Evidence-based guideline update Pharmacologictreatment for episodic migraine preventionin adultsReport of the Quality Standards Subcommittee of the American Academy ofNeurology and the American Headache Society
SD Silberstein MDFACP
S Holland PhDF Freitag DODW Dodick MDC Argoff MDE Ashman MD
ABSTRACT
Objective 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) Neurologyreg 2012781337ndash1345
GLOSSARYAAN American Academy of Neurology AE adverse event CI confidence interval ER extended-release MAM menstrually associated migraine PMP perimenstrual period RCT randomized controlled trial
Epidemiologic studies suggest approximately 38of migraineurs need preventive therapy but only3ndash13 currently use it1 In 2000 the AmericanAcademy of Neurology (AAN) published guide-lines for migraine prevention23 Since 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 severityThis article addresses the safety and efficacy ofpharmacologic therapies for migraine prevention
Separate guidelines are available for botulinumtoxin4 The 2008 guideline included a Level B re-commendation that botulinum toxin was probably
ineffective for treatment of episodic migraine A newguideline is in development An updated guidelineon nonsteroidal anti-inflammatory drugs5 and com-plementary alternative treatments has been approvedfor publication as a companion to this guideline5
DESCRIPTION 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 ldquoheadacherdquo (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 May
See page 1346
Supplemental data atwwwneurologyorg
Supplemental Data
Podcast
CME
From Thomas Jefferson University (SDS) Jefferson Headache Center Philadelphia PA the Armstrong Atlantic State University (SH) SavannahGA Comprehensive Headache Center (FF) Baylor University Headache Medicine Center Dallas TX Mayo Clinic (DD) Scottsdale AZ NewYork University School of Medicine (CA) Albany and Elmendorf Air Force Base (EA) AK
Appendices e-1ndashe-5 reference e1 and tables e-1 and e-2 are available on the Neurology Web site at wwwneurologyorg
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 SocietyNone of the authors received reimbursement honoraria or stipends for their participation in development of this guideline
Go to Neurologyorg for full disclosures Disclosures deemed relevant by the authors if any are provided at the end of this article
Correspondence amp reprintrequests to American Academy ofNeurologyguidelinesaancom
SPECIAL ARTICLE
Copyright copy 2012 by AAN Enterprises Inc 1337
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 Neurologyreg Website at wwwneurologyorg) Differences in ratings wereresolved by author panel discussion
ANALYSIS OF EVIDENCE The original searchidentified 179 articles A supplemental search(2007ndash2009) yielded 105 additional articles Of thetotal 284 articles 29 were classified as Class I or ClassII and are reviewed herein Studies were excluded ifthey
bull Assessed the efficacy of therapeutic agents forheadache other than episodic migraine in adults
bull Assessed acute migraine treatment migraineaura treatmentprevention or nonpharmaco-logic treatments (eg behavioral approaches)
bull Used quality of life measures disability assess-ment or nonstandardized outcomes as primaryefficacy endpoints
bull Tested the efficacy of drugs not available in theUnited States
Since 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 (gt2 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 use
Other Medications thatare established aspossibly or probablyineffective
Antiepileptic drugs AntidepressantsSSRISSNRITCA
ACE inhibitorsLisinopril
Carbonic anhydraseinhibitor
Established as noteffective
Divalproex sodium Amitriptyline Angiotensin receptorblockers
Acetazolamide Antiepileptic drugs
Sodium valproate Venlafaxine Candesartan Antithrombotics Lamotrigine
Topiramate -Blockers -Agonists Acenocoumarol Probably not effective
-Blockers Atenolola Clonidinea Coumadin Clomipraminea
Metoprolol Nadolola Guanfacinea Picotamide Possibly not effective
Propranolol Triptans (MRMb) Antiepileptic drugs AntidepressantsSSRISSNRI
Acebutolola
Timolola Naratriptanb Carbamazepinea Fluvoxaminea Clonazepama
Triptans (MRMb) Zolmitriptanb -Blockers Fluoxetine Nabumetonea
Frovatriptanb Nebivolol Antiepileptic drugs Oxcarbazepine
Pindolola Gabapentin Telmisartan
Antihistamines TCAs
Cyproheptadine Protriptylinea
-Blockers
Bisoprolola
Ca blockers
Nicardipinea
Nifedipinea
Nimodipine
Verapamil
Direct vascularsmooth musclerelaxants
Cyclandelate
Abbreviations ACE angiotensin-converting-enzyme MRM menstrually related migraine SSNRI selective serotoninndashnorepinephrine reuptake inhibitor SSRI selective serotonin reuptake inhibitor TCA tricyclic antidepressanta Classification based on original guideline and new evidence not found for this reportb For short-term prophylaxis of MRM
1338 Neurology 78 April 24 2012
clonazepam clonidine clomipramine fluvoxamineguanfacine 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 185 with placebo(263 reduction from baseline) vs 136 with cande-sartan (456 reduction from baseline p 0001)6
Selected secondary endpoints also favored candesar-tan headache hours (139 vs 95 p 0001) mi-graine days (126 vs 90 p 0001) migraine hours(922 vs 594 p 0001) and headache severity in-dex (293 vs 191 p 0001) No serious adverseevents (AEs) occurred The most common AEs weredizziness (31) ldquosymptoms of the musculoskeletalsystemrdquo (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) 5ndash36]headache days 197 vs 237 [20 CI 5ndash30] migrainedays 145 vs 185 [21 CI 9ndash34])7 AEs includedcough (26 10 discontinued treatment due tocough) dizziness (23) and ldquotendency to faintrdquo(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 (165 vs 114)8
Conclusions 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 sodium
500ndash1000 mgday had a mean reduction in 4-weekmigraine headache rate from 44week (baseline) to32week (12 attacksweek) in the ER divalproex so-dium group and from 42week to 36week (06attacksweek) in the placebo group (CI 02ndash12p 0006)9 No 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 use910 Treatment withthese agents requires careful follow-up and testingbecause of pancreatitis liver failure and teratogenic-ity risks11
Gabapentin Since the 2000 publication a Class IIIstudy12 reported that a stable gabapentin dose (4-week titration phase to 2400 mgday 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 study13 that failed to show asignificant effect for migraine prevention A secondnew Class I study comparing lamotrigine 50 mgdaywith placebo or topiramate 50 mgday reported lam-otrigine was not more effective than placebo (forboth primary endpoints) and was less effective thantopiramate in reducing migraine frequency and in-tensity14 The primary outcome measure (responderrate 50 monthly migraine frequency reduction)was 46 for lamotrigine vs 34 for placebo (p
0093 CI 002ndash026) and 63 for topiramate vs46 for lamotrigine (p 0019 CI 003ndash031)Treatment-related AEs (rash giddiness sleepinessand gastrointestinal intolerance) occurred in 10 ofpatients on lamotrigine
Oxcarbazepine One Class II trial evaluated the effi-cacy of oxcarbazepine (1200 mgday) vs placebo15
There was no difference between oxcarbazepine(130 [SE 0282]) and placebo for mean change innumber of migraine attacks from baseline during thelast 28 days of the double-blind 15-week treatmentphase (174 [SE 0283] p 02274)
Topiramate Four Class I studies1416ndash18 and 7 ClassII studies19ndash25 report topiramate (50ndash200 mgday) iseffective in migraine prevention
In a Class I placebo-controlled study (mean topi-ramate dose 125 mgday [range 25ndash200 mgday])patients given topiramate experienced a significantlylower 28-day migraine frequency vs with placebo(331 17 vs 383 21 p 0002)18 In a secondplacebo-controlled Class I double-crossover study(reviewed above) topiramate was more effective than
Neurology 78 April 24 2012 1339
placebo and lamotrigine for primary efficacy mea-sures14 In the topiramate groups 15 of patientsexperienced AEs most commonly paresthesiassleepiness and gastrointestinal intolerance The pla-cebo group reported gastrointestinal intolerance(3) and anorexia (3)
Two additional Class I studies report topiramate isas effective as propranolol16 or sodium valproate17
drugs previously established as effective for migraineprevention In the first study subjects given topiramate50 mgday had reduced mean migraine frequency (epi-sodesmonth) from baseline (607 189 to 183
139 p 0001) at 8 weeks decreased headache inten-sity VAS score from 71 145 to 367 21 (p
0001) and decreased headache duration from 1637
726 hours to 623 522 hours (p 0001)16 Sub-jects given topiramate reported paresthesias (23)weight loss (16) and somnolence (13) In pa-tients treated with propranolol 80 mgday meanheadache frequency (episodesmonth) decreasedfrom 583 198 to 22 167 (p 0001) at 8weeks headache intensity VAS score decreased from643 16 to 413 194 (p 0001) and head-ache duration decreased from 1510 684 hours to727 646 hours (p 0001) Although monthlyheadache frequency intensity and duration de-creased in both groups the topiramate group re-ported significantly greater mean reduction(topiramate frequency decrease 423 12 vs pro-pranolol 363 096 [p 0036 CI 039ndash116]topiramate intensity decrease 343 138 vs pro-pranolol 23 12 [p 0001 CI 046ndash18] topi-ramate duration decrease 101 43 vs propranolol783 45 [p 0048 CI 017ndash46])
In a crossover Class I trial (2-month washout be-tween therapies) comparing topiramate 50 mgdaywith sodium valproate 400 mgday both groupsshowed improvement from baseline in headache fre-quency intensity and duration17 Average monthlymigraine frequency decreased by 18 times with so-dium valproate (baseline 54 25 posttreatment36 21 CI 10ndash26 p 0001) as comparedwith a 3-time reduction with topiramate (baseline54 20 posttreatment 24 24 CI 21ndash39 p
0001) Headache intensity decreased by 37 with so-dium valproate (baseline 77 12 treatment 40
21 CI 29ndash46 p 0001) as compared with areduction of 36 with topiramate (baseline 69 12treatment phase 33 15 CI 29ndash43 p 0001)The average headache episode duration decreased by134 hours from baseline with sodium valproate(baseline 213 146 treatment 79 77 CI 75ndash193 p 0001) as compared with an 119-hourreduction with topiramate (baseline 173 84treatment 54 64 CI 82ndash156 p 0001) The
overall 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 (188) paresthesias (94) or both(25) Sodium valproate AEs were weight gain(345) hair loss (31) and somnolence (31)
Results of 5 Class II studies support those of theClass I studies showing topiramate as effective formigraine prevention19ndash25 Four studies demonstratedsignificant improvement over placebo19202324 oneincluded an active comparator arm suggestingequivalence of topiramate (100 200 mgday) andpropranolol (160 mgday)20 Two studies comparingtopiramate and amitriptyline (25ndash150 mgday) 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 monotherapy2122 In one of thesestudies21 the 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 placebo26
Conclusions 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 guideline1 Class II study27 showed fluoxetine (racemic) wassignificantly better than placebo for migraine preven-tion but the results were not duplicated in a secondstudy28
Since the original guideline a Class II study hasshown fluoxetine 20 mgday was more effective thanplacebo in reducing total pain index scores (calcu-lated as [Dl 1] [D2 2] [D3 3] where D1D2 and D3 represent headache hours calculated in amonth with pain intensity shown by 1 2 3) at 6months29 After the 6 months pain index scores for thefluoxetine group decreased from 135 (baseline) to 413(SD 638 p 0001) The placebo group pain indexwas 98 at baseline and 611 at 6 months (SD 577p 007) however differences were noted betweentreatment groups for baseline measures
1340 Neurology 78 April 24 2012
Venlafaxine In a Class I study venlafaxine XR 150mg significantly reduced the number of headachedays (median reduction in days venlafaxine 150 mg4 days venlafaxine 75 mg 2 days placebo 1day Kruskal-Wallis 10306 df 2 p 0006)30
All 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 415 [SD
224] vs 12 weeks 177 [SD 139 p 0001]amitriptyline baseline 327 [SD 161] vs 12weeks 154 [SD 154 p 0001])31 Patients tak-ing venlafaxine experienced nauseavomiting (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 20 drop-out rates) Comparative studies of amitriptyline withtopiramate2122 and 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 (200mgday) was more effective than aspirin (300 mgday) in achieving 50 migraine frequency reduction(responder rate metoprolol 452 aspirin
296 mean difference 1565 CI 443ndash2688)32
Attack frequencies (attacksmonth) at placebo run-inand week 20 are 336 to 237 respectively for aspirinand 355 to 182 respectively for metoprolol Nosignificant AEs were reported
A small Class II study reported metoprolol (475ndash1425 mgday) had similar efficacy to nebivolol 5
mgday for migraine prevention (assessed by a de-crease in mean migraine attacks)33
Propranolol The original guideline concludedpropranolol was established as effective for migraineprevention
In a Class II study propranolol (80 mgday) wasmore effective than placebo and as effective as cypro-heptadine (4 mgday) in reducing migraine fre-quency duration and attack severity34 Thedifference in attack frequency reduction was signifi-cant between treatments propranolol 285 02(SEM) vs cyproheptadine 309 031 vs combi-nation 312 01 vs placebo 177 044 (all p 005 vs placebo) For attack frequency reductioncombination therapy was more effective than mono-therapy (p 005) AEs were drowsiness sleep dis-turbance weight gain fatigue and dry mouthpercentages 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 duration35 The secondstudy (smaller underpowered n 25) found cy-clandelate significantly reduced the number of mi-graine days and duration (assessed using a contingentnegative variation measure)36
Conclusions The efficacy of cyclandelate is unknown(conflicting Class II studies)
Triptans Since the original guideline new Class Istudies have assessed the efficacy of frovatriptan3738
naratriptan39 and zolmitriptan40 for short-term pre-vention of menstrually associated migraine (MAM)
Frovatriptan Frovatriptan 25 mg BIDqd wasmore effective than placebo in reducing migraine fre-
Neurology 78 April 24 2012 1341
quency37 The mean number of headache-free peri-menstrual periods (PMPs) per patient (primaryendpoint) was higher in the 2 frovatriptan groups(25 mg qd 069 [SD 092 CI 114ndash273 p 00091] vs 25 mg BID 092 [SD 103 CI 184ndash428 p 00001] vs placebo 042 [SD 078])representing 64 (25 mgday) and 119 (5 mgday) increases in the mean number of headache-freePMPs per patient over placebo A second Class Istudy38 also reports the MAM headache incidenceduring the 6-day PMP was 67 for placebo 52 forfrovatriptan 25 mg QD (p 00001 vs placebo)and 41 for frovatriptan 25 mg BID (p 00001vs placebo p 00001 vs QD regimen) The AEincidence and type for both regimens were similar tothose for placebo The overall AE incidence for fro-vatriptan was 41 (25 mg BID) and 27 (25 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 days39 Patients treated withnaratriptan 1 mg experienced more headache-freePMPs than those on placebo (50 vs 25 p
0003) Naratriptan 1 mg reduced the number ofMAMs (20 vs 40 p 005) and MAM days (42 vs70 p 001) vs placebo The AE incidence andseverity were similar to those of placebo 10 ofpatients experienced dizziness chest pain or malaise
Zolmitriptan One Class I study reported the effi-cacy of zolmitriptan 25 BIDTID vs placebo Bothzolmitriptan regimens demonstrated superior effi-cacy vs placebo the proportion of patients with a50 MAM attack frequency reduction (zolmi-triptan 25 mg TID [586] p 00007 vs placebozolmitriptan 25 mg BID [547] p 0002 vs pla-cebo placebo 378)40 AEs were considered possi-bly treatment-related in 28 patients (333) in thezolmitriptan 25 mg TID group 29 (363) in thezolmitriptan 25 mg BID group and 18 (220) 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 more
effective than placebo in reducing migraine fre-quency duration and severitye1 This trial (n 53) 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
bull Antiepileptic drugs (AEDs) divalproex so-dium sodium valproate topiramate
bull -Blockers metoprolol propranolol timololbull Triptans frovatriptan for short-term MAMs
prevention
Level B The following medications are probablyeffective and should be considered for migraineprevention
bull Antidepressants amitriptyline venlafaxinebull -Blockers atenolol nadololbull Triptans naratriptan zolmitriptan for short-
term MAMs prevention
Level C The following medications are possibly effec-tive and may be considered for migraine prevention
bull ACE inhibitors lisinoprilbull Angiotensin receptor blockers candesartanbull -Agonists clonidine guanfacinebull AEDs carbamazepinebull -Blockers nebivolol pindolol
Level U Evidence is conflicting or inadequate to sup-port or refute the use of the following medicationsfor migraine prevention
bull AEDs gabapentinbull Antidepressants
bull Selective serotonin reuptake inhibitorselec-tive serotonin-norepinephrine reuptake in-hibitors fluoxetine fluvoxamine
bull Tricyclics protriptylinebull Antithrombotics acenocoumarol Coumadin
picotamidebull -Blockers bisoprololbull Calcium-channel blockers nicardipine nifedi-
pine nimodipine verapamilbull Acetazolamidebull Cyclandelate
Level A negative The following medication is estab-lished as ineffective and should not be offered formigraine prevention
bull Lamotrigine
1342 Neurology 78 April 24 2012
Level B negative The following medication is proba-bly ineffective and should not be considered for mi-graine prevention
bull Clomipramine
Level C negative The following medications are pos-sibly ineffective and may not be considered for mi-graine prevention
bull Acebutololbull Clonazepambull Nabumetonebull Oxcarbazepinebull Telmisartan
CLINICAL 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 coexistingcomorbid 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 agentsStudies 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 12ndash16weeks) 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 25 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 draftingrevising the manuscript
study concept or design analysis or interpretation of data acquisition of
data study supervision Dr Holland draftingrevising the manuscript
study concept or design analysis or interpretation of data Dr Freitag
draftingrevising the manuscript analysis or interpretation of data acqui-
sition of data Dr Dodick draftingrevising the manuscript study con-
cept or design analysis or interpretation of data Dr Argoff drafting
revising the manuscript study concept or design analysis or
interpretation of data Dr Ashman draftingrevising the manuscript
analysis or interpretation of data
DISCLOSUREDr Silberstein is on the advisory panel of and receives honoraria from
AGA 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 speakersrsquo bureau
of and receives honoraria from Endo Pharmaceuticals GlaxoSmithKline
and Merck He serves as a consultant for and receives honoraria from
Amgen 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 the
American Headache Society and research support from Albert Einstein
College of Medicine Dr Freitag has served on the scientific advisory
boards of Zogenix Pharmaceuticals Allergan Pharmaceuticals Nautilus
MAP Pharmaceuticals and Nupathe has received travel expenses and or
honoraria from GlaxoSmithKline Zogenix Merck Nautilus Allergan
Diamond Headache Clinic Research and Educational Foundation (not
for profit) and the American Headache Society (travel) Dr Freitag is a
member of the Board of Directors of the National Headache Foundation
Dr Dodick within the past 3 years serves on advisory boards and has
consulted for Allergan Alder Pfizer Merck Coherex Ferring Neuro-
core Neuralieve Neuraxon NuPathe Inc MAP SmithKlineBeecham
Boston Scientific Medtronic Inc Nautilus Eli Lilly amp Company No-
Neurology 78 April 24 2012 1343
vartis Colucid GlaxoSmithKline Autonomic Technologies MAP Phar-
maceuticals Inc Zogenix Inc Impax Laboratories Inc Bristol Myers
Squibb 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 SAGE
Publishing Lippincott Williams amp 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 The
Neurologist Lancet Neurology and Postgraduate Medicine and has served
as Editor-in-Chief of Headache Currents and as an Associate Editor of
Headache he receives publishing royalties for Wolff rsquos Headache 8th edi-
tion (Oxford University Press 2009) and Handbook of Headache (Cam-
bridge University Press 2010) Within the past 3 years Dr Dodick has
received research grant support from Advanced Neurostimulation Sys-
tems Boston Scientific St Jude Medical Inc Medtronic NINDSNIH
Mayo Clinic Dr Argoff has served on a scientific advisory board for the
Department of Defense and DSMB for the NIH has received funding for
travel andor speaking andor has served on a speakersrsquo bureau for Pfizer
(King) Janssen (Pricara) Millennium Laboratories Neurogesx Forest
Laboratories Eli Lilly Covidien and Endo Pharmaceuticals has received
research support from Endo Pharmaceuticals Forest Laboratories Eli
Lilly Neurogesx Pfizer and SBRT funded by the NIH and has received
stockstock options from Pfizer Dr Ashman is the Level of Evidence
editor 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 Neurologyorg for full
disclosures
DISCLAIMERThis statement is provided as an educational service of the American
Academy of Neurology and the American Headache Society It is based
on as assessment of current scientific and clinical information It is not
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 it intended to exclude any reasonable alternative
methodologies The AAN and the AHS recognize that specific patient
care decisions are the prerogative of the patient and the physician
caring for the patient based on all of the circumstances involved The
clinical context section is made available in order to place the
evidence-based guideline(s) into perspective with current practice hab-
its and challenges No formal practice recommendations should be
inferred
CONFLICT OF INTERESTThe American Academy of Neurology and the American Headache Soci-
ety are committed to producing independent critical and truthful clinical
practice guidelines (CPGs) Significant efforts are made to minimize the
potential for conflicts of interest to influence the recommendations of this
CPG To the extent possible the AAN and AHS keep separate those who
have a financial stake in the success or failure of the products appraised in
the CPGs and the developers of the guidelines Conflict of interest forms
were obtained from all authors and reviewed by an oversight committee
prior to project initiation AAN and AHS limit the participation of au-
thors with substantial conflicts of interest The AAN and AHS forbid
commercial participation in or funding of guideline projects Drafts of
the 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 of
Interest Policy can be viewed at wwwaancom
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 200768343ndash349
2 Ramadan NM Silberstein SD Freitag FG Gilbert TT
Frishberg BM Evidence-based guidelines for migraine
headache in the primary care setting pharmacological
management for prevention of migraine Available at
httpwwwaancomprofessionalspracticepdfsgl0090
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 the
American Academy of Neurology Neurology 200055
754ndash762
4 Naumann M So Y Argoff C et al Assessment Botuli-
num neurotoxin in the treatment of autonomic disorders
and pain (an evidence-based review) report of the Thera-
peutics and Technology Subcommittee of the American
Academy of Neurology Neurology 2008701707ndash1714
5 Holland S Silberstein SD Freitag F Dodick DW Argoff
C Ashman E Evidence-based guideline update NSAIDs
and other complementary treatments for episodic migraine
prevention in adults report of the Quality Standards Sub-
committee of the American Academy of Neurology and
the American Headache Society Neurology 201278
1346ndash1353
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
28965ndash69
7 Schrader H Stovner LJ Helde G Sand T Bovim G Pro-
phylactic treatment of migraine with angiotensin convert-
ing enzyme inhibitor (lisinopril) randomised placebo
controlled crossover study BMJ 200132219ndash22
8 Diener HC Gendolla A Feuersenger A et al Telmisartan
in migraine prophylaxis a randomized placebo-controlled
trial Cephalalgia 200929921ndash927
9 Freitag FG Collins SD Carlson HA et al A randomized
trial of divalproex sodium extended-release tablets in mi-
graine prophylaxis Neurology 2002581652ndash1659
10 Silberstein SD Collins SD Safety of divalproex sodium in
migraine prophylaxis an open-label long-term study
long-term safety of Depakote in Headache Prophylaxis
Study Group Headache 199939633ndash643
11 Harden CL Meador KJ Pennell PB et al American Acad-
emy of Neurology American Epilepsy Society Practice pa-
rameter update management issues for women with
epilepsyndashfocus on pregnancy (an evidence-based review)
teratogenesis and perinatal outcomes report of the Quality
Standards Subcommittee and Therapeutics and Technol-
ogy Assessment Subcommittee of the American Academy
of Neurology and American Epilepsy Society Neurology
200973133ndash141
12 Mathew NT Rapoport A Saper J et al Efficacy of gabap-
entin in migraine prophylaxis Headache 200141119ndash
128
13 Steiner TJ Findley LJ Yuen AW Lamotrigine versus pla-
cebo in the prophylaxis of migraine with and without aura
Cephalalgia 199717109ndash112
14 Gupta P Singh S Goyal V Shukla G Behari M Low-
dose topiramate versus lamotrigine in migraine prophy-
laxis (the Lotolamp study) Headache 200747402ndash412
15 Silberstein SD Saper J Berenson F Somogyi M Mc-
Cague MA DrsquoSouza JD Oxcarbazepine in migraine head-
ache a double-blind randomized placebo-controlled
study Neurology 200870548ndash555
1344 Neurology 78 April 24 2012
16 Ashtari F Shaygannejad V Akbari M A double-blindrandomized trial of low-dose topiramate vs propranolol inmigraine prophylaxis Acta Neurol Scand 2008118301ndash305
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 Headache200646642ndash 648
18 Storey JR Calder CS Hart DE Potter DL Topiramate inmigraine prevention a double-blind placebo-controlledstudy Headache 200141968ndash975
19 Brandes JL Saper JR Diamond M et al MIGR-002Study Group Topiramate for migraine prevention a ran-domized controlled trial JAMA 2004291965ndash973
20 Diener HC Matias-Guiu J Hartung E et al Topiramatein migraine prophylaxisndashresults from a placebo-controlledtrial with propranolol as an active control J Neurol 2004251943ndash950
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 200931542ndash559
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 2008110979ndash984
23 Mei D Capuano A Vollono C et al Topiramate in mi-graine prophylaxis a randomised double-blind versus pla-cebo study Neurol Sci 200425245ndash250
24 Silberstein SD Neto W Schmitt J Jacobs D MIGR-001Study Group Topiramate in migraine prevention resultsof a large controlled trial Arch Neurol 200461490ndash495
25 Millan-Guerrero RO Isais-Millan R Barreto-Vizcaiacuteno Set al Subcutaneous histamine versus topiramate in mi-graine prophylaxis a double-blind study Eur Neurol200859237ndash242
26 Silberstein SD Hulihan J Karim MR et al Efficacy andtolerability of topiramate 200 mgd in the prevention ofmigraine withwithout aura in adults a randomizedplacebo-controlled double-blind 12-week pilot studyClin Ther 2006281002ndash1011
27 Adly C Straumanis J Chesson A Fluoxetine prophylaxisof migraine Headache 199232101ndash104
28 Saper JR Silberstein SD Lake AE III Winters MEDouble-blind trial of fluoxetine chronic daily headacheand migraine Headache 199434497ndash502
29 drsquoAmato CC Pizza V Marmolo T Giordano E Alfano V
Nasta A Fluoxetine for migraine prophylaxis a double-
blind trial Headache 199939716ndash719
30 Ozyalcin SN Talu GK Kiziltan E Yucel B Ertas M Disci
R The efficacy and safety of venlafaxine in the prophylaxis
of migraine Headache 200545144ndash152
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 2004107
44ndash48
32 Diener HC Hartung E Chrubasik J et al A comparative
study of oral acetylsalicylic acid and metoprolol for the
prophylactic treatment of migraine a randomized con-
trolled double-blind parallel group phase III study Ceph-
alalgia 200121120ndash128
33 Schellenberg R Lichtenthal A Wohling H Graf C
Brixius K Nebivolol and metoprolol for treating migraine
an advance on beta-blocker treatment Headache 200848
118ndash125
34 Rao BS Das DG Taraknath VR Sarma Y A double blind
controlled study of propranolol and cyproheptadine in mi-
graine prophylaxis Neurol India 200048223ndash226
35 Diener HC Krupp P Schmitt T Steitz G Milde K
Freytag S on behalf of the Study Group Cyclandelate in
the prophylaxis of migraine a placebo-controlled study
Cephalalgia 20012166ndash70
36 Siniatchkin M Gerber WD Vein A Clinical efficacy and
central mechanisms of cyclandelate in migraine a double-
blind placebo-controlled study Funct Neurol 199813
47ndash56
37 Silberstein SD Elkind AH Schreiber C Keywood C A
randomized trial of frovatriptan for the intermittent pre-
vention of menstrual migraine Neurology 200463261ndash
269
38 Brandes JL Poole A Kallela M et al Short-term fro-
vatriptan for the prevention of difficult-to-treat menstrual
migraine attacks Cephalalgia 2009291133ndash1148
39 Newman L Mannix LK Landy S et al Naratriptan as
short-term prophylaxis of menstrually associated migraine
a randomized double-blind placebo-controlled study
Headache 200141248ndash256
40 Tuchman MM Hee A Emeribe U Silberstein S Oral
zolmitriptan in the short-term prevention of menstrual mi-
graine a randomized placebo-controlled study CNS
Drugs 200822877ndash886
Endorsed by the American Osteopathic Association on March 22 2012
Neurology 78 April 24 2012 1345
DOI 101212WNL0b013e3182535d202012781337-1345 Neurology
SD Silberstein S Holland F Freitag et al Academy of Neurology and the American Headache Society
prevention in adults Report of the Quality Standards Subcommittee of the American Evidence-based guideline update Pharmacologic treatment for episodic migraine
This information is current as of April 23 2012
rights reserved Print ISSN 0028-3878 Online ISSN 1526-632X1951 it is now a weekly with 48 issues per year Copyright Copyright copy 2012 by AAN Enterprises Inc All
reg is the official journal of the American Academy of Neurology Published continuously sinceNeurology
ServicesUpdated Information amp
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Supplementary Material
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Supplementary material can be found at
References httpnneurologyorgcontent78171337fullref-list-1
This article cites 39 articles 9 of which you can access for free at
Citations httpnneurologyorgcontent78171337fullotherarticles
This article has been cited by 5 HighWire-hosted articles
Subspecialty Collections
httpnneurologyorgcgicollectionpalliation_painPalliation pain
httpnneurologyorgcgicollectionmigraineMigrainefollowing collection(s) This article along with others on similar topics appears in the
Errata
content809871fullpdf or page
nextAn erratum has been published regarding this article Please see
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rights reserved Print ISSN 0028-3878 Online ISSN 1526-632X1951 it is now a weekly with 48 issues per year Copyright Copyright copy 2012 by AAN Enterprises Inc All
reg is the official journal of the American Academy of Neurology Published continuously sinceNeurology
CORRECTIONEvidence-based guideline update Pharmacologic treatment for episodicmigraine prevention in adults Report of the
Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society
In the special article ldquoEvidence-based guideline update Pharmacologic treatment for episodic migraine prevention in adultsReport of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Societyrdquo bySD Silberstein et al (Neurology 2012781337ndash1345) there are errors in table 1 and the text on page 1342 Due to changes inthe AANrsquos LOE classification criteria pindolol and clonidine should have been labeled as having Level U recommendations andnicardipine should have been listed as having a Level C recommendation These changes are based on studies cited in the original2001 guideline no new studies were found in the literature search for the 2012 update Please see the corrected table belowTheauthors regret the errors
Table 1 Classification of migraine preventive therapies (available in the United States)
Level A Medicationswith establishedefficacy (Dagger2 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 use
Other Medicationsthat are establishedas ineffectiveprobably ineffectiveor possiblyineffective
Antiepileptic drugs AntidepressantsSSRISSNRITCA
ACE inhibitors a-Agonists Established asineffective
Divalproex sodium Amitriptyline Lisinopril Clonidinea Lamotrigine
Sodium valproate Venlafaxine a-Agonists AntidepressantsSSRISSNRI
Probably ineffective
Topiramate b-Blockers Guanfacinea Fluoxetine Clomipraminea
b-Blockers Atenolola Angiotensin receptorblockers
Fluvoxaminea Possibly ineffective
Metoprolol Nadolola Candesartan Antiepileptic drugs Acebutolola
Propranolol Triptans (MRMb) Antiepileptic drugs Gabapentin Clonazepama
Timolola Naratriptanb Carbamazepinea Antithrombotics Nabumetonea
Triptans (MRMb) Zolmitriptanb Antihistamines Acenocoumarol Oxcarbazepine
Frovatriptanb Cyproheptadine Coumadin Telmisartan
b-Blockers Picotamide
Nebivolol b-Blockers
Ca11 blockers Bisoprolola
Nicardipinea Pindolola
Ca11 blockers
Nifedipinea
Nimodipine
Verapamil
Carbonic anhydraseinhibitor
Acetazolamide
Direct vascularsmooth musclerelaxants
Cyclandelate
TCAs
Protriptylinea
Abbreviations ACE 5 angiotensin-converting-enzyme Ca11 blockers 5 calcium channel blockers MRM 5 menstruallyrelated migraine SSNRI 5 selective serotoninndashnorepinephrine reuptake inhibitor SSRI 5 selective serotonin reuptakeinhibitor TCA 5 tricyclic antidepressanta Classification based on original guideline and new evidence not found for this reportb For short-term prophylaxis of MRM
Neurology 80 February 26 2013 871
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 Neurologyreg Website at wwwneurologyorg) Differences in ratings wereresolved by author panel discussion
ANALYSIS OF EVIDENCE The original searchidentified 179 articles A supplemental search(2007ndash2009) yielded 105 additional articles Of thetotal 284 articles 29 were classified as Class I or ClassII and are reviewed herein Studies were excluded ifthey
bull Assessed the efficacy of therapeutic agents forheadache other than episodic migraine in adults
bull Assessed acute migraine treatment migraineaura treatmentprevention or nonpharmaco-logic treatments (eg behavioral approaches)
bull Used quality of life measures disability assess-ment or nonstandardized outcomes as primaryefficacy endpoints
bull Tested the efficacy of drugs not available in theUnited States
Since 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 (gt2 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 use
Other Medications thatare established aspossibly or probablyineffective
Antiepileptic drugs AntidepressantsSSRISSNRITCA
ACE inhibitorsLisinopril
Carbonic anhydraseinhibitor
Established as noteffective
Divalproex sodium Amitriptyline Angiotensin receptorblockers
Acetazolamide Antiepileptic drugs
Sodium valproate Venlafaxine Candesartan Antithrombotics Lamotrigine
Topiramate -Blockers -Agonists Acenocoumarol Probably not effective
-Blockers Atenolola Clonidinea Coumadin Clomipraminea
Metoprolol Nadolola Guanfacinea Picotamide Possibly not effective
Propranolol Triptans (MRMb) Antiepileptic drugs AntidepressantsSSRISSNRI
Acebutolola
Timolola Naratriptanb Carbamazepinea Fluvoxaminea Clonazepama
Triptans (MRMb) Zolmitriptanb -Blockers Fluoxetine Nabumetonea
Frovatriptanb Nebivolol Antiepileptic drugs Oxcarbazepine
Pindolola Gabapentin Telmisartan
Antihistamines TCAs
Cyproheptadine Protriptylinea
-Blockers
Bisoprolola
Ca blockers
Nicardipinea
Nifedipinea
Nimodipine
Verapamil
Direct vascularsmooth musclerelaxants
Cyclandelate
Abbreviations ACE angiotensin-converting-enzyme MRM menstrually related migraine SSNRI selective serotoninndashnorepinephrine reuptake inhibitor SSRI selective serotonin reuptake inhibitor TCA tricyclic antidepressanta Classification based on original guideline and new evidence not found for this reportb For short-term prophylaxis of MRM
1338 Neurology 78 April 24 2012
clonazepam clonidine clomipramine fluvoxamineguanfacine 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 185 with placebo(263 reduction from baseline) vs 136 with cande-sartan (456 reduction from baseline p 0001)6
Selected secondary endpoints also favored candesar-tan headache hours (139 vs 95 p 0001) mi-graine days (126 vs 90 p 0001) migraine hours(922 vs 594 p 0001) and headache severity in-dex (293 vs 191 p 0001) No serious adverseevents (AEs) occurred The most common AEs weredizziness (31) ldquosymptoms of the musculoskeletalsystemrdquo (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) 5ndash36]headache days 197 vs 237 [20 CI 5ndash30] migrainedays 145 vs 185 [21 CI 9ndash34])7 AEs includedcough (26 10 discontinued treatment due tocough) dizziness (23) and ldquotendency to faintrdquo(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 (165 vs 114)8
Conclusions 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 sodium
500ndash1000 mgday had a mean reduction in 4-weekmigraine headache rate from 44week (baseline) to32week (12 attacksweek) in the ER divalproex so-dium group and from 42week to 36week (06attacksweek) in the placebo group (CI 02ndash12p 0006)9 No 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 use910 Treatment withthese agents requires careful follow-up and testingbecause of pancreatitis liver failure and teratogenic-ity risks11
Gabapentin Since the 2000 publication a Class IIIstudy12 reported that a stable gabapentin dose (4-week titration phase to 2400 mgday 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 study13 that failed to show asignificant effect for migraine prevention A secondnew Class I study comparing lamotrigine 50 mgdaywith placebo or topiramate 50 mgday reported lam-otrigine was not more effective than placebo (forboth primary endpoints) and was less effective thantopiramate in reducing migraine frequency and in-tensity14 The primary outcome measure (responderrate 50 monthly migraine frequency reduction)was 46 for lamotrigine vs 34 for placebo (p
0093 CI 002ndash026) and 63 for topiramate vs46 for lamotrigine (p 0019 CI 003ndash031)Treatment-related AEs (rash giddiness sleepinessand gastrointestinal intolerance) occurred in 10 ofpatients on lamotrigine
Oxcarbazepine One Class II trial evaluated the effi-cacy of oxcarbazepine (1200 mgday) vs placebo15
There was no difference between oxcarbazepine(130 [SE 0282]) and placebo for mean change innumber of migraine attacks from baseline during thelast 28 days of the double-blind 15-week treatmentphase (174 [SE 0283] p 02274)
Topiramate Four Class I studies1416ndash18 and 7 ClassII studies19ndash25 report topiramate (50ndash200 mgday) iseffective in migraine prevention
In a Class I placebo-controlled study (mean topi-ramate dose 125 mgday [range 25ndash200 mgday])patients given topiramate experienced a significantlylower 28-day migraine frequency vs with placebo(331 17 vs 383 21 p 0002)18 In a secondplacebo-controlled Class I double-crossover study(reviewed above) topiramate was more effective than
Neurology 78 April 24 2012 1339
placebo and lamotrigine for primary efficacy mea-sures14 In the topiramate groups 15 of patientsexperienced AEs most commonly paresthesiassleepiness and gastrointestinal intolerance The pla-cebo group reported gastrointestinal intolerance(3) and anorexia (3)
Two additional Class I studies report topiramate isas effective as propranolol16 or sodium valproate17
drugs previously established as effective for migraineprevention In the first study subjects given topiramate50 mgday had reduced mean migraine frequency (epi-sodesmonth) from baseline (607 189 to 183
139 p 0001) at 8 weeks decreased headache inten-sity VAS score from 71 145 to 367 21 (p
0001) and decreased headache duration from 1637
726 hours to 623 522 hours (p 0001)16 Sub-jects given topiramate reported paresthesias (23)weight loss (16) and somnolence (13) In pa-tients treated with propranolol 80 mgday meanheadache frequency (episodesmonth) decreasedfrom 583 198 to 22 167 (p 0001) at 8weeks headache intensity VAS score decreased from643 16 to 413 194 (p 0001) and head-ache duration decreased from 1510 684 hours to727 646 hours (p 0001) Although monthlyheadache frequency intensity and duration de-creased in both groups the topiramate group re-ported significantly greater mean reduction(topiramate frequency decrease 423 12 vs pro-pranolol 363 096 [p 0036 CI 039ndash116]topiramate intensity decrease 343 138 vs pro-pranolol 23 12 [p 0001 CI 046ndash18] topi-ramate duration decrease 101 43 vs propranolol783 45 [p 0048 CI 017ndash46])
In a crossover Class I trial (2-month washout be-tween therapies) comparing topiramate 50 mgdaywith sodium valproate 400 mgday both groupsshowed improvement from baseline in headache fre-quency intensity and duration17 Average monthlymigraine frequency decreased by 18 times with so-dium valproate (baseline 54 25 posttreatment36 21 CI 10ndash26 p 0001) as comparedwith a 3-time reduction with topiramate (baseline54 20 posttreatment 24 24 CI 21ndash39 p
0001) Headache intensity decreased by 37 with so-dium valproate (baseline 77 12 treatment 40
21 CI 29ndash46 p 0001) as compared with areduction of 36 with topiramate (baseline 69 12treatment phase 33 15 CI 29ndash43 p 0001)The average headache episode duration decreased by134 hours from baseline with sodium valproate(baseline 213 146 treatment 79 77 CI 75ndash193 p 0001) as compared with an 119-hourreduction with topiramate (baseline 173 84treatment 54 64 CI 82ndash156 p 0001) The
overall 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 (188) paresthesias (94) or both(25) Sodium valproate AEs were weight gain(345) hair loss (31) and somnolence (31)
Results of 5 Class II studies support those of theClass I studies showing topiramate as effective formigraine prevention19ndash25 Four studies demonstratedsignificant improvement over placebo19202324 oneincluded an active comparator arm suggestingequivalence of topiramate (100 200 mgday) andpropranolol (160 mgday)20 Two studies comparingtopiramate and amitriptyline (25ndash150 mgday) 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 monotherapy2122 In one of thesestudies21 the 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 placebo26
Conclusions 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 guideline1 Class II study27 showed fluoxetine (racemic) wassignificantly better than placebo for migraine preven-tion but the results were not duplicated in a secondstudy28
Since the original guideline a Class II study hasshown fluoxetine 20 mgday was more effective thanplacebo in reducing total pain index scores (calcu-lated as [Dl 1] [D2 2] [D3 3] where D1D2 and D3 represent headache hours calculated in amonth with pain intensity shown by 1 2 3) at 6months29 After the 6 months pain index scores for thefluoxetine group decreased from 135 (baseline) to 413(SD 638 p 0001) The placebo group pain indexwas 98 at baseline and 611 at 6 months (SD 577p 007) however differences were noted betweentreatment groups for baseline measures
1340 Neurology 78 April 24 2012
Venlafaxine In a Class I study venlafaxine XR 150mg significantly reduced the number of headachedays (median reduction in days venlafaxine 150 mg4 days venlafaxine 75 mg 2 days placebo 1day Kruskal-Wallis 10306 df 2 p 0006)30
All 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 415 [SD
224] vs 12 weeks 177 [SD 139 p 0001]amitriptyline baseline 327 [SD 161] vs 12weeks 154 [SD 154 p 0001])31 Patients tak-ing venlafaxine experienced nauseavomiting (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 20 drop-out rates) Comparative studies of amitriptyline withtopiramate2122 and 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 (200mgday) was more effective than aspirin (300 mgday) in achieving 50 migraine frequency reduction(responder rate metoprolol 452 aspirin
296 mean difference 1565 CI 443ndash2688)32
Attack frequencies (attacksmonth) at placebo run-inand week 20 are 336 to 237 respectively for aspirinand 355 to 182 respectively for metoprolol Nosignificant AEs were reported
A small Class II study reported metoprolol (475ndash1425 mgday) had similar efficacy to nebivolol 5
mgday for migraine prevention (assessed by a de-crease in mean migraine attacks)33
Propranolol The original guideline concludedpropranolol was established as effective for migraineprevention
In a Class II study propranolol (80 mgday) wasmore effective than placebo and as effective as cypro-heptadine (4 mgday) in reducing migraine fre-quency duration and attack severity34 Thedifference in attack frequency reduction was signifi-cant between treatments propranolol 285 02(SEM) vs cyproheptadine 309 031 vs combi-nation 312 01 vs placebo 177 044 (all p 005 vs placebo) For attack frequency reductioncombination therapy was more effective than mono-therapy (p 005) AEs were drowsiness sleep dis-turbance weight gain fatigue and dry mouthpercentages 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 duration35 The secondstudy (smaller underpowered n 25) found cy-clandelate significantly reduced the number of mi-graine days and duration (assessed using a contingentnegative variation measure)36
Conclusions The efficacy of cyclandelate is unknown(conflicting Class II studies)
Triptans Since the original guideline new Class Istudies have assessed the efficacy of frovatriptan3738
naratriptan39 and zolmitriptan40 for short-term pre-vention of menstrually associated migraine (MAM)
Frovatriptan Frovatriptan 25 mg BIDqd wasmore effective than placebo in reducing migraine fre-
Neurology 78 April 24 2012 1341
quency37 The mean number of headache-free peri-menstrual periods (PMPs) per patient (primaryendpoint) was higher in the 2 frovatriptan groups(25 mg qd 069 [SD 092 CI 114ndash273 p 00091] vs 25 mg BID 092 [SD 103 CI 184ndash428 p 00001] vs placebo 042 [SD 078])representing 64 (25 mgday) and 119 (5 mgday) increases in the mean number of headache-freePMPs per patient over placebo A second Class Istudy38 also reports the MAM headache incidenceduring the 6-day PMP was 67 for placebo 52 forfrovatriptan 25 mg QD (p 00001 vs placebo)and 41 for frovatriptan 25 mg BID (p 00001vs placebo p 00001 vs QD regimen) The AEincidence and type for both regimens were similar tothose for placebo The overall AE incidence for fro-vatriptan was 41 (25 mg BID) and 27 (25 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 days39 Patients treated withnaratriptan 1 mg experienced more headache-freePMPs than those on placebo (50 vs 25 p
0003) Naratriptan 1 mg reduced the number ofMAMs (20 vs 40 p 005) and MAM days (42 vs70 p 001) vs placebo The AE incidence andseverity were similar to those of placebo 10 ofpatients experienced dizziness chest pain or malaise
Zolmitriptan One Class I study reported the effi-cacy of zolmitriptan 25 BIDTID vs placebo Bothzolmitriptan regimens demonstrated superior effi-cacy vs placebo the proportion of patients with a50 MAM attack frequency reduction (zolmi-triptan 25 mg TID [586] p 00007 vs placebozolmitriptan 25 mg BID [547] p 0002 vs pla-cebo placebo 378)40 AEs were considered possi-bly treatment-related in 28 patients (333) in thezolmitriptan 25 mg TID group 29 (363) in thezolmitriptan 25 mg BID group and 18 (220) 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 more
effective than placebo in reducing migraine fre-quency duration and severitye1 This trial (n 53) 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
bull Antiepileptic drugs (AEDs) divalproex so-dium sodium valproate topiramate
bull -Blockers metoprolol propranolol timololbull Triptans frovatriptan for short-term MAMs
prevention
Level B The following medications are probablyeffective and should be considered for migraineprevention
bull Antidepressants amitriptyline venlafaxinebull -Blockers atenolol nadololbull Triptans naratriptan zolmitriptan for short-
term MAMs prevention
Level C The following medications are possibly effec-tive and may be considered for migraine prevention
bull ACE inhibitors lisinoprilbull Angiotensin receptor blockers candesartanbull -Agonists clonidine guanfacinebull AEDs carbamazepinebull -Blockers nebivolol pindolol
Level U Evidence is conflicting or inadequate to sup-port or refute the use of the following medicationsfor migraine prevention
bull AEDs gabapentinbull Antidepressants
bull Selective serotonin reuptake inhibitorselec-tive serotonin-norepinephrine reuptake in-hibitors fluoxetine fluvoxamine
bull Tricyclics protriptylinebull Antithrombotics acenocoumarol Coumadin
picotamidebull -Blockers bisoprololbull Calcium-channel blockers nicardipine nifedi-
pine nimodipine verapamilbull Acetazolamidebull Cyclandelate
Level A negative The following medication is estab-lished as ineffective and should not be offered formigraine prevention
bull Lamotrigine
1342 Neurology 78 April 24 2012
Level B negative The following medication is proba-bly ineffective and should not be considered for mi-graine prevention
bull Clomipramine
Level C negative The following medications are pos-sibly ineffective and may not be considered for mi-graine prevention
bull Acebutololbull Clonazepambull Nabumetonebull Oxcarbazepinebull Telmisartan
CLINICAL 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 coexistingcomorbid 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 agentsStudies 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 12ndash16weeks) 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 25 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 draftingrevising the manuscript
study concept or design analysis or interpretation of data acquisition of
data study supervision Dr Holland draftingrevising the manuscript
study concept or design analysis or interpretation of data Dr Freitag
draftingrevising the manuscript analysis or interpretation of data acqui-
sition of data Dr Dodick draftingrevising the manuscript study con-
cept or design analysis or interpretation of data Dr Argoff drafting
revising the manuscript study concept or design analysis or
interpretation of data Dr Ashman draftingrevising the manuscript
analysis or interpretation of data
DISCLOSUREDr Silberstein is on the advisory panel of and receives honoraria from
AGA 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 speakersrsquo bureau
of and receives honoraria from Endo Pharmaceuticals GlaxoSmithKline
and Merck He serves as a consultant for and receives honoraria from
Amgen 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 the
American Headache Society and research support from Albert Einstein
College of Medicine Dr Freitag has served on the scientific advisory
boards of Zogenix Pharmaceuticals Allergan Pharmaceuticals Nautilus
MAP Pharmaceuticals and Nupathe has received travel expenses and or
honoraria from GlaxoSmithKline Zogenix Merck Nautilus Allergan
Diamond Headache Clinic Research and Educational Foundation (not
for profit) and the American Headache Society (travel) Dr Freitag is a
member of the Board of Directors of the National Headache Foundation
Dr Dodick within the past 3 years serves on advisory boards and has
consulted for Allergan Alder Pfizer Merck Coherex Ferring Neuro-
core Neuralieve Neuraxon NuPathe Inc MAP SmithKlineBeecham
Boston Scientific Medtronic Inc Nautilus Eli Lilly amp Company No-
Neurology 78 April 24 2012 1343
vartis Colucid GlaxoSmithKline Autonomic Technologies MAP Phar-
maceuticals Inc Zogenix Inc Impax Laboratories Inc Bristol Myers
Squibb 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 SAGE
Publishing Lippincott Williams amp 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 The
Neurologist Lancet Neurology and Postgraduate Medicine and has served
as Editor-in-Chief of Headache Currents and as an Associate Editor of
Headache he receives publishing royalties for Wolff rsquos Headache 8th edi-
tion (Oxford University Press 2009) and Handbook of Headache (Cam-
bridge University Press 2010) Within the past 3 years Dr Dodick has
received research grant support from Advanced Neurostimulation Sys-
tems Boston Scientific St Jude Medical Inc Medtronic NINDSNIH
Mayo Clinic Dr Argoff has served on a scientific advisory board for the
Department of Defense and DSMB for the NIH has received funding for
travel andor speaking andor has served on a speakersrsquo bureau for Pfizer
(King) Janssen (Pricara) Millennium Laboratories Neurogesx Forest
Laboratories Eli Lilly Covidien and Endo Pharmaceuticals has received
research support from Endo Pharmaceuticals Forest Laboratories Eli
Lilly Neurogesx Pfizer and SBRT funded by the NIH and has received
stockstock options from Pfizer Dr Ashman is the Level of Evidence
editor 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 Neurologyorg for full
disclosures
DISCLAIMERThis statement is provided as an educational service of the American
Academy of Neurology and the American Headache Society It is based
on as assessment of current scientific and clinical information It is not
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 it intended to exclude any reasonable alternative
methodologies The AAN and the AHS recognize that specific patient
care decisions are the prerogative of the patient and the physician
caring for the patient based on all of the circumstances involved The
clinical context section is made available in order to place the
evidence-based guideline(s) into perspective with current practice hab-
its and challenges No formal practice recommendations should be
inferred
CONFLICT OF INTERESTThe American Academy of Neurology and the American Headache Soci-
ety are committed to producing independent critical and truthful clinical
practice guidelines (CPGs) Significant efforts are made to minimize the
potential for conflicts of interest to influence the recommendations of this
CPG To the extent possible the AAN and AHS keep separate those who
have a financial stake in the success or failure of the products appraised in
the CPGs and the developers of the guidelines Conflict of interest forms
were obtained from all authors and reviewed by an oversight committee
prior to project initiation AAN and AHS limit the participation of au-
thors with substantial conflicts of interest The AAN and AHS forbid
commercial participation in or funding of guideline projects Drafts of
the 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 of
Interest Policy can be viewed at wwwaancom
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 200768343ndash349
2 Ramadan NM Silberstein SD Freitag FG Gilbert TT
Frishberg BM Evidence-based guidelines for migraine
headache in the primary care setting pharmacological
management for prevention of migraine Available at
httpwwwaancomprofessionalspracticepdfsgl0090
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 the
American Academy of Neurology Neurology 200055
754ndash762
4 Naumann M So Y Argoff C et al Assessment Botuli-
num neurotoxin in the treatment of autonomic disorders
and pain (an evidence-based review) report of the Thera-
peutics and Technology Subcommittee of the American
Academy of Neurology Neurology 2008701707ndash1714
5 Holland S Silberstein SD Freitag F Dodick DW Argoff
C Ashman E Evidence-based guideline update NSAIDs
and other complementary treatments for episodic migraine
prevention in adults report of the Quality Standards Sub-
committee of the American Academy of Neurology and
the American Headache Society Neurology 201278
1346ndash1353
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
28965ndash69
7 Schrader H Stovner LJ Helde G Sand T Bovim G Pro-
phylactic treatment of migraine with angiotensin convert-
ing enzyme inhibitor (lisinopril) randomised placebo
controlled crossover study BMJ 200132219ndash22
8 Diener HC Gendolla A Feuersenger A et al Telmisartan
in migraine prophylaxis a randomized placebo-controlled
trial Cephalalgia 200929921ndash927
9 Freitag FG Collins SD Carlson HA et al A randomized
trial of divalproex sodium extended-release tablets in mi-
graine prophylaxis Neurology 2002581652ndash1659
10 Silberstein SD Collins SD Safety of divalproex sodium in
migraine prophylaxis an open-label long-term study
long-term safety of Depakote in Headache Prophylaxis
Study Group Headache 199939633ndash643
11 Harden CL Meador KJ Pennell PB et al American Acad-
emy of Neurology American Epilepsy Society Practice pa-
rameter update management issues for women with
epilepsyndashfocus on pregnancy (an evidence-based review)
teratogenesis and perinatal outcomes report of the Quality
Standards Subcommittee and Therapeutics and Technol-
ogy Assessment Subcommittee of the American Academy
of Neurology and American Epilepsy Society Neurology
200973133ndash141
12 Mathew NT Rapoport A Saper J et al Efficacy of gabap-
entin in migraine prophylaxis Headache 200141119ndash
128
13 Steiner TJ Findley LJ Yuen AW Lamotrigine versus pla-
cebo in the prophylaxis of migraine with and without aura
Cephalalgia 199717109ndash112
14 Gupta P Singh S Goyal V Shukla G Behari M Low-
dose topiramate versus lamotrigine in migraine prophy-
laxis (the Lotolamp study) Headache 200747402ndash412
15 Silberstein SD Saper J Berenson F Somogyi M Mc-
Cague MA DrsquoSouza JD Oxcarbazepine in migraine head-
ache a double-blind randomized placebo-controlled
study Neurology 200870548ndash555
1344 Neurology 78 April 24 2012
16 Ashtari F Shaygannejad V Akbari M A double-blindrandomized trial of low-dose topiramate vs propranolol inmigraine prophylaxis Acta Neurol Scand 2008118301ndash305
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 Headache200646642ndash 648
18 Storey JR Calder CS Hart DE Potter DL Topiramate inmigraine prevention a double-blind placebo-controlledstudy Headache 200141968ndash975
19 Brandes JL Saper JR Diamond M et al MIGR-002Study Group Topiramate for migraine prevention a ran-domized controlled trial JAMA 2004291965ndash973
20 Diener HC Matias-Guiu J Hartung E et al Topiramatein migraine prophylaxisndashresults from a placebo-controlledtrial with propranolol as an active control J Neurol 2004251943ndash950
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 200931542ndash559
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 2008110979ndash984
23 Mei D Capuano A Vollono C et al Topiramate in mi-graine prophylaxis a randomised double-blind versus pla-cebo study Neurol Sci 200425245ndash250
24 Silberstein SD Neto W Schmitt J Jacobs D MIGR-001Study Group Topiramate in migraine prevention resultsof a large controlled trial Arch Neurol 200461490ndash495
25 Millan-Guerrero RO Isais-Millan R Barreto-Vizcaiacuteno Set al Subcutaneous histamine versus topiramate in mi-graine prophylaxis a double-blind study Eur Neurol200859237ndash242
26 Silberstein SD Hulihan J Karim MR et al Efficacy andtolerability of topiramate 200 mgd in the prevention ofmigraine withwithout aura in adults a randomizedplacebo-controlled double-blind 12-week pilot studyClin Ther 2006281002ndash1011
27 Adly C Straumanis J Chesson A Fluoxetine prophylaxisof migraine Headache 199232101ndash104
28 Saper JR Silberstein SD Lake AE III Winters MEDouble-blind trial of fluoxetine chronic daily headacheand migraine Headache 199434497ndash502
29 drsquoAmato CC Pizza V Marmolo T Giordano E Alfano V
Nasta A Fluoxetine for migraine prophylaxis a double-
blind trial Headache 199939716ndash719
30 Ozyalcin SN Talu GK Kiziltan E Yucel B Ertas M Disci
R The efficacy and safety of venlafaxine in the prophylaxis
of migraine Headache 200545144ndash152
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 2004107
44ndash48
32 Diener HC Hartung E Chrubasik J et al A comparative
study of oral acetylsalicylic acid and metoprolol for the
prophylactic treatment of migraine a randomized con-
trolled double-blind parallel group phase III study Ceph-
alalgia 200121120ndash128
33 Schellenberg R Lichtenthal A Wohling H Graf C
Brixius K Nebivolol and metoprolol for treating migraine
an advance on beta-blocker treatment Headache 200848
118ndash125
34 Rao BS Das DG Taraknath VR Sarma Y A double blind
controlled study of propranolol and cyproheptadine in mi-
graine prophylaxis Neurol India 200048223ndash226
35 Diener HC Krupp P Schmitt T Steitz G Milde K
Freytag S on behalf of the Study Group Cyclandelate in
the prophylaxis of migraine a placebo-controlled study
Cephalalgia 20012166ndash70
36 Siniatchkin M Gerber WD Vein A Clinical efficacy and
central mechanisms of cyclandelate in migraine a double-
blind placebo-controlled study Funct Neurol 199813
47ndash56
37 Silberstein SD Elkind AH Schreiber C Keywood C A
randomized trial of frovatriptan for the intermittent pre-
vention of menstrual migraine Neurology 200463261ndash
269
38 Brandes JL Poole A Kallela M et al Short-term fro-
vatriptan for the prevention of difficult-to-treat menstrual
migraine attacks Cephalalgia 2009291133ndash1148
39 Newman L Mannix LK Landy S et al Naratriptan as
short-term prophylaxis of menstrually associated migraine
a randomized double-blind placebo-controlled study
Headache 200141248ndash256
40 Tuchman MM Hee A Emeribe U Silberstein S Oral
zolmitriptan in the short-term prevention of menstrual mi-
graine a randomized placebo-controlled study CNS
Drugs 200822877ndash886
Endorsed by the American Osteopathic Association on March 22 2012
Neurology 78 April 24 2012 1345
DOI 101212WNL0b013e3182535d202012781337-1345 Neurology
SD Silberstein S Holland F Freitag et al Academy of Neurology and the American Headache Society
prevention in adults Report of the Quality Standards Subcommittee of the American Evidence-based guideline update Pharmacologic treatment for episodic migraine
This information is current as of April 23 2012
rights reserved Print ISSN 0028-3878 Online ISSN 1526-632X1951 it is now a weekly with 48 issues per year Copyright Copyright copy 2012 by AAN Enterprises Inc All
reg is the official journal of the American Academy of Neurology Published continuously sinceNeurology
ServicesUpdated Information amp
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Supplementary Material
httpnneurologyorgcontentsuppl2013010378171337DC4 httpnneurologyorgcontentsuppl2012120378171337DC3 httpnneurologyorgcontentsuppl2012042278171337DC2 httpnneurologyorgcontentsuppl2012042278171337DC1
Supplementary material can be found at
References httpnneurologyorgcontent78171337fullref-list-1
This article cites 39 articles 9 of which you can access for free at
Citations httpnneurologyorgcontent78171337fullotherarticles
This article has been cited by 5 HighWire-hosted articles
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httpnneurologyorgcgicollectionmigraineMigrainefollowing collection(s) This article along with others on similar topics appears in the
Errata
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nextAn erratum has been published regarding this article Please see
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rights reserved Print ISSN 0028-3878 Online ISSN 1526-632X1951 it is now a weekly with 48 issues per year Copyright Copyright copy 2012 by AAN Enterprises Inc All
reg is the official journal of the American Academy of Neurology Published continuously sinceNeurology
CORRECTIONEvidence-based guideline update Pharmacologic treatment for episodicmigraine prevention in adults Report of the
Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society
In the special article ldquoEvidence-based guideline update Pharmacologic treatment for episodic migraine prevention in adultsReport of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Societyrdquo bySD Silberstein et al (Neurology 2012781337ndash1345) there are errors in table 1 and the text on page 1342 Due to changes inthe AANrsquos LOE classification criteria pindolol and clonidine should have been labeled as having Level U recommendations andnicardipine should have been listed as having a Level C recommendation These changes are based on studies cited in the original2001 guideline no new studies were found in the literature search for the 2012 update Please see the corrected table belowTheauthors regret the errors
Table 1 Classification of migraine preventive therapies (available in the United States)
Level A Medicationswith establishedefficacy (Dagger2 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 use
Other Medicationsthat are establishedas ineffectiveprobably ineffectiveor possiblyineffective
Antiepileptic drugs AntidepressantsSSRISSNRITCA
ACE inhibitors a-Agonists Established asineffective
Divalproex sodium Amitriptyline Lisinopril Clonidinea Lamotrigine
Sodium valproate Venlafaxine a-Agonists AntidepressantsSSRISSNRI
Probably ineffective
Topiramate b-Blockers Guanfacinea Fluoxetine Clomipraminea
b-Blockers Atenolola Angiotensin receptorblockers
Fluvoxaminea Possibly ineffective
Metoprolol Nadolola Candesartan Antiepileptic drugs Acebutolola
Propranolol Triptans (MRMb) Antiepileptic drugs Gabapentin Clonazepama
Timolola Naratriptanb Carbamazepinea Antithrombotics Nabumetonea
Triptans (MRMb) Zolmitriptanb Antihistamines Acenocoumarol Oxcarbazepine
Frovatriptanb Cyproheptadine Coumadin Telmisartan
b-Blockers Picotamide
Nebivolol b-Blockers
Ca11 blockers Bisoprolola
Nicardipinea Pindolola
Ca11 blockers
Nifedipinea
Nimodipine
Verapamil
Carbonic anhydraseinhibitor
Acetazolamide
Direct vascularsmooth musclerelaxants
Cyclandelate
TCAs
Protriptylinea
Abbreviations ACE 5 angiotensin-converting-enzyme Ca11 blockers 5 calcium channel blockers MRM 5 menstruallyrelated migraine SSNRI 5 selective serotoninndashnorepinephrine reuptake inhibitor SSRI 5 selective serotonin reuptakeinhibitor TCA 5 tricyclic antidepressanta Classification based on original guideline and new evidence not found for this reportb For short-term prophylaxis of MRM
Neurology 80 February 26 2013 871
clonazepam clonidine clomipramine fluvoxamineguanfacine 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 185 with placebo(263 reduction from baseline) vs 136 with cande-sartan (456 reduction from baseline p 0001)6
Selected secondary endpoints also favored candesar-tan headache hours (139 vs 95 p 0001) mi-graine days (126 vs 90 p 0001) migraine hours(922 vs 594 p 0001) and headache severity in-dex (293 vs 191 p 0001) No serious adverseevents (AEs) occurred The most common AEs weredizziness (31) ldquosymptoms of the musculoskeletalsystemrdquo (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) 5ndash36]headache days 197 vs 237 [20 CI 5ndash30] migrainedays 145 vs 185 [21 CI 9ndash34])7 AEs includedcough (26 10 discontinued treatment due tocough) dizziness (23) and ldquotendency to faintrdquo(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 (165 vs 114)8
Conclusions 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 sodium
500ndash1000 mgday had a mean reduction in 4-weekmigraine headache rate from 44week (baseline) to32week (12 attacksweek) in the ER divalproex so-dium group and from 42week to 36week (06attacksweek) in the placebo group (CI 02ndash12p 0006)9 No 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 use910 Treatment withthese agents requires careful follow-up and testingbecause of pancreatitis liver failure and teratogenic-ity risks11
Gabapentin Since the 2000 publication a Class IIIstudy12 reported that a stable gabapentin dose (4-week titration phase to 2400 mgday 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 study13 that failed to show asignificant effect for migraine prevention A secondnew Class I study comparing lamotrigine 50 mgdaywith placebo or topiramate 50 mgday reported lam-otrigine was not more effective than placebo (forboth primary endpoints) and was less effective thantopiramate in reducing migraine frequency and in-tensity14 The primary outcome measure (responderrate 50 monthly migraine frequency reduction)was 46 for lamotrigine vs 34 for placebo (p
0093 CI 002ndash026) and 63 for topiramate vs46 for lamotrigine (p 0019 CI 003ndash031)Treatment-related AEs (rash giddiness sleepinessand gastrointestinal intolerance) occurred in 10 ofpatients on lamotrigine
Oxcarbazepine One Class II trial evaluated the effi-cacy of oxcarbazepine (1200 mgday) vs placebo15
There was no difference between oxcarbazepine(130 [SE 0282]) and placebo for mean change innumber of migraine attacks from baseline during thelast 28 days of the double-blind 15-week treatmentphase (174 [SE 0283] p 02274)
Topiramate Four Class I studies1416ndash18 and 7 ClassII studies19ndash25 report topiramate (50ndash200 mgday) iseffective in migraine prevention
In a Class I placebo-controlled study (mean topi-ramate dose 125 mgday [range 25ndash200 mgday])patients given topiramate experienced a significantlylower 28-day migraine frequency vs with placebo(331 17 vs 383 21 p 0002)18 In a secondplacebo-controlled Class I double-crossover study(reviewed above) topiramate was more effective than
Neurology 78 April 24 2012 1339
placebo and lamotrigine for primary efficacy mea-sures14 In the topiramate groups 15 of patientsexperienced AEs most commonly paresthesiassleepiness and gastrointestinal intolerance The pla-cebo group reported gastrointestinal intolerance(3) and anorexia (3)
Two additional Class I studies report topiramate isas effective as propranolol16 or sodium valproate17
drugs previously established as effective for migraineprevention In the first study subjects given topiramate50 mgday had reduced mean migraine frequency (epi-sodesmonth) from baseline (607 189 to 183
139 p 0001) at 8 weeks decreased headache inten-sity VAS score from 71 145 to 367 21 (p
0001) and decreased headache duration from 1637
726 hours to 623 522 hours (p 0001)16 Sub-jects given topiramate reported paresthesias (23)weight loss (16) and somnolence (13) In pa-tients treated with propranolol 80 mgday meanheadache frequency (episodesmonth) decreasedfrom 583 198 to 22 167 (p 0001) at 8weeks headache intensity VAS score decreased from643 16 to 413 194 (p 0001) and head-ache duration decreased from 1510 684 hours to727 646 hours (p 0001) Although monthlyheadache frequency intensity and duration de-creased in both groups the topiramate group re-ported significantly greater mean reduction(topiramate frequency decrease 423 12 vs pro-pranolol 363 096 [p 0036 CI 039ndash116]topiramate intensity decrease 343 138 vs pro-pranolol 23 12 [p 0001 CI 046ndash18] topi-ramate duration decrease 101 43 vs propranolol783 45 [p 0048 CI 017ndash46])
In a crossover Class I trial (2-month washout be-tween therapies) comparing topiramate 50 mgdaywith sodium valproate 400 mgday both groupsshowed improvement from baseline in headache fre-quency intensity and duration17 Average monthlymigraine frequency decreased by 18 times with so-dium valproate (baseline 54 25 posttreatment36 21 CI 10ndash26 p 0001) as comparedwith a 3-time reduction with topiramate (baseline54 20 posttreatment 24 24 CI 21ndash39 p
0001) Headache intensity decreased by 37 with so-dium valproate (baseline 77 12 treatment 40
21 CI 29ndash46 p 0001) as compared with areduction of 36 with topiramate (baseline 69 12treatment phase 33 15 CI 29ndash43 p 0001)The average headache episode duration decreased by134 hours from baseline with sodium valproate(baseline 213 146 treatment 79 77 CI 75ndash193 p 0001) as compared with an 119-hourreduction with topiramate (baseline 173 84treatment 54 64 CI 82ndash156 p 0001) The
overall 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 (188) paresthesias (94) or both(25) Sodium valproate AEs were weight gain(345) hair loss (31) and somnolence (31)
Results of 5 Class II studies support those of theClass I studies showing topiramate as effective formigraine prevention19ndash25 Four studies demonstratedsignificant improvement over placebo19202324 oneincluded an active comparator arm suggestingequivalence of topiramate (100 200 mgday) andpropranolol (160 mgday)20 Two studies comparingtopiramate and amitriptyline (25ndash150 mgday) 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 monotherapy2122 In one of thesestudies21 the 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 placebo26
Conclusions 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 guideline1 Class II study27 showed fluoxetine (racemic) wassignificantly better than placebo for migraine preven-tion but the results were not duplicated in a secondstudy28
Since the original guideline a Class II study hasshown fluoxetine 20 mgday was more effective thanplacebo in reducing total pain index scores (calcu-lated as [Dl 1] [D2 2] [D3 3] where D1D2 and D3 represent headache hours calculated in amonth with pain intensity shown by 1 2 3) at 6months29 After the 6 months pain index scores for thefluoxetine group decreased from 135 (baseline) to 413(SD 638 p 0001) The placebo group pain indexwas 98 at baseline and 611 at 6 months (SD 577p 007) however differences were noted betweentreatment groups for baseline measures
1340 Neurology 78 April 24 2012
Venlafaxine In a Class I study venlafaxine XR 150mg significantly reduced the number of headachedays (median reduction in days venlafaxine 150 mg4 days venlafaxine 75 mg 2 days placebo 1day Kruskal-Wallis 10306 df 2 p 0006)30
All 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 415 [SD
224] vs 12 weeks 177 [SD 139 p 0001]amitriptyline baseline 327 [SD 161] vs 12weeks 154 [SD 154 p 0001])31 Patients tak-ing venlafaxine experienced nauseavomiting (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 20 drop-out rates) Comparative studies of amitriptyline withtopiramate2122 and 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 (200mgday) was more effective than aspirin (300 mgday) in achieving 50 migraine frequency reduction(responder rate metoprolol 452 aspirin
296 mean difference 1565 CI 443ndash2688)32
Attack frequencies (attacksmonth) at placebo run-inand week 20 are 336 to 237 respectively for aspirinand 355 to 182 respectively for metoprolol Nosignificant AEs were reported
A small Class II study reported metoprolol (475ndash1425 mgday) had similar efficacy to nebivolol 5
mgday for migraine prevention (assessed by a de-crease in mean migraine attacks)33
Propranolol The original guideline concludedpropranolol was established as effective for migraineprevention
In a Class II study propranolol (80 mgday) wasmore effective than placebo and as effective as cypro-heptadine (4 mgday) in reducing migraine fre-quency duration and attack severity34 Thedifference in attack frequency reduction was signifi-cant between treatments propranolol 285 02(SEM) vs cyproheptadine 309 031 vs combi-nation 312 01 vs placebo 177 044 (all p 005 vs placebo) For attack frequency reductioncombination therapy was more effective than mono-therapy (p 005) AEs were drowsiness sleep dis-turbance weight gain fatigue and dry mouthpercentages 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 duration35 The secondstudy (smaller underpowered n 25) found cy-clandelate significantly reduced the number of mi-graine days and duration (assessed using a contingentnegative variation measure)36
Conclusions The efficacy of cyclandelate is unknown(conflicting Class II studies)
Triptans Since the original guideline new Class Istudies have assessed the efficacy of frovatriptan3738
naratriptan39 and zolmitriptan40 for short-term pre-vention of menstrually associated migraine (MAM)
Frovatriptan Frovatriptan 25 mg BIDqd wasmore effective than placebo in reducing migraine fre-
Neurology 78 April 24 2012 1341
quency37 The mean number of headache-free peri-menstrual periods (PMPs) per patient (primaryendpoint) was higher in the 2 frovatriptan groups(25 mg qd 069 [SD 092 CI 114ndash273 p 00091] vs 25 mg BID 092 [SD 103 CI 184ndash428 p 00001] vs placebo 042 [SD 078])representing 64 (25 mgday) and 119 (5 mgday) increases in the mean number of headache-freePMPs per patient over placebo A second Class Istudy38 also reports the MAM headache incidenceduring the 6-day PMP was 67 for placebo 52 forfrovatriptan 25 mg QD (p 00001 vs placebo)and 41 for frovatriptan 25 mg BID (p 00001vs placebo p 00001 vs QD regimen) The AEincidence and type for both regimens were similar tothose for placebo The overall AE incidence for fro-vatriptan was 41 (25 mg BID) and 27 (25 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 days39 Patients treated withnaratriptan 1 mg experienced more headache-freePMPs than those on placebo (50 vs 25 p
0003) Naratriptan 1 mg reduced the number ofMAMs (20 vs 40 p 005) and MAM days (42 vs70 p 001) vs placebo The AE incidence andseverity were similar to those of placebo 10 ofpatients experienced dizziness chest pain or malaise
Zolmitriptan One Class I study reported the effi-cacy of zolmitriptan 25 BIDTID vs placebo Bothzolmitriptan regimens demonstrated superior effi-cacy vs placebo the proportion of patients with a50 MAM attack frequency reduction (zolmi-triptan 25 mg TID [586] p 00007 vs placebozolmitriptan 25 mg BID [547] p 0002 vs pla-cebo placebo 378)40 AEs were considered possi-bly treatment-related in 28 patients (333) in thezolmitriptan 25 mg TID group 29 (363) in thezolmitriptan 25 mg BID group and 18 (220) 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 more
effective than placebo in reducing migraine fre-quency duration and severitye1 This trial (n 53) 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
bull Antiepileptic drugs (AEDs) divalproex so-dium sodium valproate topiramate
bull -Blockers metoprolol propranolol timololbull Triptans frovatriptan for short-term MAMs
prevention
Level B The following medications are probablyeffective and should be considered for migraineprevention
bull Antidepressants amitriptyline venlafaxinebull -Blockers atenolol nadololbull Triptans naratriptan zolmitriptan for short-
term MAMs prevention
Level C The following medications are possibly effec-tive and may be considered for migraine prevention
bull ACE inhibitors lisinoprilbull Angiotensin receptor blockers candesartanbull -Agonists clonidine guanfacinebull AEDs carbamazepinebull -Blockers nebivolol pindolol
Level U Evidence is conflicting or inadequate to sup-port or refute the use of the following medicationsfor migraine prevention
bull AEDs gabapentinbull Antidepressants
bull Selective serotonin reuptake inhibitorselec-tive serotonin-norepinephrine reuptake in-hibitors fluoxetine fluvoxamine
bull Tricyclics protriptylinebull Antithrombotics acenocoumarol Coumadin
picotamidebull -Blockers bisoprololbull Calcium-channel blockers nicardipine nifedi-
pine nimodipine verapamilbull Acetazolamidebull Cyclandelate
Level A negative The following medication is estab-lished as ineffective and should not be offered formigraine prevention
bull Lamotrigine
1342 Neurology 78 April 24 2012
Level B negative The following medication is proba-bly ineffective and should not be considered for mi-graine prevention
bull Clomipramine
Level C negative The following medications are pos-sibly ineffective and may not be considered for mi-graine prevention
bull Acebutololbull Clonazepambull Nabumetonebull Oxcarbazepinebull Telmisartan
CLINICAL 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 coexistingcomorbid 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 agentsStudies 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 12ndash16weeks) 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 25 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 draftingrevising the manuscript
study concept or design analysis or interpretation of data acquisition of
data study supervision Dr Holland draftingrevising the manuscript
study concept or design analysis or interpretation of data Dr Freitag
draftingrevising the manuscript analysis or interpretation of data acqui-
sition of data Dr Dodick draftingrevising the manuscript study con-
cept or design analysis or interpretation of data Dr Argoff drafting
revising the manuscript study concept or design analysis or
interpretation of data Dr Ashman draftingrevising the manuscript
analysis or interpretation of data
DISCLOSUREDr Silberstein is on the advisory panel of and receives honoraria from
AGA 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 speakersrsquo bureau
of and receives honoraria from Endo Pharmaceuticals GlaxoSmithKline
and Merck He serves as a consultant for and receives honoraria from
Amgen 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 the
American Headache Society and research support from Albert Einstein
College of Medicine Dr Freitag has served on the scientific advisory
boards of Zogenix Pharmaceuticals Allergan Pharmaceuticals Nautilus
MAP Pharmaceuticals and Nupathe has received travel expenses and or
honoraria from GlaxoSmithKline Zogenix Merck Nautilus Allergan
Diamond Headache Clinic Research and Educational Foundation (not
for profit) and the American Headache Society (travel) Dr Freitag is a
member of the Board of Directors of the National Headache Foundation
Dr Dodick within the past 3 years serves on advisory boards and has
consulted for Allergan Alder Pfizer Merck Coherex Ferring Neuro-
core Neuralieve Neuraxon NuPathe Inc MAP SmithKlineBeecham
Boston Scientific Medtronic Inc Nautilus Eli Lilly amp Company No-
Neurology 78 April 24 2012 1343
vartis Colucid GlaxoSmithKline Autonomic Technologies MAP Phar-
maceuticals Inc Zogenix Inc Impax Laboratories Inc Bristol Myers
Squibb 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 SAGE
Publishing Lippincott Williams amp 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 The
Neurologist Lancet Neurology and Postgraduate Medicine and has served
as Editor-in-Chief of Headache Currents and as an Associate Editor of
Headache he receives publishing royalties for Wolff rsquos Headache 8th edi-
tion (Oxford University Press 2009) and Handbook of Headache (Cam-
bridge University Press 2010) Within the past 3 years Dr Dodick has
received research grant support from Advanced Neurostimulation Sys-
tems Boston Scientific St Jude Medical Inc Medtronic NINDSNIH
Mayo Clinic Dr Argoff has served on a scientific advisory board for the
Department of Defense and DSMB for the NIH has received funding for
travel andor speaking andor has served on a speakersrsquo bureau for Pfizer
(King) Janssen (Pricara) Millennium Laboratories Neurogesx Forest
Laboratories Eli Lilly Covidien and Endo Pharmaceuticals has received
research support from Endo Pharmaceuticals Forest Laboratories Eli
Lilly Neurogesx Pfizer and SBRT funded by the NIH and has received
stockstock options from Pfizer Dr Ashman is the Level of Evidence
editor 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 Neurologyorg for full
disclosures
DISCLAIMERThis statement is provided as an educational service of the American
Academy of Neurology and the American Headache Society It is based
on as assessment of current scientific and clinical information It is not
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 it intended to exclude any reasonable alternative
methodologies The AAN and the AHS recognize that specific patient
care decisions are the prerogative of the patient and the physician
caring for the patient based on all of the circumstances involved The
clinical context section is made available in order to place the
evidence-based guideline(s) into perspective with current practice hab-
its and challenges No formal practice recommendations should be
inferred
CONFLICT OF INTERESTThe American Academy of Neurology and the American Headache Soci-
ety are committed to producing independent critical and truthful clinical
practice guidelines (CPGs) Significant efforts are made to minimize the
potential for conflicts of interest to influence the recommendations of this
CPG To the extent possible the AAN and AHS keep separate those who
have a financial stake in the success or failure of the products appraised in
the CPGs and the developers of the guidelines Conflict of interest forms
were obtained from all authors and reviewed by an oversight committee
prior to project initiation AAN and AHS limit the participation of au-
thors with substantial conflicts of interest The AAN and AHS forbid
commercial participation in or funding of guideline projects Drafts of
the 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 of
Interest Policy can be viewed at wwwaancom
Received June 27 2011 Accepted in final form January 25 2012
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Stewart WF The American Migraine Prevalence and Pre-vention Advisory Group Migraine prevalence disease bur-den and the need for preventive therapy Neurology 200768343ndash349
2 Ramadan NM Silberstein SD Freitag FG Gilbert TT
Frishberg BM Evidence-based guidelines for migraine
headache in the primary care setting pharmacological
management for prevention of migraine Available at
httpwwwaancomprofessionalspracticepdfsgl0090
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 the
American Academy of Neurology Neurology 200055
754ndash762
4 Naumann M So Y Argoff C et al Assessment Botuli-
num neurotoxin in the treatment of autonomic disorders
and pain (an evidence-based review) report of the Thera-
peutics and Technology Subcommittee of the American
Academy of Neurology Neurology 2008701707ndash1714
5 Holland S Silberstein SD Freitag F Dodick DW Argoff
C Ashman E Evidence-based guideline update NSAIDs
and other complementary treatments for episodic migraine
prevention in adults report of the Quality Standards Sub-
committee of the American Academy of Neurology and
the American Headache Society Neurology 201278
1346ndash1353
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
28965ndash69
7 Schrader H Stovner LJ Helde G Sand T Bovim G Pro-
phylactic treatment of migraine with angiotensin convert-
ing enzyme inhibitor (lisinopril) randomised placebo
controlled crossover study BMJ 200132219ndash22
8 Diener HC Gendolla A Feuersenger A et al Telmisartan
in migraine prophylaxis a randomized placebo-controlled
trial Cephalalgia 200929921ndash927
9 Freitag FG Collins SD Carlson HA et al A randomized
trial of divalproex sodium extended-release tablets in mi-
graine prophylaxis Neurology 2002581652ndash1659
10 Silberstein SD Collins SD Safety of divalproex sodium in
migraine prophylaxis an open-label long-term study
long-term safety of Depakote in Headache Prophylaxis
Study Group Headache 199939633ndash643
11 Harden CL Meador KJ Pennell PB et al American Acad-
emy of Neurology American Epilepsy Society Practice pa-
rameter update management issues for women with
epilepsyndashfocus on pregnancy (an evidence-based review)
teratogenesis and perinatal outcomes report of the Quality
Standards Subcommittee and Therapeutics and Technol-
ogy Assessment Subcommittee of the American Academy
of Neurology and American Epilepsy Society Neurology
200973133ndash141
12 Mathew NT Rapoport A Saper J et al Efficacy of gabap-
entin in migraine prophylaxis Headache 200141119ndash
128
13 Steiner TJ Findley LJ Yuen AW Lamotrigine versus pla-
cebo in the prophylaxis of migraine with and without aura
Cephalalgia 199717109ndash112
14 Gupta P Singh S Goyal V Shukla G Behari M Low-
dose topiramate versus lamotrigine in migraine prophy-
laxis (the Lotolamp study) Headache 200747402ndash412
15 Silberstein SD Saper J Berenson F Somogyi M Mc-
Cague MA DrsquoSouza JD Oxcarbazepine in migraine head-
ache a double-blind randomized placebo-controlled
study Neurology 200870548ndash555
1344 Neurology 78 April 24 2012
16 Ashtari F Shaygannejad V Akbari M A double-blindrandomized trial of low-dose topiramate vs propranolol inmigraine prophylaxis Acta Neurol Scand 2008118301ndash305
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 Headache200646642ndash 648
18 Storey JR Calder CS Hart DE Potter DL Topiramate inmigraine prevention a double-blind placebo-controlledstudy Headache 200141968ndash975
19 Brandes JL Saper JR Diamond M et al MIGR-002Study Group Topiramate for migraine prevention a ran-domized controlled trial JAMA 2004291965ndash973
20 Diener HC Matias-Guiu J Hartung E et al Topiramatein migraine prophylaxisndashresults from a placebo-controlledtrial with propranolol as an active control J Neurol 2004251943ndash950
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 200931542ndash559
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 2008110979ndash984
23 Mei D Capuano A Vollono C et al Topiramate in mi-graine prophylaxis a randomised double-blind versus pla-cebo study Neurol Sci 200425245ndash250
24 Silberstein SD Neto W Schmitt J Jacobs D MIGR-001Study Group Topiramate in migraine prevention resultsof a large controlled trial Arch Neurol 200461490ndash495
25 Millan-Guerrero RO Isais-Millan R Barreto-Vizcaiacuteno Set al Subcutaneous histamine versus topiramate in mi-graine prophylaxis a double-blind study Eur Neurol200859237ndash242
26 Silberstein SD Hulihan J Karim MR et al Efficacy andtolerability of topiramate 200 mgd in the prevention ofmigraine withwithout aura in adults a randomizedplacebo-controlled double-blind 12-week pilot studyClin Ther 2006281002ndash1011
27 Adly C Straumanis J Chesson A Fluoxetine prophylaxisof migraine Headache 199232101ndash104
28 Saper JR Silberstein SD Lake AE III Winters MEDouble-blind trial of fluoxetine chronic daily headacheand migraine Headache 199434497ndash502
29 drsquoAmato CC Pizza V Marmolo T Giordano E Alfano V
Nasta A Fluoxetine for migraine prophylaxis a double-
blind trial Headache 199939716ndash719
30 Ozyalcin SN Talu GK Kiziltan E Yucel B Ertas M Disci
R The efficacy and safety of venlafaxine in the prophylaxis
of migraine Headache 200545144ndash152
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 2004107
44ndash48
32 Diener HC Hartung E Chrubasik J et al A comparative
study of oral acetylsalicylic acid and metoprolol for the
prophylactic treatment of migraine a randomized con-
trolled double-blind parallel group phase III study Ceph-
alalgia 200121120ndash128
33 Schellenberg R Lichtenthal A Wohling H Graf C
Brixius K Nebivolol and metoprolol for treating migraine
an advance on beta-blocker treatment Headache 200848
118ndash125
34 Rao BS Das DG Taraknath VR Sarma Y A double blind
controlled study of propranolol and cyproheptadine in mi-
graine prophylaxis Neurol India 200048223ndash226
35 Diener HC Krupp P Schmitt T Steitz G Milde K
Freytag S on behalf of the Study Group Cyclandelate in
the prophylaxis of migraine a placebo-controlled study
Cephalalgia 20012166ndash70
36 Siniatchkin M Gerber WD Vein A Clinical efficacy and
central mechanisms of cyclandelate in migraine a double-
blind placebo-controlled study Funct Neurol 199813
47ndash56
37 Silberstein SD Elkind AH Schreiber C Keywood C A
randomized trial of frovatriptan for the intermittent pre-
vention of menstrual migraine Neurology 200463261ndash
269
38 Brandes JL Poole A Kallela M et al Short-term fro-
vatriptan for the prevention of difficult-to-treat menstrual
migraine attacks Cephalalgia 2009291133ndash1148
39 Newman L Mannix LK Landy S et al Naratriptan as
short-term prophylaxis of menstrually associated migraine
a randomized double-blind placebo-controlled study
Headache 200141248ndash256
40 Tuchman MM Hee A Emeribe U Silberstein S Oral
zolmitriptan in the short-term prevention of menstrual mi-
graine a randomized placebo-controlled study CNS
Drugs 200822877ndash886
Endorsed by the American Osteopathic Association on March 22 2012
Neurology 78 April 24 2012 1345
DOI 101212WNL0b013e3182535d202012781337-1345 Neurology
SD Silberstein S Holland F Freitag et al Academy of Neurology and the American Headache Society
prevention in adults Report of the Quality Standards Subcommittee of the American Evidence-based guideline update Pharmacologic treatment for episodic migraine
This information is current as of April 23 2012
rights reserved Print ISSN 0028-3878 Online ISSN 1526-632X1951 it is now a weekly with 48 issues per year Copyright Copyright copy 2012 by AAN Enterprises Inc All
reg is the official journal of the American Academy of Neurology Published continuously sinceNeurology
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reg is the official journal of the American Academy of Neurology Published continuously sinceNeurology
CORRECTIONEvidence-based guideline update Pharmacologic treatment for episodicmigraine prevention in adults Report of the
Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society
In the special article ldquoEvidence-based guideline update Pharmacologic treatment for episodic migraine prevention in adultsReport of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Societyrdquo bySD Silberstein et al (Neurology 2012781337ndash1345) there are errors in table 1 and the text on page 1342 Due to changes inthe AANrsquos LOE classification criteria pindolol and clonidine should have been labeled as having Level U recommendations andnicardipine should have been listed as having a Level C recommendation These changes are based on studies cited in the original2001 guideline no new studies were found in the literature search for the 2012 update Please see the corrected table belowTheauthors regret the errors
Table 1 Classification of migraine preventive therapies (available in the United States)
Level A Medicationswith establishedefficacy (Dagger2 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 use
Other Medicationsthat are establishedas ineffectiveprobably ineffectiveor possiblyineffective
Antiepileptic drugs AntidepressantsSSRISSNRITCA
ACE inhibitors a-Agonists Established asineffective
Divalproex sodium Amitriptyline Lisinopril Clonidinea Lamotrigine
Sodium valproate Venlafaxine a-Agonists AntidepressantsSSRISSNRI
Probably ineffective
Topiramate b-Blockers Guanfacinea Fluoxetine Clomipraminea
b-Blockers Atenolola Angiotensin receptorblockers
Fluvoxaminea Possibly ineffective
Metoprolol Nadolola Candesartan Antiepileptic drugs Acebutolola
Propranolol Triptans (MRMb) Antiepileptic drugs Gabapentin Clonazepama
Timolola Naratriptanb Carbamazepinea Antithrombotics Nabumetonea
Triptans (MRMb) Zolmitriptanb Antihistamines Acenocoumarol Oxcarbazepine
Frovatriptanb Cyproheptadine Coumadin Telmisartan
b-Blockers Picotamide
Nebivolol b-Blockers
Ca11 blockers Bisoprolola
Nicardipinea Pindolola
Ca11 blockers
Nifedipinea
Nimodipine
Verapamil
Carbonic anhydraseinhibitor
Acetazolamide
Direct vascularsmooth musclerelaxants
Cyclandelate
TCAs
Protriptylinea
Abbreviations ACE 5 angiotensin-converting-enzyme Ca11 blockers 5 calcium channel blockers MRM 5 menstruallyrelated migraine SSNRI 5 selective serotoninndashnorepinephrine reuptake inhibitor SSRI 5 selective serotonin reuptakeinhibitor TCA 5 tricyclic antidepressanta Classification based on original guideline and new evidence not found for this reportb For short-term prophylaxis of MRM
Neurology 80 February 26 2013 871
placebo and lamotrigine for primary efficacy mea-sures14 In the topiramate groups 15 of patientsexperienced AEs most commonly paresthesiassleepiness and gastrointestinal intolerance The pla-cebo group reported gastrointestinal intolerance(3) and anorexia (3)
Two additional Class I studies report topiramate isas effective as propranolol16 or sodium valproate17
drugs previously established as effective for migraineprevention In the first study subjects given topiramate50 mgday had reduced mean migraine frequency (epi-sodesmonth) from baseline (607 189 to 183
139 p 0001) at 8 weeks decreased headache inten-sity VAS score from 71 145 to 367 21 (p
0001) and decreased headache duration from 1637
726 hours to 623 522 hours (p 0001)16 Sub-jects given topiramate reported paresthesias (23)weight loss (16) and somnolence (13) In pa-tients treated with propranolol 80 mgday meanheadache frequency (episodesmonth) decreasedfrom 583 198 to 22 167 (p 0001) at 8weeks headache intensity VAS score decreased from643 16 to 413 194 (p 0001) and head-ache duration decreased from 1510 684 hours to727 646 hours (p 0001) Although monthlyheadache frequency intensity and duration de-creased in both groups the topiramate group re-ported significantly greater mean reduction(topiramate frequency decrease 423 12 vs pro-pranolol 363 096 [p 0036 CI 039ndash116]topiramate intensity decrease 343 138 vs pro-pranolol 23 12 [p 0001 CI 046ndash18] topi-ramate duration decrease 101 43 vs propranolol783 45 [p 0048 CI 017ndash46])
In a crossover Class I trial (2-month washout be-tween therapies) comparing topiramate 50 mgdaywith sodium valproate 400 mgday both groupsshowed improvement from baseline in headache fre-quency intensity and duration17 Average monthlymigraine frequency decreased by 18 times with so-dium valproate (baseline 54 25 posttreatment36 21 CI 10ndash26 p 0001) as comparedwith a 3-time reduction with topiramate (baseline54 20 posttreatment 24 24 CI 21ndash39 p
0001) Headache intensity decreased by 37 with so-dium valproate (baseline 77 12 treatment 40
21 CI 29ndash46 p 0001) as compared with areduction of 36 with topiramate (baseline 69 12treatment phase 33 15 CI 29ndash43 p 0001)The average headache episode duration decreased by134 hours from baseline with sodium valproate(baseline 213 146 treatment 79 77 CI 75ndash193 p 0001) as compared with an 119-hourreduction with topiramate (baseline 173 84treatment 54 64 CI 82ndash156 p 0001) The
overall 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 (188) paresthesias (94) or both(25) Sodium valproate AEs were weight gain(345) hair loss (31) and somnolence (31)
Results of 5 Class II studies support those of theClass I studies showing topiramate as effective formigraine prevention19ndash25 Four studies demonstratedsignificant improvement over placebo19202324 oneincluded an active comparator arm suggestingequivalence of topiramate (100 200 mgday) andpropranolol (160 mgday)20 Two studies comparingtopiramate and amitriptyline (25ndash150 mgday) 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 monotherapy2122 In one of thesestudies21 the 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 placebo26
Conclusions 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 guideline1 Class II study27 showed fluoxetine (racemic) wassignificantly better than placebo for migraine preven-tion but the results were not duplicated in a secondstudy28
Since the original guideline a Class II study hasshown fluoxetine 20 mgday was more effective thanplacebo in reducing total pain index scores (calcu-lated as [Dl 1] [D2 2] [D3 3] where D1D2 and D3 represent headache hours calculated in amonth with pain intensity shown by 1 2 3) at 6months29 After the 6 months pain index scores for thefluoxetine group decreased from 135 (baseline) to 413(SD 638 p 0001) The placebo group pain indexwas 98 at baseline and 611 at 6 months (SD 577p 007) however differences were noted betweentreatment groups for baseline measures
1340 Neurology 78 April 24 2012
Venlafaxine In a Class I study venlafaxine XR 150mg significantly reduced the number of headachedays (median reduction in days venlafaxine 150 mg4 days venlafaxine 75 mg 2 days placebo 1day Kruskal-Wallis 10306 df 2 p 0006)30
All 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 415 [SD
224] vs 12 weeks 177 [SD 139 p 0001]amitriptyline baseline 327 [SD 161] vs 12weeks 154 [SD 154 p 0001])31 Patients tak-ing venlafaxine experienced nauseavomiting (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 20 drop-out rates) Comparative studies of amitriptyline withtopiramate2122 and 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 (200mgday) was more effective than aspirin (300 mgday) in achieving 50 migraine frequency reduction(responder rate metoprolol 452 aspirin
296 mean difference 1565 CI 443ndash2688)32
Attack frequencies (attacksmonth) at placebo run-inand week 20 are 336 to 237 respectively for aspirinand 355 to 182 respectively for metoprolol Nosignificant AEs were reported
A small Class II study reported metoprolol (475ndash1425 mgday) had similar efficacy to nebivolol 5
mgday for migraine prevention (assessed by a de-crease in mean migraine attacks)33
Propranolol The original guideline concludedpropranolol was established as effective for migraineprevention
In a Class II study propranolol (80 mgday) wasmore effective than placebo and as effective as cypro-heptadine (4 mgday) in reducing migraine fre-quency duration and attack severity34 Thedifference in attack frequency reduction was signifi-cant between treatments propranolol 285 02(SEM) vs cyproheptadine 309 031 vs combi-nation 312 01 vs placebo 177 044 (all p 005 vs placebo) For attack frequency reductioncombination therapy was more effective than mono-therapy (p 005) AEs were drowsiness sleep dis-turbance weight gain fatigue and dry mouthpercentages 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 duration35 The secondstudy (smaller underpowered n 25) found cy-clandelate significantly reduced the number of mi-graine days and duration (assessed using a contingentnegative variation measure)36
Conclusions The efficacy of cyclandelate is unknown(conflicting Class II studies)
Triptans Since the original guideline new Class Istudies have assessed the efficacy of frovatriptan3738
naratriptan39 and zolmitriptan40 for short-term pre-vention of menstrually associated migraine (MAM)
Frovatriptan Frovatriptan 25 mg BIDqd wasmore effective than placebo in reducing migraine fre-
Neurology 78 April 24 2012 1341
quency37 The mean number of headache-free peri-menstrual periods (PMPs) per patient (primaryendpoint) was higher in the 2 frovatriptan groups(25 mg qd 069 [SD 092 CI 114ndash273 p 00091] vs 25 mg BID 092 [SD 103 CI 184ndash428 p 00001] vs placebo 042 [SD 078])representing 64 (25 mgday) and 119 (5 mgday) increases in the mean number of headache-freePMPs per patient over placebo A second Class Istudy38 also reports the MAM headache incidenceduring the 6-day PMP was 67 for placebo 52 forfrovatriptan 25 mg QD (p 00001 vs placebo)and 41 for frovatriptan 25 mg BID (p 00001vs placebo p 00001 vs QD regimen) The AEincidence and type for both regimens were similar tothose for placebo The overall AE incidence for fro-vatriptan was 41 (25 mg BID) and 27 (25 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 days39 Patients treated withnaratriptan 1 mg experienced more headache-freePMPs than those on placebo (50 vs 25 p
0003) Naratriptan 1 mg reduced the number ofMAMs (20 vs 40 p 005) and MAM days (42 vs70 p 001) vs placebo The AE incidence andseverity were similar to those of placebo 10 ofpatients experienced dizziness chest pain or malaise
Zolmitriptan One Class I study reported the effi-cacy of zolmitriptan 25 BIDTID vs placebo Bothzolmitriptan regimens demonstrated superior effi-cacy vs placebo the proportion of patients with a50 MAM attack frequency reduction (zolmi-triptan 25 mg TID [586] p 00007 vs placebozolmitriptan 25 mg BID [547] p 0002 vs pla-cebo placebo 378)40 AEs were considered possi-bly treatment-related in 28 patients (333) in thezolmitriptan 25 mg TID group 29 (363) in thezolmitriptan 25 mg BID group and 18 (220) 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 more
effective than placebo in reducing migraine fre-quency duration and severitye1 This trial (n 53) 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
bull Antiepileptic drugs (AEDs) divalproex so-dium sodium valproate topiramate
bull -Blockers metoprolol propranolol timololbull Triptans frovatriptan for short-term MAMs
prevention
Level B The following medications are probablyeffective and should be considered for migraineprevention
bull Antidepressants amitriptyline venlafaxinebull -Blockers atenolol nadololbull Triptans naratriptan zolmitriptan for short-
term MAMs prevention
Level C The following medications are possibly effec-tive and may be considered for migraine prevention
bull ACE inhibitors lisinoprilbull Angiotensin receptor blockers candesartanbull -Agonists clonidine guanfacinebull AEDs carbamazepinebull -Blockers nebivolol pindolol
Level U Evidence is conflicting or inadequate to sup-port or refute the use of the following medicationsfor migraine prevention
bull AEDs gabapentinbull Antidepressants
bull Selective serotonin reuptake inhibitorselec-tive serotonin-norepinephrine reuptake in-hibitors fluoxetine fluvoxamine
bull Tricyclics protriptylinebull Antithrombotics acenocoumarol Coumadin
picotamidebull -Blockers bisoprololbull Calcium-channel blockers nicardipine nifedi-
pine nimodipine verapamilbull Acetazolamidebull Cyclandelate
Level A negative The following medication is estab-lished as ineffective and should not be offered formigraine prevention
bull Lamotrigine
1342 Neurology 78 April 24 2012
Level B negative The following medication is proba-bly ineffective and should not be considered for mi-graine prevention
bull Clomipramine
Level C negative The following medications are pos-sibly ineffective and may not be considered for mi-graine prevention
bull Acebutololbull Clonazepambull Nabumetonebull Oxcarbazepinebull Telmisartan
CLINICAL 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 coexistingcomorbid 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 agentsStudies 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 12ndash16weeks) 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 25 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 draftingrevising the manuscript
study concept or design analysis or interpretation of data acquisition of
data study supervision Dr Holland draftingrevising the manuscript
study concept or design analysis or interpretation of data Dr Freitag
draftingrevising the manuscript analysis or interpretation of data acqui-
sition of data Dr Dodick draftingrevising the manuscript study con-
cept or design analysis or interpretation of data Dr Argoff drafting
revising the manuscript study concept or design analysis or
interpretation of data Dr Ashman draftingrevising the manuscript
analysis or interpretation of data
DISCLOSUREDr Silberstein is on the advisory panel of and receives honoraria from
AGA 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 speakersrsquo bureau
of and receives honoraria from Endo Pharmaceuticals GlaxoSmithKline
and Merck He serves as a consultant for and receives honoraria from
Amgen 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 the
American Headache Society and research support from Albert Einstein
College of Medicine Dr Freitag has served on the scientific advisory
boards of Zogenix Pharmaceuticals Allergan Pharmaceuticals Nautilus
MAP Pharmaceuticals and Nupathe has received travel expenses and or
honoraria from GlaxoSmithKline Zogenix Merck Nautilus Allergan
Diamond Headache Clinic Research and Educational Foundation (not
for profit) and the American Headache Society (travel) Dr Freitag is a
member of the Board of Directors of the National Headache Foundation
Dr Dodick within the past 3 years serves on advisory boards and has
consulted for Allergan Alder Pfizer Merck Coherex Ferring Neuro-
core Neuralieve Neuraxon NuPathe Inc MAP SmithKlineBeecham
Boston Scientific Medtronic Inc Nautilus Eli Lilly amp Company No-
Neurology 78 April 24 2012 1343
vartis Colucid GlaxoSmithKline Autonomic Technologies MAP Phar-
maceuticals Inc Zogenix Inc Impax Laboratories Inc Bristol Myers
Squibb 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 SAGE
Publishing Lippincott Williams amp 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 The
Neurologist Lancet Neurology and Postgraduate Medicine and has served
as Editor-in-Chief of Headache Currents and as an Associate Editor of
Headache he receives publishing royalties for Wolff rsquos Headache 8th edi-
tion (Oxford University Press 2009) and Handbook of Headache (Cam-
bridge University Press 2010) Within the past 3 years Dr Dodick has
received research grant support from Advanced Neurostimulation Sys-
tems Boston Scientific St Jude Medical Inc Medtronic NINDSNIH
Mayo Clinic Dr Argoff has served on a scientific advisory board for the
Department of Defense and DSMB for the NIH has received funding for
travel andor speaking andor has served on a speakersrsquo bureau for Pfizer
(King) Janssen (Pricara) Millennium Laboratories Neurogesx Forest
Laboratories Eli Lilly Covidien and Endo Pharmaceuticals has received
research support from Endo Pharmaceuticals Forest Laboratories Eli
Lilly Neurogesx Pfizer and SBRT funded by the NIH and has received
stockstock options from Pfizer Dr Ashman is the Level of Evidence
editor 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 Neurologyorg for full
disclosures
DISCLAIMERThis statement is provided as an educational service of the American
Academy of Neurology and the American Headache Society It is based
on as assessment of current scientific and clinical information It is not
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 it intended to exclude any reasonable alternative
methodologies The AAN and the AHS recognize that specific patient
care decisions are the prerogative of the patient and the physician
caring for the patient based on all of the circumstances involved The
clinical context section is made available in order to place the
evidence-based guideline(s) into perspective with current practice hab-
its and challenges No formal practice recommendations should be
inferred
CONFLICT OF INTERESTThe American Academy of Neurology and the American Headache Soci-
ety are committed to producing independent critical and truthful clinical
practice guidelines (CPGs) Significant efforts are made to minimize the
potential for conflicts of interest to influence the recommendations of this
CPG To the extent possible the AAN and AHS keep separate those who
have a financial stake in the success or failure of the products appraised in
the CPGs and the developers of the guidelines Conflict of interest forms
were obtained from all authors and reviewed by an oversight committee
prior to project initiation AAN and AHS limit the participation of au-
thors with substantial conflicts of interest The AAN and AHS forbid
commercial participation in or funding of guideline projects Drafts of
the 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 of
Interest Policy can be viewed at wwwaancom
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 200768343ndash349
2 Ramadan NM Silberstein SD Freitag FG Gilbert TT
Frishberg BM Evidence-based guidelines for migraine
headache in the primary care setting pharmacological
management for prevention of migraine Available at
httpwwwaancomprofessionalspracticepdfsgl0090
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 the
American Academy of Neurology Neurology 200055
754ndash762
4 Naumann M So Y Argoff C et al Assessment Botuli-
num neurotoxin in the treatment of autonomic disorders
and pain (an evidence-based review) report of the Thera-
peutics and Technology Subcommittee of the American
Academy of Neurology Neurology 2008701707ndash1714
5 Holland S Silberstein SD Freitag F Dodick DW Argoff
C Ashman E Evidence-based guideline update NSAIDs
and other complementary treatments for episodic migraine
prevention in adults report of the Quality Standards Sub-
committee of the American Academy of Neurology and
the American Headache Society Neurology 201278
1346ndash1353
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
28965ndash69
7 Schrader H Stovner LJ Helde G Sand T Bovim G Pro-
phylactic treatment of migraine with angiotensin convert-
ing enzyme inhibitor (lisinopril) randomised placebo
controlled crossover study BMJ 200132219ndash22
8 Diener HC Gendolla A Feuersenger A et al Telmisartan
in migraine prophylaxis a randomized placebo-controlled
trial Cephalalgia 200929921ndash927
9 Freitag FG Collins SD Carlson HA et al A randomized
trial of divalproex sodium extended-release tablets in mi-
graine prophylaxis Neurology 2002581652ndash1659
10 Silberstein SD Collins SD Safety of divalproex sodium in
migraine prophylaxis an open-label long-term study
long-term safety of Depakote in Headache Prophylaxis
Study Group Headache 199939633ndash643
11 Harden CL Meador KJ Pennell PB et al American Acad-
emy of Neurology American Epilepsy Society Practice pa-
rameter update management issues for women with
epilepsyndashfocus on pregnancy (an evidence-based review)
teratogenesis and perinatal outcomes report of the Quality
Standards Subcommittee and Therapeutics and Technol-
ogy Assessment Subcommittee of the American Academy
of Neurology and American Epilepsy Society Neurology
200973133ndash141
12 Mathew NT Rapoport A Saper J et al Efficacy of gabap-
entin in migraine prophylaxis Headache 200141119ndash
128
13 Steiner TJ Findley LJ Yuen AW Lamotrigine versus pla-
cebo in the prophylaxis of migraine with and without aura
Cephalalgia 199717109ndash112
14 Gupta P Singh S Goyal V Shukla G Behari M Low-
dose topiramate versus lamotrigine in migraine prophy-
laxis (the Lotolamp study) Headache 200747402ndash412
15 Silberstein SD Saper J Berenson F Somogyi M Mc-
Cague MA DrsquoSouza JD Oxcarbazepine in migraine head-
ache a double-blind randomized placebo-controlled
study Neurology 200870548ndash555
1344 Neurology 78 April 24 2012
16 Ashtari F Shaygannejad V Akbari M A double-blindrandomized trial of low-dose topiramate vs propranolol inmigraine prophylaxis Acta Neurol Scand 2008118301ndash305
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 Headache200646642ndash 648
18 Storey JR Calder CS Hart DE Potter DL Topiramate inmigraine prevention a double-blind placebo-controlledstudy Headache 200141968ndash975
19 Brandes JL Saper JR Diamond M et al MIGR-002Study Group Topiramate for migraine prevention a ran-domized controlled trial JAMA 2004291965ndash973
20 Diener HC Matias-Guiu J Hartung E et al Topiramatein migraine prophylaxisndashresults from a placebo-controlledtrial with propranolol as an active control J Neurol 2004251943ndash950
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 200931542ndash559
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 2008110979ndash984
23 Mei D Capuano A Vollono C et al Topiramate in mi-graine prophylaxis a randomised double-blind versus pla-cebo study Neurol Sci 200425245ndash250
24 Silberstein SD Neto W Schmitt J Jacobs D MIGR-001Study Group Topiramate in migraine prevention resultsof a large controlled trial Arch Neurol 200461490ndash495
25 Millan-Guerrero RO Isais-Millan R Barreto-Vizcaiacuteno Set al Subcutaneous histamine versus topiramate in mi-graine prophylaxis a double-blind study Eur Neurol200859237ndash242
26 Silberstein SD Hulihan J Karim MR et al Efficacy andtolerability of topiramate 200 mgd in the prevention ofmigraine withwithout aura in adults a randomizedplacebo-controlled double-blind 12-week pilot studyClin Ther 2006281002ndash1011
27 Adly C Straumanis J Chesson A Fluoxetine prophylaxisof migraine Headache 199232101ndash104
28 Saper JR Silberstein SD Lake AE III Winters MEDouble-blind trial of fluoxetine chronic daily headacheand migraine Headache 199434497ndash502
29 drsquoAmato CC Pizza V Marmolo T Giordano E Alfano V
Nasta A Fluoxetine for migraine prophylaxis a double-
blind trial Headache 199939716ndash719
30 Ozyalcin SN Talu GK Kiziltan E Yucel B Ertas M Disci
R The efficacy and safety of venlafaxine in the prophylaxis
of migraine Headache 200545144ndash152
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 2004107
44ndash48
32 Diener HC Hartung E Chrubasik J et al A comparative
study of oral acetylsalicylic acid and metoprolol for the
prophylactic treatment of migraine a randomized con-
trolled double-blind parallel group phase III study Ceph-
alalgia 200121120ndash128
33 Schellenberg R Lichtenthal A Wohling H Graf C
Brixius K Nebivolol and metoprolol for treating migraine
an advance on beta-blocker treatment Headache 200848
118ndash125
34 Rao BS Das DG Taraknath VR Sarma Y A double blind
controlled study of propranolol and cyproheptadine in mi-
graine prophylaxis Neurol India 200048223ndash226
35 Diener HC Krupp P Schmitt T Steitz G Milde K
Freytag S on behalf of the Study Group Cyclandelate in
the prophylaxis of migraine a placebo-controlled study
Cephalalgia 20012166ndash70
36 Siniatchkin M Gerber WD Vein A Clinical efficacy and
central mechanisms of cyclandelate in migraine a double-
blind placebo-controlled study Funct Neurol 199813
47ndash56
37 Silberstein SD Elkind AH Schreiber C Keywood C A
randomized trial of frovatriptan for the intermittent pre-
vention of menstrual migraine Neurology 200463261ndash
269
38 Brandes JL Poole A Kallela M et al Short-term fro-
vatriptan for the prevention of difficult-to-treat menstrual
migraine attacks Cephalalgia 2009291133ndash1148
39 Newman L Mannix LK Landy S et al Naratriptan as
short-term prophylaxis of menstrually associated migraine
a randomized double-blind placebo-controlled study
Headache 200141248ndash256
40 Tuchman MM Hee A Emeribe U Silberstein S Oral
zolmitriptan in the short-term prevention of menstrual mi-
graine a randomized placebo-controlled study CNS
Drugs 200822877ndash886
Endorsed by the American Osteopathic Association on March 22 2012
Neurology 78 April 24 2012 1345
DOI 101212WNL0b013e3182535d202012781337-1345 Neurology
SD Silberstein S Holland F Freitag et al Academy of Neurology and the American Headache Society
prevention in adults Report of the Quality Standards Subcommittee of the American Evidence-based guideline update Pharmacologic treatment for episodic migraine
This information is current as of April 23 2012
rights reserved Print ISSN 0028-3878 Online ISSN 1526-632X1951 it is now a weekly with 48 issues per year Copyright Copyright copy 2012 by AAN Enterprises Inc All
reg is the official journal of the American Academy of Neurology Published continuously sinceNeurology
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This article cites 39 articles 9 of which you can access for free at
Citations httpnneurologyorgcontent78171337fullotherarticles
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reg is the official journal of the American Academy of Neurology Published continuously sinceNeurology
CORRECTIONEvidence-based guideline update Pharmacologic treatment for episodicmigraine prevention in adults Report of the
Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society
In the special article ldquoEvidence-based guideline update Pharmacologic treatment for episodic migraine prevention in adultsReport of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Societyrdquo bySD Silberstein et al (Neurology 2012781337ndash1345) there are errors in table 1 and the text on page 1342 Due to changes inthe AANrsquos LOE classification criteria pindolol and clonidine should have been labeled as having Level U recommendations andnicardipine should have been listed as having a Level C recommendation These changes are based on studies cited in the original2001 guideline no new studies were found in the literature search for the 2012 update Please see the corrected table belowTheauthors regret the errors
Table 1 Classification of migraine preventive therapies (available in the United States)
Level A Medicationswith establishedefficacy (Dagger2 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 use
Other Medicationsthat are establishedas ineffectiveprobably ineffectiveor possiblyineffective
Antiepileptic drugs AntidepressantsSSRISSNRITCA
ACE inhibitors a-Agonists Established asineffective
Divalproex sodium Amitriptyline Lisinopril Clonidinea Lamotrigine
Sodium valproate Venlafaxine a-Agonists AntidepressantsSSRISSNRI
Probably ineffective
Topiramate b-Blockers Guanfacinea Fluoxetine Clomipraminea
b-Blockers Atenolola Angiotensin receptorblockers
Fluvoxaminea Possibly ineffective
Metoprolol Nadolola Candesartan Antiepileptic drugs Acebutolola
Propranolol Triptans (MRMb) Antiepileptic drugs Gabapentin Clonazepama
Timolola Naratriptanb Carbamazepinea Antithrombotics Nabumetonea
Triptans (MRMb) Zolmitriptanb Antihistamines Acenocoumarol Oxcarbazepine
Frovatriptanb Cyproheptadine Coumadin Telmisartan
b-Blockers Picotamide
Nebivolol b-Blockers
Ca11 blockers Bisoprolola
Nicardipinea Pindolola
Ca11 blockers
Nifedipinea
Nimodipine
Verapamil
Carbonic anhydraseinhibitor
Acetazolamide
Direct vascularsmooth musclerelaxants
Cyclandelate
TCAs
Protriptylinea
Abbreviations ACE 5 angiotensin-converting-enzyme Ca11 blockers 5 calcium channel blockers MRM 5 menstruallyrelated migraine SSNRI 5 selective serotoninndashnorepinephrine reuptake inhibitor SSRI 5 selective serotonin reuptakeinhibitor TCA 5 tricyclic antidepressanta Classification based on original guideline and new evidence not found for this reportb For short-term prophylaxis of MRM
Neurology 80 February 26 2013 871
Venlafaxine In a Class I study venlafaxine XR 150mg significantly reduced the number of headachedays (median reduction in days venlafaxine 150 mg4 days venlafaxine 75 mg 2 days placebo 1day Kruskal-Wallis 10306 df 2 p 0006)30
All 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 415 [SD
224] vs 12 weeks 177 [SD 139 p 0001]amitriptyline baseline 327 [SD 161] vs 12weeks 154 [SD 154 p 0001])31 Patients tak-ing venlafaxine experienced nauseavomiting (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 20 drop-out rates) Comparative studies of amitriptyline withtopiramate2122 and 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 (200mgday) was more effective than aspirin (300 mgday) in achieving 50 migraine frequency reduction(responder rate metoprolol 452 aspirin
296 mean difference 1565 CI 443ndash2688)32
Attack frequencies (attacksmonth) at placebo run-inand week 20 are 336 to 237 respectively for aspirinand 355 to 182 respectively for metoprolol Nosignificant AEs were reported
A small Class II study reported metoprolol (475ndash1425 mgday) had similar efficacy to nebivolol 5
mgday for migraine prevention (assessed by a de-crease in mean migraine attacks)33
Propranolol The original guideline concludedpropranolol was established as effective for migraineprevention
In a Class II study propranolol (80 mgday) wasmore effective than placebo and as effective as cypro-heptadine (4 mgday) in reducing migraine fre-quency duration and attack severity34 Thedifference in attack frequency reduction was signifi-cant between treatments propranolol 285 02(SEM) vs cyproheptadine 309 031 vs combi-nation 312 01 vs placebo 177 044 (all p 005 vs placebo) For attack frequency reductioncombination therapy was more effective than mono-therapy (p 005) AEs were drowsiness sleep dis-turbance weight gain fatigue and dry mouthpercentages 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 duration35 The secondstudy (smaller underpowered n 25) found cy-clandelate significantly reduced the number of mi-graine days and duration (assessed using a contingentnegative variation measure)36
Conclusions The efficacy of cyclandelate is unknown(conflicting Class II studies)
Triptans Since the original guideline new Class Istudies have assessed the efficacy of frovatriptan3738
naratriptan39 and zolmitriptan40 for short-term pre-vention of menstrually associated migraine (MAM)
Frovatriptan Frovatriptan 25 mg BIDqd wasmore effective than placebo in reducing migraine fre-
Neurology 78 April 24 2012 1341
quency37 The mean number of headache-free peri-menstrual periods (PMPs) per patient (primaryendpoint) was higher in the 2 frovatriptan groups(25 mg qd 069 [SD 092 CI 114ndash273 p 00091] vs 25 mg BID 092 [SD 103 CI 184ndash428 p 00001] vs placebo 042 [SD 078])representing 64 (25 mgday) and 119 (5 mgday) increases in the mean number of headache-freePMPs per patient over placebo A second Class Istudy38 also reports the MAM headache incidenceduring the 6-day PMP was 67 for placebo 52 forfrovatriptan 25 mg QD (p 00001 vs placebo)and 41 for frovatriptan 25 mg BID (p 00001vs placebo p 00001 vs QD regimen) The AEincidence and type for both regimens were similar tothose for placebo The overall AE incidence for fro-vatriptan was 41 (25 mg BID) and 27 (25 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 days39 Patients treated withnaratriptan 1 mg experienced more headache-freePMPs than those on placebo (50 vs 25 p
0003) Naratriptan 1 mg reduced the number ofMAMs (20 vs 40 p 005) and MAM days (42 vs70 p 001) vs placebo The AE incidence andseverity were similar to those of placebo 10 ofpatients experienced dizziness chest pain or malaise
Zolmitriptan One Class I study reported the effi-cacy of zolmitriptan 25 BIDTID vs placebo Bothzolmitriptan regimens demonstrated superior effi-cacy vs placebo the proportion of patients with a50 MAM attack frequency reduction (zolmi-triptan 25 mg TID [586] p 00007 vs placebozolmitriptan 25 mg BID [547] p 0002 vs pla-cebo placebo 378)40 AEs were considered possi-bly treatment-related in 28 patients (333) in thezolmitriptan 25 mg TID group 29 (363) in thezolmitriptan 25 mg BID group and 18 (220) 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 more
effective than placebo in reducing migraine fre-quency duration and severitye1 This trial (n 53) 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
bull Antiepileptic drugs (AEDs) divalproex so-dium sodium valproate topiramate
bull -Blockers metoprolol propranolol timololbull Triptans frovatriptan for short-term MAMs
prevention
Level B The following medications are probablyeffective and should be considered for migraineprevention
bull Antidepressants amitriptyline venlafaxinebull -Blockers atenolol nadololbull Triptans naratriptan zolmitriptan for short-
term MAMs prevention
Level C The following medications are possibly effec-tive and may be considered for migraine prevention
bull ACE inhibitors lisinoprilbull Angiotensin receptor blockers candesartanbull -Agonists clonidine guanfacinebull AEDs carbamazepinebull -Blockers nebivolol pindolol
Level U Evidence is conflicting or inadequate to sup-port or refute the use of the following medicationsfor migraine prevention
bull AEDs gabapentinbull Antidepressants
bull Selective serotonin reuptake inhibitorselec-tive serotonin-norepinephrine reuptake in-hibitors fluoxetine fluvoxamine
bull Tricyclics protriptylinebull Antithrombotics acenocoumarol Coumadin
picotamidebull -Blockers bisoprololbull Calcium-channel blockers nicardipine nifedi-
pine nimodipine verapamilbull Acetazolamidebull Cyclandelate
Level A negative The following medication is estab-lished as ineffective and should not be offered formigraine prevention
bull Lamotrigine
1342 Neurology 78 April 24 2012
Level B negative The following medication is proba-bly ineffective and should not be considered for mi-graine prevention
bull Clomipramine
Level C negative The following medications are pos-sibly ineffective and may not be considered for mi-graine prevention
bull Acebutololbull Clonazepambull Nabumetonebull Oxcarbazepinebull Telmisartan
CLINICAL 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 coexistingcomorbid 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 agentsStudies 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 12ndash16weeks) 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 25 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 draftingrevising the manuscript
study concept or design analysis or interpretation of data acquisition of
data study supervision Dr Holland draftingrevising the manuscript
study concept or design analysis or interpretation of data Dr Freitag
draftingrevising the manuscript analysis or interpretation of data acqui-
sition of data Dr Dodick draftingrevising the manuscript study con-
cept or design analysis or interpretation of data Dr Argoff drafting
revising the manuscript study concept or design analysis or
interpretation of data Dr Ashman draftingrevising the manuscript
analysis or interpretation of data
DISCLOSUREDr Silberstein is on the advisory panel of and receives honoraria from
AGA 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 speakersrsquo bureau
of and receives honoraria from Endo Pharmaceuticals GlaxoSmithKline
and Merck He serves as a consultant for and receives honoraria from
Amgen 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 the
American Headache Society and research support from Albert Einstein
College of Medicine Dr Freitag has served on the scientific advisory
boards of Zogenix Pharmaceuticals Allergan Pharmaceuticals Nautilus
MAP Pharmaceuticals and Nupathe has received travel expenses and or
honoraria from GlaxoSmithKline Zogenix Merck Nautilus Allergan
Diamond Headache Clinic Research and Educational Foundation (not
for profit) and the American Headache Society (travel) Dr Freitag is a
member of the Board of Directors of the National Headache Foundation
Dr Dodick within the past 3 years serves on advisory boards and has
consulted for Allergan Alder Pfizer Merck Coherex Ferring Neuro-
core Neuralieve Neuraxon NuPathe Inc MAP SmithKlineBeecham
Boston Scientific Medtronic Inc Nautilus Eli Lilly amp Company No-
Neurology 78 April 24 2012 1343
vartis Colucid GlaxoSmithKline Autonomic Technologies MAP Phar-
maceuticals Inc Zogenix Inc Impax Laboratories Inc Bristol Myers
Squibb 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 SAGE
Publishing Lippincott Williams amp 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 The
Neurologist Lancet Neurology and Postgraduate Medicine and has served
as Editor-in-Chief of Headache Currents and as an Associate Editor of
Headache he receives publishing royalties for Wolff rsquos Headache 8th edi-
tion (Oxford University Press 2009) and Handbook of Headache (Cam-
bridge University Press 2010) Within the past 3 years Dr Dodick has
received research grant support from Advanced Neurostimulation Sys-
tems Boston Scientific St Jude Medical Inc Medtronic NINDSNIH
Mayo Clinic Dr Argoff has served on a scientific advisory board for the
Department of Defense and DSMB for the NIH has received funding for
travel andor speaking andor has served on a speakersrsquo bureau for Pfizer
(King) Janssen (Pricara) Millennium Laboratories Neurogesx Forest
Laboratories Eli Lilly Covidien and Endo Pharmaceuticals has received
research support from Endo Pharmaceuticals Forest Laboratories Eli
Lilly Neurogesx Pfizer and SBRT funded by the NIH and has received
stockstock options from Pfizer Dr Ashman is the Level of Evidence
editor 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 Neurologyorg for full
disclosures
DISCLAIMERThis statement is provided as an educational service of the American
Academy of Neurology and the American Headache Society It is based
on as assessment of current scientific and clinical information It is not
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 it intended to exclude any reasonable alternative
methodologies The AAN and the AHS recognize that specific patient
care decisions are the prerogative of the patient and the physician
caring for the patient based on all of the circumstances involved The
clinical context section is made available in order to place the
evidence-based guideline(s) into perspective with current practice hab-
its and challenges No formal practice recommendations should be
inferred
CONFLICT OF INTERESTThe American Academy of Neurology and the American Headache Soci-
ety are committed to producing independent critical and truthful clinical
practice guidelines (CPGs) Significant efforts are made to minimize the
potential for conflicts of interest to influence the recommendations of this
CPG To the extent possible the AAN and AHS keep separate those who
have a financial stake in the success or failure of the products appraised in
the CPGs and the developers of the guidelines Conflict of interest forms
were obtained from all authors and reviewed by an oversight committee
prior to project initiation AAN and AHS limit the participation of au-
thors with substantial conflicts of interest The AAN and AHS forbid
commercial participation in or funding of guideline projects Drafts of
the 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 of
Interest Policy can be viewed at wwwaancom
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 200768343ndash349
2 Ramadan NM Silberstein SD Freitag FG Gilbert TT
Frishberg BM Evidence-based guidelines for migraine
headache in the primary care setting pharmacological
management for prevention of migraine Available at
httpwwwaancomprofessionalspracticepdfsgl0090
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 the
American Academy of Neurology Neurology 200055
754ndash762
4 Naumann M So Y Argoff C et al Assessment Botuli-
num neurotoxin in the treatment of autonomic disorders
and pain (an evidence-based review) report of the Thera-
peutics and Technology Subcommittee of the American
Academy of Neurology Neurology 2008701707ndash1714
5 Holland S Silberstein SD Freitag F Dodick DW Argoff
C Ashman E Evidence-based guideline update NSAIDs
and other complementary treatments for episodic migraine
prevention in adults report of the Quality Standards Sub-
committee of the American Academy of Neurology and
the American Headache Society Neurology 201278
1346ndash1353
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
28965ndash69
7 Schrader H Stovner LJ Helde G Sand T Bovim G Pro-
phylactic treatment of migraine with angiotensin convert-
ing enzyme inhibitor (lisinopril) randomised placebo
controlled crossover study BMJ 200132219ndash22
8 Diener HC Gendolla A Feuersenger A et al Telmisartan
in migraine prophylaxis a randomized placebo-controlled
trial Cephalalgia 200929921ndash927
9 Freitag FG Collins SD Carlson HA et al A randomized
trial of divalproex sodium extended-release tablets in mi-
graine prophylaxis Neurology 2002581652ndash1659
10 Silberstein SD Collins SD Safety of divalproex sodium in
migraine prophylaxis an open-label long-term study
long-term safety of Depakote in Headache Prophylaxis
Study Group Headache 199939633ndash643
11 Harden CL Meador KJ Pennell PB et al American Acad-
emy of Neurology American Epilepsy Society Practice pa-
rameter update management issues for women with
epilepsyndashfocus on pregnancy (an evidence-based review)
teratogenesis and perinatal outcomes report of the Quality
Standards Subcommittee and Therapeutics and Technol-
ogy Assessment Subcommittee of the American Academy
of Neurology and American Epilepsy Society Neurology
200973133ndash141
12 Mathew NT Rapoport A Saper J et al Efficacy of gabap-
entin in migraine prophylaxis Headache 200141119ndash
128
13 Steiner TJ Findley LJ Yuen AW Lamotrigine versus pla-
cebo in the prophylaxis of migraine with and without aura
Cephalalgia 199717109ndash112
14 Gupta P Singh S Goyal V Shukla G Behari M Low-
dose topiramate versus lamotrigine in migraine prophy-
laxis (the Lotolamp study) Headache 200747402ndash412
15 Silberstein SD Saper J Berenson F Somogyi M Mc-
Cague MA DrsquoSouza JD Oxcarbazepine in migraine head-
ache a double-blind randomized placebo-controlled
study Neurology 200870548ndash555
1344 Neurology 78 April 24 2012
16 Ashtari F Shaygannejad V Akbari M A double-blindrandomized trial of low-dose topiramate vs propranolol inmigraine prophylaxis Acta Neurol Scand 2008118301ndash305
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 Headache200646642ndash 648
18 Storey JR Calder CS Hart DE Potter DL Topiramate inmigraine prevention a double-blind placebo-controlledstudy Headache 200141968ndash975
19 Brandes JL Saper JR Diamond M et al MIGR-002Study Group Topiramate for migraine prevention a ran-domized controlled trial JAMA 2004291965ndash973
20 Diener HC Matias-Guiu J Hartung E et al Topiramatein migraine prophylaxisndashresults from a placebo-controlledtrial with propranolol as an active control J Neurol 2004251943ndash950
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 200931542ndash559
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 2008110979ndash984
23 Mei D Capuano A Vollono C et al Topiramate in mi-graine prophylaxis a randomised double-blind versus pla-cebo study Neurol Sci 200425245ndash250
24 Silberstein SD Neto W Schmitt J Jacobs D MIGR-001Study Group Topiramate in migraine prevention resultsof a large controlled trial Arch Neurol 200461490ndash495
25 Millan-Guerrero RO Isais-Millan R Barreto-Vizcaiacuteno Set al Subcutaneous histamine versus topiramate in mi-graine prophylaxis a double-blind study Eur Neurol200859237ndash242
26 Silberstein SD Hulihan J Karim MR et al Efficacy andtolerability of topiramate 200 mgd in the prevention ofmigraine withwithout aura in adults a randomizedplacebo-controlled double-blind 12-week pilot studyClin Ther 2006281002ndash1011
27 Adly C Straumanis J Chesson A Fluoxetine prophylaxisof migraine Headache 199232101ndash104
28 Saper JR Silberstein SD Lake AE III Winters MEDouble-blind trial of fluoxetine chronic daily headacheand migraine Headache 199434497ndash502
29 drsquoAmato CC Pizza V Marmolo T Giordano E Alfano V
Nasta A Fluoxetine for migraine prophylaxis a double-
blind trial Headache 199939716ndash719
30 Ozyalcin SN Talu GK Kiziltan E Yucel B Ertas M Disci
R The efficacy and safety of venlafaxine in the prophylaxis
of migraine Headache 200545144ndash152
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 2004107
44ndash48
32 Diener HC Hartung E Chrubasik J et al A comparative
study of oral acetylsalicylic acid and metoprolol for the
prophylactic treatment of migraine a randomized con-
trolled double-blind parallel group phase III study Ceph-
alalgia 200121120ndash128
33 Schellenberg R Lichtenthal A Wohling H Graf C
Brixius K Nebivolol and metoprolol for treating migraine
an advance on beta-blocker treatment Headache 200848
118ndash125
34 Rao BS Das DG Taraknath VR Sarma Y A double blind
controlled study of propranolol and cyproheptadine in mi-
graine prophylaxis Neurol India 200048223ndash226
35 Diener HC Krupp P Schmitt T Steitz G Milde K
Freytag S on behalf of the Study Group Cyclandelate in
the prophylaxis of migraine a placebo-controlled study
Cephalalgia 20012166ndash70
36 Siniatchkin M Gerber WD Vein A Clinical efficacy and
central mechanisms of cyclandelate in migraine a double-
blind placebo-controlled study Funct Neurol 199813
47ndash56
37 Silberstein SD Elkind AH Schreiber C Keywood C A
randomized trial of frovatriptan for the intermittent pre-
vention of menstrual migraine Neurology 200463261ndash
269
38 Brandes JL Poole A Kallela M et al Short-term fro-
vatriptan for the prevention of difficult-to-treat menstrual
migraine attacks Cephalalgia 2009291133ndash1148
39 Newman L Mannix LK Landy S et al Naratriptan as
short-term prophylaxis of menstrually associated migraine
a randomized double-blind placebo-controlled study
Headache 200141248ndash256
40 Tuchman MM Hee A Emeribe U Silberstein S Oral
zolmitriptan in the short-term prevention of menstrual mi-
graine a randomized placebo-controlled study CNS
Drugs 200822877ndash886
Endorsed by the American Osteopathic Association on March 22 2012
Neurology 78 April 24 2012 1345
DOI 101212WNL0b013e3182535d202012781337-1345 Neurology
SD Silberstein S Holland F Freitag et al Academy of Neurology and the American Headache Society
prevention in adults Report of the Quality Standards Subcommittee of the American Evidence-based guideline update Pharmacologic treatment for episodic migraine
This information is current as of April 23 2012
rights reserved Print ISSN 0028-3878 Online ISSN 1526-632X1951 it is now a weekly with 48 issues per year Copyright Copyright copy 2012 by AAN Enterprises Inc All
reg is the official journal of the American Academy of Neurology Published continuously sinceNeurology
ServicesUpdated Information amp
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Supplementary material can be found at
References httpnneurologyorgcontent78171337fullref-list-1
This article cites 39 articles 9 of which you can access for free at
Citations httpnneurologyorgcontent78171337fullotherarticles
This article has been cited by 5 HighWire-hosted articles
Subspecialty Collections
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httpnneurologyorgcgicollectionmigraineMigrainefollowing collection(s) This article along with others on similar topics appears in the
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reg is the official journal of the American Academy of Neurology Published continuously sinceNeurology
CORRECTIONEvidence-based guideline update Pharmacologic treatment for episodicmigraine prevention in adults Report of the
Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society
In the special article ldquoEvidence-based guideline update Pharmacologic treatment for episodic migraine prevention in adultsReport of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Societyrdquo bySD Silberstein et al (Neurology 2012781337ndash1345) there are errors in table 1 and the text on page 1342 Due to changes inthe AANrsquos LOE classification criteria pindolol and clonidine should have been labeled as having Level U recommendations andnicardipine should have been listed as having a Level C recommendation These changes are based on studies cited in the original2001 guideline no new studies were found in the literature search for the 2012 update Please see the corrected table belowTheauthors regret the errors
Table 1 Classification of migraine preventive therapies (available in the United States)
Level A Medicationswith establishedefficacy (Dagger2 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 use
Other Medicationsthat are establishedas ineffectiveprobably ineffectiveor possiblyineffective
Antiepileptic drugs AntidepressantsSSRISSNRITCA
ACE inhibitors a-Agonists Established asineffective
Divalproex sodium Amitriptyline Lisinopril Clonidinea Lamotrigine
Sodium valproate Venlafaxine a-Agonists AntidepressantsSSRISSNRI
Probably ineffective
Topiramate b-Blockers Guanfacinea Fluoxetine Clomipraminea
b-Blockers Atenolola Angiotensin receptorblockers
Fluvoxaminea Possibly ineffective
Metoprolol Nadolola Candesartan Antiepileptic drugs Acebutolola
Propranolol Triptans (MRMb) Antiepileptic drugs Gabapentin Clonazepama
Timolola Naratriptanb Carbamazepinea Antithrombotics Nabumetonea
Triptans (MRMb) Zolmitriptanb Antihistamines Acenocoumarol Oxcarbazepine
Frovatriptanb Cyproheptadine Coumadin Telmisartan
b-Blockers Picotamide
Nebivolol b-Blockers
Ca11 blockers Bisoprolola
Nicardipinea Pindolola
Ca11 blockers
Nifedipinea
Nimodipine
Verapamil
Carbonic anhydraseinhibitor
Acetazolamide
Direct vascularsmooth musclerelaxants
Cyclandelate
TCAs
Protriptylinea
Abbreviations ACE 5 angiotensin-converting-enzyme Ca11 blockers 5 calcium channel blockers MRM 5 menstruallyrelated migraine SSNRI 5 selective serotoninndashnorepinephrine reuptake inhibitor SSRI 5 selective serotonin reuptakeinhibitor TCA 5 tricyclic antidepressanta Classification based on original guideline and new evidence not found for this reportb For short-term prophylaxis of MRM
Neurology 80 February 26 2013 871
quency37 The mean number of headache-free peri-menstrual periods (PMPs) per patient (primaryendpoint) was higher in the 2 frovatriptan groups(25 mg qd 069 [SD 092 CI 114ndash273 p 00091] vs 25 mg BID 092 [SD 103 CI 184ndash428 p 00001] vs placebo 042 [SD 078])representing 64 (25 mgday) and 119 (5 mgday) increases in the mean number of headache-freePMPs per patient over placebo A second Class Istudy38 also reports the MAM headache incidenceduring the 6-day PMP was 67 for placebo 52 forfrovatriptan 25 mg QD (p 00001 vs placebo)and 41 for frovatriptan 25 mg BID (p 00001vs placebo p 00001 vs QD regimen) The AEincidence and type for both regimens were similar tothose for placebo The overall AE incidence for fro-vatriptan was 41 (25 mg BID) and 27 (25 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 days39 Patients treated withnaratriptan 1 mg experienced more headache-freePMPs than those on placebo (50 vs 25 p
0003) Naratriptan 1 mg reduced the number ofMAMs (20 vs 40 p 005) and MAM days (42 vs70 p 001) vs placebo The AE incidence andseverity were similar to those of placebo 10 ofpatients experienced dizziness chest pain or malaise
Zolmitriptan One Class I study reported the effi-cacy of zolmitriptan 25 BIDTID vs placebo Bothzolmitriptan regimens demonstrated superior effi-cacy vs placebo the proportion of patients with a50 MAM attack frequency reduction (zolmi-triptan 25 mg TID [586] p 00007 vs placebozolmitriptan 25 mg BID [547] p 0002 vs pla-cebo placebo 378)40 AEs were considered possi-bly treatment-related in 28 patients (333) in thezolmitriptan 25 mg TID group 29 (363) in thezolmitriptan 25 mg BID group and 18 (220) 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 more
effective than placebo in reducing migraine fre-quency duration and severitye1 This trial (n 53) 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
bull Antiepileptic drugs (AEDs) divalproex so-dium sodium valproate topiramate
bull -Blockers metoprolol propranolol timololbull Triptans frovatriptan for short-term MAMs
prevention
Level B The following medications are probablyeffective and should be considered for migraineprevention
bull Antidepressants amitriptyline venlafaxinebull -Blockers atenolol nadololbull Triptans naratriptan zolmitriptan for short-
term MAMs prevention
Level C The following medications are possibly effec-tive and may be considered for migraine prevention
bull ACE inhibitors lisinoprilbull Angiotensin receptor blockers candesartanbull -Agonists clonidine guanfacinebull AEDs carbamazepinebull -Blockers nebivolol pindolol
Level U Evidence is conflicting or inadequate to sup-port or refute the use of the following medicationsfor migraine prevention
bull AEDs gabapentinbull Antidepressants
bull Selective serotonin reuptake inhibitorselec-tive serotonin-norepinephrine reuptake in-hibitors fluoxetine fluvoxamine
bull Tricyclics protriptylinebull Antithrombotics acenocoumarol Coumadin
picotamidebull -Blockers bisoprololbull Calcium-channel blockers nicardipine nifedi-
pine nimodipine verapamilbull Acetazolamidebull Cyclandelate
Level A negative The following medication is estab-lished as ineffective and should not be offered formigraine prevention
bull Lamotrigine
1342 Neurology 78 April 24 2012
Level B negative The following medication is proba-bly ineffective and should not be considered for mi-graine prevention
bull Clomipramine
Level C negative The following medications are pos-sibly ineffective and may not be considered for mi-graine prevention
bull Acebutololbull Clonazepambull Nabumetonebull Oxcarbazepinebull Telmisartan
CLINICAL 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 coexistingcomorbid 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 agentsStudies 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 12ndash16weeks) 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 25 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 draftingrevising the manuscript
study concept or design analysis or interpretation of data acquisition of
data study supervision Dr Holland draftingrevising the manuscript
study concept or design analysis or interpretation of data Dr Freitag
draftingrevising the manuscript analysis or interpretation of data acqui-
sition of data Dr Dodick draftingrevising the manuscript study con-
cept or design analysis or interpretation of data Dr Argoff drafting
revising the manuscript study concept or design analysis or
interpretation of data Dr Ashman draftingrevising the manuscript
analysis or interpretation of data
DISCLOSUREDr Silberstein is on the advisory panel of and receives honoraria from
AGA 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 speakersrsquo bureau
of and receives honoraria from Endo Pharmaceuticals GlaxoSmithKline
and Merck He serves as a consultant for and receives honoraria from
Amgen 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 the
American Headache Society and research support from Albert Einstein
College of Medicine Dr Freitag has served on the scientific advisory
boards of Zogenix Pharmaceuticals Allergan Pharmaceuticals Nautilus
MAP Pharmaceuticals and Nupathe has received travel expenses and or
honoraria from GlaxoSmithKline Zogenix Merck Nautilus Allergan
Diamond Headache Clinic Research and Educational Foundation (not
for profit) and the American Headache Society (travel) Dr Freitag is a
member of the Board of Directors of the National Headache Foundation
Dr Dodick within the past 3 years serves on advisory boards and has
consulted for Allergan Alder Pfizer Merck Coherex Ferring Neuro-
core Neuralieve Neuraxon NuPathe Inc MAP SmithKlineBeecham
Boston Scientific Medtronic Inc Nautilus Eli Lilly amp Company No-
Neurology 78 April 24 2012 1343
vartis Colucid GlaxoSmithKline Autonomic Technologies MAP Phar-
maceuticals Inc Zogenix Inc Impax Laboratories Inc Bristol Myers
Squibb 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 SAGE
Publishing Lippincott Williams amp 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 The
Neurologist Lancet Neurology and Postgraduate Medicine and has served
as Editor-in-Chief of Headache Currents and as an Associate Editor of
Headache he receives publishing royalties for Wolff rsquos Headache 8th edi-
tion (Oxford University Press 2009) and Handbook of Headache (Cam-
bridge University Press 2010) Within the past 3 years Dr Dodick has
received research grant support from Advanced Neurostimulation Sys-
tems Boston Scientific St Jude Medical Inc Medtronic NINDSNIH
Mayo Clinic Dr Argoff has served on a scientific advisory board for the
Department of Defense and DSMB for the NIH has received funding for
travel andor speaking andor has served on a speakersrsquo bureau for Pfizer
(King) Janssen (Pricara) Millennium Laboratories Neurogesx Forest
Laboratories Eli Lilly Covidien and Endo Pharmaceuticals has received
research support from Endo Pharmaceuticals Forest Laboratories Eli
Lilly Neurogesx Pfizer and SBRT funded by the NIH and has received
stockstock options from Pfizer Dr Ashman is the Level of Evidence
editor 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 Neurologyorg for full
disclosures
DISCLAIMERThis statement is provided as an educational service of the American
Academy of Neurology and the American Headache Society It is based
on as assessment of current scientific and clinical information It is not
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 it intended to exclude any reasonable alternative
methodologies The AAN and the AHS recognize that specific patient
care decisions are the prerogative of the patient and the physician
caring for the patient based on all of the circumstances involved The
clinical context section is made available in order to place the
evidence-based guideline(s) into perspective with current practice hab-
its and challenges No formal practice recommendations should be
inferred
CONFLICT OF INTERESTThe American Academy of Neurology and the American Headache Soci-
ety are committed to producing independent critical and truthful clinical
practice guidelines (CPGs) Significant efforts are made to minimize the
potential for conflicts of interest to influence the recommendations of this
CPG To the extent possible the AAN and AHS keep separate those who
have a financial stake in the success or failure of the products appraised in
the CPGs and the developers of the guidelines Conflict of interest forms
were obtained from all authors and reviewed by an oversight committee
prior to project initiation AAN and AHS limit the participation of au-
thors with substantial conflicts of interest The AAN and AHS forbid
commercial participation in or funding of guideline projects Drafts of
the 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 of
Interest Policy can be viewed at wwwaancom
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 200768343ndash349
2 Ramadan NM Silberstein SD Freitag FG Gilbert TT
Frishberg BM Evidence-based guidelines for migraine
headache in the primary care setting pharmacological
management for prevention of migraine Available at
httpwwwaancomprofessionalspracticepdfsgl0090
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 the
American Academy of Neurology Neurology 200055
754ndash762
4 Naumann M So Y Argoff C et al Assessment Botuli-
num neurotoxin in the treatment of autonomic disorders
and pain (an evidence-based review) report of the Thera-
peutics and Technology Subcommittee of the American
Academy of Neurology Neurology 2008701707ndash1714
5 Holland S Silberstein SD Freitag F Dodick DW Argoff
C Ashman E Evidence-based guideline update NSAIDs
and other complementary treatments for episodic migraine
prevention in adults report of the Quality Standards Sub-
committee of the American Academy of Neurology and
the American Headache Society Neurology 201278
1346ndash1353
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
28965ndash69
7 Schrader H Stovner LJ Helde G Sand T Bovim G Pro-
phylactic treatment of migraine with angiotensin convert-
ing enzyme inhibitor (lisinopril) randomised placebo
controlled crossover study BMJ 200132219ndash22
8 Diener HC Gendolla A Feuersenger A et al Telmisartan
in migraine prophylaxis a randomized placebo-controlled
trial Cephalalgia 200929921ndash927
9 Freitag FG Collins SD Carlson HA et al A randomized
trial of divalproex sodium extended-release tablets in mi-
graine prophylaxis Neurology 2002581652ndash1659
10 Silberstein SD Collins SD Safety of divalproex sodium in
migraine prophylaxis an open-label long-term study
long-term safety of Depakote in Headache Prophylaxis
Study Group Headache 199939633ndash643
11 Harden CL Meador KJ Pennell PB et al American Acad-
emy of Neurology American Epilepsy Society Practice pa-
rameter update management issues for women with
epilepsyndashfocus on pregnancy (an evidence-based review)
teratogenesis and perinatal outcomes report of the Quality
Standards Subcommittee and Therapeutics and Technol-
ogy Assessment Subcommittee of the American Academy
of Neurology and American Epilepsy Society Neurology
200973133ndash141
12 Mathew NT Rapoport A Saper J et al Efficacy of gabap-
entin in migraine prophylaxis Headache 200141119ndash
128
13 Steiner TJ Findley LJ Yuen AW Lamotrigine versus pla-
cebo in the prophylaxis of migraine with and without aura
Cephalalgia 199717109ndash112
14 Gupta P Singh S Goyal V Shukla G Behari M Low-
dose topiramate versus lamotrigine in migraine prophy-
laxis (the Lotolamp study) Headache 200747402ndash412
15 Silberstein SD Saper J Berenson F Somogyi M Mc-
Cague MA DrsquoSouza JD Oxcarbazepine in migraine head-
ache a double-blind randomized placebo-controlled
study Neurology 200870548ndash555
1344 Neurology 78 April 24 2012
16 Ashtari F Shaygannejad V Akbari M A double-blindrandomized trial of low-dose topiramate vs propranolol inmigraine prophylaxis Acta Neurol Scand 2008118301ndash305
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 Headache200646642ndash 648
18 Storey JR Calder CS Hart DE Potter DL Topiramate inmigraine prevention a double-blind placebo-controlledstudy Headache 200141968ndash975
19 Brandes JL Saper JR Diamond M et al MIGR-002Study Group Topiramate for migraine prevention a ran-domized controlled trial JAMA 2004291965ndash973
20 Diener HC Matias-Guiu J Hartung E et al Topiramatein migraine prophylaxisndashresults from a placebo-controlledtrial with propranolol as an active control J Neurol 2004251943ndash950
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 200931542ndash559
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 2008110979ndash984
23 Mei D Capuano A Vollono C et al Topiramate in mi-graine prophylaxis a randomised double-blind versus pla-cebo study Neurol Sci 200425245ndash250
24 Silberstein SD Neto W Schmitt J Jacobs D MIGR-001Study Group Topiramate in migraine prevention resultsof a large controlled trial Arch Neurol 200461490ndash495
25 Millan-Guerrero RO Isais-Millan R Barreto-Vizcaiacuteno Set al Subcutaneous histamine versus topiramate in mi-graine prophylaxis a double-blind study Eur Neurol200859237ndash242
26 Silberstein SD Hulihan J Karim MR et al Efficacy andtolerability of topiramate 200 mgd in the prevention ofmigraine withwithout aura in adults a randomizedplacebo-controlled double-blind 12-week pilot studyClin Ther 2006281002ndash1011
27 Adly C Straumanis J Chesson A Fluoxetine prophylaxisof migraine Headache 199232101ndash104
28 Saper JR Silberstein SD Lake AE III Winters MEDouble-blind trial of fluoxetine chronic daily headacheand migraine Headache 199434497ndash502
29 drsquoAmato CC Pizza V Marmolo T Giordano E Alfano V
Nasta A Fluoxetine for migraine prophylaxis a double-
blind trial Headache 199939716ndash719
30 Ozyalcin SN Talu GK Kiziltan E Yucel B Ertas M Disci
R The efficacy and safety of venlafaxine in the prophylaxis
of migraine Headache 200545144ndash152
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 2004107
44ndash48
32 Diener HC Hartung E Chrubasik J et al A comparative
study of oral acetylsalicylic acid and metoprolol for the
prophylactic treatment of migraine a randomized con-
trolled double-blind parallel group phase III study Ceph-
alalgia 200121120ndash128
33 Schellenberg R Lichtenthal A Wohling H Graf C
Brixius K Nebivolol and metoprolol for treating migraine
an advance on beta-blocker treatment Headache 200848
118ndash125
34 Rao BS Das DG Taraknath VR Sarma Y A double blind
controlled study of propranolol and cyproheptadine in mi-
graine prophylaxis Neurol India 200048223ndash226
35 Diener HC Krupp P Schmitt T Steitz G Milde K
Freytag S on behalf of the Study Group Cyclandelate in
the prophylaxis of migraine a placebo-controlled study
Cephalalgia 20012166ndash70
36 Siniatchkin M Gerber WD Vein A Clinical efficacy and
central mechanisms of cyclandelate in migraine a double-
blind placebo-controlled study Funct Neurol 199813
47ndash56
37 Silberstein SD Elkind AH Schreiber C Keywood C A
randomized trial of frovatriptan for the intermittent pre-
vention of menstrual migraine Neurology 200463261ndash
269
38 Brandes JL Poole A Kallela M et al Short-term fro-
vatriptan for the prevention of difficult-to-treat menstrual
migraine attacks Cephalalgia 2009291133ndash1148
39 Newman L Mannix LK Landy S et al Naratriptan as
short-term prophylaxis of menstrually associated migraine
a randomized double-blind placebo-controlled study
Headache 200141248ndash256
40 Tuchman MM Hee A Emeribe U Silberstein S Oral
zolmitriptan in the short-term prevention of menstrual mi-
graine a randomized placebo-controlled study CNS
Drugs 200822877ndash886
Endorsed by the American Osteopathic Association on March 22 2012
Neurology 78 April 24 2012 1345
DOI 101212WNL0b013e3182535d202012781337-1345 Neurology
SD Silberstein S Holland F Freitag et al Academy of Neurology and the American Headache Society
prevention in adults Report of the Quality Standards Subcommittee of the American Evidence-based guideline update Pharmacologic treatment for episodic migraine
This information is current as of April 23 2012
rights reserved Print ISSN 0028-3878 Online ISSN 1526-632X1951 it is now a weekly with 48 issues per year Copyright Copyright copy 2012 by AAN Enterprises Inc All
reg is the official journal of the American Academy of Neurology Published continuously sinceNeurology
ServicesUpdated Information amp
httpnneurologyorgcontent78171337fullincluding high resolution figures can be found at
Supplementary Material
httpnneurologyorgcontentsuppl2013010378171337DC4 httpnneurologyorgcontentsuppl2012120378171337DC3 httpnneurologyorgcontentsuppl2012042278171337DC2 httpnneurologyorgcontentsuppl2012042278171337DC1
Supplementary material can be found at
References httpnneurologyorgcontent78171337fullref-list-1
This article cites 39 articles 9 of which you can access for free at
Citations httpnneurologyorgcontent78171337fullotherarticles
This article has been cited by 5 HighWire-hosted articles
Subspecialty Collections
httpnneurologyorgcgicollectionpalliation_painPalliation pain
httpnneurologyorgcgicollectionmigraineMigrainefollowing collection(s) This article along with others on similar topics appears in the
Errata
content809871fullpdf or page
nextAn erratum has been published regarding this article Please see
Permissions amp Licensing
httpwwwneurologyorgaboutabout_the_journalpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpnneurologyorgsubscribersadvertiseInformation about ordering reprints can be found online
rights reserved Print ISSN 0028-3878 Online ISSN 1526-632X1951 it is now a weekly with 48 issues per year Copyright Copyright copy 2012 by AAN Enterprises Inc All
reg is the official journal of the American Academy of Neurology Published continuously sinceNeurology
CORRECTIONEvidence-based guideline update Pharmacologic treatment for episodicmigraine prevention in adults Report of the
Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society
In the special article ldquoEvidence-based guideline update Pharmacologic treatment for episodic migraine prevention in adultsReport of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Societyrdquo bySD Silberstein et al (Neurology 2012781337ndash1345) there are errors in table 1 and the text on page 1342 Due to changes inthe AANrsquos LOE classification criteria pindolol and clonidine should have been labeled as having Level U recommendations andnicardipine should have been listed as having a Level C recommendation These changes are based on studies cited in the original2001 guideline no new studies were found in the literature search for the 2012 update Please see the corrected table belowTheauthors regret the errors
Table 1 Classification of migraine preventive therapies (available in the United States)
Level A Medicationswith establishedefficacy (Dagger2 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 use
Other Medicationsthat are establishedas ineffectiveprobably ineffectiveor possiblyineffective
Antiepileptic drugs AntidepressantsSSRISSNRITCA
ACE inhibitors a-Agonists Established asineffective
Divalproex sodium Amitriptyline Lisinopril Clonidinea Lamotrigine
Sodium valproate Venlafaxine a-Agonists AntidepressantsSSRISSNRI
Probably ineffective
Topiramate b-Blockers Guanfacinea Fluoxetine Clomipraminea
b-Blockers Atenolola Angiotensin receptorblockers
Fluvoxaminea Possibly ineffective
Metoprolol Nadolola Candesartan Antiepileptic drugs Acebutolola
Propranolol Triptans (MRMb) Antiepileptic drugs Gabapentin Clonazepama
Timolola Naratriptanb Carbamazepinea Antithrombotics Nabumetonea
Triptans (MRMb) Zolmitriptanb Antihistamines Acenocoumarol Oxcarbazepine
Frovatriptanb Cyproheptadine Coumadin Telmisartan
b-Blockers Picotamide
Nebivolol b-Blockers
Ca11 blockers Bisoprolola
Nicardipinea Pindolola
Ca11 blockers
Nifedipinea
Nimodipine
Verapamil
Carbonic anhydraseinhibitor
Acetazolamide
Direct vascularsmooth musclerelaxants
Cyclandelate
TCAs
Protriptylinea
Abbreviations ACE 5 angiotensin-converting-enzyme Ca11 blockers 5 calcium channel blockers MRM 5 menstruallyrelated migraine SSNRI 5 selective serotoninndashnorepinephrine reuptake inhibitor SSRI 5 selective serotonin reuptakeinhibitor TCA 5 tricyclic antidepressanta Classification based on original guideline and new evidence not found for this reportb For short-term prophylaxis of MRM
Neurology 80 February 26 2013 871
Level B negative The following medication is proba-bly ineffective and should not be considered for mi-graine prevention
bull Clomipramine
Level C negative The following medications are pos-sibly ineffective and may not be considered for mi-graine prevention
bull Acebutololbull Clonazepambull Nabumetonebull Oxcarbazepinebull Telmisartan
CLINICAL 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 coexistingcomorbid 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 agentsStudies 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 12ndash16weeks) 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 25 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 draftingrevising the manuscript
study concept or design analysis or interpretation of data acquisition of
data study supervision Dr Holland draftingrevising the manuscript
study concept or design analysis or interpretation of data Dr Freitag
draftingrevising the manuscript analysis or interpretation of data acqui-
sition of data Dr Dodick draftingrevising the manuscript study con-
cept or design analysis or interpretation of data Dr Argoff drafting
revising the manuscript study concept or design analysis or
interpretation of data Dr Ashman draftingrevising the manuscript
analysis or interpretation of data
DISCLOSUREDr Silberstein is on the advisory panel of and receives honoraria from
AGA 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 speakersrsquo bureau
of and receives honoraria from Endo Pharmaceuticals GlaxoSmithKline
and Merck He serves as a consultant for and receives honoraria from
Amgen 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 the
American Headache Society and research support from Albert Einstein
College of Medicine Dr Freitag has served on the scientific advisory
boards of Zogenix Pharmaceuticals Allergan Pharmaceuticals Nautilus
MAP Pharmaceuticals and Nupathe has received travel expenses and or
honoraria from GlaxoSmithKline Zogenix Merck Nautilus Allergan
Diamond Headache Clinic Research and Educational Foundation (not
for profit) and the American Headache Society (travel) Dr Freitag is a
member of the Board of Directors of the National Headache Foundation
Dr Dodick within the past 3 years serves on advisory boards and has
consulted for Allergan Alder Pfizer Merck Coherex Ferring Neuro-
core Neuralieve Neuraxon NuPathe Inc MAP SmithKlineBeecham
Boston Scientific Medtronic Inc Nautilus Eli Lilly amp Company No-
Neurology 78 April 24 2012 1343
vartis Colucid GlaxoSmithKline Autonomic Technologies MAP Phar-
maceuticals Inc Zogenix Inc Impax Laboratories Inc Bristol Myers
Squibb 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 SAGE
Publishing Lippincott Williams amp 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 The
Neurologist Lancet Neurology and Postgraduate Medicine and has served
as Editor-in-Chief of Headache Currents and as an Associate Editor of
Headache he receives publishing royalties for Wolff rsquos Headache 8th edi-
tion (Oxford University Press 2009) and Handbook of Headache (Cam-
bridge University Press 2010) Within the past 3 years Dr Dodick has
received research grant support from Advanced Neurostimulation Sys-
tems Boston Scientific St Jude Medical Inc Medtronic NINDSNIH
Mayo Clinic Dr Argoff has served on a scientific advisory board for the
Department of Defense and DSMB for the NIH has received funding for
travel andor speaking andor has served on a speakersrsquo bureau for Pfizer
(King) Janssen (Pricara) Millennium Laboratories Neurogesx Forest
Laboratories Eli Lilly Covidien and Endo Pharmaceuticals has received
research support from Endo Pharmaceuticals Forest Laboratories Eli
Lilly Neurogesx Pfizer and SBRT funded by the NIH and has received
stockstock options from Pfizer Dr Ashman is the Level of Evidence
editor 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 Neurologyorg for full
disclosures
DISCLAIMERThis statement is provided as an educational service of the American
Academy of Neurology and the American Headache Society It is based
on as assessment of current scientific and clinical information It is not
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 it intended to exclude any reasonable alternative
methodologies The AAN and the AHS recognize that specific patient
care decisions are the prerogative of the patient and the physician
caring for the patient based on all of the circumstances involved The
clinical context section is made available in order to place the
evidence-based guideline(s) into perspective with current practice hab-
its and challenges No formal practice recommendations should be
inferred
CONFLICT OF INTERESTThe American Academy of Neurology and the American Headache Soci-
ety are committed to producing independent critical and truthful clinical
practice guidelines (CPGs) Significant efforts are made to minimize the
potential for conflicts of interest to influence the recommendations of this
CPG To the extent possible the AAN and AHS keep separate those who
have a financial stake in the success or failure of the products appraised in
the CPGs and the developers of the guidelines Conflict of interest forms
were obtained from all authors and reviewed by an oversight committee
prior to project initiation AAN and AHS limit the participation of au-
thors with substantial conflicts of interest The AAN and AHS forbid
commercial participation in or funding of guideline projects Drafts of
the 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 of
Interest Policy can be viewed at wwwaancom
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 200768343ndash349
2 Ramadan NM Silberstein SD Freitag FG Gilbert TT
Frishberg BM Evidence-based guidelines for migraine
headache in the primary care setting pharmacological
management for prevention of migraine Available at
httpwwwaancomprofessionalspracticepdfsgl0090
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 the
American Academy of Neurology Neurology 200055
754ndash762
4 Naumann M So Y Argoff C et al Assessment Botuli-
num neurotoxin in the treatment of autonomic disorders
and pain (an evidence-based review) report of the Thera-
peutics and Technology Subcommittee of the American
Academy of Neurology Neurology 2008701707ndash1714
5 Holland S Silberstein SD Freitag F Dodick DW Argoff
C Ashman E Evidence-based guideline update NSAIDs
and other complementary treatments for episodic migraine
prevention in adults report of the Quality Standards Sub-
committee of the American Academy of Neurology and
the American Headache Society Neurology 201278
1346ndash1353
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
28965ndash69
7 Schrader H Stovner LJ Helde G Sand T Bovim G Pro-
phylactic treatment of migraine with angiotensin convert-
ing enzyme inhibitor (lisinopril) randomised placebo
controlled crossover study BMJ 200132219ndash22
8 Diener HC Gendolla A Feuersenger A et al Telmisartan
in migraine prophylaxis a randomized placebo-controlled
trial Cephalalgia 200929921ndash927
9 Freitag FG Collins SD Carlson HA et al A randomized
trial of divalproex sodium extended-release tablets in mi-
graine prophylaxis Neurology 2002581652ndash1659
10 Silberstein SD Collins SD Safety of divalproex sodium in
migraine prophylaxis an open-label long-term study
long-term safety of Depakote in Headache Prophylaxis
Study Group Headache 199939633ndash643
11 Harden CL Meador KJ Pennell PB et al American Acad-
emy of Neurology American Epilepsy Society Practice pa-
rameter update management issues for women with
epilepsyndashfocus on pregnancy (an evidence-based review)
teratogenesis and perinatal outcomes report of the Quality
Standards Subcommittee and Therapeutics and Technol-
ogy Assessment Subcommittee of the American Academy
of Neurology and American Epilepsy Society Neurology
200973133ndash141
12 Mathew NT Rapoport A Saper J et al Efficacy of gabap-
entin in migraine prophylaxis Headache 200141119ndash
128
13 Steiner TJ Findley LJ Yuen AW Lamotrigine versus pla-
cebo in the prophylaxis of migraine with and without aura
Cephalalgia 199717109ndash112
14 Gupta P Singh S Goyal V Shukla G Behari M Low-
dose topiramate versus lamotrigine in migraine prophy-
laxis (the Lotolamp study) Headache 200747402ndash412
15 Silberstein SD Saper J Berenson F Somogyi M Mc-
Cague MA DrsquoSouza JD Oxcarbazepine in migraine head-
ache a double-blind randomized placebo-controlled
study Neurology 200870548ndash555
1344 Neurology 78 April 24 2012
16 Ashtari F Shaygannejad V Akbari M A double-blindrandomized trial of low-dose topiramate vs propranolol inmigraine prophylaxis Acta Neurol Scand 2008118301ndash305
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 Headache200646642ndash 648
18 Storey JR Calder CS Hart DE Potter DL Topiramate inmigraine prevention a double-blind placebo-controlledstudy Headache 200141968ndash975
19 Brandes JL Saper JR Diamond M et al MIGR-002Study Group Topiramate for migraine prevention a ran-domized controlled trial JAMA 2004291965ndash973
20 Diener HC Matias-Guiu J Hartung E et al Topiramatein migraine prophylaxisndashresults from a placebo-controlledtrial with propranolol as an active control J Neurol 2004251943ndash950
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 200931542ndash559
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 2008110979ndash984
23 Mei D Capuano A Vollono C et al Topiramate in mi-graine prophylaxis a randomised double-blind versus pla-cebo study Neurol Sci 200425245ndash250
24 Silberstein SD Neto W Schmitt J Jacobs D MIGR-001Study Group Topiramate in migraine prevention resultsof a large controlled trial Arch Neurol 200461490ndash495
25 Millan-Guerrero RO Isais-Millan R Barreto-Vizcaiacuteno Set al Subcutaneous histamine versus topiramate in mi-graine prophylaxis a double-blind study Eur Neurol200859237ndash242
26 Silberstein SD Hulihan J Karim MR et al Efficacy andtolerability of topiramate 200 mgd in the prevention ofmigraine withwithout aura in adults a randomizedplacebo-controlled double-blind 12-week pilot studyClin Ther 2006281002ndash1011
27 Adly C Straumanis J Chesson A Fluoxetine prophylaxisof migraine Headache 199232101ndash104
28 Saper JR Silberstein SD Lake AE III Winters MEDouble-blind trial of fluoxetine chronic daily headacheand migraine Headache 199434497ndash502
29 drsquoAmato CC Pizza V Marmolo T Giordano E Alfano V
Nasta A Fluoxetine for migraine prophylaxis a double-
blind trial Headache 199939716ndash719
30 Ozyalcin SN Talu GK Kiziltan E Yucel B Ertas M Disci
R The efficacy and safety of venlafaxine in the prophylaxis
of migraine Headache 200545144ndash152
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 2004107
44ndash48
32 Diener HC Hartung E Chrubasik J et al A comparative
study of oral acetylsalicylic acid and metoprolol for the
prophylactic treatment of migraine a randomized con-
trolled double-blind parallel group phase III study Ceph-
alalgia 200121120ndash128
33 Schellenberg R Lichtenthal A Wohling H Graf C
Brixius K Nebivolol and metoprolol for treating migraine
an advance on beta-blocker treatment Headache 200848
118ndash125
34 Rao BS Das DG Taraknath VR Sarma Y A double blind
controlled study of propranolol and cyproheptadine in mi-
graine prophylaxis Neurol India 200048223ndash226
35 Diener HC Krupp P Schmitt T Steitz G Milde K
Freytag S on behalf of the Study Group Cyclandelate in
the prophylaxis of migraine a placebo-controlled study
Cephalalgia 20012166ndash70
36 Siniatchkin M Gerber WD Vein A Clinical efficacy and
central mechanisms of cyclandelate in migraine a double-
blind placebo-controlled study Funct Neurol 199813
47ndash56
37 Silberstein SD Elkind AH Schreiber C Keywood C A
randomized trial of frovatriptan for the intermittent pre-
vention of menstrual migraine Neurology 200463261ndash
269
38 Brandes JL Poole A Kallela M et al Short-term fro-
vatriptan for the prevention of difficult-to-treat menstrual
migraine attacks Cephalalgia 2009291133ndash1148
39 Newman L Mannix LK Landy S et al Naratriptan as
short-term prophylaxis of menstrually associated migraine
a randomized double-blind placebo-controlled study
Headache 200141248ndash256
40 Tuchman MM Hee A Emeribe U Silberstein S Oral
zolmitriptan in the short-term prevention of menstrual mi-
graine a randomized placebo-controlled study CNS
Drugs 200822877ndash886
Endorsed by the American Osteopathic Association on March 22 2012
Neurology 78 April 24 2012 1345
DOI 101212WNL0b013e3182535d202012781337-1345 Neurology
SD Silberstein S Holland F Freitag et al Academy of Neurology and the American Headache Society
prevention in adults Report of the Quality Standards Subcommittee of the American Evidence-based guideline update Pharmacologic treatment for episodic migraine
This information is current as of April 23 2012
rights reserved Print ISSN 0028-3878 Online ISSN 1526-632X1951 it is now a weekly with 48 issues per year Copyright Copyright copy 2012 by AAN Enterprises Inc All
reg is the official journal of the American Academy of Neurology Published continuously sinceNeurology
ServicesUpdated Information amp
httpnneurologyorgcontent78171337fullincluding high resolution figures can be found at
Supplementary Material
httpnneurologyorgcontentsuppl2013010378171337DC4 httpnneurologyorgcontentsuppl2012120378171337DC3 httpnneurologyorgcontentsuppl2012042278171337DC2 httpnneurologyorgcontentsuppl2012042278171337DC1
Supplementary material can be found at
References httpnneurologyorgcontent78171337fullref-list-1
This article cites 39 articles 9 of which you can access for free at
Citations httpnneurologyorgcontent78171337fullotherarticles
This article has been cited by 5 HighWire-hosted articles
Subspecialty Collections
httpnneurologyorgcgicollectionpalliation_painPalliation pain
httpnneurologyorgcgicollectionmigraineMigrainefollowing collection(s) This article along with others on similar topics appears in the
Errata
content809871fullpdf or page
nextAn erratum has been published regarding this article Please see
Permissions amp Licensing
httpwwwneurologyorgaboutabout_the_journalpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpnneurologyorgsubscribersadvertiseInformation about ordering reprints can be found online
rights reserved Print ISSN 0028-3878 Online ISSN 1526-632X1951 it is now a weekly with 48 issues per year Copyright Copyright copy 2012 by AAN Enterprises Inc All
reg is the official journal of the American Academy of Neurology Published continuously sinceNeurology
CORRECTIONEvidence-based guideline update Pharmacologic treatment for episodicmigraine prevention in adults Report of the
Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society
In the special article ldquoEvidence-based guideline update Pharmacologic treatment for episodic migraine prevention in adultsReport of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Societyrdquo bySD Silberstein et al (Neurology 2012781337ndash1345) there are errors in table 1 and the text on page 1342 Due to changes inthe AANrsquos LOE classification criteria pindolol and clonidine should have been labeled as having Level U recommendations andnicardipine should have been listed as having a Level C recommendation These changes are based on studies cited in the original2001 guideline no new studies were found in the literature search for the 2012 update Please see the corrected table belowTheauthors regret the errors
Table 1 Classification of migraine preventive therapies (available in the United States)
Level A Medicationswith establishedefficacy (Dagger2 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 use
Other Medicationsthat are establishedas ineffectiveprobably ineffectiveor possiblyineffective
Antiepileptic drugs AntidepressantsSSRISSNRITCA
ACE inhibitors a-Agonists Established asineffective
Divalproex sodium Amitriptyline Lisinopril Clonidinea Lamotrigine
Sodium valproate Venlafaxine a-Agonists AntidepressantsSSRISSNRI
Probably ineffective
Topiramate b-Blockers Guanfacinea Fluoxetine Clomipraminea
b-Blockers Atenolola Angiotensin receptorblockers
Fluvoxaminea Possibly ineffective
Metoprolol Nadolola Candesartan Antiepileptic drugs Acebutolola
Propranolol Triptans (MRMb) Antiepileptic drugs Gabapentin Clonazepama
Timolola Naratriptanb Carbamazepinea Antithrombotics Nabumetonea
Triptans (MRMb) Zolmitriptanb Antihistamines Acenocoumarol Oxcarbazepine
Frovatriptanb Cyproheptadine Coumadin Telmisartan
b-Blockers Picotamide
Nebivolol b-Blockers
Ca11 blockers Bisoprolola
Nicardipinea Pindolola
Ca11 blockers
Nifedipinea
Nimodipine
Verapamil
Carbonic anhydraseinhibitor
Acetazolamide
Direct vascularsmooth musclerelaxants
Cyclandelate
TCAs
Protriptylinea
Abbreviations ACE 5 angiotensin-converting-enzyme Ca11 blockers 5 calcium channel blockers MRM 5 menstruallyrelated migraine SSNRI 5 selective serotoninndashnorepinephrine reuptake inhibitor SSRI 5 selective serotonin reuptakeinhibitor TCA 5 tricyclic antidepressanta Classification based on original guideline and new evidence not found for this reportb For short-term prophylaxis of MRM
Neurology 80 February 26 2013 871
vartis Colucid GlaxoSmithKline Autonomic Technologies MAP Phar-
maceuticals Inc Zogenix Inc Impax Laboratories Inc Bristol Myers
Squibb 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 SAGE
Publishing Lippincott Williams amp 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 The
Neurologist Lancet Neurology and Postgraduate Medicine and has served
as Editor-in-Chief of Headache Currents and as an Associate Editor of
Headache he receives publishing royalties for Wolff rsquos Headache 8th edi-
tion (Oxford University Press 2009) and Handbook of Headache (Cam-
bridge University Press 2010) Within the past 3 years Dr Dodick has
received research grant support from Advanced Neurostimulation Sys-
tems Boston Scientific St Jude Medical Inc Medtronic NINDSNIH
Mayo Clinic Dr Argoff has served on a scientific advisory board for the
Department of Defense and DSMB for the NIH has received funding for
travel andor speaking andor has served on a speakersrsquo bureau for Pfizer
(King) Janssen (Pricara) Millennium Laboratories Neurogesx Forest
Laboratories Eli Lilly Covidien and Endo Pharmaceuticals has received
research support from Endo Pharmaceuticals Forest Laboratories Eli
Lilly Neurogesx Pfizer and SBRT funded by the NIH and has received
stockstock options from Pfizer Dr Ashman is the Level of Evidence
editor 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 Neurologyorg for full
disclosures
DISCLAIMERThis statement is provided as an educational service of the American
Academy of Neurology and the American Headache Society It is based
on as assessment of current scientific and clinical information It is not
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 it intended to exclude any reasonable alternative
methodologies The AAN and the AHS recognize that specific patient
care decisions are the prerogative of the patient and the physician
caring for the patient based on all of the circumstances involved The
clinical context section is made available in order to place the
evidence-based guideline(s) into perspective with current practice hab-
its and challenges No formal practice recommendations should be
inferred
CONFLICT OF INTERESTThe American Academy of Neurology and the American Headache Soci-
ety are committed to producing independent critical and truthful clinical
practice guidelines (CPGs) Significant efforts are made to minimize the
potential for conflicts of interest to influence the recommendations of this
CPG To the extent possible the AAN and AHS keep separate those who
have a financial stake in the success or failure of the products appraised in
the CPGs and the developers of the guidelines Conflict of interest forms
were obtained from all authors and reviewed by an oversight committee
prior to project initiation AAN and AHS limit the participation of au-
thors with substantial conflicts of interest The AAN and AHS forbid
commercial participation in or funding of guideline projects Drafts of
the 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 of
Interest Policy can be viewed at wwwaancom
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 200768343ndash349
2 Ramadan NM Silberstein SD Freitag FG Gilbert TT
Frishberg BM Evidence-based guidelines for migraine
headache in the primary care setting pharmacological
management for prevention of migraine Available at
httpwwwaancomprofessionalspracticepdfsgl0090
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 the
American Academy of Neurology Neurology 200055
754ndash762
4 Naumann M So Y Argoff C et al Assessment Botuli-
num neurotoxin in the treatment of autonomic disorders
and pain (an evidence-based review) report of the Thera-
peutics and Technology Subcommittee of the American
Academy of Neurology Neurology 2008701707ndash1714
5 Holland S Silberstein SD Freitag F Dodick DW Argoff
C Ashman E Evidence-based guideline update NSAIDs
and other complementary treatments for episodic migraine
prevention in adults report of the Quality Standards Sub-
committee of the American Academy of Neurology and
the American Headache Society Neurology 201278
1346ndash1353
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
28965ndash69
7 Schrader H Stovner LJ Helde G Sand T Bovim G Pro-
phylactic treatment of migraine with angiotensin convert-
ing enzyme inhibitor (lisinopril) randomised placebo
controlled crossover study BMJ 200132219ndash22
8 Diener HC Gendolla A Feuersenger A et al Telmisartan
in migraine prophylaxis a randomized placebo-controlled
trial Cephalalgia 200929921ndash927
9 Freitag FG Collins SD Carlson HA et al A randomized
trial of divalproex sodium extended-release tablets in mi-
graine prophylaxis Neurology 2002581652ndash1659
10 Silberstein SD Collins SD Safety of divalproex sodium in
migraine prophylaxis an open-label long-term study
long-term safety of Depakote in Headache Prophylaxis
Study Group Headache 199939633ndash643
11 Harden CL Meador KJ Pennell PB et al American Acad-
emy of Neurology American Epilepsy Society Practice pa-
rameter update management issues for women with
epilepsyndashfocus on pregnancy (an evidence-based review)
teratogenesis and perinatal outcomes report of the Quality
Standards Subcommittee and Therapeutics and Technol-
ogy Assessment Subcommittee of the American Academy
of Neurology and American Epilepsy Society Neurology
200973133ndash141
12 Mathew NT Rapoport A Saper J et al Efficacy of gabap-
entin in migraine prophylaxis Headache 200141119ndash
128
13 Steiner TJ Findley LJ Yuen AW Lamotrigine versus pla-
cebo in the prophylaxis of migraine with and without aura
Cephalalgia 199717109ndash112
14 Gupta P Singh S Goyal V Shukla G Behari M Low-
dose topiramate versus lamotrigine in migraine prophy-
laxis (the Lotolamp study) Headache 200747402ndash412
15 Silberstein SD Saper J Berenson F Somogyi M Mc-
Cague MA DrsquoSouza JD Oxcarbazepine in migraine head-
ache a double-blind randomized placebo-controlled
study Neurology 200870548ndash555
1344 Neurology 78 April 24 2012
16 Ashtari F Shaygannejad V Akbari M A double-blindrandomized trial of low-dose topiramate vs propranolol inmigraine prophylaxis Acta Neurol Scand 2008118301ndash305
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 Headache200646642ndash 648
18 Storey JR Calder CS Hart DE Potter DL Topiramate inmigraine prevention a double-blind placebo-controlledstudy Headache 200141968ndash975
19 Brandes JL Saper JR Diamond M et al MIGR-002Study Group Topiramate for migraine prevention a ran-domized controlled trial JAMA 2004291965ndash973
20 Diener HC Matias-Guiu J Hartung E et al Topiramatein migraine prophylaxisndashresults from a placebo-controlledtrial with propranolol as an active control J Neurol 2004251943ndash950
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 200931542ndash559
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 2008110979ndash984
23 Mei D Capuano A Vollono C et al Topiramate in mi-graine prophylaxis a randomised double-blind versus pla-cebo study Neurol Sci 200425245ndash250
24 Silberstein SD Neto W Schmitt J Jacobs D MIGR-001Study Group Topiramate in migraine prevention resultsof a large controlled trial Arch Neurol 200461490ndash495
25 Millan-Guerrero RO Isais-Millan R Barreto-Vizcaiacuteno Set al Subcutaneous histamine versus topiramate in mi-graine prophylaxis a double-blind study Eur Neurol200859237ndash242
26 Silberstein SD Hulihan J Karim MR et al Efficacy andtolerability of topiramate 200 mgd in the prevention ofmigraine withwithout aura in adults a randomizedplacebo-controlled double-blind 12-week pilot studyClin Ther 2006281002ndash1011
27 Adly C Straumanis J Chesson A Fluoxetine prophylaxisof migraine Headache 199232101ndash104
28 Saper JR Silberstein SD Lake AE III Winters MEDouble-blind trial of fluoxetine chronic daily headacheand migraine Headache 199434497ndash502
29 drsquoAmato CC Pizza V Marmolo T Giordano E Alfano V
Nasta A Fluoxetine for migraine prophylaxis a double-
blind trial Headache 199939716ndash719
30 Ozyalcin SN Talu GK Kiziltan E Yucel B Ertas M Disci
R The efficacy and safety of venlafaxine in the prophylaxis
of migraine Headache 200545144ndash152
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 2004107
44ndash48
32 Diener HC Hartung E Chrubasik J et al A comparative
study of oral acetylsalicylic acid and metoprolol for the
prophylactic treatment of migraine a randomized con-
trolled double-blind parallel group phase III study Ceph-
alalgia 200121120ndash128
33 Schellenberg R Lichtenthal A Wohling H Graf C
Brixius K Nebivolol and metoprolol for treating migraine
an advance on beta-blocker treatment Headache 200848
118ndash125
34 Rao BS Das DG Taraknath VR Sarma Y A double blind
controlled study of propranolol and cyproheptadine in mi-
graine prophylaxis Neurol India 200048223ndash226
35 Diener HC Krupp P Schmitt T Steitz G Milde K
Freytag S on behalf of the Study Group Cyclandelate in
the prophylaxis of migraine a placebo-controlled study
Cephalalgia 20012166ndash70
36 Siniatchkin M Gerber WD Vein A Clinical efficacy and
central mechanisms of cyclandelate in migraine a double-
blind placebo-controlled study Funct Neurol 199813
47ndash56
37 Silberstein SD Elkind AH Schreiber C Keywood C A
randomized trial of frovatriptan for the intermittent pre-
vention of menstrual migraine Neurology 200463261ndash
269
38 Brandes JL Poole A Kallela M et al Short-term fro-
vatriptan for the prevention of difficult-to-treat menstrual
migraine attacks Cephalalgia 2009291133ndash1148
39 Newman L Mannix LK Landy S et al Naratriptan as
short-term prophylaxis of menstrually associated migraine
a randomized double-blind placebo-controlled study
Headache 200141248ndash256
40 Tuchman MM Hee A Emeribe U Silberstein S Oral
zolmitriptan in the short-term prevention of menstrual mi-
graine a randomized placebo-controlled study CNS
Drugs 200822877ndash886
Endorsed by the American Osteopathic Association on March 22 2012
Neurology 78 April 24 2012 1345
DOI 101212WNL0b013e3182535d202012781337-1345 Neurology
SD Silberstein S Holland F Freitag et al Academy of Neurology and the American Headache Society
prevention in adults Report of the Quality Standards Subcommittee of the American Evidence-based guideline update Pharmacologic treatment for episodic migraine
This information is current as of April 23 2012
rights reserved Print ISSN 0028-3878 Online ISSN 1526-632X1951 it is now a weekly with 48 issues per year Copyright Copyright copy 2012 by AAN Enterprises Inc All
reg is the official journal of the American Academy of Neurology Published continuously sinceNeurology
ServicesUpdated Information amp
httpnneurologyorgcontent78171337fullincluding high resolution figures can be found at
Supplementary Material
httpnneurologyorgcontentsuppl2013010378171337DC4 httpnneurologyorgcontentsuppl2012120378171337DC3 httpnneurologyorgcontentsuppl2012042278171337DC2 httpnneurologyorgcontentsuppl2012042278171337DC1
Supplementary material can be found at
References httpnneurologyorgcontent78171337fullref-list-1
This article cites 39 articles 9 of which you can access for free at
Citations httpnneurologyorgcontent78171337fullotherarticles
This article has been cited by 5 HighWire-hosted articles
Subspecialty Collections
httpnneurologyorgcgicollectionpalliation_painPalliation pain
httpnneurologyorgcgicollectionmigraineMigrainefollowing collection(s) This article along with others on similar topics appears in the
Errata
content809871fullpdf or page
nextAn erratum has been published regarding this article Please see
Permissions amp Licensing
httpwwwneurologyorgaboutabout_the_journalpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpnneurologyorgsubscribersadvertiseInformation about ordering reprints can be found online
rights reserved Print ISSN 0028-3878 Online ISSN 1526-632X1951 it is now a weekly with 48 issues per year Copyright Copyright copy 2012 by AAN Enterprises Inc All
reg is the official journal of the American Academy of Neurology Published continuously sinceNeurology
CORRECTIONEvidence-based guideline update Pharmacologic treatment for episodicmigraine prevention in adults Report of the
Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society
In the special article ldquoEvidence-based guideline update Pharmacologic treatment for episodic migraine prevention in adultsReport of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Societyrdquo bySD Silberstein et al (Neurology 2012781337ndash1345) there are errors in table 1 and the text on page 1342 Due to changes inthe AANrsquos LOE classification criteria pindolol and clonidine should have been labeled as having Level U recommendations andnicardipine should have been listed as having a Level C recommendation These changes are based on studies cited in the original2001 guideline no new studies were found in the literature search for the 2012 update Please see the corrected table belowTheauthors regret the errors
Table 1 Classification of migraine preventive therapies (available in the United States)
Level A Medicationswith establishedefficacy (Dagger2 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 use
Other Medicationsthat are establishedas ineffectiveprobably ineffectiveor possiblyineffective
Antiepileptic drugs AntidepressantsSSRISSNRITCA
ACE inhibitors a-Agonists Established asineffective
Divalproex sodium Amitriptyline Lisinopril Clonidinea Lamotrigine
Sodium valproate Venlafaxine a-Agonists AntidepressantsSSRISSNRI
Probably ineffective
Topiramate b-Blockers Guanfacinea Fluoxetine Clomipraminea
b-Blockers Atenolola Angiotensin receptorblockers
Fluvoxaminea Possibly ineffective
Metoprolol Nadolola Candesartan Antiepileptic drugs Acebutolola
Propranolol Triptans (MRMb) Antiepileptic drugs Gabapentin Clonazepama
Timolola Naratriptanb Carbamazepinea Antithrombotics Nabumetonea
Triptans (MRMb) Zolmitriptanb Antihistamines Acenocoumarol Oxcarbazepine
Frovatriptanb Cyproheptadine Coumadin Telmisartan
b-Blockers Picotamide
Nebivolol b-Blockers
Ca11 blockers Bisoprolola
Nicardipinea Pindolola
Ca11 blockers
Nifedipinea
Nimodipine
Verapamil
Carbonic anhydraseinhibitor
Acetazolamide
Direct vascularsmooth musclerelaxants
Cyclandelate
TCAs
Protriptylinea
Abbreviations ACE 5 angiotensin-converting-enzyme Ca11 blockers 5 calcium channel blockers MRM 5 menstruallyrelated migraine SSNRI 5 selective serotoninndashnorepinephrine reuptake inhibitor SSRI 5 selective serotonin reuptakeinhibitor TCA 5 tricyclic antidepressanta Classification based on original guideline and new evidence not found for this reportb For short-term prophylaxis of MRM
Neurology 80 February 26 2013 871
16 Ashtari F Shaygannejad V Akbari M A double-blindrandomized trial of low-dose topiramate vs propranolol inmigraine prophylaxis Acta Neurol Scand 2008118301ndash305
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 Headache200646642ndash 648
18 Storey JR Calder CS Hart DE Potter DL Topiramate inmigraine prevention a double-blind placebo-controlledstudy Headache 200141968ndash975
19 Brandes JL Saper JR Diamond M et al MIGR-002Study Group Topiramate for migraine prevention a ran-domized controlled trial JAMA 2004291965ndash973
20 Diener HC Matias-Guiu J Hartung E et al Topiramatein migraine prophylaxisndashresults from a placebo-controlledtrial with propranolol as an active control J Neurol 2004251943ndash950
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 200931542ndash559
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 2008110979ndash984
23 Mei D Capuano A Vollono C et al Topiramate in mi-graine prophylaxis a randomised double-blind versus pla-cebo study Neurol Sci 200425245ndash250
24 Silberstein SD Neto W Schmitt J Jacobs D MIGR-001Study Group Topiramate in migraine prevention resultsof a large controlled trial Arch Neurol 200461490ndash495
25 Millan-Guerrero RO Isais-Millan R Barreto-Vizcaiacuteno Set al Subcutaneous histamine versus topiramate in mi-graine prophylaxis a double-blind study Eur Neurol200859237ndash242
26 Silberstein SD Hulihan J Karim MR et al Efficacy andtolerability of topiramate 200 mgd in the prevention ofmigraine withwithout aura in adults a randomizedplacebo-controlled double-blind 12-week pilot studyClin Ther 2006281002ndash1011
27 Adly C Straumanis J Chesson A Fluoxetine prophylaxisof migraine Headache 199232101ndash104
28 Saper JR Silberstein SD Lake AE III Winters MEDouble-blind trial of fluoxetine chronic daily headacheand migraine Headache 199434497ndash502
29 drsquoAmato CC Pizza V Marmolo T Giordano E Alfano V
Nasta A Fluoxetine for migraine prophylaxis a double-
blind trial Headache 199939716ndash719
30 Ozyalcin SN Talu GK Kiziltan E Yucel B Ertas M Disci
R The efficacy and safety of venlafaxine in the prophylaxis
of migraine Headache 200545144ndash152
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 2004107
44ndash48
32 Diener HC Hartung E Chrubasik J et al A comparative
study of oral acetylsalicylic acid and metoprolol for the
prophylactic treatment of migraine a randomized con-
trolled double-blind parallel group phase III study Ceph-
alalgia 200121120ndash128
33 Schellenberg R Lichtenthal A Wohling H Graf C
Brixius K Nebivolol and metoprolol for treating migraine
an advance on beta-blocker treatment Headache 200848
118ndash125
34 Rao BS Das DG Taraknath VR Sarma Y A double blind
controlled study of propranolol and cyproheptadine in mi-
graine prophylaxis Neurol India 200048223ndash226
35 Diener HC Krupp P Schmitt T Steitz G Milde K
Freytag S on behalf of the Study Group Cyclandelate in
the prophylaxis of migraine a placebo-controlled study
Cephalalgia 20012166ndash70
36 Siniatchkin M Gerber WD Vein A Clinical efficacy and
central mechanisms of cyclandelate in migraine a double-
blind placebo-controlled study Funct Neurol 199813
47ndash56
37 Silberstein SD Elkind AH Schreiber C Keywood C A
randomized trial of frovatriptan for the intermittent pre-
vention of menstrual migraine Neurology 200463261ndash
269
38 Brandes JL Poole A Kallela M et al Short-term fro-
vatriptan for the prevention of difficult-to-treat menstrual
migraine attacks Cephalalgia 2009291133ndash1148
39 Newman L Mannix LK Landy S et al Naratriptan as
short-term prophylaxis of menstrually associated migraine
a randomized double-blind placebo-controlled study
Headache 200141248ndash256
40 Tuchman MM Hee A Emeribe U Silberstein S Oral
zolmitriptan in the short-term prevention of menstrual mi-
graine a randomized placebo-controlled study CNS
Drugs 200822877ndash886
Endorsed by the American Osteopathic Association on March 22 2012
Neurology 78 April 24 2012 1345
DOI 101212WNL0b013e3182535d202012781337-1345 Neurology
SD Silberstein S Holland F Freitag et al Academy of Neurology and the American Headache Society
prevention in adults Report of the Quality Standards Subcommittee of the American Evidence-based guideline update Pharmacologic treatment for episodic migraine
This information is current as of April 23 2012
rights reserved Print ISSN 0028-3878 Online ISSN 1526-632X1951 it is now a weekly with 48 issues per year Copyright Copyright copy 2012 by AAN Enterprises Inc All
reg is the official journal of the American Academy of Neurology Published continuously sinceNeurology
ServicesUpdated Information amp
httpnneurologyorgcontent78171337fullincluding high resolution figures can be found at
Supplementary Material
httpnneurologyorgcontentsuppl2013010378171337DC4 httpnneurologyorgcontentsuppl2012120378171337DC3 httpnneurologyorgcontentsuppl2012042278171337DC2 httpnneurologyorgcontentsuppl2012042278171337DC1
Supplementary material can be found at
References httpnneurologyorgcontent78171337fullref-list-1
This article cites 39 articles 9 of which you can access for free at
Citations httpnneurologyorgcontent78171337fullotherarticles
This article has been cited by 5 HighWire-hosted articles
Subspecialty Collections
httpnneurologyorgcgicollectionpalliation_painPalliation pain
httpnneurologyorgcgicollectionmigraineMigrainefollowing collection(s) This article along with others on similar topics appears in the
Errata
content809871fullpdf or page
nextAn erratum has been published regarding this article Please see
Permissions amp Licensing
httpwwwneurologyorgaboutabout_the_journalpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpnneurologyorgsubscribersadvertiseInformation about ordering reprints can be found online
rights reserved Print ISSN 0028-3878 Online ISSN 1526-632X1951 it is now a weekly with 48 issues per year Copyright Copyright copy 2012 by AAN Enterprises Inc All
reg is the official journal of the American Academy of Neurology Published continuously sinceNeurology
CORRECTIONEvidence-based guideline update Pharmacologic treatment for episodicmigraine prevention in adults Report of the
Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society
In the special article ldquoEvidence-based guideline update Pharmacologic treatment for episodic migraine prevention in adultsReport of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Societyrdquo bySD Silberstein et al (Neurology 2012781337ndash1345) there are errors in table 1 and the text on page 1342 Due to changes inthe AANrsquos LOE classification criteria pindolol and clonidine should have been labeled as having Level U recommendations andnicardipine should have been listed as having a Level C recommendation These changes are based on studies cited in the original2001 guideline no new studies were found in the literature search for the 2012 update Please see the corrected table belowTheauthors regret the errors
Table 1 Classification of migraine preventive therapies (available in the United States)
Level A Medicationswith establishedefficacy (Dagger2 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 use
Other Medicationsthat are establishedas ineffectiveprobably ineffectiveor possiblyineffective
Antiepileptic drugs AntidepressantsSSRISSNRITCA
ACE inhibitors a-Agonists Established asineffective
Divalproex sodium Amitriptyline Lisinopril Clonidinea Lamotrigine
Sodium valproate Venlafaxine a-Agonists AntidepressantsSSRISSNRI
Probably ineffective
Topiramate b-Blockers Guanfacinea Fluoxetine Clomipraminea
b-Blockers Atenolola Angiotensin receptorblockers
Fluvoxaminea Possibly ineffective
Metoprolol Nadolola Candesartan Antiepileptic drugs Acebutolola
Propranolol Triptans (MRMb) Antiepileptic drugs Gabapentin Clonazepama
Timolola Naratriptanb Carbamazepinea Antithrombotics Nabumetonea
Triptans (MRMb) Zolmitriptanb Antihistamines Acenocoumarol Oxcarbazepine
Frovatriptanb Cyproheptadine Coumadin Telmisartan
b-Blockers Picotamide
Nebivolol b-Blockers
Ca11 blockers Bisoprolola
Nicardipinea Pindolola
Ca11 blockers
Nifedipinea
Nimodipine
Verapamil
Carbonic anhydraseinhibitor
Acetazolamide
Direct vascularsmooth musclerelaxants
Cyclandelate
TCAs
Protriptylinea
Abbreviations ACE 5 angiotensin-converting-enzyme Ca11 blockers 5 calcium channel blockers MRM 5 menstruallyrelated migraine SSNRI 5 selective serotoninndashnorepinephrine reuptake inhibitor SSRI 5 selective serotonin reuptakeinhibitor TCA 5 tricyclic antidepressanta Classification based on original guideline and new evidence not found for this reportb For short-term prophylaxis of MRM
Neurology 80 February 26 2013 871
DOI 101212WNL0b013e3182535d202012781337-1345 Neurology
SD Silberstein S Holland F Freitag et al Academy of Neurology and the American Headache Society
prevention in adults Report of the Quality Standards Subcommittee of the American Evidence-based guideline update Pharmacologic treatment for episodic migraine
This information is current as of April 23 2012
rights reserved Print ISSN 0028-3878 Online ISSN 1526-632X1951 it is now a weekly with 48 issues per year Copyright Copyright copy 2012 by AAN Enterprises Inc All
reg is the official journal of the American Academy of Neurology Published continuously sinceNeurology
ServicesUpdated Information amp
httpnneurologyorgcontent78171337fullincluding high resolution figures can be found at
Supplementary Material
httpnneurologyorgcontentsuppl2013010378171337DC4 httpnneurologyorgcontentsuppl2012120378171337DC3 httpnneurologyorgcontentsuppl2012042278171337DC2 httpnneurologyorgcontentsuppl2012042278171337DC1
Supplementary material can be found at
References httpnneurologyorgcontent78171337fullref-list-1
This article cites 39 articles 9 of which you can access for free at
Citations httpnneurologyorgcontent78171337fullotherarticles
This article has been cited by 5 HighWire-hosted articles
Subspecialty Collections
httpnneurologyorgcgicollectionpalliation_painPalliation pain
httpnneurologyorgcgicollectionmigraineMigrainefollowing collection(s) This article along with others on similar topics appears in the
Errata
content809871fullpdf or page
nextAn erratum has been published regarding this article Please see
Permissions amp Licensing
httpwwwneurologyorgaboutabout_the_journalpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpnneurologyorgsubscribersadvertiseInformation about ordering reprints can be found online
rights reserved Print ISSN 0028-3878 Online ISSN 1526-632X1951 it is now a weekly with 48 issues per year Copyright Copyright copy 2012 by AAN Enterprises Inc All
reg is the official journal of the American Academy of Neurology Published continuously sinceNeurology
CORRECTIONEvidence-based guideline update Pharmacologic treatment for episodicmigraine prevention in adults Report of the
Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society
In the special article ldquoEvidence-based guideline update Pharmacologic treatment for episodic migraine prevention in adultsReport of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Societyrdquo bySD Silberstein et al (Neurology 2012781337ndash1345) there are errors in table 1 and the text on page 1342 Due to changes inthe AANrsquos LOE classification criteria pindolol and clonidine should have been labeled as having Level U recommendations andnicardipine should have been listed as having a Level C recommendation These changes are based on studies cited in the original2001 guideline no new studies were found in the literature search for the 2012 update Please see the corrected table belowTheauthors regret the errors
Table 1 Classification of migraine preventive therapies (available in the United States)
Level A Medicationswith establishedefficacy (Dagger2 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 use
Other Medicationsthat are establishedas ineffectiveprobably ineffectiveor possiblyineffective
Antiepileptic drugs AntidepressantsSSRISSNRITCA
ACE inhibitors a-Agonists Established asineffective
Divalproex sodium Amitriptyline Lisinopril Clonidinea Lamotrigine
Sodium valproate Venlafaxine a-Agonists AntidepressantsSSRISSNRI
Probably ineffective
Topiramate b-Blockers Guanfacinea Fluoxetine Clomipraminea
b-Blockers Atenolola Angiotensin receptorblockers
Fluvoxaminea Possibly ineffective
Metoprolol Nadolola Candesartan Antiepileptic drugs Acebutolola
Propranolol Triptans (MRMb) Antiepileptic drugs Gabapentin Clonazepama
Timolola Naratriptanb Carbamazepinea Antithrombotics Nabumetonea
Triptans (MRMb) Zolmitriptanb Antihistamines Acenocoumarol Oxcarbazepine
Frovatriptanb Cyproheptadine Coumadin Telmisartan
b-Blockers Picotamide
Nebivolol b-Blockers
Ca11 blockers Bisoprolola
Nicardipinea Pindolola
Ca11 blockers
Nifedipinea
Nimodipine
Verapamil
Carbonic anhydraseinhibitor
Acetazolamide
Direct vascularsmooth musclerelaxants
Cyclandelate
TCAs
Protriptylinea
Abbreviations ACE 5 angiotensin-converting-enzyme Ca11 blockers 5 calcium channel blockers MRM 5 menstruallyrelated migraine SSNRI 5 selective serotoninndashnorepinephrine reuptake inhibitor SSRI 5 selective serotonin reuptakeinhibitor TCA 5 tricyclic antidepressanta Classification based on original guideline and new evidence not found for this reportb For short-term prophylaxis of MRM
Neurology 80 February 26 2013 871
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CORRECTIONEvidence-based guideline update Pharmacologic treatment for episodicmigraine prevention in adults Report of the
Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society
In the special article ldquoEvidence-based guideline update Pharmacologic treatment for episodic migraine prevention in adultsReport of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Societyrdquo bySD Silberstein et al (Neurology 2012781337ndash1345) there are errors in table 1 and the text on page 1342 Due to changes inthe AANrsquos LOE classification criteria pindolol and clonidine should have been labeled as having Level U recommendations andnicardipine should have been listed as having a Level C recommendation These changes are based on studies cited in the original2001 guideline no new studies were found in the literature search for the 2012 update Please see the corrected table belowTheauthors regret the errors
Table 1 Classification of migraine preventive therapies (available in the United States)
Level A Medicationswith establishedefficacy (Dagger2 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 use
Other Medicationsthat are establishedas ineffectiveprobably ineffectiveor possiblyineffective
Antiepileptic drugs AntidepressantsSSRISSNRITCA
ACE inhibitors a-Agonists Established asineffective
Divalproex sodium Amitriptyline Lisinopril Clonidinea Lamotrigine
Sodium valproate Venlafaxine a-Agonists AntidepressantsSSRISSNRI
Probably ineffective
Topiramate b-Blockers Guanfacinea Fluoxetine Clomipraminea
b-Blockers Atenolola Angiotensin receptorblockers
Fluvoxaminea Possibly ineffective
Metoprolol Nadolola Candesartan Antiepileptic drugs Acebutolola
Propranolol Triptans (MRMb) Antiepileptic drugs Gabapentin Clonazepama
Timolola Naratriptanb Carbamazepinea Antithrombotics Nabumetonea
Triptans (MRMb) Zolmitriptanb Antihistamines Acenocoumarol Oxcarbazepine
Frovatriptanb Cyproheptadine Coumadin Telmisartan
b-Blockers Picotamide
Nebivolol b-Blockers
Ca11 blockers Bisoprolola
Nicardipinea Pindolola
Ca11 blockers
Nifedipinea
Nimodipine
Verapamil
Carbonic anhydraseinhibitor
Acetazolamide
Direct vascularsmooth musclerelaxants
Cyclandelate
TCAs
Protriptylinea
Abbreviations ACE 5 angiotensin-converting-enzyme Ca11 blockers 5 calcium channel blockers MRM 5 menstruallyrelated migraine SSNRI 5 selective serotoninndashnorepinephrine reuptake inhibitor SSRI 5 selective serotonin reuptakeinhibitor TCA 5 tricyclic antidepressanta Classification based on original guideline and new evidence not found for this reportb For short-term prophylaxis of MRM
Neurology 80 February 26 2013 871
CORRECTIONEvidence-based guideline update Pharmacologic treatment for episodicmigraine prevention in adults Report of the
Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society
In the special article ldquoEvidence-based guideline update Pharmacologic treatment for episodic migraine prevention in adultsReport of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Societyrdquo bySD Silberstein et al (Neurology 2012781337ndash1345) there are errors in table 1 and the text on page 1342 Due to changes inthe AANrsquos LOE classification criteria pindolol and clonidine should have been labeled as having Level U recommendations andnicardipine should have been listed as having a Level C recommendation These changes are based on studies cited in the original2001 guideline no new studies were found in the literature search for the 2012 update Please see the corrected table belowTheauthors regret the errors
Table 1 Classification of migraine preventive therapies (available in the United States)
Level A Medicationswith establishedefficacy (Dagger2 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 use
Other Medicationsthat are establishedas ineffectiveprobably ineffectiveor possiblyineffective
Antiepileptic drugs AntidepressantsSSRISSNRITCA
ACE inhibitors a-Agonists Established asineffective
Divalproex sodium Amitriptyline Lisinopril Clonidinea Lamotrigine
Sodium valproate Venlafaxine a-Agonists AntidepressantsSSRISSNRI
Probably ineffective
Topiramate b-Blockers Guanfacinea Fluoxetine Clomipraminea
b-Blockers Atenolola Angiotensin receptorblockers
Fluvoxaminea Possibly ineffective
Metoprolol Nadolola Candesartan Antiepileptic drugs Acebutolola
Propranolol Triptans (MRMb) Antiepileptic drugs Gabapentin Clonazepama
Timolola Naratriptanb Carbamazepinea Antithrombotics Nabumetonea
Triptans (MRMb) Zolmitriptanb Antihistamines Acenocoumarol Oxcarbazepine
Frovatriptanb Cyproheptadine Coumadin Telmisartan
b-Blockers Picotamide
Nebivolol b-Blockers
Ca11 blockers Bisoprolola
Nicardipinea Pindolola
Ca11 blockers
Nifedipinea
Nimodipine
Verapamil
Carbonic anhydraseinhibitor
Acetazolamide
Direct vascularsmooth musclerelaxants
Cyclandelate
TCAs
Protriptylinea
Abbreviations ACE 5 angiotensin-converting-enzyme Ca11 blockers 5 calcium channel blockers MRM 5 menstruallyrelated migraine SSNRI 5 selective serotoninndashnorepinephrine reuptake inhibitor SSRI 5 selective serotonin reuptakeinhibitor TCA 5 tricyclic antidepressanta Classification based on original guideline and new evidence not found for this reportb For short-term prophylaxis of MRM
Neurology 80 February 26 2013 871