neurology 2012 holland 1346 53

DOI 101212WNL0b013e3182535d0c2012781346-1353 Neurology

S Holland SD Silberstein F Freitag et al Society

American Academy of Neurology and the American Headache adults Report of the Quality Standards Subcommittee of the

complementary treatments for episodic migraine prevention in Evidence-based guideline update NSAIDs and other

This information is current as of April 23 2012

httpwwwneurologyorgcontent78171346fullhtmllocated on the World Wide Web at

The online version of this article along with updated information and services is

Enterprises Inc All rights reserved Print ISSN 0028-3878 Online ISSN 1526-632Xsince 1951 it is now a weekly with 48 issues per year Copyright Copyright copy 2012 by AAN

reg is the official journal of the American Academy of Neurology Published continuouslyNeurology

Evidence-based guideline update NSAIDs andother complementary treatments for episodicmigraine prevention in adultsReport of the Quality Standards Subcommittee of the American Academy ofNeurology and the American Headache Society

S Holland PhDSD Silberstein MD

FACPF 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 Are nonsteroidal anti-inflammatorydrugs (NSAIDs) or other complementary treatments effective for migraine prevention

Methods The authors analyzed published studies from June 1999 to May 2009 using a struc-tured review process to classify the evidence relative to the efficacy of various medications formigraine prevention

Results The author panel reviewed 284 abstracts which ultimately yielded 49 Class I or Class IIarticles on migraine prevention of these 49 15 were classified as involving nontraditional thera-pies NSAIDs and other complementary therapies that are reviewed herein

Recommendations Petasites (butterbur) is effective for migraine prevention and should beoffered to patients with migraine to reduce the frequency and severity of migraine attacks(Level A) Fenoprofen ibuprofen ketoprofen naproxen naproxen sodium MIG-99 (feverfew)magnesium riboflavin and subcutaneous histamine are probably effective for migraine pre-vention (Level B) Treatments considered possibly effective are cyproheptadine Co-Q10 es-trogen mefenamic acid and flurbiprofen (Level C) Data are conflicting or inadequate tosupport or refute use of aspirin indomethacin omega-3 or hyperbaric oxygen for migraineprevention Montelukast is established as probably ineffective for migraine prevention (LevelB) Neurologyreg 2012781346ndash1353

GLOSSARYAAN American Academy of Neurology AE adverse effect CI confidence interval HBO hyperbaric oxygen NSAID nonsteroidal anti-inflammatory drug OR odds ratio RR relative risk

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 anti-inflammatory or com-plementary treatments are effective for preventionas measured by reduced migraine attack frequency

reduced number of migraine days or reduced at-tack severity This article addresses the efficacyand safety of histaminesantihistamines non-steroidal anti-inflammatory drugs (NSAIDs) andanalgesics and several herbal vitamin and min-eral preparations whereas a companion article ad-dresses standard pharmacologic treatments formigraine prevention4

DESCRIPTION OF THE ANALYTIC PROCESSThe AAN and the American Headache Society par-ticipated in the development process An author

See page 1337

Supplemental data atwwwneurologyorg

Supplemental Data

Podcast

CME

Correspondence amp reprintrequests to American Academyof Neurologyguidelinesaancom

From the Armstrong Atlantic State University (SH) Savannah GA Thomas Jefferson University (SDS) Jefferson Headache Center PhiladelphiaPA 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 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 November 7 2011

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 the 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

SPECIAL ARTICLE

1346 Copyright copy 2012 by AAN Enterprises Inc

panel of headache and methodologic experts was as-sembled to review the evidence

Computerized searches of the MEDLINE Psyc-INFO and CINAHL databases identified newstudies The search strategy used the MeSH termldquoheadacherdquo (exploded) and a published search strat-egy for identifying randomized controlled trials inadults that were published in English between June1999 and May 2007 Additional MEDLINEsearches revealed studies published through May2009 which were reviewed and are included as sup-plemental articles

Studies of NSAIDs and complementary treat-ments available in the United States were included inthe analysis if they randomized patients with mi-graine to the agent under study or a comparatortreatment (including placebo) and utilized masked(blinded) outcome assessment At least 2 panelistsindependently reviewed each selected study and ratedit using the AAN therapeutic classification of evi-dence scheme (appendix e-3 on the Neurologyreg Website at wwwneurologyorg) Differences in ratingswere resolved by author panel discussion

ANALYSIS OF EVIDENCE The original searchidentified 179 articles and included pharmacologicand complementary treatments and NSAIDs Thesupplemental search from 2007 to 2009 yielded anadditional 105 articles Of the total 284 articles 15were classified as Class I or Class II and identified as

relating to NSAIDs and complementary treatmentsthey are reviewed herein Clinical studies reviewedwere limited to those assessing efficacy of NSAIDsand complementary treatments for prevention of ep-isodic migraine in adults (eg 15 daysmonth)Studies were excluded if they assessed the efficacy oftherapeutic agents for prevention or treatment ofchronic migraine intractable migraine tension-typeheadache or headache in adolescents or childrenAlso excluded were studies that assessed acute mi-graine treatment migraine aura treatment or preven-tion or nonpharmacologic treatments Studies usingquality of life measures disability assessment ornonstandardized outcomes as primary efficacy end-points were not included NSAIDs and complemen-tary treatments not commonly or readily available inthe United States are not reviewed in this guideline

Since the 2000 guideline publication the AANrevised its evidence classification criteria to includestudy completion rates Studies whose completionrates are below 80 were downgraded

We found no additional Class I or Class II studiespublished since the original guideline for fenoprofenibuprofen ketoprofen naproxen naproxen sodiumor indomethacin Recommendations regarding thesetreatments are based on the evidence reviewed in theoriginal guideline (denoted in table 1)

Following is a summary of Class I and Class IIevidence for the efficacy of NSAIDs and comple-

Table 1 Classification of migraine preventive therapies (available in the United States)

Level A Medicationswith establishedefficacy (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

Herbal preparationsvitamins mineralsand other

NSAIDs NSAIDs NSAIDs Probably not effective

Petasites Fenoprofena Flurbiprofena Aspirin Leukotriene receptorantagonist

Ibuprofena Mefenamic acida Indomethacina Montelukast

Ketoprofena Herbal preparationsvitamins mineralsand other


Naproxena Co-Q10 Omega-3

Naproxen sodiuma Estrogen Other


Antihistamine Hyperbaricoxygen

Magnesium Cyproheptadine

MIG-99 (feverfew)

Riboflavin

Histamines

Histamine SC

Abbreviation NSAID nonsteroidal anti-inflammatory druga Indicates classification based on original guideline and new evidence not found for this report

Neurology 78 April 24 2012 1347

mentary treatments for migraine prevention Assess-ment of relative safety and tolerability of these agentsas compared with placebo or other active treatmentsfalls outside the scope of this efficacy assessment butgeneral information regarding safety and tolerability isincluded Additionally efficacy results from the sum-marized trials may be dependent on study design in-cluding study duration (8 weeks vs 6 months)medication doses (low vs high) and dosing regimensand titrationsmdashall of which may influence efficacy on-set relative efficacy and quality of the evidence

Histaminesantihistaminesleukotriene receptor an-tagonists In the 2000 guideline there were no stud-ies of histamines antihistamines or leukotrienereceptor antagonists for migraine prevention Sincethat publication several studies of histamine cypro-heptadine and montelukast have been performed

Histamine Three Class II single-center studies (allfrom the same center) show the efficacy of histaminefor migraine prevention5ndash7 N-alpha-methyl hista-mine (1ndash10 ng 2 timesweek) SC injections reducedattack frequency from baseline as compared with pla-cebo5 Headache frequency at 4 weeks was reducedfrom 38 to 05 in the histamine group as comparedwith reduction from 36 to 29 attacks for placebo(p 00001) Histamine was statistically superior toplacebo at all treatment visits through 12 weeks forreduction in migraine frequency severity and dura-tion (p 00001) Transient itching at the injectionsites was the only reported adverse effect (AE) but itdid not reach significance

In a second Class II study histamine was shownto be as effective as sodium valproate in reducingattack frequency and better than sodium valproate inreducing headache duration and intensity6 Specifi-cally both sodium valproate 500 mgday and hista-mine (1ndash10 ng 2 timesweek) SC injectionsimproved headache frequency duration and inten-sity as early as 8 weeks following treatment whencompared with baseline (p 005) No patients onhistamine presented with AEs Conversely 37 ofpatients on sodium valproate experienced nausea34 had tremor 24 had weight gain and 12had alopecia

A third study reported the efficacy of histamine inmigraine prevention as compared with topiramateTopiramate 100 mgday was compared with hista-mine (1ndash10 ng 2 timesweek SC) and both activetreatments showed improvement over baseline mea-sures for attack frequency intensity and use of res-cue medication7 Eleven percent (545) of subjectstreated with histamine withdrew from the hista-mine group because they were not satisfied withthe speed of results although no AEs were re-ported Few subjects reported transitory burning

and itching at the injection site Similar AEs andwithdrawal rates (for slow reaction speed) were re-ported for the sodium valproate study6 HistamineSC was associated with transitory burning anditching at the injection site

Cyproheptadine A single Class II study (describedin the companion guideline) showed cyproheptadine(4 mgday) was as effective as propranolol (80 mgday) in reducing migraine frequency and severity8

Montelukast One Class I study of montelukast (20mg) for migraine prevention reported no significantdifference between treatments in the percentage ofpatients with a 50 decrease in migraine attackfrequency per month (154 for montelukast vs103 for placebo [odds ratio (OR) 164 confi-dence interval (CI) 064ndash420])9 As compared withthe placebo group the montelukast group reportedno differences in incidence frequency or severity ofAEs in this 3-month treatment phase

Conclusions Histamine SC is established as proba-bly effective (3 Class II studies) for migraine preven-tion Cyproheptadine is possibly effective formigraine prevention and possibly as effective as pro-pranolol for migraine prevention (single Class IIstudy) Montelukast is probably ineffective for mi-graine prevention (1 Class I study table 1)

NSAIDs The efficacy of NSAIDs for migraine pre-vention was reported in the original guideline in-cluding 23 controlled trials of 10 different NSAIDsthat showed a modest but significant benefit fornaproxen sodium with similar trends for flurbipro-fen ketoprofen and mefenamic acid In the absenceof new clinical reports recommendations for NSAIDuse for migraine prevention are based on data fromthe original guideline Regarding aspirin new clini-cal evidence is available and included herein

Aspirin In the original guideline studies of aspi-rin were found to have conflicting results Sincethe original report 2 additional Class II studieshave been reported As summarized in the com-panion article aspirin was found to be as effectiveas metoprolol for migraine prevention10 In a sec-ond study aspirin 100 mg in combination withvitamin E 600 IU every other day was comparedwith placebo in combination with vitamin E11 Nodifferences were noted between aspirin and pla-cebo treatments for migraine frequency or severityat 12 months or 36 months

Conclusions The efficacy of aspirin for migraine pre-vention is unknown (conflicting Class II studiestable 1)

Clinical context Regular or daily use of selectedNSAIDs for the treatment of frequent migraine at-tacks may exacerbate headache because of develop-ment of a condition called medication overuse

1348 Neurology 78 April 24 2012

headache12 Therefore use of aspirin selected analge-sics and NSAIDs may exacerbate headache use ofthese agents in migraine prevention studies may con-found the clinical interpretation of the study results

Herbal preparations vitamins minerals and other in-

terventions Since the original guideline additionalstudies have been identified that assess the efficacy ofCo-Q10 estrogen hyperbaric oxygen (HBO) mag-nesium MIG-99 omega-3 Petasites and riboflavinfor migraine prevention

Co-Q10 (water-soluble disbursable form of Co-Q10)

One small Class II study showed that Co-Q10 100mg TID was significantly more effective than pla-cebo in reducing attack frequency from baseline to 4months following treatment13 The 50 responderrate for attack frequency (50 reduction) was476 for CoQ10 vs 143 for placebo (p 002)The actual reduction in attack frequency was19 19 for CoQ10 and 009 19 for placebo(p 005) One patient withdrew from the Co-Q10treatment group because of cutaneous allergy

Estrogen A combination of soy isoflavones (60mg) dong quai (100 mg) and black cohosh (50 mg)(each component standardized to its primary alka-loid) reduced migraine attack frequency vs placebo ina small Class II study14 The mean frequency of men-strually associated migraine attacks during weeks9ndash24 was reduced from 103 SEM 24 in patientstreated with placebo to 47 SEM 18 (p 001) inpatients treated with the phytoestrogen preparation

In a second Class II trial percutaneous estradiolwas applied 6 days before the first full day of bleedingup to and including the second full day of menstrua-tion15 Estradiol 15 mg (gel patch applied to the up-per thigh or arm) was associated with a 22reduction in migraine days (estradiol 133 mi-graine days placebo 171 migraine days relativerisk [RR] 078 CI 062ndash099 p 004) This im-provement was temporary as subjects reported a40 increase in migraine days in the 5 days followingtreatment (RR 140 CI 103ndash192 p 003) No seri-ous AEs were otherwise reported although commonrisks associated with estrogen supplementation are welldocumented throughout the literature Limited studiesare available regarding estrogenrsquos safety specifically forlong-term use in migraine prevention

Hyperbaric oxygen In a single Class II study nodifferences were found between the HBO group (330-minute treatmentsweek) and control group butan increase in headache hours was experienced byboth groups vs the pretreatment level16 Correctedfor the number of days the increase was 69 hoursweek for HBO vs 47 hoursweek for controls Thisstudy reports no assessment of tolerability or safety of

HBO vs control for migraine preventionMagnesium In the original guideline magnesium

was found to be probably effective for migraine pre-vention on the basis of 2 positive Class II studies and1 negative Class III study Since the 2000 report 1additional Class II study compared the combinationof magnesium (300 mg) riboflavin (400 mg) andMIG-99 (100 mg) with placebo (25 mg of ribofla-vin which was thought to be a subtherapeutic dosebut sufficient to provide urine discoloration to pre-vent unblinding of the study)17 Both treatmentgroups showed improvement over baseline but nobetween-group differences were noted (42 re-sponders [defined as 50 reduction in attacks] intreatment group and 44 in placebo group p

087) The study was not powered to show between-group differences and involved administration ofmagnesium only as combination therapy thus theresults cannot be clearly interpreted regarding the ef-ficacy of magnesium for migraine prevention AEswere not reported

MIG-99 MIG-99 is a relatively new stable extractof tanacetum parthenium (feverfew) which is repro-ducibly manufactured with supercritical CO2 fromfeverfew In the original guideline 3 positive studiesand 1 negative study (feverfew given as alcohol ex-tract) are reviewed that suggest possible efficacy formigraine prevention Since the original guideline 3new studies on MIG-99 for migraine prophylaxis havebeen published In 1 Class I study the migraine fre-quency decreased from 476 by 19 attacksmonth inthe MIG-99 group and by 13 attacks in the placebogroup (p 005) A logistic regression analysis of re-sponder rates showed an OR of 34 in favor of MIG-99(p 0005)18 AEs reported were similar to those fromplacebo the most common being gastrointestinal sys-tem disorders or respiratory system disorders

In a Class II dose-finding study MIG-99 625 mgTID (other doses tested 208 and 1875 mg TID)was effective in reducing migraine frequency by 18attacksmonth (baseline 45 08 to 30 15attacks at week 12) The placebo group reduced mi-graine frequency by 03 attacksmonth (baseline

49 09 to 46 22 attacks at week 12 p 002CI 107ndash249)19

In a second Class II study described above formagnesium the efficacy of the combination of mag-nesium (300 mg) riboflavin (400 mg) and MIG-99(100 mg) was not shown in comparison with a pla-cebo (25 mg of riboflavin)17

Omega-3 One Class I study assessed the efficacy ofomega-3 polyunsaturated fatty acids (3 g BID) vsplacebo and found no difference in mean number ofattacks during the last 4 weeks of the study (month4) but the total number of attacks in 4 months was


lower in the omega-3 treatment group20 A verystrong placebo effect was observed in this trial 45reduction of attacks between run-in and 4-monthtreatment period for placebo as compared with 55in the omega-3 group (p 0058) AEs associatedwith omega-3 treatment included significantly morefrequent eructation (8) than with placebo (1)otherwise no differences in AEs between treatmentswere reported

Petasites Petasites is a purified extract from thebutterbur plant Two Class I studies show Petasites(50ndash75 mg BID) to be effective in reducing migraineattack frequency2122 In the first study the frequencyof migraine attacks decreased by a maximum of 60vs baseline and the reduction in the number of mi-graine attacks vs placebo was significant (p

005)21 Petasites reduced the frequency of attacksfrom 33 15 to 18 08 attacksmonth after 4weeks to 13 09 attacksmonth after 8 weeks andto 17 09 attacksmonth after 12 weeks (p

005) Following placebo attack frequency decreasedfrom 29 12 to 22 07 after 4 weeks (p

005) to 24 08 after 8 weeks (p 005) and to26 11 after 12 weeks (p 005) No AEs werereported

In the second Class I study migraine attack fre-quency was reduced by 48 for Petasites extract 75mg BID (p 00012 vs placebo) by 36 for Peta-sites extract 50 mg BID (p 0127 vs placebo) andby 26 for the placebo group22 The incidence ofburping increased for Petasites extract 75 mg or 50mg vs placebo Importantly safety of prolonged useof Petasites is not established by the short-term stud-ies included in this review

Riboflavin In the original guideline 1 Class Itrial reported riboflavin to be superior to placebosuggesting probable efficacy for migraine preven-tion Since then 1 additional Class II study (re-viewed above) failed to show the efficacy of thecombination of magnesium (300 mg) riboflavin(400 mg) and MIG-99 (100 mg) vs 25 mg ofriboflavin16

CONCLUSIONS

bull Petasites is established as effective for migraineprevention (2 Class I studies)

bull Riboflavin is probably effective for migraineprevention (1 Class I trial and 1 imprecise ClassII study)

bull Co-Q10 is possibly effective for migraine pre-vention (1 Class II study)

bull A combination of soy isoflavones (60 mg)dong quai (100 mg) and black cohosh (50mg) is possibly effective for migraine preven-tion (1 Class II study) Percutaneous estra-

diol is possibly effective for migraineprevention (1 Class II study) however thereis an increased risk of migraine recurring af-ter estradiol patch discontinuation

bull Magnesium is probably effective for migraineprevention (multiple Class II trials) MIG-99(feverfew) is probably effective for migraineprevention (1 Class I study 1 positive Class IIstudy and 1 underpowered negative Class IIstudy)

bull The efficacy of HBO for migraine prevention isunclear (1 imprecise negative Class II study)

bull The efficacy of omega-3 for migraine preven-tion is unclear (1 imprecise Class I study)

RECOMMENDATIONS Level A The followingtherapy is established as effective and should be of-fered for migraine prevention

bull Petasites (butterbur)

Level B The following therapies are probably effectiveand should be considered for migraine prevention

bull NSAIDS fenoprofen ibuprofen ketoprofennaproxen naproxen sodium

bull Herbal therapies vitamins and minerals ribo-flavin magnesium MIG-99 (feverfew)

bull Histamines histamine SC

Level C The following therapies are possibly effectiveand may be considered for migraine prevention

bull NSAIDs flurbiprofen mefenamic acidbull Herbal therapies vitamins and minerals Co-

Q10 estrogenbull Antihistamines cyproheptadine

Level U Evidence is inadequate or conflicting to sup-port or refute the use of the following therapies formigraine prevention

bull NSAIDs aspirin indomethacinbull Herbal therapies vitamins and minerals

omega-3bull Other HBO

Level B negative The following therapy is probablyineffective and should not be considered for migraineprevention

bull Leukotriene receptor antagonists montelukast

CLINICAL CONTEXT In a previous epidemiologicstudy 387 of study participants had ever used amigraine preventive treatment of which only 124were current users and 172 were coincident users(taking a migraine preventive treatment for otherreasons)23 The proportion of those who use NSAIDsor individual complementary treatments specifically


for migraine prevention is unclear at this time and isa topic which warrants further study Additionallythe treatments reviewed herein are those available inthe United States In other countries treatments maynot be available commercially or may be available inother dosages or in other preparations or combina-tions Therefore the results from this and otherguidelines are limited to those treatments available inthe United States

Additionally studies assessing the efficacy ofNSAIDs and complementary treatments for migraineprevention are limited and should be considered relativeto other available pharmacologic therapies reviewed in aseparate guideline4 Silberstein and colleagues report di-valproex sodium sodium valproate topiramate meto-prolol propranolol and timolol are effective formigraine prevention and should be offered to patientswith migraine to reduce migraine attack frequency andseverity (Level A)

Additionally the clinical evidence for NSAIDsand complementary treatments for migraine preven-tion should be reviewed with caution because thereare clear discrepancies in how patients were selectedfor study inclusion how severe frequent or dis-abling their attacks were and how severity was as-sessed Also these treatments are unregulated Thereare few or no studies on how these medicationsshould be takenmdashspecifically relative to dosing strat-egies and coadministration with other prescriptionpharmacologic treatments When patients are in-structed or choose to take NSAIDs or complemen-tary treatments for migraine prevention it isimportant that they be followed over the course oftreatment so dosing and titration modifications andAE risk can be monitored Prospective long-termsafety of many of these agents is not well studiedspecifically regarding their use as preventive migrainetreatments

It is reasonable also for clinicians to inquire aboutthe doses being used and frequency of use of NSAIDsand complementary treatments Frequent medica-tion use or high dose levels may increase the risk ofheadache progression or medication overuse whichmay lead to other secondary health complications(eg gastrointestinal upsetbleeding with aspirin orNSAIDs or headache rebound with discontinuationof feverfew) Complete review and disclosure of coex-isting conditions are warranted as complementary orpharmacologic therapies taken for coexisting condi-tions (eg depression) may exacerbate headache Be-cause migraine is frequent in women of childbearingage the potential for adverse fetal effects related tomigraine prevention strategies is of particular con-cern Little has been done to establish the long-term

safety and efficacy of these agents during pregnancyor breastfeeding

Additionally when patients have unlimited accessto over-the-counter medications they may be un-aware of the continued need for routine physicianfollow-up for a chronic illness such as migraine asillness severity may progress or improve often war-ranting medication changes (see table e-1) It also isimportant for patients to understand the magnitudeof benefit that can be expected from preventive mi-graine therapies moreover patient education aboutmigraine and appropriate management is importantin successful patient care For some patients a 35reduction in headache frequency or intensity may bedeemed an insufficient level of improvement thusleading them to risk dose escalation Additionallypatients with migraine may need to be educatedabout appropriate use and risks of these agents

Finally recent studies suggest that some medica-tions used for migraine may offer long-term protec-tion against headache progression whereas otheragents may elevate progression risk Specifically oneepidemiologic study assessing medication use in thegeneral migraine population reports that aspirin oribuprofen use may protect against progression fromepisodic to chronic headache conditions24 In con-trast opioid use was positively associated withchronic headache conditions Although conclusionsare preliminary regarding the benefits and risks ofselected agents for long-term use studies suggest thatthese agents may play a significant role in headacheprogression and patterns lending further emphasisto the importance of following patients closely in-cluding regular assessment of NSAIDs and othercomplementary treatments for migraine prevention

RECOMMENDATIONS FOR FUTURE RESEARCH Lit-tle is known about many of the NSAIDs and com-plementary treatments reviewed in this guidelinetherefore additional studies are needed to furtherunderstand the optimal doses of these migraine pre-vention treatments Additionally many of thesetreatments are readily available but not for migraineprevention so little is known about increased AErisks when treatments are used one or more timesdaily for migraine prevention More studies areneeded that further assess the relative efficacy of thesetreatments in relation to other pharmacologic thera-pies Other shortcomings of the existing evidence be-came apparent during this review and analysis andseveral areas worthy of future investigation may in-clude the following

bull Acceptability long-term use safety and effec-tiveness of specific preventive therapies


bull Use of combination therapies including drugtherapy with behavioral treatment or combina-tions of 2 or more drugs

bull Best duration for giving preventive treatmentand how to discontinue treatment

bull Predictors of remission with or response to pre-ventive treatment

bull Treatment of migraine and associated commoncomorbidities (eg depression obesity epi-lepsy hypertension) and use of specific mono-therapies or combination therapies in thesepatient subpopulations

bull Development of stepped care and other treat-ment strategies for particular migraine head-ache types or particular migraine patientsubgroups

bull Compliance with preventive therapiesbull Value of follow-up and patient education in

disease managementbull Use of preventive therapies to prevent illness

progression (to chronic migraine)bull Effect of preventive treatments on acute ther-

apy effectivenessbull The role of acute medication overuse in limit-

ing the therapeutic efficacy of migraine preven-tive therapies

bull Prospective trials that investigate standardizedoutcomes

AUTHOR CONTRIBUTIONSDr Holland manuscript preparation draftingrevising the manuscript

study concept or design analysis or interpretation of data Dr Silberstein

draftingrevising the manuscript study concept or design analysis or in-

terpretation of data study supervision Dr Freitag draftingrevising the

manuscript analysis or interpretation of data acquisition of data Dr

Dodick draftingrevising the manuscript study concept or design analy-

sis or interpretation of data Dr Argoff draftingrevising the manuscript

study concept or design analysis or interpretation of data Dr Ashman

draftingrevising the manuscript analysis or interpretation of data

DISCLOSUREDr 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 Silberstein is on

the advisory panel of and receives honoraria from AGA Allergan Amgen

Capnia Coherex Colucid Cydex GlaxoSmithKline Lilly MAP

Medtronic Merck Minster Neuralieve NINDS NuPathe Pfizer St

Jude Medical and Valeant He is on the 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 Scien-

tific Capnia Coherex Endo Pharmaceuticals GlaxoSmithKline Lilly

MAP Medtronic Merck NINDS NuPathe St Jude Medical and Vale-

ant Pharmaceuticals Dr Freitag has served on the scientific 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 assess-

ment of current scientific and clinical information It is not intended to in-

clude all possible proper methods of care for a particular neurologic 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 circum-

stances involved The clinical context section is made available in order to

place the evidence-based guideline(s) into perspective with current practice

habits 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 October 26 2011

REFERENCES1 Lipton RB Bigal ME Diamond M Freitag F Reed ML

Stewart WF The American Migraine Prevalence and Pre-vention Advisory Group Migraine prevalence disease bur-den and the need for preventive therapy Neurology 200768343ndash349


2 Ramadan NM Silberstein SD Freitag FG Gilbert TTFrishberg BM Evidence-based guidelines for migraineheadache in the primary care setting pharmacologicalmanagement for prevention of migraine Available athttpwwwaancomprofessionalspracticepdfsgl0090pdf Accessed April 10 2010

3 Silberstein SD Practice parameter evidence-based guidelinesfor migraine headache (an evidence-based review) report ofthe Quality Standards Subcommittee of the American Acad-emy of Neurology Neurology 200055754ndash762

4 Silberstein SD Holland S Freitag F Dodick DW ArgoffC Ashman E Evidence-based guideline update pharma-cologic treatment for episodic migraine prevention inadults report of the Quality Standards Subcommittee ofthe American Academy of Neurology and the AmericanHeadache Society Neurology 2012781337ndash1345

5 Millan-Guerrero RO Isais-Millan R Benjamiacuten TH TeneCE N-alpha-methyl histamine safety and efficacy in mi-graine prophylaxis phase III study Can J Neurol Sci200633195ndash199

6 Millan-Guerrero RO Isais-Millan R Barreto-Vizcaiacuteno Set al Subcutaneous histamine versus sodium valproate inmigraine prophylaxis a randomized controlled double-blind study Eur J Neurol 2007141079ndash1084

7 Millan-Guerrero RO Isais-Millan R Barreto-Vizcaiacuteno Set al Subcutaneous histamine versus topiramate in mi-graine prophylaxis a double-blind study Eur Neurol200859237ndash242

8 Rao BS Das DG Taraknath VR Sarma Y A double blindcontrolled study of propranolol and cyproheptadine in mi-graine prophylaxis Neurol India 200048223ndash226

9 Brandes JL Visser WH Farmer MV et al Montelukastfor migraine prophylaxis a randomized double-blindplacebo-controlled study Headache 2004S44581ndash586

10 Diener HC Hartung E Chrubasik J et al Study group Acomparative study of oral acetylsalicylic acid and meto-prolol for the prophylactic treatment of migraine a ran-domized controlled double-blind parallel group phase IIIstudy Cephalalgia 200121120ndash128

11 Bensenor IM Cook NR Lee IM Chown MJ HennekensCH Buring JE Low-dose aspirin for migraine prophylaxisin women Cephalalgia 200121175ndash183

12 Silberstein SD Olesen J Bousser MG et al InternationalHeadache Society The International Classification ofHeadache Disorders 2nd Edition (ICHD-II) revision ofcriteria for 82 Medication-overuse headache [erratum in200626360] Cephalalgia 200525460ndash465

13 Sandor PS Di Clemente L Coppola G et al Efficacy ofcoenzyme Q10 in migraine prophylaxis a randomizedcontrolled trial Neurology 200564713ndash715

14 Burke BE Olson RD Cusack BJ Randomized controlled

trial of phytoestrogen in the prophylactic treatment of

menstrual migraine Biomed Pharmacother 200256283ndash

288

15 MacGregor EA Frith A Ellis J Aspinall L Hackshaw A

Prevention of menstrual attacks of migraine a double-

blind placebo-controlled crossover study Neurology 2006

672159ndash2163

16 Eftedal OS Lydersen S Helde G White L Brubakk AO

Stovner LJ A randomized double blind study of the pro-

phylactic effect of hyperbaric oxygen therapy on migraine

Cephalalgia 200424639ndash644

17 Maizels M Blumenfeld A Burchette R A combination of

riboflavin magnesium and feverfew for migraine prophy-

laxis a randomized trial Headache 200444885ndash890

18 Pfaffenrath V Diener HC Fischer M Friede M

Henneicke-von Zepelin HH The efficacy and safety of

Tanacetum parthenium (feverfew) in migraine prophy-

laxisndasha double-blind multicentre randomized placebo-

controlled dose-response study Cephalalgia 200222

523ndash532

19 Diener HC Pfaffenrath V Schnitker J Friede M

Henneicke-von Zepelin HH Efficacy and safety of 625

mg tid feverfew CO2-extract (MIG-99) in migraine pre-

ventionndasha randomized double-blind multicentre

placebo-controlled study Cephalalgia 2005251031ndash

1041

20 Pradalier A Bakouche P Baudesson G et al Failure of

omega-3 polyunsaturated fatty acids in prevention of mi-

graine a double-blind study versus placebo Cephalalgia

200121818ndash822

21 Grossman W Schmidramsl H An extract of Petasites hy-

bridus is effective in the prophylaxis of migraine Altern

Med Rev 20016303ndash310

22 Lipton RB Gobel H Einhaupl KM Wilks K Mauskop A

Petasites hybridus root (butterbur) is an effective preven-

tive treatment for migraine Neurology 2004632240ndash

2244

23 Diamond S Bigal ME Silberstein S Loder E Reed M

Lipton RB Patterns of diagnosis and acute and preventive

treatment for migraine in the United States results from

the American Migraine Prevalence and Prevention study

Headache 200747355ndash363

24 Scher AI Lipton RB Stewart WF Bigal M Patterns of

medication use by chronic and episodic headache suffer-

ers in the general population results from the frequent

headache epidemiology study Cephalalgia 201030

321ndash328

Endorsed by the American Osteopathic Association on March 22 2012



S Holland SD Silberstein F Freitag et al Headache Society

Subcommittee of the American Academy of Neurology and the Americanfor episodic migraine prevention in adults Report of the Quality Standards

Evidence-based guideline update NSAIDs and other complementary treatments


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httpwwwneurologyorgcgicollectionmigraineMigrainefollowing collection(s) This article along with others on similar topics appears in the

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Evidence-based guideline update NSAIDs andother complementary treatments for episodicmigraine prevention in adultsReport of the Quality Standards Subcommittee of the American Academy ofNeurology and the American Headache Society

S Holland PhDSD Silberstein MD

FACPF 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 Are nonsteroidal anti-inflammatorydrugs (NSAIDs) or other complementary treatments effective for migraine prevention

Methods The authors analyzed published studies from June 1999 to May 2009 using a struc-tured review process to classify the evidence relative to the efficacy of various medications formigraine prevention

Results The author panel reviewed 284 abstracts which ultimately yielded 49 Class I or Class IIarticles on migraine prevention of these 49 15 were classified as involving nontraditional thera-pies NSAIDs and other complementary therapies that are reviewed herein

Recommendations Petasites (butterbur) is effective for migraine prevention and should beoffered to patients with migraine to reduce the frequency and severity of migraine attacks(Level A) Fenoprofen ibuprofen ketoprofen naproxen naproxen sodium MIG-99 (feverfew)magnesium riboflavin and subcutaneous histamine are probably effective for migraine pre-vention (Level B) Treatments considered possibly effective are cyproheptadine Co-Q10 es-trogen mefenamic acid and flurbiprofen (Level C) Data are conflicting or inadequate tosupport or refute use of aspirin indomethacin omega-3 or hyperbaric oxygen for migraineprevention Montelukast is established as probably ineffective for migraine prevention (LevelB) Neurologyreg 2012781346ndash1353

GLOSSARYAAN American Academy of Neurology AE adverse effect CI confidence interval HBO hyperbaric oxygen NSAID nonsteroidal anti-inflammatory drug OR odds ratio RR relative risk

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 anti-inflammatory or com-plementary treatments are effective for preventionas measured by reduced migraine attack frequency

reduced number of migraine days or reduced at-tack severity This article addresses the efficacyand safety of histaminesantihistamines non-steroidal anti-inflammatory drugs (NSAIDs) andanalgesics and several herbal vitamin and min-eral preparations whereas a companion article ad-dresses standard pharmacologic treatments formigraine prevention4

DESCRIPTION OF THE ANALYTIC PROCESSThe AAN and the American Headache Society par-ticipated in the development process An author

See page 1337

Supplemental data atwwwneurologyorg

Supplemental Data

Podcast

CME

Correspondence amp reprintrequests to American Academyof Neurologyguidelinesaancom

From the Armstrong Atlantic State University (SH) Savannah GA Thomas Jefferson University (SDS) Jefferson Headache Center PhiladelphiaPA 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 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 November 7 2011

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 the 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

SPECIAL ARTICLE

1346 Copyright copy 2012 by AAN Enterprises Inc


























MIG-99 (feverfew)

Riboflavin

Histamines

Histamine SC









































CONCLUSIONS








































































































disclosures












inferred



































288




672159ndash2163













523ndash532






1041




200121818ndash822







2244










321ndash328














References


Citations







Reprints



























MIG-99 (feverfew)

Riboflavin

Histamines

Histamine SC









































CONCLUSIONS








































































































disclosures












inferred



































288




672159ndash2163













523ndash532






1041




200121818ndash822







2244










321ndash328














References


Citations







Reprints








































CONCLUSIONS








































































































disclosures












inferred



































288




672159ndash2163













523ndash532






1041




200121818ndash822







2244










321ndash328














References


Citations







Reprints

















































































disclosures












inferred



































288




672159ndash2163













523ndash532






1041




200121818ndash822







2244










321ndash328














References


Citations







Reprints

















288




672159ndash2163













523ndash532






1041




200121818ndash822







2244










321ndash328














References


Citations







Reprints













References


Citations







Reprints


neurology 2012 holland 1346 53

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