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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, S. Holland, F. Freitag, et al.
Neurology 2012;78;1337
DOI 10.1212/WNL.0b013e3182535d20
This information is current as of April 26, 2012
The online version of this article, along with updated information and services, is
located on the World Wide Web at:
Neurology ® is the official journal of the American Academy of Neurology. Published continuously
since 1951, it is now a weekly with 48 issues per year. Copyright © 2012 by AAN Enterprises, Inc. All
rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
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,
S. Holland, PhD
F. Freitag, DO
D.W. Dodick, MD
C. Argoff, MD
E. Ashman, MD
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 structured review process to classify the evidence relative to the efficacy of various medications available in the United States for migraine prevention.
Results and Recommendations: The author panel reviewed 284 abstracts, which ultimately
Correspondence & reprint
requests to American Academy of
[email protected]
yielded 29 Class I or Class II articles that are reviewed herein. Divalproex sodium, sodium valproate, 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
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.
See page 1346
Supplemental data at
Supplemental Data
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 guidelines 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 answer the following clinical question: For patients
with migraine, which pharmacologic therapies are
proven effective for prevention, as measured by
reduced migraine attack frequency, reduced number 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 recommendation 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 complementary alternative treatments has been approved
for publication as a companion to this guideline.5
The AAN and the American Headache Society participated 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 identified new studies (published in English). The search
strategy used the MeSH term “headache” (exploded)
and a published search strategy for identifying randomized controlled trials (RCTs) published between
June 1999 and May 2007. Additional MEDLINE
searches revealed studies published through May
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威 Web site at
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 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.
Table 1
Classification of migraine preventive therapies (available in the United States)
Level A: Medications
with established
efficacy (>2 Class I
Level B: Medications
are probably
effective (1 Class I
or 2 Class II studies)
Level C: Medications
are possibly
effective (1 Class II
Level U: Inadequate
or conflicting data
to support or refute
medication use
Other: Medications that
are established as
possibly or probably
Antiepileptic drugs
ACE inhibitors
Carbonic anhydrase
Established as not
Antiepileptic drugs
Divalproex sodium
Sodium valproate
Triptans (MRM )
Triptans (MRMb)
Angiotensin receptor
Antiepileptic drugs
Possibly not effective
Probably not effective
Antiepileptic drugs
Ca⫹⫹ blockers
Direct vascular
smooth muscle
Abbreviations: ACE ⫽ angiotensin-converting-enzyme; MRM ⫽ menstrually related migraine; SSNRI ⫽ selective serotonin–
norepinephrine reuptake inhibitor; SSRI ⫽ selective serotonin reuptake inhibitor; TCA ⫽ tricyclic antidepressant.
Classification based on original guideline and new evidence not found for this report.
For short-term prophylaxis of MRM.
2009, which were reviewed and included as supplemental 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 evidence scheme (appendix e-3 on the Neurology® Web
site at Differences in ratings were
resolved by author panel discussion.
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
Neurology 78
April 24, 2012
• Assessed the efficacy of therapeutic agents for
headache other than episodic migraine in adults
• Assessed acute migraine treatment, migraine
aura treatment/prevention, or nonpharmacologic treatments (e.g., behavioral approaches)
• Used quality of life measures, disability assessment, 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 include study completion rates. Studies with completion rates below 80% were downgraded; several
studies in the original guideline have thus been
We found no new Class I or II studies published
for acebutolol, atenolol, bisoprolol, carbamazepine,
clonazepam, clonidine, clomipramine, fluvoxamine,
guanfacine, nabumetone, nadolol, nicardipine, nifedipine, 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; table 1 includes anticoagulants).
Angiotensin receptor blockers and angiotensinconverting-enzyme inhibitors. In the 2000 guide-
line, there were no studies testing the efficacy of
angiotensin receptor blockers or angiotensinconverting-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 candesartan (45.6% reduction from baseline; p ⫽ 0.001).6
Selected secondary endpoints also favored candesartan: headache hours (139 vs 95; p ⬍ 0.001), migraine days (12.6 vs 9.0; p ⬍ 0.001), migraine hours
(92.2 vs 59.4; p ⬍ 0.001), and headache severity index (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 placebocontrolled 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
Antiepileptic drugs. Divalproex. The original guideline
found strong, consistent support (5 studies) for the efficacy of divalproex sodium and its corresponding compound, sodium valproate, for migraine prevention.
Since the 2000 publication, 1 double-blind, randomized, 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 sodium 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 detected between groups in the number of
treatment-emergent AEs.
Clinical context. In most headache trials, patients
taking divalproex sodium or sodium valproate reported no more AEs than those on placebo. However, 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 teratogenicity risks.11
Gabapentin. Since the 2000 publication, a Class III
study12 reported that a stable gabapentin dose (4week titration phase to 2,400 mg/day; 8-week maintenance 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 single 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 lamotrigine was not more effective than placebo (for
both primary endpoints) and was less effective than
topiramate in reducing migraine frequency and intensity.14 The primary outcome measure (responder
rate: ⱖ50% 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 efficacy 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 topiramate 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
placebo and lamotrigine for primary efficacy measures.14 In the topiramate groups, 15% of patients
experienced AEs, most commonly paresthesias,
sleepiness, and gastrointestinal intolerance. The placebo 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 (episodes/month) from baseline (6.07 ⫾ 1.89 to 1.83 ⫾
1.39; p ⬍ 0.001) at 8 weeks, decreased headache intensity 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 Subjects given topiramate reported paresthesias (23%),
weight loss (16%), and somnolence (13%). In patients 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 headache duration decreased from 15.10 ⫾ 6.84 hours to
7.27 ⫾ 6.46 hours ( p ⬍ 0.001). Although monthly
headache frequency, intensity, and duration decreased in both groups, the topiramate group reported significantly greater mean reduction
(topiramate frequency decrease 4.23 ⫾ 1.2 vs propranolol 3.63 ⫾ 0.96 [ p ⫽ 0.036; CI 0.39 –1.16];
topiramate intensity decrease 3.43 ⫾ 1.38 vs propranolol 2.3 ⫾ 1.2 [ p ⫽ 0.001; CI 0.46 –1.8]; topiramate 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 between therapies) comparing topiramate 50 mg/day
with sodium valproate 400 mg/day, both groups
showed improvement from baseline in headache frequency, intensity, and duration.17 Average monthly
migraine frequency decreased by 1.8 times with sodium 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 sodium 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
Neurology 78
April 24, 2012
overall analysis of repeated-measures analysis of variance demonstrated no differences in monthly headache 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) reported no difference in efficacy for primary endpoints; however, amitriptyline was associated with a
significant AE increase, and the amitriptylinetopiramate 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 efficacy between topiramate 200 mg and placebo.26
Conclusions. Divalproex sodium and sodium valproate are established as effective in migraine prevention (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). Oxcarbazepine is possibly ineffective for migraine prevention
(1 Class II study). Topiramate is established as effective for migraine prevention (4 Class I studies, multiple Class II studies; 1 negative Class II study).
Topiramate is probably as effective for migraine prevention as propranolol (1 Class I study), sodium valproate (1 Class I study), and amitriptyline (2 Class II
Antidepressants. Fluoxetine. In the original guideline,
1 Class II study27 showed fluoxetine (racemic) was
significantly better than placebo for migraine prevention, but the results were not duplicated in a second
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 (calculated 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.
Venlafaxine. In a Class I study, venlafaxine XR 150
mg significantly reduced the number of headache
days (median reduction in days: venlafaxine 150 mg
⫺4 days; venlafaxine 75 mg ⫺2 days; placebo ⫺1
day; Kruskal-Wallis ⫽ 10.306, df ⫽ 2; p ⬍ 0.006).30
All 3 groups showed decreased headache severity and
duration from baseline; no differences were observed
between treatment groups for these endpoints. The
most common AEs were nausea (41%), vomiting
(27%), and drowsiness (27%). Fourteen percent of patients receiving venlafaxine withdrew because of AEs.
A Class II trial assessed the efficacy of venlafaxine
vs amitriptyline; both were effective in reducing attack frequency (venlafaxine: baseline ⫽ 4.15 [SD ⫾
2.24] vs 12 weeks ⫽ 1.77 [SD ⫾ 1.39; p ⬍ 0.001];
amitriptyline: baseline ⫽ 3.27 [SD ⫾ 1.61] vs 12
weeks 1.54 [SD ⫾ 1.54; p ⬍ 0.001]).31 Patients taking venlafaxine experienced nausea/vomiting (23%)
and tachycardia (15%); 1 patient withdrew because
of AEs. Patients taking amitriptyline reported hypersomnolence (80%), dry mouth (69%), and concentration difficulties (54%).
Tricyclic antidepressants. The original guideline concluded amitriptyline was established as effective for migraine prevention; that evidence has since been
downgraded to Class II (all 3 studies had ⬎20% dropout rates). Comparative studies of amitriptyline with
topiramate21,22 and venlafaxine31 (reviewed above) report similar efficacy at the doses tested.
Conclusions. There is conflicting Class II evidence
for use of fluoxetine. Venlafaxine is probably effective for migraine prevention (1 Class I study) and is
possibly as effective as amitriptyline in migraine prevention (1 Class II study). Amitriptyline is probably
effective for migraine prevention (multiple Class II
studies); it is probably as effective as topiramate (2
Class II studies) and possibly as effective as venlafaxine (1 Class II study) for migraine prevention.
␤-Blockers. Metoprolol. The original guideline con-
cluded metoprolol was probably effective in migraine
prevention. We reclassified these studies as Class I
using the revised AAN criteria.
One new Class II study reported metoprolol (200
mg/day) was more effective than aspirin (300 mg/
day) in achieving 50% migraine frequency reduction
(responder rate metoprolol ⫽ 45.2%; aspirin ⫽
29.6%; mean difference 15.65; CI 4.43–26.88).32
Attack frequencies (attacks/month) at placebo run-in
and week 20 are 3.36 to 2.37, respectively, for aspirin
and 3.55 to 1.82, respectively, for metoprolol. No
significant AEs were reported.
A small Class II study reported metoprolol (47.5–
142.5 mg/day) had similar efficacy to nebivolol 5
mg/day for migraine prevention (assessed by a decrease in mean migraine attacks).33
Propranolol. The original guideline concluded
propranolol was established as effective for migraine
In a Class II study, propranolol (80 mg/day) was
more effective than placebo and as effective as cyproheptadine (4 mg/day) in reducing migraine frequency, duration, and attack severity.34 The
difference in attack frequency reduction was significant between treatments: propranolol ⫺2.85 ⫾ 0.2
(SEM) vs cyproheptadine ⫺3.09 ⫾ 0.31 vs combination 3.12 ⫾ 0.1 vs placebo ⫺1.77 ⫾ 0.44 (all p ⬍
0.05 vs placebo). For attack frequency reduction,
combination therapy was more effective than monotherapy ( p ⬍ 0.05). AEs were drowsiness, sleep disturbance, weight gain, fatigue, and dry mouth;
percentages of patients affected were not reported.
Conclusions. Metoprolol is established as effective
for migraine prevention (2 Class I studies) and is possibly as effective as nebivolol or aspirin for migraine
prevention (1 Class II study each). Propranolol is established as effective for migraine prevention (multiple
Class I studies) and is possibly as effective as cyproheptadine for migraine prevention (1 Class II study).
Calcium-channel blockers. The original guideline
concluded that verapamil and nimodipine were probably effective for migraine prevention. The original
studies on verapamil and nimodipine were found to
have conflicting Class III evidence on the basis of current classification criteria and were downgraded accordingly, yielding Level U recommendations.
Conclusions. Data from older studies regarding verapamil and nimodipine are insufficient when current
AAN classification criteria are applied.
Direct vascular smooth muscle relaxants. The original
guideline concluded cyclandelate was probably effective for migraine prevention.
Cyclandelate. Two new Class II studies reported
conflicting results. The first study showed cyclandelate to be no more effective than placebo in reducing
migraine days, attacks, or duration.35 The second
study (smaller, underpowered; n ⫽ 25) found cyclandelate significantly reduced the number of migraine days and duration (assessed using a contingent
negative variation measure).36
Conclusions. The efficacy of cyclandelate is unknown
(conflicting Class II studies).
Triptans. Since the original guideline, new Class I
studies have assessed the efficacy of frovatriptan,37,38
naratriptan,39 and zolmitriptan40 for short-term prevention of menstrually associated migraine (MAM).
Frovatriptan. Frovatriptan 2.5 mg BID/qd was
more effective than placebo in reducing migraine freNeurology 78
April 24, 2012
quency.37 The mean number of headache-free perimenstrual periods (PMPs) per patient (primary
endpoint) was higher in the 2 frovatriptan groups
(2.5 mg qd ⫽ 0.69 [SD ⫾ 0.92; CI 1.14 –2.73; p ⫽
0.0091] vs 2.5 mg BID ⫽ 0.92 [SD 1.03; CI 1.84 –
4.28; p ⬍ 0.0001] vs placebo ⫽ 0.42 [SD ⫾ 0.78]),
representing 64% (2.5 mg/day) and 119% (5 mg/
day) increases in the mean number of headache-free
PMPs per patient over placebo. A second Class I
study38 also reports the MAM headache incidence
during the 6-day PMP was 67% for placebo, 52% for
frovatriptan 2.5 mg QD ( p ⬍ 0.0001 vs placebo),
and 41% for frovatriptan 2.5 mg BID ( p ⬍ 0.0001
vs placebo; p ⬍ 0.0001 vs QD regimen). The AE
incidence and type for both regimens were similar to
those for placebo. The overall AE incidence for frovatriptan was 4.1% (2.5 mg BID) and 2.7% (2.5 mg
qd) higher than during placebo treatment.
Naratriptan. In a Class I study, 1 mg BID (given
for 5 days, starting 2 days before menses onset) reduced the number of perimenstrual migraine attacks
and migraine days.39 Patients treated with
naratriptan 1 mg experienced more headache-free
PMPs than those on placebo (50% vs 25%, p ⴝ
0.003). Naratriptan 1 mg reduced the number of
MAMs (2.0 vs 4.0, p ⬍ 0.05) and MAM days (4.2 vs
7.0, p ⬍ 0.01) vs placebo. The AE incidence and
severity were similar to those of placebo; ⬍10% of
patients experienced dizziness, chest pain, or malaise.
Zolmitriptan. One Class I study reported the efficacy of zolmitriptan 2.5 BID/TID vs placebo. Both
zolmitriptan regimens demonstrated superior efficacy vs placebo: the proportion of patients with a
ⱖ50% MAM attack frequency reduction (zolmitriptan 2.5 mg TID [58.6%], p ⫽ 0.0007 vs placebo;
zolmitriptan 2.5 mg BID [54.7%], p ⫽ 0.002 vs placebo; placebo 37.8%).40 AEs were considered possibly treatment-related in 28 patients (33.3%) in the
zolmitriptan 2.5 mg TID group, 29 (36.3%) in the
zolmitriptan 2.5 mg BID group, and 18 (22.0%) in
the placebo group. The most common AEs were asthenia, headache, dizziness, and nausea.
Conclusions. Frovatriptan is established as effective for
the short-term prevention of MAMs (2 Class I studies).
Zolmitriptan and naratriptan are probably effective for
the short-term prevention of MAMs (1 Class I study
each). The utility of these agents in receiving a separate
indication for pure menstrual migraine is currently being deliberated by US regulatory authorities.
Other agents. Since the original guideline, additional
studies have been identified that assess the efficacy of
a carbonic anhydrase inhibitor and a neurokinin inhibitor for migraine prevention.
Carbonic anhydrase inhibitor. In a single Class II
study, acetazolamide 250 mg BID was no more
Neurology 78
April 24, 2012
effective than placebo in reducing migraine frequency, duration, and severity.e1 This trial (n ⫽
53) was stopped prematurely because of a high
number of withdrawals (34%), primarily due to
acetazolamide-associated AEs, including paresthesias and asthenia.
Conclusions. The efficacy of acetazolamide is unknown at this time (1 Class II study terminated early).
The following
medications are established as effective and should be
offered for migraine prevention:
• Antiepileptic drugs (AEDs): divalproex sodium, sodium valproate, topiramate
• ␤-Blockers: metoprolol, propranolol, timolol
• Triptans: frovatriptan for short-term MAMs
Level B. The following medications are probably
effective and should be considered for migraine
• Antidepressants: amitriptyline, venlafaxine
• ␤-Blockers: atenolol, nadolol
• Triptans: naratriptan, zolmitriptan for shortterm MAMs prevention
Level C. The following medications are possibly effec-
tive and may be considered for migraine prevention:
ACE inhibitors: lisinopril
Angiotensin receptor blockers: candesartan
␣-Agonists: clonidine, guanfacine
AEDs: carbamazepine
␤-Blockers: nebivolol, pindolol
Level U. Evidence is conflicting or inadequate to sup-
port or refute the use of the following medications
for migraine prevention:
• AEDs: gabapentin
• Antidepressants
• Selective serotonin reuptake inhibitor/selective serotonin-norepinephrine reuptake inhibitors: fluoxetine, fluvoxamine
• Tricyclics: protriptyline
• Antithrombotics: acenocoumarol, Coumadin,
• ␤-Blockers: bisoprolol
• Calcium-channel blockers: nicardipine, nifedipine, nimodipine, verapamil
• Acetazolamide
• Cyclandelate
Level A negative. The following medication is estab-
lished as ineffective and should not be offered for
migraine prevention:
• Lamotrigine
Level B negative. The following medication is probably ineffective and should not be considered for migraine prevention:
• Clomipramine
Level C negative. The following medications are possibly ineffective and may not be considered for migraine prevention:
Evidence to support pharmacologic treatment strategies for migraine prevention
indicates which treatments might be effective but is
insufficient to establish how to choose an optimal
therapy. Consequently, although Level A recommendations can be made for pharmacologic migraine prevention, similar evidence is unavailable to help the
practitioner choose one therapy over another. Treatment regimens, therefore, need to be designed case
by case, which may include complex or even nontraditional approaches. Moreover, decision-making
must remain with the physician and the patient to
determine the optimal therapy, accounting for efficacy, AEs, coexisting/comorbid conditions, and personal considerations. Often trial and error is needed.
Evidence is also unavailable for making broad-range
comparisons among multiple agents within a single
class; such evidence would provide a more comprehensive understanding of relative efficacy and tolerability
profiles across a broader range of therapeutic agents.
Studies are needed that specifically evaluate when preventive therapy is warranted and how medications
should be titrated. Table e-1 lists some specific
consensus-based clinical circumstances wherein considering preventive therapy would be reasonable. A shortcoming of migraine prevention clinical studies is the
relatively brief treatment duration (often only 12–16
weeks). Long-term assessment of the efficacy and safety
of migraine preventive treatments is needed. Additionally, overall cost is a consideration when prescribing
medications; cost may influence compliance, especially
It seems reasonable that a clinician be mindful of
comorbid and coexistent conditions in patients with
migraine, to maximize potential treatment efficacy
and minimize AE risk. Table e-2 identifies which
therapies to consider or avoid when common migraine coexisting conditions are present. Because migraine is frequent in women of childbearing age, the
potential for adverse fetal effects related to migraine
prevention strategies is particularly concerning.
Evidence from the 2 Class I frovatriptan studies
meets the AAN threshold for a Level A recommendation for short-term use to prevent menstrual migraine (reduction in MAM headache incidence by
26% on 2.5 mg BID). However, the Food and Drug
Administration questions whether the benefit demonstrated is clinically meaningful and has not approved frovatriptan for this indication.
RECOMMENDATIONS FOR FUTURE RESEARCH Although many preventive therapies reviewed herein
are rated as Level C or U on the basis of the quality of
evidence available, for some treatments extensive
clinical experience supports a possible role in migraine prevention. Many of the older approaches to
treating episodic migraine lack the financial justification for high-quality clinical study because they are
not currently patentable drugs or otherwise do not
promise a financial return for the cost of a major
study. Until such treatments can be accurately studied, practitioners are cautioned not to discount these
agents because Class I prospective clinical studies are
lacking. A case-by-case evaluation of these agents as
treatment options is prudent. Future directions
should include validating these initial clinical observations in scientifically sound RCTs.
Dr. Silberstein: manuscript preparation, drafting/revising the manuscript,
study concept or design, analysis or interpretation of data, acquisition of
data, study supervision. Dr. Holland: drafting/revising the manuscript,
study concept or design, analysis or interpretation of data. Dr. Freitag:
drafting/revising the manuscript, analysis or interpretation of data, acquisition of data. Dr. Dodick: drafting/revising the manuscript, study concept or design, analysis or interpretation of data. Dr. Argoff: drafting/
revising the manuscript, study concept or design, analysis or
interpretation of data. Dr. Ashman: drafting/revising the manuscript,
analysis or interpretation of data.
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 speakers’ bureau
of and receives honoraria from Endo Pharmaceuticals, GlaxoSmithKline,
and Merck. He serves as a consultant for and receives honoraria from
Amgen and Novartis. His employer receives research support from AGA,
Allergan, Boston Scientific, Capnia, Coherex, Endo Pharmaceuticals,
GlaxoSmithKline, Lilly, MAP, Medtronic, Merck, NINDS, NuPathe, St.
Jude Medical, and Valeant Pharmaceuticals. Dr. Holland (formerly Dr.
Pearlman) receives consulting income from Map Pharmaceuticals and the
American Headache Society and research support from Albert Einstein
College of Medicine. Dr. Freitag has served on the scientific advisory
boards of Zogenix Pharmaceuticals, Allergan Pharmaceuticals, Nautilus,
MAP Pharmaceuticals, and Nupathe; has received travel expenses and or
honoraria from GlaxoSmithKline, Zogenix, Merck, Nautilus, Allergan,
Diamond Headache Clinic Research and Educational Foundation (not
for profit), and the American Headache Society (travel). Dr. Freitag is a
member of the Board of Directors of the National Headache Foundation.
Dr. Dodick, within the past 3 years, serves on advisory boards and has
consulted for Allergan, Alder, Pfizer, Merck, Coherex, Ferring, Neurocore, Neuralieve, Neuraxon, NuPathe Inc., MAP, SmithKlineBeecham,
Boston Scientific, Medtronic, Inc., Nautilus, Eli Lilly & Company, NoNeurology 78
April 24, 2012
vartis, Colucid, GlaxoSmithKline, Autonomic Technologies, MAP Pharmaceuticals, 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, speaking, or editorial activities from CogniMed, Scientiae, Intramed, SAGE
Publishing, Lippincott Williams & Wilkins, Oxford University Press,
Cambridge University Press, Miller Medical, Annenberg for Health Sciences; 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 ’s Headache, 8th edition (Oxford University Press, 2009) and Handbook of Headache (Cambridge University Press, 2010). Within the past 3 years, Dr. Dodick has
received research grant support from Advanced Neurostimulation Systems, Boston Scientific, St Jude Medical, Inc., Medtronic, NINDS/NIH,
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 and/or speaking and/or has served on a speakers’ 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
stock/stock options from Pfizer. Dr. Ashman is the Level of Evidence
editor for Neurology and serves on the AAN Guideline Development Subcommittee. He reports no other disclosures. Full disclosures were provided at the time of Board approval. Go to for full
This statement is provided as an educational service of the American
Academy of Neurology and the American Headache Society. It is based
on as assessment of current scientific and clinical information. It is not
intended to include all possible proper methods of care for a particular
neurologic problem or all legitimate criteria for choosing to use a specific
procedure. Neither is it intended to exclude any reasonable alternative
methodologies. The AAN and the AHS recognize that specific patient
care decisions are the prerogative of the patient and the physician
caring for the patient, based on all of the circumstances involved. The
clinical context section is made available in order to place the
evidence-based guideline(s) into perspective with current practice habits and challenges. No formal practice recommendations should be
The American Academy of Neurology and the American Headache Society 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 authors 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 committees, a network of neurologists, Neurology peer reviewers, and representatives from related fields. The AAN Guideline Author Conflict of
Interest Policy can be viewed at
Received June 27, 2011. Accepted in final form January 25, 2012.
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Endorsed by the American Osteopathic Association on March 22, 2012.
Neurology 78
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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, S. Holland, F. Freitag, et al.
Neurology 2012;78;1337
DOI 10.1212/WNL.0b013e3182535d20
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