DOI 10.1212/WNL.0b013e3182535d20
2012;78;1337Neurology
S.D. Silberstein, S. Holland, F. Freitag, et al.
and the American Headache Society
Standards Subcommittee of the American Academy of Neurology
episodic migraine prevention in adults : Report of the Quality
Evidence-based guideline update: Pharmacologic treatment for
May 7, 2012This information is current as of
http://www.neurology.org/content/78/17/1337.full.html
located on the World Wide Web at:
The online version of this article, along with updated information and services, is
rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
Allsince 1951, it is now a weekly with 48 issues per year. Copyright © 2012 by AAN Enterprises, Inc.
® is the official journal of the American Academy of Neurology. Published continuouslyNeurology
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Evidence-based guideline update: Pharmacologic
treatment for episodic migraine prevention
in adults
Report of the Quality Standards Subcommittee of the American Academy of
Neurology and the American Headache Society
S.D. Silberstein, MD,
FACP
S. Holland, PhD
F. Freitag, DO
D.W. Dodick, MD
C. Argoff, MD
E. Ashman, MD
ABSTRACT
Objective: To provide updated evidence-based recommendations for the preventive treatment of
migraine headache. The clinical question addressed was: What pharmacologic therapies are
proven 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 ultimately
yielded 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 and
should 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 is
ineffective for migraine prevention (Level A). Neurology® 2012;78:1337–1345
GLOSSARY
AAN � 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 38%
of migraineurs need preventive therapy, but only
3%–13% currently use it.1 In 2000, the American
Academy of Neurology (AAN) published guide-
lines for migraine prevention.2,3 Since then, new
clinical studies have been published on the efficacy
and safety of migraine preventive therapies. This
guideline seeks to assess this new evidence to an-
swer the following clinical question: For patients
with migraine, which pharmacologic therapies are
proven effective for prevention, as measured by
reduced migraine attack frequency, reduced num-
ber of migraine days, or reduced attack severity?
This article addresses the safety and efficacy of
pharmacologic therapies for migraine prevention.
Separate guidelines are available for botulinum
toxin.4 The 2008 guideline included a Level B re-
commendation that botulinum toxin was probably
ineffective for treatment of episodic migraine. A new
guideline is in development. An updated guideline
on nonsteroidal anti-inflammatory drugs5 and com-
plementary alternative treatments has been approved
for publication as a companion to this guideline.5
DESCRIPTION OF THE ANALYTIC PROCESS
The AAN and the American Headache Society partic-
ipated in the development process. An author panel of
headache and methodologic experts was assembled to
review the evidence. Computerized searches of the
MEDLINE, PsycINFO, and CINAHL databases iden-
tified new studies (published in English). The search
strategy used the MeSH term “headache” (exploded)
and a published search strategy for identifying ran-
domized controlled trials (RCTs) published between
June 1999 and May 2007. Additional MEDLINE
searches revealed studies published through May
Seepage1346
Supplemental data at
www.neurology.org
Supplemental Data
Podcast
CME
From Thomas Jefferson University (S.D.S.), Jefferson Headache Center, Philadelphia, PA; the Armstrong Atlantic State University (S.H.), Savannah,
GA; Comprehensive Headache Center (F.F.), Baylor University Headache Medicine Center, Dallas, TX; Mayo Clinic (D.D.), Scottsdale, AZ; New
York University School of Medicine (C.A.), Albany; and Elmendorf Air Force Base (E.A.), AK.
Appendices e-1–e-5, reference e1, and tables e-1 and e-2 are available on the Neurology�Web site at www.neurology.org.
Approved by the Quality Standards Subcommittee on February 19, 2011; by the Practice Committee on June 19, 2011; by the AHS Board of
Directors on March 29, 2012; and by the AAN Board of Directors on January 27, 2012.
Study funding: This guideline was developed with financial support from the American Academy of Neurology and the American Headache Society.
None of the authors received reimbursement, honoraria, or stipends for their participation in development of this guideline.
Go to Neurology.org for full disclosures. Disclosures deemed relevant by the authors, if any, are provided at the end of this article.
Correspondence & reprint
requests to American Academy of
Neurology:
guidelines@aan.com
SPECIAL ARTICLE
Copyright © 2012 by AAN Enterprises, Inc. 1337
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2009, which were reviewed and included as supple-
mental articles.
Studies of pharmacologic agents available in the
United States were included in the analysis if they
randomized adult patients with migraine to the agent
under study or a comparator drug (including placebo)
and utilized masked outcome assessment. At least 2
panelists independently reviewed each study and rated
it according to the AAN therapeutic classification of ev-
idence scheme (appendix e-3 on the Neurology® Web
site at www.neurology.org). Differences in ratings were
resolved by author panel discussion.
ANALYSIS OF EVIDENCE The original search
identified 179 articles. A supplemental search
(2007–2009) yielded 105 additional articles. Of the
total 284 articles, 29 were classified as Class I or Class
II and are reviewed herein. Studies were excluded if
they:
• Assessed the efficacy of therapeutic agents for
headache other than episodic migraine in adults
• Assessed acute migraine treatment, migraine
aura treatment/prevention, or nonpharmaco-
logic treatments (e.g., behavioral approaches)
• Used quality of life measures, disability assess-
ment, or nonstandardized outcomes as primary
efficacy endpoints
• Tested the efficacy of drugs not available in the
United States
Since the 2000 guideline publication, the AAN
revised its evidence classification criteria to in-
clude study completion rates. Studies with com-
pletion rates below 80% were downgraded; several
studies in the original guideline have thus been
downgraded.
We found no new Class I or II studies published
for acebutolol, atenolol, bisoprolol, carbamazepine,
Table 1 Classification of migraine preventive therapies (available in the United States)
Level A: Medications
with established
efficacy (>2 Class I
trials)
Level B: Medications
are probably
effective (1 Class I
or 2 Class II studies)
Level C: Medications
are possibly
effective (1 Class II
study)
Level U: Inadequate
or conflicting data
to support or refute
medication use
Other: Medications that
are established as
possibly or probably
ineffective
Antiepileptic drugs Antidepressants/
SSRI/SSNRI/TCA
ACE inhibitors
Lisinopril
Carbonic anhydrase
inhibitor
Established as not
effective
Divalproex sodium Amitriptyline Angiotensin receptor
blockers
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 Antidepressants
SSRI/SSNRI
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 vascular
smooth muscle
relaxants
Cyclandelate
Abbreviations: ACE� angiotensin-converting-enzyme; MRM�menstrually relatedmigraine; SSNRI� selective serotonin–
norepinephrine reuptake inhibitor; SSRI� selective serotonin reuptake inhibitor; TCA� tricyclic antidepressant.
a Classification based on original guideline and new evidence not found for this report.
b For short-term prophylaxis of MRM.
1338 Neurology 78 April 24, 2012
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clonazepam, clonidine, clomipramine, fluvoxamine,
guanfacine, nabumetone, nadolol, nicardipine, ni-
fedipine, or protriptyline. Recommendations for
these agents are based on the evidence reviewed in
the original guideline (see table 1). Currently, no
Class 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 of
angiotensin receptor blockers or angiotensin-
converting-enzyme (ACE) inhibitors for migraine
prevention. Since that publication, 3 reports have
been published.
Candesartan. In a Class II crossover study (12-week
treatment separated by 4-week washout), the mean
number of headache days was 18.5 with placebo
(26.3% reduction from baseline) vs 13.6 with cande-
sartan (45.6% reduction from baseline; p � 0.001).6
Selected secondary endpoints also favored candesar-
tan: headache hours (139 vs 95; p � 0.001), mi-
graine days (12.6 vs 9.0; p � 0.001), migraine hours
(92.2 vs 59.4; p � 0.001), and headache severity in-
dex (293 vs 191; p � 0.001). No serious adverse
events (AEs) occurred. The most common AEs were
dizziness (31%), “symptoms of the musculoskeletal
system” (21%), and fatigue (14%); none occurred
significantly more often than with placebo.
Lisinopril. One Class II study reported significant
reduction in all 3 primary endpoints with lisinopril
vs placebo (headache hours: 129 vs 162 [mean
change in hours 20, confidence interval (CI) 5–36];
headache days: 19.7 vs 23.7 [20, CI 5–30]; migraine
days: 14.5 vs 18.5 [21, CI 9–34]).7 AEs included
cough (26%; 10% discontinued treatment due to
cough), dizziness (23%), and “tendency to faint”
(10%). No serious AEs were reported.
Telmisartan. In a single Class II placebo-
controlled trial, telmisartan 80 mg did not show a
significant difference from placebo for reduction
in migraine days (�1.65 vs �1.14).8
Conclusions. Lisinopril and candesartan are possibly
effective for migraine prevention (1 Class II study
each). Telmisartan is possibly ineffective for reducing
the number of migraine days (1 negative Class II
study).
Antiepileptic drugs. Divalproex. The original guideline
found 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 trial
showed extended-release (ER) divalproex sodium
500–1,000 mg/day had a mean reduction in 4-week
migraine headache rate from 4.4/week (baseline) to
3.2/week (�1.2 attacks/week) in the ER divalproex so-
dium group and from 4.2/week to 3.6/week (�0.6
attacks/week) in the placebo group (CI 0.2–1.2;
p � 0.006).9 No significant differences were de-
tected between groups in the number of
treatment-emergent AEs.
Clinical context. In most headache trials, patients
taking divalproex sodium or sodium valproate re-
ported no more AEs than those on placebo. How-
ever, weight gain has been clinically observed with
divalproex sodium long-term use.9,10 Treatment with
these agents requires careful follow-up and testing
because of pancreatitis, liver failure, and teratogenic-
ity risks.11
Gabapentin. Since the 2000 publication, a Class III
study12 reported that a stable gabapentin dose (4-
week titration phase to 2,400 mg/day; 8-week main-
tenance phase) significantly reduced the median
monthly migraine rate vs placebo on the basis of a
modified intention-to-treat analysis.
Lamotrigine. The original guideline reported a sin-
gle Class I lamotrigine study13 that failed to show a
significant effect for migraine prevention. A second,
new Class I study comparing lamotrigine 50 mg/day
with placebo or topiramate 50 mg/day reported lam-
otrigine was not more effective than placebo (for
both primary endpoints) and was less effective than
topiramate in reducing migraine frequency and in-
tensity.14 The primary outcome measure (responder
rate: �50% monthly migraine frequency reduction)
was 46% for lamotrigine vs 34% for placebo (p �
0.093, CI 0.02–0.26) and 63% for topiramate vs
46% for lamotrigine (p � 0.019, CI 0.03–0.31).
Treatment-related AEs (rash, giddiness, sleepiness,
and gastrointestinal intolerance) occurred in 10% of
patients on lamotrigine.
Oxcarbazepine.One Class II trial evaluated the effi-
cacy of oxcarbazepine (1,200 mg/day) vs placebo.15
There was no difference between oxcarbazepine
(�1.30 [SE 0.282]) and placebo for mean change in
number of migraine attacks from baseline during the
last 28 days of the double-blind 15-week treatment
phase (�1.74 [SE 0.283]; p � 0.2274).
Topiramate. Four Class I studies14,16–18 and 7 Class
II studies19–25 report topiramate (50–200 mg/day) is
effective in migraine prevention.
In a Class I placebo-controlled study (mean topi-
ramate dose 125 mg/day [range 25–200 mg/day]),
patients given topiramate experienced a significantly
lower 28-day migraine frequency vs with placebo
(3.31� 1.7 vs 3.83� 2.1; p� 0.002).18 In a second
placebo-controlled Class I double-crossover study
(reviewed above), topiramate was more effective than
Neurology 78 April 24, 2012 1339
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placebo and lamotrigine for primary efficacy mea-
sures.14 In the topiramate groups, 15% of patients
experienced AEs, most commonly paresthesias,
sleepiness, and gastrointestinal intolerance. The pla-
cebo group reported gastrointestinal intolerance
(3%) and anorexia (3%).
Two additional Class I studies report topiramate is
as effective as propranolol16 or sodium valproate,17
drugs previously established as effective for migraine
prevention. In the first study, subjects given topiramate
50 mg/day had reduced mean migraine frequency (epi-
sodes/month) from baseline (6.07 � 1.89 to 1.83 �
1.39; p� 0.001) at 8 weeks, decreased headache inten-
sity VAS score from 7.1 � 1.45 to 3.67 � 2.1 (p �
0.001), and decreased headache duration from 16.37�
7.26 hours to 6.23 � 5.22 hours (p � 0.001).16 Sub-
jects given topiramate reported paresthesias (23%),
weight loss (16%), and somnolence (13%). In pa-
tients treated with propranolol 80 mg/day, mean
headache frequency (episodes/month) decreased
from 5.83 � 1.98 to 2.2 � 1.67 (p � 0.001) at 8
weeks, headache intensity VAS score decreased from
6.43 � 1.6 to 4.13 � 1.94 (p � 0.001), and head-
ache duration decreased from 15.10� 6.84 hours to
7.27 � 6.46 hours (p � 0.001). Although monthly
headache frequency, intensity, and duration de-
creased in both groups, the topiramate group re-
ported significantly greater mean reduction
(topiramate frequency decrease 4.23 � 1.2 vs pro-
pranolol 3.63 � 0.96 [p � 0.036; CI 0.39–1.16];
topiramate intensity decrease 3.43 � 1.38 vs pro-
pranolol 2.3 � 1.2 [p � 0.001; CI 0.46–1.8]; topi-
ramate duration decrease 10.1 � 4.3 vs propranolol
7.83 � 4.5 [p � 0.048; CI 0.17–4.6]).
In a crossover Class I trial (2-month washout be-
tween therapies) comparing topiramate 50 mg/day
with sodium valproate 400 mg/day, both groups
showed improvement from baseline in headache fre-
quency, intensity, and duration.17 Average monthly
migraine frequency decreased by 1.8 times with so-
dium valproate (baseline 5.4 � 2.5; posttreatment
3.6 � 2.1; CI 1.0–2.6; p � 0.001), as compared
with a 3-time reduction with topiramate (baseline
5.4� 2.0; posttreatment 2.4� 2.4; CI 2.1–3.9; p�
0.001). Headache intensity decreased by 3.7 with so-
dium valproate (baseline 7.7� 1.2; treatment 4.0�
2.1; CI 2.9–4.6; p � 0.001), as compared with a
reduction of 3.6 with topiramate (baseline 6.9� 1.2,
treatment phase 3.3� 1.5; CI 2.9–4.3; p� 0.001).
The average headache episode duration decreased by
13.4 hours from baseline with sodium valproate
(baseline 21.3� 14.6; treatment 7.9� 7.7; CI 7.5–
19.3; p � 0.001) as compared with an 11.9-hour
reduction with topiramate (baseline 17.3 � 8.4;
treatment 5.4 � 6.4; CI 8.2–15.6; p � 0.001). The
overall analysis of repeated-measures analysis of vari-
ance demonstrated no differences in monthly head-
ache frequency, intensity, or duration after the first
or second treatment rounds. Topiramate AEs were
weight loss (18.8%), paresthesias (9.4%), or both
(25%). Sodium valproate AEs were weight gain
(34.5%), hair loss (3.1%), and somnolence (3.1%).
Results of 5 Class II studies support those of the
Class I studies showing topiramate as effective for
migraine prevention.19–25 Four studies demonstrated
significant improvement over placebo19,20,23,24; one
included an active comparator arm, suggesting
equivalence of topiramate (100, 200 mg/day) and
propranolol (160 mg/day).20 Two studies comparing
topiramate and amitriptyline (25–150 mg/day) re-
ported no difference in efficacy for primary end-
points; however, amitriptyline was associated with a
significant AE increase, and the amitriptyline-
topiramate combination suggested improvement in
depression scores vs monotherapy.21,22 In one of these
studies,21 the most common AEs were similar to those
previously reported. One Class II placebo-controlled
24-week pilot study failed to show a difference in effi-
cacy between topiramate 200 mg and placebo.26
Conclusions. Divalproex sodium and sodium val-
proate are established as effective in migraine preven-
tion (multiple Class I studies). Data are insufficient
to determine the effectiveness of gabapentin (1 Class
III study). Lamotrigine is established as ineffective
for 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 II
studies).
Antidepressants. Fluoxetine. In the original guideline,
1 Class II study27 showed fluoxetine (racemic) was
significantly better than placebo for migraine preven-
tion, but the results were not duplicated in a second
study.28
Since the original guideline, a Class II study has
shown fluoxetine 20 mg/day was more effective than
placebo in reducing total pain index scores (calcu-
lated as [Dl � 1]� [D2 � 2]� [D3 � 3], where D1,
D2, and D3 represent headache hours calculated in a
month, with pain intensity shown by 1, 2, 3) at 6
months.29 After the 6 months, pain index scores for the
fluoxetine group decreased from 135 (baseline) to 41.3
(SD� 63.8; p� 0.001). The placebo group pain index
was 98 at baseline and 61.1 at 6 months (SD � 57.7;
p � 0.07); however, differences were noted between
treatment groups for baseline measures.
1340 Neurology 78 April 24, 2012
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Venlafax
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