin-norepinephrine reuptake in-hibitors: fluoxetine, fluvoxamine• Tricyclics: protriptyline• Antithrombotics: acenocoumarol, Coumadin,picotamide• ␤-Blockers: bisoprolol• Calcium-channel blockers: nicardipine, nifedi-pine, nimodipine, verapamil• Acetazolamide• CyclandelateLevel A negative. The following medication is estab-lished as ineffective and should not be offered formigraine prevention:• Lamotrigine1342 Neurology 78 April 24, 2012
  • 10. Level B negative. The following medication is proba-bly ineffective and should not be considered for mi-graine prevention:• ClomipramineLevel C negative. The following medications are pos-sibly ineffective and may not be considered for mi-graine prevention:• Acebutolol• Clonazepam• Nabumetone• Oxcarbazepine• TelmisartanCLINICAL CONTEXT Evidence to support pharma-cologic treatment strategies for migraine preventionindicates which treatments might be effective but isinsufficient to establish how to choose an optimaltherapy. Consequently, although Level A recommen-dations can be made for pharmacologic migraine pre-vention, similar evidence is unavailable to help thepractitioner choose one therapy over another. Treat-ment regimens, therefore, need to be designed caseby case, which may include complex or even nontra-ditional approaches. Moreover, decision-makingmust remain with the physician and the patient todetermine the optimal therapy, accounting for effi-cacy, AEs, coexisting/comorbid conditions, and per-sonal considerations. Often trial and error is needed.Evidence is also unavailable for making broad-rangecomparisons among multiple agents within a singleclass; such evidence would provide a more comprehen-sive understanding of relative efficacy and tolerabilityprofiles across a broader range of therapeutic agents.Studies are needed that specifically evaluate when pre-ventive therapy is warranted and how medicationsshould be titrated. Table e-1 lists some specificconsensus-based clinical circumstances wherein consid-ering preventive therapy would be reasonable. A short-coming of migraine prevention clinical studies is therelatively brief treatment duration (often only 12–16weeks). Long-term assessment of the efficacy and safetyof migraine preventive treatments is needed. Addition-ally, overall cost is a consideration when prescribingmedications; cost may influence compliance, especiallylong-term.It seems reasonable that a clinician be mindful ofcomorbid and coexistent conditions in patients withmigraine, to maximize potential treatment efficacyand minimize AE risk. Table e-2 identifies whichtherapies to consider or avoid when common mi-graine coexisting conditions are present. Because mi-graine is frequent in women of childbearing age, thepotential for adverse fetal effects related to migraineprevention strategies is particularly concerning.Evidence from the 2 Class I frovatriptan studiesmeets the AAN threshold for a Level A recommenda-tion for short-term use to prevent menstrual mi-graine (reduction in MAM headache incidence by26% on 2.5 mg BID). However, the Food and DrugAdministration questions whether the benefit dem-onstrated is clinically meaningful and has not ap-proved frovatriptan for this indication.RECOMMENDATIONS FOR FUTURE RESEARCH Al-though many preventive therapies reviewed hereinare rated as Level C or U on the basis of the quality ofevidence available, for some treatments extensiveclinical experience supports a possible role in mi-graine prevention. Many of the older approaches totreating episodic migraine lack the financial justifica-tion for high-quality clinical study because they arenot currently patentable drugs or otherwise do notpromise a financial return for the cost of a majorstudy. Until such treatments can be accurately stud-ied, practitioners are cautioned not to discount theseagents because Class I prospective clinical studies arelacking. A case-by-case evaluation of these agents astreatment options is prudent. Future directionsshould include validating these initial clinical obser-vations in scientifically sound RCTs.AUTHOR CONTRIBUTIONSDr. Silberstein: manuscript preparation, drafting/revising the manuscript,study concept or design, analysis or interpretation of data, acquisition ofdata, study supervision. Dr. Holland: drafting/revising the manuscript,study concept or design, analysis or interpretation of data. Dr. Freitag:drafting/revising the manuscript, analysis or interpretation of data, acqui-sition of data. Dr. Dodick: drafting/revising the manuscript, study con-cept or design, analysis or interpretation of data. Dr. Argoff: drafting/revising the manuscript, study concept or design, analysis orinterpretation of data. Dr. Ashman: drafting/revising the manuscript,analysis or interpretation of data.DISCLOSUREDr. Silberstein is on the advisory panel of and receives honoraria fromAGA, Allergan, Amgen, Capnia, Coherex, Colucid, Cydex, GlaxoSmith-Kline, Lilly, MAP, Medtronic, Merck, Minster, Neuralieve, NINDS, Nu-Pathe, Pfizer, St. Jude Medical, and Valeant. He is on the speakers’ bureauof and receives honoraria from Endo Pharmaceuticals, GlaxoSmithKline,and Merck. He serves as a consultant for and receives honoraria fromAmgen and Novartis. His employer receives research support from AGA,Allergan, Boston Scientific, Capnia, Coherex, Endo Pharmaceuticals,GlaxoSmithKline, Lilly, MAP, Medtronic, Merck, NINDS, NuPathe, St.Jude Medical, and Valeant Pharmaceuticals. Dr. Holland (formerly Dr.Pearlman) receives consulting income from Map Pharmaceuticals and theAmerican Headache Society and research support from Albert EinsteinCollege of Medicine. Dr. Freitag has served on the scientific advisoryboards of Zogenix Pharmaceuticals, Allergan Pharmaceuticals, Nautilus,MAP Pharmaceuticals, and Nupathe; has received travel expenses and orhonoraria from GlaxoSmithKline, Zogenix, Merck, Nautilus, Allergan,Diamond Headache Clinic Research and Educational Foundation (notfor profit), and the American Headache Society (travel). Dr. Freitag is amember of the Board of Directors of the National Headache Foundation.Dr. Dodick, within the past 3 years, serves on advisory boards and hasconsulted for Allergan, Alder, Pfizer, Merck, Coherex, Ferring, Neuro-core, Neuralieve, Neuraxon, NuPathe Inc., MAP, SmithKlineBeecham,Boston Scientific, Medtronic, Inc., Nautilus, Eli Lilly & Company, No-Neurology 78 April 24, 2012 1343
  • 11. vartis, Colucid, GlaxoSmithKline, Autonomic Technologies, MAP Phar-maceuticals, Inc., Zogenix, Inc., Impax Laboratories, Inc., Bristol MyersSquibb, Nevro Corporation, Atlas, Arteaus, and Alder Pharmaceuticals.Within the past 3 years, Dr. Dodick has received funding for travel, speak-ing, or editorial activities from CogniMed, Scientiae, Intramed, SAGEPublishing, Lippincott Williams & Wilkins, Oxford University Press,Cambridge University Press, Miller Medical, Annenberg for Health Sci-ences; he serves as Editor-in-Chief and on the editorial boards of TheNeurologist, Lancet Neurology, and Postgraduate Medicine; and has servedas Editor-in-Chief of Headache Currents and as an Associate Editor ofHeadache; he receives publishing royalties for Wolff ’s Headache, 8th edi-tion (Oxford University Press, 2009) and Handbook of Headache (Cam-bridge University Press, 2010). Within the past 3 years, Dr. Dodick hasreceived research grant support from Advanced Neurostimulation Sys-tems, Boston Scientific, St Jude Medical, Inc., Medtronic, NINDS/NIH,Mayo Clinic. Dr. Argoff has served on a scientific advisory board for theDepartment of Defense and DSMB for the NIH; has received funding fortravel and/or speaking and/or has served on a speakers’ bureau for Pfizer(King), Janssen (Pricara), Millennium Laboratories, Neurogesx, ForestLaboratories, Eli Lilly, Covidien, and Endo Pharmaceuticals; has receivedresearch support from Endo Pharmaceuticals, Forest Laboratories, EliLilly, Neurogesx, Pfizer, and SBRT funded by the NIH; and has receivedstock/stock options from Pfizer. Dr. Ashman is the Level of Evidenceeditor for Neurology and serves on the AAN Guideline Development Sub-committee. He reports no other disclosures. Full disclosures were pro-vided at the time of Board approval. Go to Neurology.org for fulldisclosures.DISCLAIMERThis statement is provided as an educational service of the AmericanAcademy of Neurology and the American Headache Society. It is basedon as assessment of current scientific and clinical information. It is notintended to include all possible proper methods of care for a particularneurologic problem or all legitimate criteria for choosing to use a specificprocedure. Neither is it intended to exclude any reasonable alternativemethodologies. The AAN and the AHS recognize that specific patientcare decisions are the prerogative of the patient and the physiciancaring for the patient, based on all of the circumstances involved. Theclinical context section is made available in order to place theevidence-based guideline(s) into perspective with current practice hab-its and challenges. No formal practice recommendations should beinferred.CONFLICT OF INTERESTThe American Academy of Neurology and the American Headache Soci-ety are committed to producing independent, critical and truthful clinicalpractice guidelines (CPGs). Significant efforts are made to minimize thepotential for conflicts of interest to influence the recommendations of thisCPG. To the extent possible, the AAN and AHS keep separate those whohave a financial stake in the success or failure of the products appraised inthe CPGs and the developers of the guidelines. Conflict of interest formswere obtained from all authors and reviewed by an oversight committeeprior to project initiation. AAN and AHS limit the participation of au-thors with substantial conflicts of interest. The AAN and AHS forbidcommercial participation in, or funding of, guideline projects. Drafts ofthe guidelines have been reviewed by at least three AAN and AHS com-mittees, a network of neurologists, Neurology peer reviewers, and represen-tatives from related fields. The AAN Guideline Author Conflict ofInterest Policy can be viewed at www.aan.com.Received June 27, 2011. Accepted in final form January 25, 2012.REFERENCES1. Lipton RB, Bigal ME, Diamond M, Freitag F, Reed ML,Stewart WF; The American Migraine Prevalence and Pre-vention Advisory Group. Migraine prevalence, disease bur-den, and the need for preventive therapy. Neurology 2007;68:343–349.2. Ramadan NM, Silberstein SD, Freitag FG, Gilbert TT,Frishberg BM. Evidence-based guidelines for migraineheadache in the primary care setting: pharmacologicalmanagement for prevention of migraine. Available at:http://www.aan.com/professionals/practice/pdfs/gl0090.pdf. Accessed April 10, 1010.3. Silberstein SD. Practice parameter: evidence-based guide-lines for migraine headache (an evidence-based review): re-port of the Quality Standards Subcommittee of theAmerican Academy of Neurology. Neurology 2000;55:754–762.4. Naumann M, So Y, Argoff C, et al. Assessment: Botuli-num neurotoxin in the treatment of autonomic disordersand pain (an evidence-based review): report of the Thera-peutics and Technology Subcommittee of the AmericanAcademy of Neurology. Neurology 2008;70:1707–1714.5. Holland S, Silberstein SD, Freitag F, Dodick DW, ArgoffC, Ashman E. Evidence-based guideline update: NSAIDsand other complementary treatments for episodic migraineprevention in adults: report of the Quality Standards Sub-committee of the American Academy of Neurology andthe American Headache Society. Neurology 2012;78:1346–1353.6. Tronvik E, Stovner LJ, Helde G, Sant T, Bovim G. Pro-phylactic treatment of migraine with an angiotensin II re-ceptor blocker: a randomized controlled trial. JAMA 2003;289:65–69.7. Schrader H, Stovner LJ, Helde G, Sand T, Bovim G. Pro-phylactic treatment of migraine with angiotensin convert-ing enzyme inhibitor (lisinopril): randomised, placebocontrolled, crossover study. BMJ 2001;322:19–22.8. Diener HC, Gendolla A, Feuersenger A, et al. Telmisartanin migraine prophylaxis: a randomized, placebo-controlledtrial. Cephalalgia 2009;29:921–927.9. Freitag FG, Collins SD, Carlson HA, et al. A randomizedtrial of divalproex sodium extended-release tablets in mi-graine prophylaxis. Neurology 2002;58:1652–1659.10. Silberstein SD, Collins SD. Safety of divalproex sodium inmigraine prophylaxis: an open-label, long-term study:long-term safety of Depakote in Headache ProphylaxisStudy Group. Headache 1999;39:633–643.11. Harden CL, Meador KJ, Pennell PB, et al; American Acad-emy of Neurology; American Epilepsy Society. 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  • 12. 16. Ashtari F, Shaygannejad V, Akbari M. A double-blind,randomized trial of low-dose topiramate vs propranolol inmigraine prophylaxis. Acta Neurol Scand 2008;118:301–305.17. Shaygannejad V, Janghorbani M, Ghorbani A, AshtaryF, Zakizade N, Nasr V. Comparison of the effect oftopiramate and sodium valproate in migraine preven-tion: a randomized blinded crossover study. Headache2006;46:642–648.18. Storey JR, Calder CS, Hart DE, Potter DL. Topiramate inmigraine prevention: a double-blind, placebo-controlledstudy. Headache 2001;41:968–975.19. Brandes JL, Saper JR, Diamond M, et al; MIGR-002Study Group. Topiramate for migraine prevention: a ran-domized controlled trial. JAMA 2004;291:965–973.20. Diener HC, Matias-Guiu J, Hartung E, et al. Topiramatein migraine prophylaxis–results from a placebo-controlledtrial with propranolol as an active control. J Neurol 2004;251:943–950.21. Dodick DW, Freitag F, Banks J, et al; CAPSS-277 Investi-gator Group. Topiramate versus amitriptyline in migraineprevention: a 26-wk, multicenter, randomized, double-blind, double-dummy, parallel-group noninferiority trialin adult migraineurs. Clin Ther 2009;31:542–559.22. Keskinbora K, Aydinli I. A double-blind randomized con-trolled trial of topiramate and amitriptyline either alone orin combination for the prevention of migraine. Clin Neu-rol Neurosurg 2008;110:979–984.23. Mei D, Capuano A, Vollono C, et al. Topiramate in mi-graine prophylaxis: a randomised double-blind versus pla-cebo study. Neurol Sci 2004;25:245–250.24. Silberstein SD, Neto W, Schmitt J, Jacobs D; MIGR-001Study Group. Topiramate in migraine prevention: resultsof a large controlled trial. Arch Neurol 2004;61:490–495.25. Milla´n-Guerrero RO, Isais-Milla´n R, Barreto-Vizcaíno S,et al. Subcutaneous histamine versus topiramate in mi-graine prophylaxis: a double-blind study. Eur Neurol2008;59:237–242.26. Silberstein SD, Hulihan J, Karim MR, et al. Efficacy andtolerability of topiramate 200 mg/d in the prevention ofmigraine with/without aura in adults: a randomized,placebo-controlled, double-blind, 12-week pilot study.Clin Ther 2006;28:1002–1011.27. Adly C, Straumanis J, Chesson A. Fluoxetine prophylaxisof migraine. Headache 1992;32:101–104.28. Saper JR, Silberstein SD, Lake AE III, Winters ME.Double-blind trial of fluoxetine: chronic daily headacheand migraine. Headache 1994;34:497–502.29. d’Amato CC, Pizza V, Marmolo T, Giordano E, Alfano V,Nasta A. Fluoxetine for migraine prophylaxis: a double-blind trial. Headache 1999;39:716–719.30. Ozyalcin SN, Talu GK, Kiziltan E, Yucel B, Ertas M, DisciR. The efficacy and safety of venlafaxine in the prophylaxisof migraine. Headache 2005;45:144–152.31. Bulut S, Berilgen MS, Baran A, Tekatas A, Atmaca M,Mungen B. Venlafaxine versus amitriptyline in the pro-phylactic treatment of migraine: randomized, double-blind, crossover study. Clin Neurol Neurosurg 2004;107:44–48.32. Diener HC, Hartung E, Chrubasik J, et al. A comparativestudy of oral acetylsalicylic acid and metoprolol for theprophylactic treatment of migraine: a randomized, con-trolled, double-blind, parallel group phase III study. Ceph-alalgia 2001;21:120–128.33. Schellenberg R, Lichtenthal A, Wo¨hling H, Graf C,Brixius K. Nebivolol and metoprolol for treating migraine:an advance on beta-blocker treatment? Headache 2008;48:118–125.34. Rao BS, Das DG, Taraknath VR, Sarma Y. A double blindcontrolled study of propranolol and cyproheptadine in mi-graine prophylaxis. Neurol India 2000;48:223–226.35. Diener HC, Krupp P, Schmitt T, Steitz G, Milde K,Freytag S; on behalf of the Study Group. Cyclandelate inthe prophylaxis of migraine: a placebo-controlled study.Cephalalgia 2001;21:66–70.36. Siniatchkin M, Gerber WD, Vein A. Clinical efficacy andcentral mechanisms of cyclandelate in migraine: a double-blind placebo-controlled study. Funct Neurol 1998;13:47–56.37. Silberstein SD, Elkind AH, Schreiber C, Keywood C. Arandomized trial of frovatriptan for the intermittent pre-vention of menstrual migraine. Neurology 2004;63:261–269.38. Brandes JL, Poole A, Kallela M, et al. Short-term fro-vatriptan for the prevention of difficult-to-treat menstrualmigraine attacks. Cephalalgia 2009;29:1133–1148.39. Newman L, Mannix LK, Landy S, et al. Naratriptan asshort-term prophylaxis of menstrually associated migraine:a randomized, double-blind, placebo-controlled study.Headache 2001;41:248–256.40. Tuchman MM, Hee A, Emeribe U, Silberstein S. Oralzolmitriptan in the short-term prevention of menstrual mi-graine: a randomized, placebo-controlled study. CNSDrugs 2008;22:877–886.Endorsed by the American Osteopathic Association on March 22, 2012.Neurology 78 April 24, 2012 1345
  • 13. Evidence-based guideline update: NSAIDs andother complementary treatments for episodicmigraine prevention in adultsReport of the Quality Standards Subcommittee of the American Academy ofNeurology and the American Headache SocietyS. Holland, PhDS.D. Silberstein, MD,FACPF. Freitag, DOD.W. Dodick, MDC. Argoff, MDE. Ashman, MDABSTRACTObjective: To provide updated evidence-based recommendations for the preventive treatment ofmigraine headache. The clinical question addressed was: Are nonsteroidal anti-inflammatorydrugs (NSAIDs) or other complementary treatments effective for migraine prevention?Methods: The authors analyzed published studies from June 1999 to May 2009 using a struc-tured review process to classify the evidence relative to the efficacy of various medications formigraine prevention.Results: The author panel reviewed 284 abstracts, which ultimately yielded 49 Class I or Class IIarticles on migraine prevention; of these 49, 15 were classified as involving nontraditional thera-pies, NSAIDs, and other complementary therapies that are reviewed herein.Recommendations: Petasites (butterbur) is effective for migraine prevention and should beoffered to patients with migraine to reduce the frequency and severity of migraine attacks(Level A). Fenoprofen, ibuprofen, ketoprofen, naproxen, naproxen sodium, MIG-99 (feverfew),magnesium, riboflavin, and subcutaneous histamine are probably effective for migraine pre-vention (Level B). Treatments considered possibly effective are cyproheptadine, Co-Q10, es-trogen, mefenamic acid, and flurbiprofen (Level C). Data are conflicting or inadequate tosupport or refute use of aspirin, indomethacin, omega-3, or hyperbaric oxygen for migraineprevention. Montelukast is established as probably ineffective for migraine prevention (LevelB). Neurology®2012;78:1346–1353GLOSSARYAAN ϭ American Academy of Neurology; AE ϭ adverse effect; CI ϭ confidence interval; HBO ϭ hyperbaric oxygen; NSAID ϭnonsteroidal anti-inflammatory drug; OR ϭ odds ratio; RR ϭ relative risk.Epidemiologic studies suggest approximately 38%of migraineurs need preventive therapy, but only3%–13% currently use it.1In 2000, the AmericanAcademy of Neurology (AAN) published guide-lines for migraine prevention.2,3Since then, newclinical studies have been published on the efficacyand safety of migraine preventive therapies. Thisguideline seeks to assess this new evidence to an-swer the following clinical question: For patientswith migraine, which anti-inflammatory or com-plementary treatments are effective for prevention,as measured by reduced migraine attack frequency,reduced number of migraine days, or reduced at-tack severity? This article addresses the efficacyand safety of histamines/antihistamines; non-steroidal anti-inflammatory drugs (NSAIDs) andanalgesics; and several herbal, vitamin, and min-eral preparations, whereas a companion article ad-dresses standard pharmacologic treatments formigraine prevention.4DESCRIPTION OF THE ANALYTIC PROCESSThe AAN and the American Headache Society par-ticipated in the development process. An authorSee page 1337Supplemental data atwww.neurology.orgSupplemental DataPodcastCMECorrespondence & reprintrequests to American Academyof Neurology:guidelines@aan.comFrom the Armstrong Atlantic State University (S.H.), Savannah, GA; Thomas Jefferson University (S.D.S.), Jefferson Headache Center, Philadelphia,PA; Comprehensive Headache Center (F.F.), Baylor University Headache Medicine Center, Dallas, TX; Mayo Clinic (D.D.), Scottsdale, AZ; NewYork University School of Medicine (C.A.), Albany; and Elmendorf Air Force Base (E.A.), AK.Appendices e-1–e-5 and tables e-1 and e-2 are available on the Neurology௡ Web site at www.neurology.org.Approved by the Quality Standards Subcommittee on February 19, 2011; by the Practice Committee on June 19, 2011; by the AHS Board ofDirectors on March 29, 2012; and by the AAN Board of Directors on November 7, 2011.Study funding: This guideline was developed with financial support from the American Academy of Neurology and the American Headache Society.None of the authors received reimbursement, honoraria, or stipends for their participation in the development of this guideline.Go to Neurology.org for full disclosures. Disclosures deemed relevant by the authors, if any, are provided at the end of this article.SPECIAL ARTICLE1346 Copyright © 2012 by AAN Enterprises, Inc.
  • 14. panel of headache and methodologic experts was as-sembled to review the evidence.Computerized searches of the MEDLINE, Psyc-INFO, and CINAHL databases identified newstudies. The search strategy used the MeSH term“headache” (exploded) and a published search strat-egy for identifying randomized controlled trials inadults that were published in English between June1999 and May 2007. Additional MEDLINEsearches revealed studies published through May2009, which were reviewed and are included as sup-plemental articles.Studies of NSAIDs and complementary treat-ments available in the United States were included inthe analysis if they randomized patients with mi-graine to the agent under study or a comparatortreatment (including placebo) and utilized masked(blinded) outcome assessment. At least 2 panelistsindependently reviewed each selected study and ratedit using the AAN therapeutic classification of evi-dence scheme (appendix e-3 on the Neurology®Website at www.neurology.org). Differences in ratingswere resolved by author panel discussion.ANALYSIS OF EVIDENCE The original searchidentified 179 articles and included pharmacologicand complementary treatments and NSAIDs. Thesupplemental search from 2007 to 2009 yielded anadditional 105 articles. Of the total 284 articles, 15were classified as Class I or Class II and identified asrelating to NSAIDs and complementary treatments;they are reviewed herein. Clinical studies reviewedwere limited to those assessing efficacy of NSAIDsand complementary treatments for prevention of ep-isodic migraine in adults (e.g., Ͻ15 days/month).Studies were excluded if they assessed the efficacy oftherapeutic agents for prevention or treatment ofchronic migraine, intractable migraine, tension-typeheadache, or headache in adolescents or children.Also excluded were studies that assessed acute mi-graine treatment, migraine aura treatment or preven-tion, or nonpharmacologic treatments. Studies usingquality of life measures, disability assessment, ornonstandardized outcomes as primary efficacy end-points were not included. NSAIDs and complemen-tary treatments not commonly or readily available inthe United States are not reviewed in this guideline.Since the 2000 guideline publication, the AANrevised its evidence classification criteria to includestudy completion rates. Studies whose completionrates are below 80% were downgraded.We found no additional Class I or Class II studiespublished since the original guideline for fenoprofen,ibuprofen, ketoprofen, naproxen, naproxen sodium,or indomethacin. Recommendations regarding thesetreatments are based on the evidence reviewed in theoriginal guideline (denoted in table 1).Following is a summary of Class I and Class IIevidence for the efficacy of NSAIDs and comple-Table 1 Classification of migraine preventive therapies (available in the United States)Level A: Medicationswith establishedefficacy (>2 Class Itrials)Level B: Medicationsare probablyeffective (1 Class Ior 2 Class II studies)Level C: Medicationsare possiblyeffective (1 Class IIstudy)Level U: Inadequateor conflicting datato support or refutemedication useOther: Medications thatare established aspossibly or probablyineffectiveHerbal preparations,vitamins, minerals,and otherNSAIDs NSAIDs NSAIDs Probably not effectivePetasites FenoprofenaFlurbiprofenaAspirin Leukotriene receptorantagonistIbuprofenaMefenamic acidaIndomethacinaMontelukastKetoprofenaHerbal preparationsvitamins, minerals,and otherHerbal preparationsvitamins, minerals,and otherNaproxenaCo-Q10 Omega-3Naproxen sodiumaEstrogen OtherHerbal preparations,vitamins, minerals,and otherAntihistamine HyperbaricoxygenMagnesium CyproheptadineMIG-99 (feverfew)RiboflavinHistaminesHistamine SCAbbreviation: NSAID ϭ nonsteroidal anti-inflammatory drug.aIndicates classification based on original guideline and new evidence not found for this report.Neurology 78 April 24, 2012 1347
  • 15. mentary treatments for migraine prevention. Assess-ment of relative safety and tolerability of these agentsas compared with placebo or other active treatmentsfalls outside the scope of this efficacy assessment, butgeneral information regarding safety and tolerability isincluded. Additionally, efficacy results from the sum-marized trials may be dependent on study design, in-cluding study duration (8 weeks vs 6 months),medication doses (low vs high), and dosing regimensand titrations—all of which may influence efficacy on-set, relative efficacy, and quality of the evidence.Histamines/antihistamines/leukotriene receptor an-tagonists. In the 2000 guideline, there were no stud-ies of histamines, antihistamines, or leukotrienereceptor antagonists for migraine prevention. Sincethat publication, several studies of histamine, cypro-heptadine, and montelukast have been performed.Histamine. Three Class II single-center studies (allfrom the same center) show the efficacy of histaminefor migraine prevention.5–7N-alpha-methyl hista-mine (1–10 ng 2 times/week) SC injections reducedattack frequency from baseline as compared with pla-cebo.5Headache frequency at 4 weeks was reducedfrom 3.8 to 0.5 in the histamine group, as comparedwith reduction from 3.6 to 2.9 attacks for placebo(p Ͻ 0.0001). Histamine was statistically superior toplacebo at all treatment visits through 12 weeks forreduction in migraine frequency, severity, and dura-tion (p Ͻ 0.0001). Transient itching at the injectionsites was the only reported adverse effect (AE), but itdid not reach significance.In a second Class II study, histamine was shownto be as effective as sodium valproate in reducingattack frequency and better than sodium valproate inreducing headache duration and intensity.6Specifi-cally, both sodium valproate 500 mg/day and hista-mine (1–10 ng 2 times/week) SC injectionsimproved headache frequency, duration, and inten-sity as early as 8 weeks following treatment whencompared with baseline (p Ͻ 0.05). No patients onhistamine presented with AEs. Conversely, 37% ofpatients on sodium valproate experienced nausea,34% had tremor, 24% had weight gain, and 12%had alopecia.A third study reported the efficacy of histamine inmigraine prevention as compared with topiramate.Topiramate 100 mg/day was compared with hista-mine (1–10 ng 2 times/week SC), and both activetreatments showed improvement over baseline mea-sures for attack frequency, intensity, and use of res-cue medication.7Eleven percent (5/45) of subjectstreated with histamine withdrew from the hista-mine group because they were not satisfied withthe speed of results, although no AEs were re-ported. Few subjects reported transitory burningand itching at the injection site. Similar AEs andwithdrawal rates (for slow reaction speed) were re-ported for the sodium valproate study.6HistamineSC was associated with transitory burning anditching at the injection site.Cyproheptadine. A single Class II study (describedin the companion guideline) showed cyproheptadine(4 mg/day) was as effective as propranolol (80 mg/day) in reducing migraine frequency and severity.8Montelukast. One Class I study of montelukast (20mg) for migraine prevention reported no significantdifference between treatments in the percentage ofpatients with a Ն50% decrease in migraine attackfrequency per month (15.4% for montelukast vs10.3% for placebo [odds ratio (OR) ϭ 1.64; confi-dence interval (CI) 0.64–4.20]).9As compared withthe placebo group, the montelukast group reportedno differences in incidence, frequency, or severity ofAEs in this 3-month treatment phase.Conclusions. Histamine SC is established as proba-bly effective (3 Class II studies) for migraine preven-tion. Cyproheptadine is possibly effective formigraine prevention and possibly as effective as pro-pranolol for migraine prevention (single Class IIstudy). Montelukast is probably ineffective for mi-graine prevention (1 Class I study; table 1).NSAIDs. The efficacy of NSAIDs for migraine pre-vention was reported in the original guideline, in-cluding 23 controlled trials of 10 different NSAIDsthat showed a modest but significant benefit fornaproxen sodium, with similar trends for flurbipro-fen, ketoprofen, and mefenamic acid. In the absenceof new clinical reports, recommendations for NSAIDuse for migraine prevention are based on data fromthe original guideline. Regarding aspirin, new clini-cal evidence is available and included herein.Aspirin. In the original guideline, studies of aspi-rin were found to have conflicting results. Sincethe original report, 2 additional Class II studieshave been reported. As summarized in the com-panion article, aspirin was found to be as effectiveas metoprolol for migraine prevention.10In a sec-ond study, aspirin 100 mg in combination withvitamin E 600 IU every other day was comparedwith placebo in combination with vitamin E.11Nodifferences were noted between aspirin and pla-cebo treatments for migraine frequency or severityat 12 months or 36 months.Conclusions. The efficacy of aspirin for migraine pre-vention is unknown (conflicting Class II studies;table 1).Clinical context. Regular or daily use of selectedNSAIDs for the treatment of frequent migraine at-tacks may exacerbate headache because of develop-ment of a condition called medication overuse1348 Neurology 78 April 24, 2012
  • 16. headache.12Therefore, use of aspirin, selected analge-sics, and NSAIDs may exacerbate headache; use ofthese agents in migraine prevention studies may con-found the clinical interpretation of the study results.Herbal preparations, vitamins, minerals, and other in-terventions. Since the original guideline, additionalstudies have been identified that assess the efficacy ofCo-Q10, estrogen, hyperbaric oxygen (HBO), mag-nesium, MIG-99, omega-3, Petasites, and riboflavinfor migraine prevention.Co-Q10 (water-soluble disbursable form of Co-Q10).One small Class II study showed that Co-Q10 100mg TID was significantly more effective than pla-cebo in reducing attack frequency from baseline to 4months following treatment.13The 50% responderrate for attack frequency (Ն50% reduction) was47.6% for CoQ10 vs 14.3% for placebo (p ϭ 0.02).The actual reduction in attack frequency wasϪ1.9 Ϯ 1.9 for CoQ10 and 0.09 Ϯ 1.9 for placebo(p ϭ 0.05). One patient withdrew from the Co-Q10treatment group because of cutaneous allergy.Estrogen. A combination of soy isoflavones (60mg), dong quai (100 mg), and black cohosh (50 mg)(each component standardized to its primary alka-loid) reduced migraine attack frequency vs placebo ina small Class II study.14The mean frequency of men-strually associated migraine attacks during weeks9–24 was reduced from 10.3 Ϯ SEM 2.4 in patientstreated with placebo to 4.7 Ϯ SEM 1.8 (p Ͻ 0.01) inpatients treated with the phytoestrogen preparation.In a second Class II trial, percutaneous estradiolwas applied 6 days before the first full day of bleedingup to and including the second full day of menstrua-tion.15Estradiol 1.5 mg (gel patch applied to the up-per thigh or arm) was associated with a 22%reduction in migraine days (estradiol ϭ 133 mi-graine days, placebo ϭ 171 migraine days; relativerisk [RR] 0.78; CI 0.62–0.99, p ϭ 0.04). This im-provement was temporary, as subjects reported a40% increase in migraine days in the 5 days followingtreatment (RR 1.40; CI 1.03–1.92, p ϭ 0.03). No seri-ous AEs were otherwise reported, although commonrisks associated with estrogen supplementation are welldocumented throughout the literature. Limited studiesare available regarding estrogen’s safety specifically forlong-term use in migraine prevention.Hyperbaric oxygen. In a single Class II study, nodifferences were found between the HBO group (330-minute treatments/week) and control group, butan increase in headache hours was experienced byboth groups vs the pretreatment level.16Correctedfor the number of days, the increase was 6.9 hours/week for HBO vs 4.7 hours/week for controls. Thisstudy reports no assessment of tolerability or safety ofHBO vs control for migraine prevention.Magnesium. In the original guideline, magnesiumwas found to be probably effective for migraine pre-vention on the basis of 2 positive Class II studies and1 negative Class III study. Since the 2000 report, 1additional Class II study compared the combinationof magnesium (300 mg), riboflavin (400 mg), andMIG-99 (100 mg) with placebo (25 mg of ribofla-vin, which was thought to be a subtherapeutic dosebut sufficient to provide urine discoloration to pre-vent unblinding of the study).17Both treatmentgroups showed improvement over baseline, but nobetween-group differences were noted (42% re-sponders [defined as Ն50% reduction in attacks] intreatment group and 44% in placebo group; p ϭ0.87). The study was not powered to show between-group differences and involved administration ofmagnesium only as combination therapy; thus, theresults cannot be clearly interpreted regarding the ef-ficacy of magnesium for migraine prevention. AEswere not reported.MIG-99. MIG-99 is a relatively new stable extractof tanacetum parthenium (feverfew), which is repro-ducibly manufactured with supercritical CO2 fromfeverfew. In the original guideline, 3 positive studiesand 1 negative study (feverfew given as alcohol ex-tract) are reviewed that suggest possible efficacy formigraine prevention. Since the original guideline, 3new studies on MIG-99 for migraine prophylaxis havebeen published. In 1 Class I study, the migraine fre-quency decreased from 4.76 by 1.9 attacks/month inthe MIG-99 group and by 1.3 attacks in the placebogroup (p Ͻ 0.05). A logistic regression analysis of re-sponder rates showed an OR of 3.4 in favor of MIG-99(p Ͻ 0.005).18AEs reported were similar to those fromplacebo, the most common being gastrointestinal sys-tem disorders or respiratory system disorders.In a Class II dose-finding study, MIG-99 6.25 mgTID (other doses tested: 2.08 and 18.75 mg TID)was effective in reducing migraine frequency by 1.8attacks/month (baseline ϭ 4.5 Ϯ 0.8 to 3.0 Ϯ 1.5attacks at week 12). The placebo group reduced mi-graine frequency by 0.3 attacks/month (baseline ϭ4.9 Ϯ 0.9 to 4.6 Ϯ 2.2 attacks at week 12; p ϭ 0.02,CI 1.07–2.49).19In a second Class II study, described above formagnesium, the efficacy of the combination of mag-nesium (300 mg), riboflavin (400 mg), and MIG-99(100 mg) was not shown in comparison with a pla-cebo (25 mg of riboflavin).17Omega-3. One Class I study assessed the efficacy ofomega-3 polyunsaturated fatty acids (3 g BID) vsplacebo and found no difference in mean number ofattacks during the last 4 weeks of the study (month4), but the total number of attacks in 4 months wasNeurology 78 April 24, 2012 1349
  • 17. lower in the omega-3 treatment group.20A verystrong placebo effect was observed in this trial: 45%reduction of attacks between run-in and 4-monthtreatment period for placebo as compared with 55%in the omega-3 group (p ϭ 0.058). AEs associatedwith omega-3 treatment included significantly morefrequent eructation (8%) than with placebo (1%);otherwise, no differences in AEs between treatmentswere reported.Petasites. Petasites is a purified extract from thebutterbur plant. Two Class I studies show Petasites(50–75 mg BID) to be effective in reducing migraineattack frequency.21,22In the first study, the frequencyof migraine attacks decreased by a maximum of 60%vs baseline, and the reduction in the number of mi-graine attacks vs placebo was significant (p Յ0.05).21Petasites reduced the frequency of attacksfrom 3.3 Ϯ 1.5 to 1.8 Ϯ 0.8 attacks/month after 4weeks, to 1.3 Ϯ 0.9 attacks/month after 8 weeks, andto 1.7 Ϯ 0.9 attacks/month after 12 weeks (p Յ0.05). Following placebo, attack frequency decreasedfrom 2.9 Ϯ 1.2 to 2.2 Ϯ 0.7 after 4 weeks (p Յ0.05), to 2.4 Ϯ 0.8 after 8 weeks (p Յ 0.05), and to2.6 Ϯ 1.1 after 12 weeks (p Յ 0.05). No AEs werereported.In the second Class I study, migraine attack fre-quency was reduced by 48% for Petasites extract 75mg BID (p ϭ 0.0012 vs placebo), by 36% for Peta-sites extract 50 mg BID (p ϭ 0.127 vs placebo), andby 26% for the placebo group.22The incidence ofburping increased for Petasites extract 75 mg or 50mg vs placebo. Importantly, safety of prolonged useof Petasites is not established by the short-term stud-ies included in this review.Riboflavin. In the original guideline, 1 Class Itrial reported riboflavin to be superior to placebo,suggesting probable efficacy for migraine preven-tion. Since then, 1 additional Class II study (re-viewed above) failed to show the efficacy of thecombination of magnesium (300 mg), riboflavin(400 mg), and MIG-99 (100 mg) vs 25 mg ofriboflavin.16CONCLUSIONS• Petasites is established as effective for migraineprevention (2 Class I studies).• Riboflavin is probably effective for migraineprevention (1 Class I trial and 1 imprecise ClassII study).• Co-Q10 is possibly effective for migraine pre-vention (1 Class II study).• A combination of soy isoflavones (60 mg),dong quai (100 mg), and black cohosh (50mg) is possibly effective for migraine preven-tion (1 Class II study). Percutaneous estra-diol is possibly effective for migraineprevention (1 Class II study); however, thereis an increased risk of migraine recurring af-ter estradiol patch discontinuation.• Magnesium is probably effective for migraineprevention (multiple Class II trials). MIG-99(feverfew) is probably effective for migraineprevention (1 Class I study, 1 positive Class IIstudy, and 1 underpowered negative Class IIstudy).• The efficacy of HBO for migraine prevention isunclear (1 imprecise negative Class II study).• The efficacy of omega-3 for migraine preven-tion is unclear (1 imprecise Class I study).RECOMMENDATIONS Level A. The followingtherapy is established as effective and should be of-fered for migraine prevention:• Petasites (butterbur)Level B. The following therapies are probably effectiveand should be considered for migraine prevention:• NSAIDS: fenoprofen, ibuprofen, ketoprofen,naproxen, naproxen sodium• Herbal therapies, vitamins, and minerals: ribo-flavin, magnesium, MIG-99 (feverfew)• Histamines: histamine SCLevel C. The following therapies are possibly effectiveand may be considered for migraine prevention:• NSAIDs: flurbiprofen, mefenamic acid• Herbal therapies, vitamins, and minerals: Co-Q10, estrogen• Antihistamines: cyproheptadineLevel U. Evidence is inadequate or conflicting to sup-port or refute the use of the following therapies formigraine prevention:• NSAIDs: aspirin, indomethacin• Herbal therapies, vitamins, and minerals:omega-3• Other: HBOLevel B negative. The following therapy is probablyineffective and should not be considered for migraineprevention:• Leukotriene receptor antagonists: montelukastCLINICAL CONTEXT In a previous epidemiologicstudy, 38.7% of study participants had ever used amigraine preventive treatment, of which only 12.4%were current users and 17.2% were coincident users(taking a migraine preventive treatment for otherreasons).23The proportion of those who use NSAIDsor individual complementary treatments specifically1350 Neurology 78 April 24, 2012
  • 18. for migraine prevention is unclear at this time, and isa topic which warrants further study. Additionally,the treatments reviewed herein are those available inthe United States. In other countries, treatments maynot be available commercially or may be available inother dosages or in other preparations or combina-tions. Therefore, the results from this and otherguidelines are limited to those treatments available inthe United States.Additionally, studies assessing the efficacy ofNSAIDs and complementary treatments for migraineprevention are limited and should be considered relativeto other available pharmacologic therapies reviewed in aseparate guideline.4Silberstein and colleagues report di-valproex sodium, sodium valproate, topiramate, meto-prolol, propranolol, and timolol are effective formigraine prevention and should be offered to patientswith migraine to reduce migraine attack frequency andseverity (Level A).Additionally, the clinical evidence for NSAIDsand complementary treatments for migraine preven-tion should be reviewed with caution because thereare clear discrepancies in how patients were selectedfor study inclusion; how severe, frequent, or dis-abling their attacks were; and how severity was as-sessed. Also, these treatments are unregulated. Thereare few or no studies on how these medicationsshould be taken—specifically relative to dosing strat-egies and coadministration with other prescriptionpharmacologic treatments. When patients are in-structed or choose to take NSAIDs or complemen-tary treatments for migraine prevention, it isimportant that they be followed over the course oftreatment so dosing and titration modifications andAE risk can be monitored. Prospective long-termsafety of many of these agents is not well studiedspecifically regarding their use as preventive migrainetreatments.It is reasonable also for clinicians to inquire aboutthe doses being used and frequency of use of NSAIDsand complementary treatments. Frequent medica-tion use or high dose levels may increase the risk ofheadache progression or medication overuse, whichmay lead to other secondary health complications(e.g., gastrointestinal upset/bleeding with aspirin orNSAIDs or headache rebound with discontinuationof feverfew). Complete review and disclosure of coex-isting conditions are warranted, as complementary orpharmacologic therapies taken for coexisting condi-tions (e.g., depression) may exacerbate headache. Be-cause migraine is frequent in women of childbearingage, the potential for adverse fetal effects related tomigraine prevention strategies is of particular con-cern. Little has been done to establish the long-termsafety and efficacy of these agents during pregnancyor breastfeeding.Additionally, when patients have unlimited accessto over-the-counter medications, they may be un-aware of the continued need for routine physicianfollow-up for a chronic illness such as migraine, asillness severity may progress or improve, often war-ranting medication changes (see table e-1). It also isimportant for patients to understand the magnitudeof benefit that can be expected from preventive mi-graine therapies; moreover, patient education aboutmigraine and appropriate management is importantin successful patient care. For some patients, a 35%reduction in headache frequency or intensity may bedeemed an insufficient level of improvement, thusleading them to risk dose escalation. Additionally,patients with migraine may need to be educatedabout appropriate use and risks of these agents.Finally, recent studies suggest that some medica-tions used for migraine may offer long-term protec-tion against headache progression whereas otheragents may elevate progression risk. Specifically, oneepidemiologic study assessing medication use in thegeneral migraine population reports that aspirin oribuprofen use may protect against progression fromepisodic to chronic headache conditions.24In con-trast, opioid use was positively associated withchronic headache conditions. Although conclusionsare preliminary regarding the benefits and risks ofselected agents for long-term use, studies suggest thatthese agents may play a significant role in headacheprogression and patterns, lending further emphasisto the importance of following patients closely, in-cluding regular assessment of NSAIDs, and othercomplementary treatments for migraine prevention.RECOMMENDATIONS FOR FUTURE RESEARCH Lit-tle is known about many of the NSAIDs and com-plementary treatments reviewed in this guideline;therefore, additional studies are needed to furtherunderstand the optimal doses of these migraine pre-vention treatments. Additionally, many of thesetreatments are readily available but not for migraineprevention, so little is known about increased AErisks when treatments are used one or more timesdaily for migraine prevention. More studies areneeded that further assess the relative efficacy of thesetreatments in relation to other pharmacologic thera-pies. Other shortcomings of the existing evidence be-came apparent during this review and analysis, andseveral areas worthy of future investigation may in-clude the following:• Acceptability, long-term use, safety, and effec-tiveness of specific preventive therapiesNeurology 78 April 24, 2012 1351
  • 19. • Use of combination therapies, including drugtherapy with behavioral treatment or combina-tions of 2 or more drugs• Best duration for giving preventive treatmentand how to discontinue treatment• Predictors of remission with or response to pre-ventive treatment• Treatment of migraine and associated commoncomorbidities (e.g., depression, obesity, epi-lepsy, hypertension) and use of specific mono-therapies or combination therapies in thesepatient subpopulations• Development of stepped care and other treat-ment strategies for particular migraine head-ache types or particular migraine patientsubgroups• Compliance with preventive therapies• Value of follow-up and patient education indisease management• Use of preventive therapies to prevent illnessprogression (to chronic migraine)• Effect of preventive treatments on acute ther-apy effectiveness• The role of acute medication overuse in limit-ing the therapeutic efficacy of migraine preven-tive therapies• Prospective trials that investigate standardizedoutcomesAUTHOR CONTRIBUTIONSDr. Holland: manuscript preparation, drafting/revising the manuscript,study concept or design, analysis or interpretation of data. Dr. Silberstein:drafting/revising the manuscript, study concept or design, analysis or in-terpretation of data, study supervision. Dr. Freitag: drafting/revising themanuscript, analysis or interpretation of data, acquisition of data. Dr.Dodick: drafting/revising the manuscript, study concept or design, analy-sis or interpretation of data. Dr. Argoff: drafting/revising the manuscript,study concept or design, analysis or interpretation of data. Dr. Ashman:drafting/revising the manuscript, analysis or interpretation of data.DISCLOSUREDr. Holland (formerly Dr. Pearlman) receives consulting income fromMap Pharmaceuticals and the American Headache Society and researchsupport from Albert Einstein College of Medicine. Dr. Silberstein is onthe advisory panel of and receives honoraria from AGA, Allergan, Amgen,Capnia, Coherex, Colucid, Cydex, GlaxoSmithKline, Lilly, MAP,Medtronic, Merck, Minster, Neuralieve, NINDS, NuPathe, Pfizer, St.Jude Medical, and Valeant. He is on the speakers’ bureau of and receiveshonoraria from Endo Pharmaceuticals, GlaxoSmithKline, and Merck. Heserves as a consultant for and receives honoraria from Amgen and Novartis.His employer receives research support from AGA, Allergan, Boston Scien-tific, Capnia, Coherex, Endo Pharmaceuticals, GlaxoSmithKline, Lilly,MAP, Medtronic, Merck, NINDS, NuPathe, St. Jude Medical, and Vale-ant Pharmaceuticals. Dr. Freitag has served on the scientific advisoryboards of Zogenix Pharmaceuticals, Allergan Pharmaceuticals, Nautilus,MAP Pharmaceuticals, and Nupathe; has received travel expenses and orhonoraria from GlaxoSmithKline, Zogenix, Merck, Nautilus, Allergan,Diamond Headache Clinic Research and Educational Foundation (notfor profit), and the American Headache Society (travel). Dr. Freitag is amember of the Board of Directors of the National Headache Foundation.Dr. Dodick, within the past 3 years, serves on advisory boards and hasconsulted for Allergan, Alder, Pfizer, Merck, Coherex, Ferring, Neuro-core, Neuralieve, Neuraxon, NuPathe Inc., MAP, SmithKlineBeecham,Boston Scientific, Medtronic, Inc., Nautilus, Eli Lilly & Company, No-vartis, Colucid, GlaxoSmithKline, Autonomic Technologies, MAP Phar-maceuticals, Inc., Zogenix, Inc., Impax Laboratories, Inc., Bristol MyersSquibb, Nevro Corporation, Atlas, Arteaus, and Alder Pharmaceuticals.Within the past 3 years, Dr. Dodick has received funding for travel, speak-ing, or editorial activities from CogniMed, Scientiae, Intramed, SAGEPublishing, Lippincott Williams & Wilkins, Oxford University Press,Cambridge University Press, Miller Medical, Annenberg for Health Sci-ences; he serves as Editor-in-Chief and on the editorial boards of TheNeurologist, Lancet Neurology, and Postgraduate Medicine; and has servedas Editor-in-Chief of Headache Currents and as an Associate Editor ofHeadache; he receives publishing royalties for Wolff ’s Headache, 8th edi-tion (Oxford University Press, 2009) and Handbook of Headache (Cam-bridge University Press, 2010). Within the past 3 years, Dr. Dodick hasreceived research grant support from Advanced Neurostimulation Sys-tems, Boston Scientific, St Jude Medical, Inc., Medtronic, NINDS/NIH,Mayo Clinic. Dr. Argoff has served on a scientific advisory board for theDepartment of Defense and DSMB for the NIH; has received funding fortravel and/or speaking and/or has served on a speakers’ bureau for Pfizer(King), Janssen (Pricara), Millennium Laboratories, Neurogesx, ForestLaboratories, Eli Lilly, Covidien, and Endo Pharmaceuticals; has receivedresearch support from Endo Pharmaceuticals, Forest Laboratories, EliLilly, Neurogesx, Pfizer, and SBRT funded by the NIH; and has receivedstock/stock options from Pfizer. Dr. Ashman is the Level of Evidenceeditor for Neurology and serves on the AAN Guideline Development Sub-committee. He reports no other disclosures. Full disclosures were pro-vided at the time of Board approval. Go to Neurology.org for fulldisclosures.DISCLAIMERThis statement is provided as an educational service of the American Academyof Neurology and the American Headache Society. It is based on as assess-ment of current scientific and clinical information. It is not intended to in-clude all possible proper methods of care for a particular neurologic problemor all legitimate criteria for choosing to use a specific procedure. Neither is itintended to exclude any reasonable alternative methodologies. The AAN andthe AHS recognize that specific patient care decisions are the prerogative ofthe patient and the physician caring for the patient, based on all of the circum-stances involved. The clinical context section is made available in order toplace the evidence-based guideline(s) into perspective with current practicehabits and challenges. No formal practice recommendations should beinferred.CONFLICT OF INTERESTThe American Academy of Neurology and the American Headache Soci-ety are committed to producing independent, critical and truthful clinicalpractice guidelines (CPGs). Significant efforts are made to minimize thepotential for conflicts of interest to influence the recommendations of thisCPG. To the extent possible, the AAN and AHS keep separate those whohave a financial stake in the success or failure of the products appraised inthe CPGs and the developers of the guidelines. Conflict of interest formswere obtained from all authors and reviewed by an oversight committeeprior to project initiation. AAN and AHS limit the participation of au-thors with substantial conflicts of interest. The AAN and AHS forbidcommercial participation in, or funding of, guideline projects. Drafts ofthe guidelines have been reviewed by at least three AAN and AHS com-mittees, a network of neurologists, Neurology peer reviewers, and represen-tatives from related fields. The AAN Guideline Author Conflict ofInterest Policy can be viewed at www.aan.com.Received June 27, 2011. Accepted in final form October 26, 2011.REFERENCES1. Lipton RB, Bigal ME, Diamond M, Freitag F, Reed ML,Stewart WF; The American Migraine Prevalence and Pre-vention Advisory Group. Migraine prevalence, disease bur-den, and the need for preventive therapy. Neurology 2007;68:343–349.1352 Neurology 78 April 24, 2012
  • 20. 2. Ramadan NM, Silberstein SD, Freitag FG, Gilbert TT,Frishberg BM. Evidence-based guidelines for migraineheadache in the primary care setting: pharmacologicalmanagement for prevention of migraine. Available at:http://www.aan.com/professionals/practice/pdfs/gl0090.pdf. Accessed April 10, 2010.3. Silberstein SD. Practice parameter: evidence-based guidelinesfor migraine headache (an evidence-based review): report ofthe Quality Standards Subcommittee of the American Acad-emy of Neurology. Neurology 2000;55:754–762.4. Silberstein SD, Holland S, Freitag F, Dodick DW, ArgoffC, Ashman E. Evidence-based guideline update: pharma-cologic treatment for episodic migraine prevention inadults: report of the Quality Standards Subcommittee ofthe American Academy of Neurology and the AmericanHeadache Society. Neurology 2012;78:1337–1345.5. Milla´n-Guerrero RO, Isais-Milla´n R, Benjamín TH, TeneCE. N-alpha-methyl histamine safety and efficacy in mi-graine prophylaxis: phase III study. Can J Neurol Sci2006;33:195–199.6. Milla´n-Guerrero RO, Isais-Milla´n R, Barreto-Vizcaíno S,et al. Subcutaneous histamine versus sodium valproate inmigraine prophylaxis: a randomized, controlled, double-blind study. Eur J Neurol 2007;14:1079–1084.7. Milla´n-Guerrero RO, Isais-Milla´n R, Barreto-Vizcaíno S,et al. Subcutaneous histamine versus topiramate in mi-graine prophylaxis: a double-blind study. Eur Neurol2008;59:237–242.8. Rao BS, Das DG, Taraknath VR, Sarma Y. A double blindcontrolled study of propranolol and cyproheptadine in mi-graine prophylaxis. Neurol India 2000;48:223–226.9. Brandes JL, Visser WH, Farmer MV, et al. Montelukastfor migraine prophylaxis: a randomized, double-blind,placebo-controlled study. Headache 2004S;44:581–586.10. Diener HC, Hartung E, Chrubasik J, et al; Study group. Acomparative study of oral acetylsalicylic acid and meto-prolol for the prophylactic treatment of migraine: a ran-domized, controlled, double-blind, parallel group phase IIIstudy. Cephalalgia 2001;21:120–128.11. Bensen˜or IM, Cook NR, Lee IM, Chown MJ, HennekensCH, Buring JE. Low-dose aspirin for migraine prophylaxisin women. Cephalalgia 2001;21:175–183.12. Silberstein SD, Olesen J, Bousser MG, et al; InternationalHeadache Society. The International Classification ofHeadache Disorders, 2nd Edition (ICHD-II): revision ofcriteria for 82 Medication-overuse headache [erratum in2006;26:360]. Cephalalgia 2005;25:460–465.13. Sandor PS, Di Clemente L, Coppola G, et al. Efficacy ofcoenzyme Q10 in migraine prophylaxis: a randomizedcontrolled trial. Neurology 2005;64:713–715.14. Burke BE, Olson RD, Cusack BJ. Randomized, controlledtrial of phytoestrogen in the prophylactic treatment ofmenstrual migraine. Biomed Pharmacother 2002;56:283–288.15. MacGregor EA, Frith A, Ellis J, Aspinall L, Hackshaw A.Prevention of menstrual attacks of migraine: a double-blind placebo-controlled crossover study. Neurology 2006;67:2159–2163.16. Eftedal OS, Lydersen S, Helde G, White L, Brubakk AO,Stovner LJ. A randomized, double blind study of the pro-phylactic effect of hyperbaric oxygen therapy on migraine.Cephalalgia 2004;24:639–644.17. Maizels M, Blumenfeld A, Burchette R. A combination ofriboflavin, magnesium, and feverfew for migraine prophy-laxis: a randomized trial. Headache 2004;44:885–890.18. Pfaffenrath V, Diener HC, Fischer M, Friede M,Henneicke-von Zepelin HH. The efficacy and safety ofTanacetum parthenium (feverfew) in migraine prophy-laxis–a double-blind, multicentre, randomized placebo-controlled dose-response study. Cephalalgia 2002;22:523–532.19. Diener HC, Pfaffenrath V, Schnitker J, Friede M,Henneicke-von Zepelin HH. Efficacy and safety of 6.25mg tid feverfew CO2-extract (MIG-99) in migraine pre-vention–a randomized, double-blind, multicentre,placebo-controlled study. Cephalalgia 2005;25:1031–1041.20. Pradalier A, Bakouche P, Baudesson G, et al. Failure ofomega-3 polyunsaturated fatty acids in prevention of mi-graine: a double-blind study versus placebo. Cephalalgia2001;21:818–822.21. Grossman W, Schmidramsl H. An extract of Petasites hy-bridus is effective in the prophylaxis of migraine. AlternMed Rev 2001;6:303–310.22. Lipton RB, Gobel H, Einhaupl KM, Wilks K, Mauskop A.Petasites hybridus root (butterbur) is an effective preven-tive treatment for migraine. Neurology 2004;63:2240–2244.23. Diamond S, Bigal ME, Silberstein S, Loder E, Reed M,Lipton RB. Patterns of diagnosis and acute and preventivetreatment for migraine in the United States: results fromthe American Migraine Prevalence and Prevention study.Headache 2007;47:355–363.24. Scher AI, Lipton RB, Stewart WF, Bigal M. Patterns ofmedication use by chronic and episodic headache suffer-ers in the general population: results from the frequentheadache epidemiology study. Cephalalgia 2010;30:321–328.Endorsed by the American Osteopathic Association on March 22, 2012.Neurology 78 April 24, 2012 1353
  • 21. AAN Summary of Evidence-based Guideline for PATIENTS and their FAMILIESPRESCRIPTION DRUG TREATMENT FORMIGRAINE PREVENTION IN ADULTSThis information sheet may help you understand which prescription drugs help prevent migraine headaches in adults. Thisinformation is a service of the American Academy of Neurology (AAN) and the American Headache Society. A companioninformation sheet is available regarding complementary treatments for migraine prevention.Neurologists from the AAN are doctors who identify and treat diseases of the brain and nervous system. The following evidence-based information* is provided by experts who carefully reviewed all available scientific studies on use of prescription drugs formigraine prevention in adults.Research shows many prescription treatments can help prevent migraine in people who are candidates for treatment. However,other treatments used in some people have been shown not to be helpful.DRUG WARNINGSThe US Food and Drug Administration has issued warnings for the following drugs:Divalproex sodium: www.fda.gov/Safety/MedWatch/SafetyInformation/Safety-RelatedDrugLabelingChanges/ucm153869.htmTopiramate: www.fda.gov/Drugs/DrugSafety/ucm245085.htmValproate: www.fda.gov/Drugs/DrugSafety/ucm261543.htmWhat is migraine?Migraine is a condition that involves recurring headaches. Each headache may last from four hours to two days. It can causethrobbing pain in the head. Other symptoms may include nausea (upset stomach), vomiting, and extreme sensitivity to light orsound. Most people with migraine have attacks that happen repeatedly. In some people, the headaches can be triggered by certainfoods, drinks, or odors. Stress and release from stress also may trigger migraine attacks.Migraine can interfere with daily life activities. It can be disabling. The person may feel unable to go to work or perform otherdaily tasks. If a person has a migraine headache and goes to work or performs activities anyway, performance may be impaired.For this reason, it is important to try to prevent migraine attacks. Talk with your doctor about strategies for avoiding them.Who can benefit from preventive treatment?Evidence suggests that migraine headaches often are not recognized or treated effectively in many people who have them.According to one study, about 38% of people who suffer from migraine attacks could benefit from preventive treatments.However, less than a third of those people currently use these treatments. Fortunately, in many people the frequency and severityof migraine attacks can be reduced with preventive treatment. In fact, some studies suggest migraine attacks may be reduced bymore than half.At the same time, it is important to be aware that not everyone with migraines is a candidate for preventive treatment. Forexample, people whose attacks are mild or occur infrequently may not qualify.What prescription drugs help prevent migraine attacks?Blood Pressure DrugsSeveral blood pressure drugs have been studied for migraine prevention. Strong evidence shows metoprolol, propranolol, andtimolol can help prevent migraine, and moderate evidence shows atenolol and nadolol can be helpful to reduce the frequencyand/or intensity of attacks. There is weak evidence that candesartan, lisinopril, nebivolol, and pindolol are helpful.Other blood pressure drugs may not be effective for preventing migraine. Weak evidence shows acebutolol and telmisartan maynot help. There is not enough evidence to show if bisoprolol is helpful.Depression DrugsModerate evidence shows amitriptyline and venlafaxine can help prevent migraine. There is not enough evidence to show iffluoxetine, fluvoxamine, or protriptyline is helpful.In contrast, there is moderate evidence that clomipramine does not help prevent migraine.Epilepsy DrugsSome epilepsy drugs can help prevent migraine. Strong evidence shows divalproex sodium, sodium valproate, and topiramatecan help prevent migraine. There is weak evidence that carbamazepine may be helpful.
  • 22. ©2012 American Academy of NeurologyCopies of this summary and additional companiontools are available at www.aan.com or throughAAN Member Services at (800) 879-1960. 201 Chicago Avenue South • Minneapolis, MN 55415www.aan.com • (800) 879-1960Other epilepsy drugs may not be effective for preventing migraine. Strong evidence shows lamotrigine does not help preventmigraine. There is weak evidence that oxcarbazepine may not be helpful. There is not enough evidence to show if gabapentinis helpful.Other DrugsWeak evidence shows the alpha agonists clonidine and guanfacine may help prevent migraine. In contrast, there is weakevidence that the anxiety drug clonazepam and the arthritis drug nabumetone may not be helpful.There is not enough evidence to show if the following drugs help prevent migraine:• The antiplatelet drug picotamide• The blood thinners acenocoumarol and Coumadin• The calcium channel blockers nicardipine, nifedipine, nimodipine, and verapamil• The carbonic anhydrase inhibitor acetazolamide• The muscle relaxant cyclandelateHow can I know which drug is right for me?There are several prescription drugs available with evidence to support their use. Before choosing a drug, it is important to discussdrug options with a doctor experienced in migraine prevention. It also is important to share with your doctor any other healthconditions you may have. Use of some drugs can lead to worsening of headaches.A drug that works for one person may not help another person. Moreover, some drugs for preventing migraine can be costly. Alldrugs for preventing migraine have side effects. Discuss these matters with your doctor when choosing a treatment. Be aware thatyour doctor may need to monitor your treatment in the long-term. It is important to inform your doctor of all treatments you aretaking, including those available over the counter. Your migraine headaches may worsen or improve over time. You also mayexperience general health or lifestyle changes. These may require adjusting the dose or changing to another drug.At this time, there is not enough evidence to show how one drug compares with another. In addition, more research is needed tounderstand the long-term effects of drugs for preventing migraine.This AAN and AHS guideline was endorsed by the American Osteopathic Association.This statement is provided as an educational service of the American Academy of Neurology. It is based on an assessment of current scientific and clinical information. It isnot intended to include all possible proper methods of care for a particular neurologic problem or all legitimate criteria for choosing to use a specific procedure. Neither is itintended to exclude any reasonable alternative methodologies. The AAN recognizes that specific patient care decisions are the prerogative of the patient and the physiciancaring for the patient, based on all of the circumstances involved.*After the experts review all of the published research studies, they describe the strength of the evidence supporting each recommendation:Strong evidence = more than one high-quality scientific studyModerate evidence = at least one high-quality scientific study or two or more studies of a lesser qualityWeak evidence = the studies, while supportive, are weak in design or strength of the findingsNot enough evidence = either different studies have come to conflicting results or there are no studies of reasonable quality
  • 23. AAN Summary of Evidence-based Guideline for PATIENTS and their FAMILIESNSAIDS AND COMPLEMENTARY TREATMENTSFOR MIGRAINE PREVENTION IN ADULTSThis information sheet may help you understand which antiinflammatory and complementary treatments help prevent migraineheadaches in adults. This information is a service of the American Academy of Neurology (AAN) and the American HeadacheSociety. A companion information sheet is available regarding prescription drug treatments for migraine prevention.Neurologists from the AAN are doctors who identify and treat diseases of the brain and nervous system. The following evidence-based information* is provided by experts who carefully reviewed all available scientific studies on use of antiinflammatory andcomplementary treatments for migraine prevention in adults.Research shows many antiinflammatory and complementary treatments can help prevent migraine in people who are candidatesfor treatment. However, other treatments used in some people have been shown not to be helpful.DRUG WARNINGThe US Food and Drug Administration has issued a warning for the following treatment:Petasites (butterbur): www.accessdata.fda.gov/scripts/plantox/detail.cfm?id=23110What is migraine?Migraine is a condition that involves recurring headaches. Each headache may last from four hours to two days. It can causethrobbing pain in the head. Other symptoms may include nausea (upset stomach), vomiting, and extreme sensitivity to light orsound. Most people with migraine have attacks that happen repeatedly. In some people, these can be triggered by certain foods,drinks, or odors. Stress and release from stress also may trigger migraine attacks.Migraine can interfere with daily life activities. It can be disabling. The person may feel unable to go to work or perform otherdaily tasks. If a person has a migraine headache and goes to work or performs activities anyway, performance may be impaired.For this reason, it is important to try to prevent migraine attacks. Talk with your doctor about strategies for avoiding them.Who can benefit from preventive treatment?Evidence suggests that migraine headaches often are not recognized or treated effectively in many people who have them.According to one study, about 38% of people who suffer from migraine attacks could benefit from preventive treatments.However, less than a third of those people currently use these treatments. Fortunately, in many people the frequency and severityof migraine attacks can be reduced with preventive treatment. In fact, some studies suggest migraine attacks may be reduced bymore than half.At the same time, it is important to be aware that not everyone with migraines is a candidate for preventive treatment. Forexample, people whose attacks are mild or occur infrequently may not qualify.What complementary treatments help prevent migraine attacks?Allergy/Asthma TreatmentsHistamine injection has been studied for migraine prevention. Histamine is a chemical the body produces as part of an allergicreaction. Some experts say that some migraine attacks are triggered by exposure to allergens. It is thought that histamine,when injected, can make the body less sensitive to an allergen. Moderate evidence shows histamine injections can helpprevent migraine. Likewise, some antihistamines have been studied for migraine prevention. The antihistamine suppressesan allergic response that may be the cause of a person’s migraine headaches. There is weak evidence that the antihistaminecyproheptadine may help prevent migraine headaches.In contrast, there is moderate evidence that montelukast, an allergy and asthma treatment, is not helpful in preventingmigraine attacks.Antiinflammatory DrugsSeveral drugs for inflammation have been studied for migraine prevention. These are known as nonsteroidal antiinflammatorydrugs or NSAIDs. Moderate evidence shows the NSAIDs fenoprofen, ibuprofen, ketoprofen, naproxen, and naproxen sodiumcan help prevent migraine. There is weak evidence that the NSAIDs flurbiprofen and mefenamic acid may help preventmigraine. There is not enough evidence to show if aspirin or indomethacin is helpful.It is important to be aware that regular or daily use of certain NSAIDs for acute migraine treatment may make headacheworse. This may lead to a condition known as medication overuse headache. NSAIDS also are associated with stomach upsetor bleeding.
  • 24. ©2012 American Academy of NeurologyCopies of this summary and additional companiontools are available at www.aan.com or throughAAN Member Services at (800) 879-1960. 201 Chicago Avenue South • Minneapolis, MN 55415www.aan.com • (800) 879-1960Herbal Preparations, Vitamins, Minerals, and Other TreatmentsSeveral herbal preparations, vitamins, and minerals are used for preventing migraine. Strong evidence shows that the herbalpreparation Petasites (butterbur) can help prevent migraine. There is moderate evidence that riboflavin (vitamin B2), the mineralmagnesium, and the herbal preparation MIG-99 (feverfew) help prevent migraine.Coenzyme Q10 and estrogen are both substances produced in the body. They also are used as health supplements. Weakevidence shows coenzyme Q10 and estrogen help prevent migraine. There is not enough evidence to show if omega 3 orhyperbaric oxygen therapy is helpful.How can I know which drug is right for me?There are several complementary treatments available with evidence to support their use. Before choosing a treatment, it isimportant to discuss treatment options with a doctor experienced in migraine prevention. It also is important to share with yourdoctor any other health conditions you may have.A treatment that works for one person may not help another person. Moreover, some treatments for preventing migraine can becostly. All treatments for preventing migraine have side effects. Discuss these matters with your doctor when choosing a treatment.Be aware that your doctor may need to monitor your treatment in the long-term. Communication with your doctor is especiallyimportant given that many NSAID and complementary treatments are available over the counter and may be unregulated. Itis important to inform your doctor of all treatments you are taking, including those available over the counter. Your migraineheadaches may worsen or improve over time. You also may experience general health or lifestyle changes. These may requireadjusting the dose or changing to another treatment.At this time, there is not enough evidence to know how one treatment compares with another. In addition, more research isneeded to understand the long-term effects of treatments for preventing migraine.This AAN and AHS guideline was endorsed by the American Osteopathic Association.This statement is provided as an educational service of the American Academy of Neurology. It is based on an assessment of current scientific and clinical information. It isnot intended to include all possible proper methods of care for a particular neurologic problem or all legitimate criteria for choosing to use a specific procedure. Neither is itintended to exclude any reasonable alternative methodologies. The AAN recognizes that specific patient care decisions are the prerogative of the patient and the physiciancaring for the patient, based on all of the circumstances involved.*After the experts review all of the published research studies, they describe the strength of the evidence supporting each recommendation:Strong evidence = more than one high-quality scientific studyModerate evidence = at least one high-quality scientific study or two or more studies of a lesser qualityWeak evidence = the studies, while supportive, are weak in design or strength of the findingsNot enough evidence = either different studies have come to conflicting results or there are no studies of reasonable quality
  • 25. AAN Summary of Evidence-based Guideline for CLINICIANSUpdate: Pharmacologic Treatment forEpisodic Migraine Prevention in AdultsThis is a summary of the American Academy of Neurology (AAN) and American Headache Society guideline update regarding use ofpharmacologic treatment for episodic migraine prevention.Please refer to the full guideline at www.aan.com for more information, including definitions of the classifications of evidence andrecommendations and the complete clinical context section.DRUG WARNINGSThe following treatments have associated US Food and Drug Administration warnings:Divalproex sodium: www.fda.gov/Safety/MedWatch/SafetyInformation/Safety-RelatedDrugLabelingChanges/ucm153869.htmTopiramate: www.fda.gov/Drugs/DrugSafety/ucm245085.htmValproate: www.fda.gov/Drugs/DrugSafety/ucm261543.htmFor patients with migraine, which pharmacologic therapies are proven effective for prevention, as measured by reduced migraine attackfrequency, reduced number of migraine days, and/or reduced attack severity?Angiotensin Receptor BlockersWeak evidence Candesartan is possibly effective and may be considered for migraine prevention (Level C).Telmisartan is possibly ineffective and may not be considered for migraine prevention (Level C negative).Ace InhibitorsWeak evidence Lisinopril is possibly effective and may be considered for migraine prevention (Level C).Alpha AgonistsWeak evidence Clonidine and guanfacine are possibly effective and may be considered for migraine prevention (Level C).AntithromboticsInsufficient evidence Evidence is conflicting or inadequate to support or refute the use of acenocoumarol or Coumadin for migraineprevention (Level U).AntidepressantsModerate evidence Amitriptyline and venlafaxine are probably effective and should be considered for migraine prevention (Level B).Clomipramine is probably ineffective and should not be considered for migraine prevention (Level B negative).Insufficient evidence Evidence is conflicting or inadequate to support or refute the use of fluoxetine, fluvoxamine, or protriptyline for migraineprevention (Level U).Antiepileptic DrugsStrong evidence Divalproex sodium, sodium valproate, and topiramate are established as effective and should be offered for migraineprevention (Level A).Lamotrigine is established as ineffective and should not be offered for migraine prevention (Level A negative).Weak evidence Carbamazepine is possibly effective and may be considered for migraine prevention (Level C).Oxcarbazepine is possibly ineffective and may not be considered for migraine prevention (Level C negative).Insufficient evidence Evidence is conflicting or inadequate to support or refute the use of gabapentin for migraine prevention (Level U).Clinical context In most headache trials, patients taking divalproex sodium or sodium valproate reported no more adverse events(AEs) than those on placebo. However, weight gain has been clinically observed with divalproex sodium long-termuse. Treatment with these agents requires careful follow-up and testing because of pancreatitis, liver failure, andteratogenicity risks.Beta-blockersStrong evidence Metoprolol, propranolol, and timolol are established as effective and should be offered for migraine prevention (Level A).Moderate evidence Atenolol and nadolol are probably effective and should be considered for migraine prevention (Level B).Weak evidence Nebivolol and pindolol are possibly effective and may be considered for migraine prevention (Level C).Acebutolol is possibly ineffective and may not be considered for migraine prevention (Level C negative).Insufficient evidence Evidence is conflicting or inadequate to support or refute the use of bisoprolol for migraine prevention (Level U).
  • 26. ©2012 American Academy of NeurologyCopies of this summary and additional companiontools are available at www.aan.com or throughAAN Member Services at (800) 879-1960. 201 Chicago Avenue South • Minneapolis, MN 55415www.aan.com • (800) 879-1960Calcium-channel BlockersInsufficient evidence Evidence is conflicting or inadequate to support or refute the use of nicardipine, nifedipine, nimodipine, or verapamil formigraine prevention (Level U).TriptansStrong evidence Frovatriptan is established as effective and should be offered for short-term menstrually associated migraine (MAMs)prevention (Level A).Moderate evidence Naratriptan and zolmitriptan are probably effective and should be considered for short-term MAMs prevention (Level B).Other AgentsWeak evidence Clonazepam and nabumetone are possibly ineffective and may not be considered for migraine prevention (Level Cnegative).Insufficient evidence Evidence is conflicting or inadequate to support or refute the use of acetazolamide, cyclandelate, or picotamide formigraine prevention (Level U).CLINICAL CONTEXT*Evidence to support pharmacologic treatment strategies for migraine prevention indicates which treatments might be effective but is insufficientto establish how to choose an optimal therapy. Consequently, although Level A recommendations can be made for pharmacologic migraineprevention, similar evidence is unavailable to help the practitioner choose one therapy over another. Treatment regimens, therefore, need to bedesigned case by case. Moreover, decision making must remain with the physician and the patient to determine the optimal therapy. Often trialand error is needed.Evidence is also unavailable for making broad-range comparisons among multiple agents within a single class; such evidence would provide amore comprehensive understanding of relative efficacy and tolerability profiles across a broader range of therapeutic agents. Studies are neededthat specifically evaluate when preventive therapy is warranted and how medications should be titrated. Table e-1 of the published guideline listssome specific consensus-based clinical circumstances wherein considering preventive therapy would be reasonable. A shortcoming of migraineprevention clinical studies is the relatively brief treatment duration. Long-term assessment of the efficacy and safety of migraine preventivetreatments is needed. Additionally, overall cost is a consideration when prescribing medications; cost may influence compliance, especiallylong-term.It seems reasonable that a clinician be mindful of comorbid and coexistent conditions in patients with migraine, to maximize potential treatmentefficacy and minimize AE risk. Table e-2 of the published guideline identifies which therapies to consider or avoid when common migrainecoexisting conditions are present. Because migraine is frequent in women of childbearing age, the potential for fetal AEs related to migraineprevention strategies is particularly concerning.Evidence from the two Class I frovatriptan studies meets the AAN threshold for a Level A recommendation for short-term use to prevent menstrualmigraine (reduction in MAM headache incidence by 26% on 2.5 mg bid). However, the FDA questions whether the benefit demonstrated isclinically meaningful and has not approved frovatriptan for this indication.This AAN and AHS guideline was endorsed by the American Osteopathic Association.*See the published guideline for the complete clinical context section.This is an educational service of the American Academy of Neurology. It is designed to provide members with evidence-based guideline recommendations to assistthe decision making in patient care. It is based on an assessment of current scientific and clinical information and is not intended to exclude any reasonable alternativemethodologies. The AAN recognizes that specific patient care decisions are the prerogative of the patient and the physician caring for the patient, and are based on thecircumstances involved. Physicians are encouraged to carefully review the full AAN guidelines so they understand all recommendations associated with care of thesepatients.
  • 27. AAN Summary of Evidence-based Guideline for CLINICIANSUpdate: NSAIDs and Other ComplementaryTreatments for Episodic MigrainePrevention in AdultsThis is a summary of the American Academy of Neurology (AAN) and American Headache Society guideline update regarding use of nonsteroidalantiinflammatory drugs (NSAIDs) and other complementary treatments for episodic migraine prevention.Please refer to the full guideline at www.aan.com for more information, including definitions of the classifications of evidence andrecommendations and the complete clinical context section.DRUG WARNINGThe following treatment has an associated US Food and Drug Administration warning:Petasites (butterbur): www.accessdata.fda.gov/scripts/plantox/detail.cfm?id=23110Are nonsteroidal antiinflammatory drugs (NSAIDs) or other complementary treatments effective for migraine prevention?Histamines/Antihistamines/Leukotriene Receptor AntagonistsModerate evidence Histamine sc is probably effective and should be considered for migraine prevention (Level B).Montelukast is probably ineffective and should not be considered for migraine prevention (Level B negative).Weak evidence Cyproheptadine is possibly effective and may be considered for migraine prevention (Level C).NSAIDsModerate evidence Fenoprofen, ibuprofen, ketoprofen, naproxen, and naproxen sodium are probably effective and should be consideredfor migraine prevention (Level B).Weak evidence Flurbiprofen and mefenamic acid are possibly effective and may be considered for migraine prevention (Level C).Insufficient evidence Evidence is inadequate or conflicting to support or refute the use of aspirin or indomethacin for migraine prevention(Level U).Clinical context Regular or daily use of selected NSAIDs for the treatment of frequent migraine attacks may exacerbate headachebecause of development of a condition called medication overuse headache. Therefore, use of aspirin, selectedanalgesics, and NSAIDs may exacerbate headache; use of these agents in migraine prevention studies may confound theclinical interpretation of the study results.Herbal Preparations, Vitamins, Minerals, and Other InterventionsStrong evidence Petasites (butterbur) is established as effective and should be offered for migraine prevention (Level A).Moderate evidence Riboflavin, magnesium, and MIG-99 (feverfew) are probably effective and should be considered for migraine prevention(Level B).Weak evidence Coenzyme Q10 and estrogen are possibly effective and may be considered for migraine prevention (Level C).Insufficient evidence Evidence is inadequate or conflicting to support or refute the use of omega 3 or hyperbaric oxygen therapy for migraineprevention (Level U).CLINICAL CONTEXT*In a previous epidemiologic study, 38.7% of study participants had ever used a migraine preventive treatment, of which only 12.4% were currentusers and 17.2% were coincident users (taking a migraine preventive treatment for other reasons). The proportion of those who use NSAIDs orindividual complementary treatments specifically for migraine prevention is unclear, and warrants further study. Additionally, the treatmentsreviewed herein are those available in the United States. The results from this and other guidelines are limited to those treatments available in theUnited States.Additionally, studies assessing the efficacy of NSAIDs and complementary treatments for migraine prevention are limited and should be consideredrelative to other available pharmacologic therapies reviewed in a separate guideline available at www.aan.com/guidelines.Additionally, the clinical evidence for NSAIDs and complementary treatments for migraine prevention should be reviewed with caution becausethere are clear discrepancies in how patients were selected for study inclusion; how severe, frequent, or disabling their attacks were; and howseverity was assessed. Also, these treatments are unregulated. There are few or no studies on how these medications should be taken. Whenpatients are instructed or choose to take NSAIDs or complementary treatments for migraine prevention, it is important that they be followed overthe course of treatment. Prospective long-term safety of many of these agents is not well studied specifically regarding their use as preventivemigraine treatments.It is reasonable also for clinicians to inquire about the doses being used and frequency of use of NSAIDs and complementary treatments. Frequentmedication use or high dose levels may increase the risk of headache progression or medication overuse, which may lead to other secondary
  • 28. ©2012 American Academy of NeurologyCopies of this summary and additional companiontools are available at www.aan.com or throughAAN Member Services at (800) 879-1960. 201 Chicago Avenue South • Minneapolis, MN 55415www.aan.com • (800) 879-1960health complications (e.g., gastrointestinal upset/bleeding with aspirin or NSAIDs or headache rebound with discontinuation of feverfew).Complete review and disclosure of coexisting conditions are warranted, as complementary or pharmacologic therapies taken for coexistingconditions (e.g., depression) may exacerbate headache. Because migraine is frequent in women of childbearing age, the potential for adverse fetaleffects related to migraine prevention strategies is of particular concern. Little has been done to establish the long-term safety and efficacy of theseagents during pregnancy or breastfeeding.Additionally, when patients have unlimited access to over-the-counter medications, they may be unaware of the continued need for routinephysician follow-up for a chronic illness such as migraine, as illness severity may progress or improve, often warranting medication changes. Italso is important for patients to understand the magnitude of benefit that can be expected from preventive migraine therapies; moreover, patienteducation about migraine and appropriate management are important in successful patient care. For some patients, a 35% reduction in headachefrequency or intensity may be deemed an insufficient level of improvement, thus leading them to risk dose escalation. Additionally, patients withmigraine may need to be educated about appropriate use and risks of these agents.Finally, recent studies suggest that some medications used for migraine may offer long-term protection against headache progression whereas otheragents may elevate progression risk. Specifically, one epidemiologic study assessing medication use in the general migraine population reportsthat aspirin or ibuprofen use may protect against progression from episodic to chronic headache conditions (CDH). In contrast, opioid use waspositively associated with CDH. Although conclusions are preliminary regarding the benefits and risks of selected agents for long-term use, studiessuggest that these agents may play a significant role in headache progression and patterns, lending further emphasis to the importance of followingpatients closely, including regular assessment of NSAIDs, and other complementary treatments for migraine prevention.This AAN and AHS guideline was endorsed by the American Osteopathic Association.*See the published guideline for the complete clinical context section.This is an educational service of the American Academy of Neurology. It is designed to provide members with evidence-based guideline recommendations to assistthe decision making in patient care. It is based on an assessment of current scientific and clinical information and is not intended to exclude any reasonable alternativemethodologies. The AAN recognizes that specific patient care decisions are the prerogative of the patient and the physician caring for the patient, and are based on thecircumstances involved. Physicians are encouraged to carefully review the full AAN guidelines so they understand all recommendations associated with care of thesepatients.
  • 29. LEAD AUTHOR BIOStephen D. Silberstein, MD, FACP, FAHS, FAAN, is a board-certified neurologist and Professorof Neurology and Director of the Jefferson Headache Center at Thomas Jefferson University. Heis presently Editor of Headache Review and a member of the Editorial Board of Headache,Journal of Neurology, Neurosurgery and Psychiatry, CNS Drugs, and Cephalalgia. Author ofmore than 100 peer-reviewed articles, and over 100 books, book chapters, and miscellaneouspublications, Dr. Silberstein lectures extensively on the pathogenesis, neurobiology, diagnosis,treatment and prevention of headache.

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