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Evidence-based guideline update: NSAIDs and other
complementary treatments for episodic migraine prevention in
adults : Report of the Quality Standards Subcommittee of the
American Academy of Neurology and the American Headache
S. Holland, S.D. Silberstein, F. Freitag, et al.
April 24, 2012
This information is current as of
The online version of this article, along with updated information and services, is located on the World Wide Web at: ® is the official journal of the American Academy of Neurology. Published continuously Neurology since 1951, it is now a weekly with 48 issues per year. Copyright 2012 by AAN Enterprises, Inc. Allrights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.

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.D. Silberstein, MD, Objective: To provide updated evidence-based recommendations for the preventive treatment of
migraine headache. The clinical question addressed was: Are nonsteroidal anti-inflammatory drugs (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 for Results: The author panel reviewed 284 abstracts, which ultimately yielded 49 Class I or Class II
Correspondence & reprint articles on migraine prevention; of these 49, 15 were classified as involving nontraditional thera- requests to American Academy pies, NSAIDs, and other complementary therapies that are reviewed herein.
Recommendations: Petasites (butterbur) is effective for migraine prevention and should be
offered 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 to
support or refute use of aspirin, indomethacin, omega-3, or hyperbaric oxygen for migraine
prevention. Montelukast is established as probably ineffective for migraine prevention (Level
B). Neurology® 2012;78:1346–1353
GLOSSARY
AAN ⫽ 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 38% reduced number of migraine days, or reduced at- See page 1337
of migraineurs need preventive therapy, but only tack severity? This article addresses the efficacy 3%–13% currently use it.1 In 2000, the American and safety of histamines/antihistamines; non- Academy of Neurology (AAN) published guide- steroidal anti-inflammatory drugs (NSAIDs) and lines for migraine prevention.2,3 Since then, new analgesics; and several herbal, vitamin, and min- clinical studies have been published on the efficacy eral preparations, whereas a companion article ad- and safety of migraine preventive therapies. This dresses standard pharmacologic treatments for guideline seeks to assess this new evidence to an- migraine prevention.4 swer the following clinical question: For patientswith migraine, which anti-inflammatory or com- DESCRIPTION OF THE ANALYTIC PROCESS
plementary treatments are effective for prevention, The AAN and the American Headache Society par- as measured by reduced migraine attack frequency, ticipated in the development process. An author From the Armstrong Atlantic State University (S.H.), Savannah, GA; Thomas Jefferson University (S.D.S.), Jefferson Headache Center, Philadelphia,PA; Comprehensive Headache Center (F.F.), Baylor University Headache Medicine Center, Dallas, TX; Mayo Clinic (D.D.), Scottsdale, AZ; NewYork University School of Medicine (C.A.), Albany; and Elmendorf Air Force Base (E.A.), AK.
Appendices e-1– e-5 and tables e-1 and e-2 are available on the Neurology威 Web site at www.neurology.org.
Approved by the Quality Standards Subcommittee on February 19, 2011; by the Practice Committee on June 19, 2011; by the AHS Board ofDirectors on March 29, 2012; and by the AAN Board of Directors on November 7, 2011.
Study funding: This guideline was developed with financial support from the American Academy of Neurology and the American Headache Society.
None of the authors received reimbursement, honoraria, or stipends for their participation in the development of this guideline.
Go to Neurology.org for full disclosures. Disclosures deemed relevant by the authors, if any, are provided at the end of this article.
Copyright 2012 by AAN Enterprises, Inc.

Classification of migraine preventive therapies (available in the United States)
Level A: Medications
Level B: Medications
Level C: Medications
Level U: Inadequate
Other: Medications that
are probably
are possibly
or conflicting data
are established as
efficacy (>2 Class I
effective (1 Class I
effective (1 Class II
to support or refute
possibly or probably
or 2 Class II studies)
Herbal preparations, Probably not effective vitamins, minerals,and other Herbal preparations Herbal preparations vitamins, minerals, vitamins, minerals, Herbal preparations, vitamins, minerals, MIG-99 (feverfew) Abbreviation: NSAID ⫽ nonsteroidal anti-inflammatory drug.
a Indicates classification based on original guideline and new evidence not found for this report.
panel of headache and methodologic experts was as- relating to NSAIDs and complementary treatments; sembled to review the evidence.
they are reviewed herein. Clinical studies reviewed Computerized searches of the MEDLINE, Psyc- were limited to those assessing efficacy of NSAIDs INFO, and CINAHL databases identified new and complementary treatments for prevention of ep- studies. The search strategy used the MeSH term isodic migraine in adults (e.g., ⬍15 days/month).
"headache" (exploded) and a published search strat- Studies were excluded if they assessed the efficacy of egy for identifying randomized controlled trials in therapeutic agents for prevention or treatment of adults that were published in English between June chronic migraine, intractable migraine, tension-type 1999 and May 2007. Additional MEDLINE headache, or headache in adolescents or children.
searches revealed studies published through May Also excluded were studies that assessed acute mi- 2009, which were reviewed and are included as sup- graine treatment, migraine aura treatment or preven- plemental articles.
tion, or nonpharmacologic treatments. Studies using Studies of NSAIDs and complementary treat- quality of life measures, disability assessment, or ments available in the United States were included in nonstandardized outcomes as primary efficacy end- the analysis if they randomized patients with mi- points were not included. NSAIDs and complemen- graine to the agent under study or a comparator tary treatments not commonly or readily available in treatment (including placebo) and utilized masked the United States are not reviewed in this guideline.
(blinded) outcome assessment. At least 2 panelists Since the 2000 guideline publication, the AAN independently reviewed each selected study and rated revised its evidence classification criteria to include it using the AAN therapeutic classification of evi- study completion rates. Studies whose completion dence scheme (appendix e-3 on the Neurology® Website at Differences in ratings rates are below 80% were downgraded.
were resolved by author panel discussion.
We found no additional Class I or Class II studies published since the original guideline for fenoprofen, ANALYSIS OF EVIDENCE The original search
ibuprofen, ketoprofen, naproxen, naproxen sodium, identified 179 articles and included pharmacologic or indomethacin. Recommendations regarding these and complementary treatments and NSAIDs. The treatments are based on the evidence reviewed in the supplemental search from 2007 to 2009 yielded an original guideline (denoted in table 1).
additional 105 articles. Of the total 284 articles, 15 Following is a summary of Class I and Class II were classified as Class I or Class II and identified as evidence for the efficacy of NSAIDs and comple- Neurology 78 April 24, 2012

mentary treatments for migraine prevention. Assess- and itching at the injection site. Similar AEs and ment of relative safety and tolerability of these agents withdrawal rates (for slow reaction speed) were re- as compared with placebo or other active treatments ported for the sodium valproate study.6 Histamine falls outside the scope of this efficacy assessment, but SC was associated with transitory burning and general information regarding safety and tolerability is itching at the injection site.
included. Additionally, efficacy results from the sum- Cyproheptadine. A single Class II study (described
marized trials may be dependent on study design, in- in the companion guideline) showed cyproheptadine cluding study duration (8 weeks vs 6 months), (4 mg/day) was as effective as propranolol (80 mg/ medication doses (low vs high), and dosing regimens day) in reducing migraine frequency and severity.8 and titrations—all of which may influence efficacy on- Montelukast. One Class I study of montelukast (20
set, relative efficacy, and quality of the evidence.
mg) for migraine prevention reported no significantdifference between treatments in the percentage of patients with a ⱖ50% decrease in migraine attack tagonists. In the 2000 guideline, there were no stud-
ies of histamines, antihistamines, or leukotriene
frequency per month (15.4% for montelukast vs receptor antagonists for migraine prevention. Since 10.3% for placebo [odds ratio (OR) ⫽ 1.64; confi- that publication, several studies of histamine, cypro- dence interval (CI) 0.64 – 4.20]).9 As compared with heptadine, and montelukast have been performed.
the placebo group, the montelukast group reportedno differences in incidence, frequency, or severity of Histamine. Three Class II single-center studies (all
from the same center) show the efficacy of histamine AEs in this 3-month treatment phase.
for migraine prevention.5–7 N-alpha-methyl hista- Conclusions. Histamine SC is established as proba- bly effective (3 Class II studies) for migraine preven- mine (1–10 ng 2 times/week) SC injections reduced tion. Cyproheptadine is possibly effective for attack frequency from baseline as compared with pla- migraine prevention and possibly as effective as pro- cebo.5 Headache frequency at 4 weeks was reduced pranolol for migraine prevention (single Class II from 3.8 to 0.5 in the histamine group, as compared study). Montelukast is probably ineffective for mi- with reduction from 3.6 to 2.9 attacks for placebo graine prevention (1 Class I study; table 1).
( p ⬍ 0.0001). Histamine was statistically superior toplacebo at all treatment visits through 12 weeks for NSAIDs. The efficacy of NSAIDs for migraine pre-
reduction in migraine frequency, severity, and dura- vention was reported in the original guideline, in- tion ( p ⬍ 0.0001). Transient itching at the injection cluding 23 controlled trials of 10 different NSAIDs sites was the only reported adverse effect (AE), but it that showed a modest but significant benefit for did not reach significance.
naproxen sodium, with similar trends for flurbipro- In a second Class II study, histamine was shown fen, ketoprofen, and mefenamic acid. In the absence to be as effective as sodium valproate in reducing of new clinical reports, recommendations for NSAID attack frequency and better than sodium valproate in use for migraine prevention are based on data from reducing headache duration and intensity.6 Specifi- the original guideline. Regarding aspirin, new clini- cally, both sodium valproate 500 mg/day and hista- cal evidence is available and included herein.
mine (1–10 ng 2 times/week) SC injections Aspirin. In the original guideline, studies of aspi-
improved headache frequency, duration, and inten- rin were found to have conflicting results. Since sity as early as 8 weeks following treatment when the original report, 2 additional Class II studies compared with baseline ( p ⬍ 0.05). No patients on have been reported. As summarized in the com- histamine presented with AEs. Conversely, 37% of panion article, aspirin was found to be as effective patients on sodium valproate experienced nausea, as metoprolol for migraine prevention.10 In a sec- 34% had tremor, 24% had weight gain, and 12% ond study, aspirin 100 mg in combination with had alopecia.
vitamin E 600 IU every other day was compared A third study reported the efficacy of histamine in with placebo in combination with vitamin E.11 No migraine prevention as compared with topiramate.
differences were noted between aspirin and pla- Topiramate 100 mg/day was compared with hista- cebo treatments for migraine frequency or severity mine (1–10 ng 2 times/week SC), and both active at 12 months or 36 months.
treatments showed improvement over baseline mea- Conclusions. The efficacy of aspirin for migraine pre- sures for attack frequency, intensity, and use of res- vention is unknown (conflicting Class II studies; cue medication.7 Eleven percent (5/45) of subjects treated with histamine withdrew from the hista- Clinical context. Regular or daily use of selected mine group because they were not satisfied with NSAIDs for the treatment of frequent migraine at- the speed of results, although no AEs were re- tacks may exacerbate headache because of develop- ported. Few subjects reported transitory burning ment of a condition called medication overuse Neurology 78 April 24, 2012

headache.12 Therefore, use of aspirin, selected analge- HBO vs control for migraine prevention.
sics, and NSAIDs may exacerbate headache; use of Magnesium. In the original guideline, magnesium
these agents in migraine prevention studies may con- was found to be probably effective for migraine pre- found the clinical interpretation of the study results.
vention on the basis of 2 positive Class II studies and1 negative Class III study. Since the 2000 report, 1 Herbal preparations, vitamins, minerals, and other in-
additional Class II study compared the combination terventions. Since the original guideline, additional
of magnesium (300 mg), riboflavin (400 mg), and studies have been identified that assess the efficacy of MIG-99 (100 mg) with placebo (25 mg of ribofla- Co-Q10, estrogen, hyperbaric oxygen (HBO), mag- vin, which was thought to be a subtherapeutic dose nesium, MIG-99, omega-3, Petasites, and riboflavin but sufficient to provide urine discoloration to pre- for migraine prevention.
vent unblinding of the study).17 Both treatment Co-Q10 (water-soluble disbursable form of Co-Q10).
One small Class II study showed that Co-Q10 100 groups showed improvement over baseline, but nobetween-group differences were noted (42% re- mg TID was significantly more effective than pla- sponders [defined as ⱖ50% reduction in attacks] in cebo in reducing attack frequency from baseline to 4 treatment group and 44% in placebo group; p ⫽ months following treatment.13 The 50% responder 0.87). The study was not powered to show between- rate for attack frequency (ⱖ50% reduction) was group differences and involved administration of 47.6% for CoQ10 vs 14.3% for placebo ( p ⫽ 0.02).
magnesium only as combination therapy; thus, the The actual reduction in attack frequency was⫺ results cannot be clearly interpreted regarding the ef- 1.9 ⫾ 1.9 for CoQ10 and 0.09 ⫾ 1.9 for placebo ficacy of magnesium for migraine prevention. AEs ( p ⫽ 0.05). One patient withdrew from the Co-Q10 were not reported.
treatment group because of cutaneous allergy.
MIG-99. MIG-99 is a relatively new stable extract
Estrogen. A combination of soy isoflavones (60
of tanacetum parthenium (feverfew), which is repro- mg), dong quai (100 mg), and black cohosh (50 mg) ducibly manufactured with supercritical CO from (each component standardized to its primary alka- feverfew. In the original guideline, 3 positive studies loid) reduced migraine attack frequency vs placebo in and 1 negative study (feverfew given as alcohol ex- a small Class II study.14 The mean frequency of men- tract) are reviewed that suggest possible efficacy for strually associated migraine attacks during weeks migraine prevention. Since the original guideline, 3 9 –24 was reduced from 10.3 ⫾ SEM 2.4 in patients new studies on MIG-99 for migraine prophylaxis have treated with placebo to 4.7 ⫾ SEM 1.8 (p ⬍ 0.01) in been published. In 1 Class I study, the migraine fre- patients treated with the phytoestrogen preparation.
quency decreased from 4.76 by 1.9 attacks/month in In a second Class II trial, percutaneous estradiol the MIG-99 group and by 1.3 attacks in the placebo was applied 6 days before the first full day of bleeding group (p ⬍ 0.05). A logistic regression analysis of re- up to and including the second full day of menstrua- sponder rates showed an OR of 3.4 in favor of MIG-99 tion.15 Estradiol 1.5 mg (gel patch applied to the up- (p ⬍ 0.005).18 AEs reported were similar to those from per thigh or arm) was associated with a 22% placebo, the most common being gastrointestinal sys- reduction in migraine days (estradiol ⫽ 133 mi- tem disorders or respiratory system disorders.
graine days, placebo ⫽ 171 migraine days; relative In a Class II dose-finding study, MIG-99 6.25 mg risk [RR] 0.78; CI 0.62– 0.99, p ⫽ 0.04). This im- TID (other doses tested: 2.08 and 18.75 mg TID) provement was temporary, as subjects reported a was effective in reducing migraine frequency by 1.8 40% increase in migraine days in the 5 days following attacks/month (baseline ⫽ 4.5 ⫾ 0.8 to 3.0 ⫾ 1.5 treatment (RR 1.40; CI 1.03–1.92, p ⫽ 0.03). No seri- attacks at week 12). The placebo group reduced mi- ous AEs were otherwise reported, although common graine frequency by 0.3 attacks/month (baseline ⫽ risks associated with estrogen supplementation are well 4.9 ⫾ 0.9 to 4.6 ⫾ 2.2 attacks at week 12; p ⫽ 0.02, documented throughout the literature. Limited studies CI 1.07–2.49).19 are available regarding estrogen's safety specifically for In a second Class II study, described above for long-term use in migraine prevention.
magnesium, the efficacy of the combination of mag- Hyperbaric oxygen. In a single Class II study, no
nesium (300 mg), riboflavin (400 mg), and MIG-99 differences were found between the HBO group (3 (100 mg) was not shown in comparison with a pla- 30-minute treatments/week) and control group, but cebo (25 mg of riboflavin).17 an increase in headache hours was experienced by Omega-3. One Class I study assessed the efficacy of
both groups vs the pretreatment level.16 Corrected omega-3 polyunsaturated fatty acids (3 g BID) vs for the number of days, the increase was 6.9 hours/ placebo and found no difference in mean number of week for HBO vs 4.7 hours/week for controls. This attacks during the last 4 weeks of the study (month study reports no assessment of tolerability or safety of 4), but the total number of attacks in 4 months was Neurology 78 April 24, 2012

lower in the omega-3 treatment group.20 A very diol is possibly effective for migraine strong placebo effect was observed in this trial: 45% prevention (1 Class II study); however, there reduction of attacks between run-in and 4-month is an increased risk of migraine recurring af- treatment period for placebo as compared with 55% ter estradiol patch discontinuation.
in the omega-3 group ( p ⫽ 0.058). AEs associated • Magnesium is probably effective for migraine with omega-3 treatment included significantly more prevention (multiple Class II trials). MIG-99 frequent eructation (8%) than with placebo (1%); (feverfew) is probably effective for migraine otherwise, no differences in AEs between treatments prevention (1 Class I study, 1 positive Class II were reported.
study, and 1 underpowered negative Class II Petasites. Petasites is a purified extract from the
butterbur plant. Two Class I studies show Petasites • The efficacy of HBO for migraine prevention is (50 –75 mg BID) to be effective in reducing migraine unclear (1 imprecise negative Class II study).
attack frequency.21,22 In the first study, the frequency • The efficacy of omega-3 for migraine preven- of migraine attacks decreased by a maximum of 60% tion is unclear (1 imprecise Class I study).
vs baseline, and the reduction in the number of mi-graine attacks vs placebo was significant ( p ⱕ RECOMMENDATIONS Level A. The following
0.05).21 Petasites reduced the frequency of attacks therapy is established as effective and should be of- from 3.3 ⫾ 1.5 to 1.8 ⫾ 0.8 attacks/month after 4 fered for migraine prevention: weeks, to 1.3 ⫾ 0.9 attacks/month after 8 weeks, and • Petasites (butterbur) to 1.7 ⫾ 0.9 attacks/month after 12 weeks (p ⱕ0.05). Following placebo, attack frequency decreased Level B. The following therapies are probably effective
from 2.9 ⫾ 1.2 to 2.2 ⫾ 0.7 after 4 weeks (p ⱕ and should be considered for migraine prevention: 0.05), to 2.4 ⫾ 0.8 after 8 weeks (p ⱕ 0.05), and to • NSAIDS: fenoprofen, ibuprofen, ketoprofen, 2.6 ⫾ 1.1 after 12 weeks (p ⱕ 0.05). No AEs were naproxen, naproxen sodium • Herbal therapies, vitamins, and minerals: ribo- In the second Class I study, migraine attack fre- flavin, magnesium, MIG-99 (feverfew) quency was reduced by 48% for Petasites extract 75 • Histamines: histamine SC mg BID ( p ⫽ 0.0012 vs placebo), by 36% for Peta-sites extract 50 mg BID ( p ⫽ 0.127 vs placebo), and Level C. The following therapies are possibly effective
by 26% for the placebo group.22 The incidence of and may be considered for migraine prevention: burping increased for Petasites extract 75 mg or 50 • NSAIDs: flurbiprofen, mefenamic acid mg vs placebo. Importantly, safety of prolonged use • Herbal therapies, vitamins, and minerals: Co- of Petasites is not established by the short-term stud- ies included in this review.
• Antihistamines: cyproheptadine Riboflavin. In the original guideline, 1 Class I
trial reported riboflavin to be superior to placebo, Level U. Evidence is inadequate or conflicting to sup-
suggesting probable efficacy for migraine preven- port or refute the use of the following therapies for tion. Since then, 1 additional Class II study (re- migraine prevention: viewed above) failed to show the efficacy of the • NSAIDs: aspirin, indomethacin combination of magnesium (300 mg), riboflavin • Herbal therapies, vitamins, and minerals: (400 mg), and MIG-99 (100 mg) vs 25 mg of Level B negative. The following therapy is probably
ineffective and should not be considered for migraine
• Petasites is established as effective for migraine prevention (2 Class I studies).
• Riboflavin is probably effective for migraine • Leukotriene receptor antagonists: montelukast prevention (1 Class I trial and 1 imprecise ClassII study).
CLINICAL CONTEXT In a previous epidemiologic
• Co-Q10 is possibly effective for migraine pre- study, 38.7% of study participants had ever used a vention (1 Class II study).
migraine preventive treatment, of which only 12.4% • A combination of soy isoflavones (60 mg), were current users and 17.2% were coincident users dong quai (100 mg), and black cohosh (50 (taking a migraine preventive treatment for other mg) is possibly effective for migraine preven- reasons).23 The proportion of those who use NSAIDs tion (1 Class II study). Percutaneous estra- or individual complementary treatments specifically Neurology 78 April 24, 2012

for migraine prevention is unclear at this time, and is safety and efficacy of these agents during pregnancy a topic which warrants further study. Additionally, or breastfeeding.
the treatments reviewed herein are those available in Additionally, when patients have unlimited access the United States. In other countries, treatments may to over-the-counter medications, they may be un- not be available commercially or may be available in aware of the continued need for routine physician other dosages or in other preparations or combina- follow-up for a chronic illness such as migraine, as tions. Therefore, the results from this and other illness severity may progress or improve, often war- guidelines are limited to those treatments available in ranting medication changes (see table e-1). It also is the United States.
important for patients to understand the magnitude Additionally, studies assessing the efficacy of of benefit that can be expected from preventive mi- NSAIDs and complementary treatments for migraine graine therapies; moreover, patient education about prevention are limited and should be considered relative migraine and appropriate management is important to other available pharmacologic therapies reviewed in a in successful patient care. For some patients, a 35% separate guideline.4 Silberstein and colleagues report di- reduction in headache frequency or intensity may be valproex sodium, sodium valproate, topiramate, meto- deemed an insufficient level of improvement, thus prolol, propranolol, and timolol are effective for leading them to risk dose escalation. Additionally, migraine prevention and should be offered to patients patients with migraine may need to be educated with migraine to reduce migraine attack frequency and about appropriate use and risks of these agents.
severity (Level A).
Finally, recent studies suggest that some medica- Additionally, the clinical evidence for NSAIDs tions used for migraine may offer long-term protec- and complementary treatments for migraine preven- tion against headache progression whereas other tion should be reviewed with caution because there agents may elevate progression risk. Specifically, one are clear discrepancies in how patients were selected epidemiologic study assessing medication use in the for study inclusion; how severe, frequent, or dis- general migraine population reports that aspirin or abling their attacks were; and how severity was as- ibuprofen use may protect against progression from sessed. Also, these treatments are unregulated. There episodic to chronic headache conditions.24 In con- are few or no studies on how these medications trast, opioid use was positively associated with should be taken—specifically relative to dosing strat- chronic headache conditions. Although conclusions egies and coadministration with other prescription are preliminary regarding the benefits and risks of pharmacologic treatments. When patients are in- selected agents for long-term use, studies suggest thatthese agents may play a significant role in headache structed or choose to take NSAIDs or complemen- progression and patterns, lending further emphasis tary treatments for migraine prevention, it is to the importance of following patients closely, in- important that they be followed over the course of cluding regular assessment of NSAIDs, and other treatment so dosing and titration modifications and complementary treatments for migraine prevention.
AE risk can be monitored. Prospective long-termsafety of many of these agents is not well studied RECOMMENDATIONS FOR FUTURE RESEARCH Lit-
specifically regarding their use as preventive migraine tle is known about many of the NSAIDs and com- plementary treatments reviewed in this guideline; It is reasonable also for clinicians to inquire about therefore, additional studies are needed to further the doses being used and frequency of use of NSAIDs understand the optimal doses of these migraine pre- and complementary treatments. Frequent medica- vention treatments. Additionally, many of these tion use or high dose levels may increase the risk of treatments are readily available but not for migraine headache progression or medication overuse, which prevention, so little is known about increased AE may lead to other secondary health complications risks when treatments are used one or more times (e.g., gastrointestinal upset/bleeding with aspirin or daily for migraine prevention. More studies are NSAIDs or headache rebound with discontinuation needed that further assess the relative efficacy of these of feverfew). Complete review and disclosure of coex- treatments in relation to other pharmacologic thera- isting conditions are warranted, as complementary or pies. Other shortcomings of the existing evidence be- pharmacologic therapies taken for coexisting condi- came apparent during this review and analysis, and tions (e.g., depression) may exacerbate headache. Be- several areas worthy of future investigation may in- cause migraine is frequent in women of childbearing clude the following: age, the potential for adverse fetal effects related tomigraine prevention strategies is of particular con- • Acceptability, long-term use, safety, and effec- cern. Little has been done to establish the long-term tiveness of specific preventive therapies Neurology 78 April 24, 2012 • Use of combination therapies, including drug core, Neuralieve, Neuraxon, NuPathe Inc., MAP, SmithKlineBeecham, therapy with behavioral treatment or combina- Boston Scientific, Medtronic, Inc., Nautilus, Eli Lilly & Company, No-vartis, Colucid, GlaxoSmithKline, Autonomic Technologies, MAP Phar- tions of 2 or more drugs maceuticals, Inc., Zogenix, Inc., Impax Laboratories, Inc., Bristol Myers • Best duration for giving preventive treatment Squibb, Nevro Corporation, Atlas, Arteaus, and Alder Pharmaceuticals.
and how to discontinue treatment Within the past 3 years, Dr. Dodick has received funding for travel, speak- • Predictors of remission with or response to pre- ing, or editorial activities from CogniMed, Scientiae, Intramed, SAGEPublishing, Lippincott Williams & Wilkins, Oxford University Press, ventive treatment Cambridge University Press, Miller Medical, Annenberg for Health Sci- • Treatment of migraine and associated common ences; he serves as Editor-in-Chief and on the editorial boards of The comorbidities (e.g., depression, obesity, epi- Neurologist, Lancet Neurology, and Postgraduate Medicine; and has servedas Editor-in-Chief of Headache Currents and as an Associate Editor of lepsy, hypertension) and use of specific mono- Headache; he receives publishing royalties for Wolff 's Headache, 8th edi- therapies or combination therapies in these tion (Oxford University Press, 2009) and Handbook of Headache (Cam- patient subpopulations bridge University Press, 2010). Within the past 3 years, Dr. Dodick has • Development of stepped care and other treat- received research grant support from Advanced Neurostimulation Sys-tems, Boston Scientific, St Jude Medical, Inc., Medtronic, NINDS/NIH, ment strategies for particular migraine head- Mayo Clinic. Dr. Argoff has served on a scientific advisory board for the ache types or particular migraine patient Department of Defense and DSMB for the NIH; has received funding for travel and/or speaking and/or has served on a speakers' bureau for Pfizer(King), Janssen (Pricara), Millennium Laboratories, Neurogesx, Forest • Compliance with preventive therapies Laboratories, Eli Lilly, Covidien, and Endo Pharmaceuticals; has received • Value of follow-up and patient education in research support from Endo Pharmaceuticals, Forest Laboratories, Eli disease management Lilly, Neurogesx, Pfizer, and SBRT funded by the NIH; and has received • Use of preventive therapies to prevent illness stock/stock options from Pfizer. Dr. Ashman is the Level of Evidenceeditor for Neurology and serves on the AAN Guideline Development Sub- progression (to chronic migraine) committee. He reports no other disclosures. Full disclosures were pro-
• Effect of preventive treatments on acute ther- vided at the time of Board approval. Go to Neurology.org for full
apy effectiveness • The role of acute medication overuse in limit- ing the therapeutic efficacy of migraine preven- This statement is provided as an educational service of the American Academy of Neurology and the American Headache Society. It is based on as assess- • Prospective trials that investigate standardized ment of current scientific and clinical information. It is not intended to in- clude all possible proper methods of care for a particular neurologic problemor all legitimate criteria for choosing to use a specific procedure. Neither is itintended to exclude any reasonable alternative methodologies. The AAN and the AHS recognize that specific patient care decisions are the prerogative of Dr. Holland: manuscript preparation, drafting/revising the manuscript, the patient and the physician caring for the patient, based on all of the circum- study concept or design, analysis or interpretation of data. Dr. Silberstein: stances involved. The clinical context section is made available in order to drafting/revising the manuscript, study concept or design, analysis or in- place the evidence-based guideline(s) into perspective with current practice terpretation of data, study supervision. Dr. Freitag: drafting/revising the habits and challenges. No formal practice recommendations should be manuscript, analysis or interpretation of data, acquisition of data. Dr.
Dodick: drafting/revising the manuscript, study concept or design, analy-sis or interpretation of data. Dr. Argoff: drafting/revising the manuscript, CONFLICT OF INTEREST
study concept or design, analysis or interpretation of data. Dr. Ashman: The American Academy of Neurology and the American Headache Soci- drafting/revising the manuscript, analysis or interpretation of data.
ety are committed to producing independent, critical and truthful clinicalpractice guidelines (CPGs). Significant efforts are made to minimize the potential for conflicts of interest to influence the recommendations of this Dr. Holland (formerly Dr. Pearlman) receives consulting income from CPG. To the extent possible, the AAN and AHS keep separate those who Map Pharmaceuticals and the American Headache Society and research have a financial stake in the success or failure of the products appraised in support from Albert Einstein College of Medicine. Dr. Silberstein is on the CPGs and the developers of the guidelines. Conflict of interest forms the advisory panel of and receives honoraria from AGA, Allergan, Amgen, were obtained from all authors and reviewed by an oversight committee Capnia, Coherex, Colucid, Cydex, GlaxoSmithKline, Lilly, MAP, prior to project initiation. AAN and AHS limit the participation of au- Medtronic, Merck, Minster, Neuralieve, NINDS, NuPathe, Pfizer, St.
thors with substantial conflicts of interest. The AAN and AHS forbid Jude Medical, and Valeant. He is on the speakers' bureau of and receives commercial participation in, or funding of, guideline projects. Drafts of honoraria from Endo Pharmaceuticals, GlaxoSmithKline, and Merck. He the guidelines have been reviewed by at least three AAN and AHS com- serves as a consultant for and receives honoraria from Amgen and Novartis.
mittees, a network of neurologists, Neurology peer reviewers, and represen- His employer receives research support from AGA, Allergan, Boston Scien- tatives from related fields. The AAN Guideline Author Conflict of tific, Capnia, Coherex, Endo Pharmaceuticals, GlaxoSmithKline, Lilly, Interest Policy can be viewed at MAP, Medtronic, Merck, NINDS, NuPathe, St. Jude Medical, and Vale-ant Pharmaceuticals. Dr. Freitag has served on the scientific advisory Received June 27, 2011. Accepted in final form October 26, 2011. boards of Zogenix Pharmaceuticals, Allergan Pharmaceuticals, Nautilus,MAP Pharmaceuticals, and Nupathe; has received travel expenses and or honoraria from GlaxoSmithKline, Zogenix, Merck, Nautilus, Allergan, Lipton RB, Bigal ME, Diamond M, Freitag F, Reed ML, Diamond Headache Clinic Research and Educational Foundation (notfor profit), and the American Headache Society (travel). Dr. Freitag is a Stewart WF; The American Migraine Prevalence and Pre- member of the Board of Directors of the National Headache Foundation.
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Endorsed by the American Osteopathic Association on March 22, 2012.
Neurology 78 April 24, 2012 Evidence-based guideline update: NSAIDs and other complementary treatments
for episodic migraine prevention in adults : Report of the Quality Standards
Subcommittee of the American Academy of Neurology and the American
S. Holland, S.D. Silberstein, F. Freitag, et al.
April 23, 2012
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