special article evidence-based guideline update: pharmacologic

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


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-


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


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-


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


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


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


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

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nextAn erratum has been published regarding this article Please see

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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


Level A Medicationswith establishedefficacy (Dagger2 Class Itrials)




Other Medicationsthat are establishedas ineffectiveprobably ineffectiveor possiblyineffective


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


Acetazolamide


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


Level A Medicationswith establishedefficacy (gt2 Class Itrials)




Other Medications thatare established aspossibly or probablyineffective


ACE inhibitorsLisinopril


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


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








































































prevention













bull Lamotrigine



bull Clomipramine




































































disclosures













inferred





























754ndash762












1346ndash1353




28965ndash69























200973133ndash141



128



































44ndash48









118ndash125











47ndash56




269
































Errata





Reprints






























Ca11 blockers

Nifedipinea

Nimodipine

Verapamil


Acetazolamide


Cyclandelate

TCAs

Protriptylinea









































































prevention













bull Lamotrigine



bull Clomipramine




































































disclosures













inferred





























754ndash762












1346ndash1353




28965ndash69























200973133ndash141



128



































44ndash48









118ndash125











47ndash56




269
































Errata





Reprints






























Ca11 blockers

Nifedipinea

Nimodipine

Verapamil


Acetazolamide


Cyclandelate

TCAs

Protriptylinea




bull Clomipramine




































































disclosures













inferred





























754ndash762












1346ndash1353




28965ndash69























200973133ndash141



128



































44ndash48









118ndash125











47ndash56




269
































Errata





Reprints






























Ca11 blockers

Nifedipinea

Nimodipine

Verapamil


Acetazolamide


Cyclandelate

TCAs

Protriptylinea





























disclosures













inferred





























754ndash762












1346ndash1353




28965ndash69























200973133ndash141



128



































44ndash48









118ndash125











47ndash56




269
































Errata





Reprints






























Ca11 blockers

Nifedipinea

Nimodipine

Verapamil


Acetazolamide


Cyclandelate

TCAs

Protriptylinea


























44ndash48









118ndash125











47ndash56




269
































Errata





Reprints






























Ca11 blockers

Nifedipinea

Nimodipine

Verapamil


Acetazolamide


Cyclandelate

TCAs

Protriptylinea





















Errata





Reprints






























Ca11 blockers

Nifedipinea

Nimodipine

Verapamil


Acetazolamide


Cyclandelate

TCAs

Protriptylinea





























Ca11 blockers

Nifedipinea

Nimodipine

Verapamil


Acetazolamide


Cyclandelate

TCAs

Protriptylinea



special article evidence-based guideline update: pharmacologic

Documents