RECONSTRUCTIVE

Botulinum Toxin versus Placebo: A Meta-

Analysis of Prophylactic Treatment for Migraine
Eva Bruloy, M.D.
Raphael Sinna, Ph.D., M.D.,
M.B.A.
Jean-Louis Grolleau, M.D.
Apolline Bout-Roumazeilles,
M.D.
Emilie Berard, M.D.
Benoit Chaput, M.D., Ph.D.
Amiens and Toulouse, France
Background: The purpose of this study was to assess the efficacy of botulinum
toxin in reducing the frequency of migraine headaches.
Methods: The MEDLINE, Embase, and Cochrane Library databases were
searched to identify randomized, double-blind, placebo-controlled trials that
compared patients receiving botulinum toxin versus placebo injections in the
head and neck muscles, for the preventive treatment of migraine. The primary
outcome was change in the number of headache episodes per month from
baseline to 3 months.
Results: There were 17 studies including a total of 3646 patients. Overall
analysis reported a tendency in favor of botulinum toxin over placebo at
3 months, with a mean difference in the change of migraine frequency of
−0.23 (95 percent CI, −0.47 to 0.02; p = 0.08). The reduction in frequency
of chronic migraines was significant, with a mean differential change of
−1.56 (95 percent CI, −3.05 to −0.07; p = 0.04). Analysis of chronic migraine
frequency was also significant after 2 months. The findings also highlighted
an improvement of the patient’s quality of life at 3 months in the botuli-
num toxin group (p < 0.00001). Further adverse events were traced in the
botulinum toxin type A group with a statistically significant risk ratio of 1.32
(p = 0.002).
Conclusions: This meta-analysis reveals that botulinum toxin type A injections
are superior to placebo for chronic migraines after 3 months of therapy. For
the first time, a real benefit in patient quality of life is demonstrated with only
few and mild adverse events.   (Plast. Reconstr. Surg. 143: 239, 2019.)
CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II.

M
igraine is a common medical complaint
that causes significant disability, reducing
the patient’s quality of life and capacity
for work. In North American and European popu-
lations, the frequency of migraines varies between
14.8 and 18.5 percent1,2 and represents a serious
public health problem, with an estimated annual
cost of approximately $17 billion.3
From the Department of Plastic Reconstructive and Aesthetic
Surgery, University Hospital of Picardie, Amiens Picardie
University Hospital; the Department of Plastic, Reconstruc-
tive and Aesthetic Surgery, CHRU Rangueil; and the De-
partment of Epidemiology, Health Economics and Public
Health, UMR1027 INSERM-Université de Toulouse III,
Centre Hospitalier Universitaire de Toulouse.
Received for publication December 6, 2017; accepted July
20, 2018.
This trial is registered under that name “Botulinum Toxin
for Treatment of Migraine: A Meta-Analysis,” PROSPERO
identification number CRD42016048772 (http://www.
crd.york.ac.uk/PROSPERO/display_record.asp?ID=C
RD42016048772).
Copyright © 2018 by the American Society of Plastic Surgeons
DOI: 10.1097/PRS.0000000000005111
Botulinum toxin type A was discovered in
1998 by Binder to treat headaches and other facial
pains after cosmetic injections, and was used for
hyperkinetic facial lines.4 Its effect is explained by
the local activity of botulinum neurotoxin on the
neuromuscular junction and peripheral signals.
The resulting protein complex produced by Clos-
tridium botulinum blocks release of acetylcholine
within the neuromuscular junction, and decreases
peripheral sensory signals by reducing muscle
activity and release of neuromediators such as glu-
tamate, substance P, and calcitonin gene-related
peptide.5,6 This inhibition of inflammatory media-
tors partially explains its ability to reduce pain.
The U.S. Food and Drug Administration
approved botulinum toxin type A for the prophy-
lactic treatment of chronic migraine in October
of 2010. This was primarily based on two phase-3,
Disclosure: None of the authors has a financial in-
terest in any of the products, devices, or drugs men-
tioned in this article.

www.PRSJournal.com 239
Copyright © 2018 American Society of Plastic Surgeons. Unauthorized reproduction of this article is prohibited.
 Plastic and Reconstructive Surgery • January 2019
placebo-controlled, multicenter studies [PRE-
EMPT 1 and 2 (Phase-3 REsearch Evaluating
Migraine Prophylaxis Therapy)].7,8 The literature
provides contradictory results on the efficacy of
this treatment. Thus, the objective of this meta-
analysis, which includes double-blind randomized
clinical trials, was to assess the effectiveness of
botulinum toxin type A injections on changes in
the frequency of migraines, its impact on the qual-
ity of life, but also its safety versus placebo when
injected into pericranial muscles as a preventive
treatment for migraines in adults.
MATERIALS AND METHODS
Using Cochrane Handbook instructions, we
followed the Preferred Reporting Items for Sys-
tematic Reviews and Meta-Analysis principles.9
Inclusion Criteria
Studies included in the meta-analysis were
randomized, double-blinded, and placebo-con-
trolled trials that compared patients receiving
botulinum toxin versus placebo injections into
head and neck muscles as preventive treatment
for migraine, as defined by the criteria of the
International Headache Society.10 Acute migraine
therapies were authorized to end the crisis stage
(i.e., nonsteroidal antiinflammatory drugs, trip-
tans, acetaminophen, and dihydroergotamine).
Search Strategy
Two researchers (E.B. and B.C.), using MED-
LINE, Embase, and the Cochrane Library from
inception to August of 2016, reviewed the elec-
tronic data. Keywords used were “migraine”
AND “botulinum toxin type A” OR “Onabotuli-
num toxin” OR “BOTOX.” We also conducted
a manual search using citations from included
trials and reviewed similar articles. We included
foreign-language articles, and there was no
restriction of countries in which the trial was per-
formed. We also searched for ongoing trials using
ClinicalTrials.gov11 and the Centre Watch Clinical
Trials listing service.12 The online search was sup-
plemented with the bibliographies of identified
articles to retrieve any other relevant published
material.
Data Extraction
The two researchers included articles in the
meta-analysis after reading titles, abstracts, and
full texts. Descriptive data including study fea-
tures (i.e., methods, participants, interventions,
240
Copyright © 2018 American Society of Plastic Surgeons. Unauthorized reproduction of this article is prohibited.
and outcomes) and quantitative data on primary
or secondary outcomes (i.e., frequency, global
assessment scales, and adverse events) were then
extracted independently. If original data were
missing, we contacted the authors by e-mail
(twice) and by mailed letter. Reviewers’ discrep-
ancies were resolved after discussion and reach-
ing consensus with the methodologist (E.B.).
We excluded open-label studies, retrospective
studies, and nonrandomized studies. We also
excluded non–placebo-controlled trials13,14 and
studies without a well-defined migraine popula-
tion or those including other headache disor-
ders, such as tension headaches, chronic daily
headache, dystonia, and all secondary headaches.
We also selected studies with a minimum 3-month
follow-up without considering analgesic medica-
tions and other symptomatic treatments. Studies
included were evaluated using the Review Man-
ager program to assess level of evidence and risk
of bias.15
Statistical Analyses
We considered episodic and chronic migraine
according to the International Headache Society
criteria10: chronic migraine was defined by at least
15 headache attacks per month for more than 3
months, with typical features of migraine on at
least 8 days per month. Episodic migraine refers
to syndromes in patients who experience frequent
migraine attacks but do not meet all the criteria
for chronic migraines.
Our primary outcome was the change in the
number of headache episodes per month from
baseline to month 3. This change was also ana-
lyzed from baseline to month 2 as a secondary
outcome, together with quality of life and adverse
events at month 3. Study results were tabulated
according to the total number of subjects receiv-
ing botulinum toxin type A or placebo, together
with the mean and standard deviation for changes
in the numbers of headache episodes per month
from baseline to month 3, and from baseline to
month 2. Missing standard deviations for changes
were assessed according to the formula for vari-
ance of change:
V ( X-Y ) = V ( X ) + V ( Y ) -2cov ( X, Y ) ,
where cov(X, Y) = r.SD(X).SD(Y), and r was fixed
at 0.5. To assess heterogeneity across studies, we
used forest plots, Cochran’s heterogeneity statis-
tics, and Higgins I2 coefficients.16 A value of p < 0.1
or I2 > 50 percent was considered suggestive of sta-
tistical heterogeneity, prompting random-effect
 Volume 143, Number 1 • Botulinum Toxin Type A versus Placebo
modeling. Three studies that reported changes
in numbers of headache days per month were
also included in the meta-analysis to decrease
heterogeneity.8,17,18
We estimated the mean differences between
botulinum toxin type A and placebo groups using
an inverse variance approach with 95 percent
confidence intervals. We also estimated the stan-
dardized mean differences between botulinum
toxin type A and placebo groups using scales that
reflected quality of life at month 3 (Headache
Disability Inventory,19 Beck Depression Inventory–
II,20 Migraine Disability Assessment,21,22 and Head-
ache Impact Test),23 where higher scores indicate
a lower quality of life. Three studies that used a
change in quality of life from baseline to month
3 were included in the meta-analysis to decrease
heterogeneity.7,8,24 We also calculated the risk ratio
of adverse events with botulinum toxin type A ver-
sus placebo, and produced funnel plots to assess
small-study effects.24 Review Manager 5.3 software
was used for all analyses.15
RESULTS
Literature Search
Our literature screening process identified
18 articles: the process for selection of stud-
ies is shown in Figure 1. Our initial search had
produced 582 articles on migraines and botuli-
num toxin: of these, 416 were excluded after we
read the title. Of the remaining 43 articles, we
excluded four non–placebo-controlled trials,
three meta-analyses, and seven subgroup analy-
ses after reading of abstracts. After consulting
the full articles, we eliminated 11 more studies
that had no exclusively migrainous population.
Ultimately, we selected 18 studies for inclusion
in our meta-analysis but were unable to use
the results of one study because of the lack of
data.25
Study Characteristics and Patient Demographics
The 17 studies included 3646 patients, of
which 3143 were female (86.21 percent), 2095
had episodic migraines (57 percent), and 1551
had chronic migraines (43 percent). Most
patients used a fixed-site protocol (16 of 17). The
median frequency of migraine crises per month
was 6.5 (range, 4.37 to 25.1). The average age of
included patients was 42.8 years (range, 18 to 65
years) in studies where they were clearly defined
in the inclusion criteria (14 of 17). Prophylactic
treatments were allowed in 10 studies but had to
Copyright © 2018 American Society of Plastic Surgeons. Unauthorized reproduction of this article is prohibited.
have stable doses and regimens given for 1 to 3
months before the first injections and through-
out the study. All of the selected studies described
symptomatic treatments and the use of analgesic
medications (Table 1).
Efficacy
Our analysis included 17 trials, of which six
evaluated chronic migraine and 11 evaluated epi-
sodic migraine attacks (Fig. 2). Funnel plots did
not show any evidence of small-study bias.
Primary Outcome
Changes in Numbers of Headache Episodes
per Month between Baseline and Month 3
Overall analyses (Fig. 3) found a tendency
for less frequent episodic and chronic migraines
with botulinum toxin type A compared to placebo
at month 3, with a mean difference of change
in migraine frequency (per month) of −0.23
(95 percent CI, −0.47 to 0.02; p = 0.08). More
precise statistical analyses revealed a significant
reduction in the frequency of chronic migraines
with botulinum toxin, with a mean difference in
change in migraine frequency per month of −1.56
(95 percent CI, −3.05 to −0.07; p = 0.04), with no
statistical heterogeneity (I2 = 37 percent; p = 0.16).
Frequency of episodic migraines was not signifi-
cantly reduced, but there was a tendency toward
a reduction, with a mean difference in change
of migraine frequency (per month) of −0.17
(95 percent CI, −0.41 to 0.08; p = 0.18), with sta-
tistical heterogeneity (I2 = 52 percent; p = 0.001),
which prompted random-effect modeling.
Secondary Outcomes
Change in Frequency of Headache Episodes
per Month between Baseline and Month 2
Overall analyses indicated that botulinum toxin
tended to be more effective than placebo at month
2, with a mean difference in rates of migraines (per
month) of −0.21 (95 percent CI, −0.47 to 0.06;
p = 0.13) (Fig. 4). More specifically, month 2 sta-
tistical analyses revealed a significant reduction
in the frequency of chronic migraines with botu-
linum toxin type A, and a mean difference in rates
of migraine (per month) of −1.60 (95 percent CI,
−2.72 to −0.47; p = 0.005), with no statistical hetero-
geneity (I2 = 8 percent; p = 0.005) (Fig. 4).
The mean change of reduction in episodic
migraine rates (per month) at month 2 was not
significant (−0.12; 95 percent CI, −0.39 to 0.14; p
= 0.36), and had statistical heterogeneity (I2 = 57
241
 Plastic and Reconstructive Surgery • January 2019

Fig. 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram, literature search, and selection process.

percent; p = 0.0002), which prompted random- Safety

effect modeling (Fig. 4).
Quality of Life at Month 3
There was significant improvement in patients’
quality of life at month 3 (higher scores indicating
lower quality of life) in the botulinum toxin type
A group, with a standardized mean difference of
−0.43 (95 percent CI, −0.59 to −0.27; p < 0.00001)
(Fig. 5). Statistical heterogeneity was not signifi-
cant (I2 = 41 percent; p = 0.09).
Adverse Events at Month 3
More adverse events were reported in the
botulinum toxin type A group than in the pla-
cebo group at month 3, with a statistically signifi-
cant risk ratio of 1.32 (95 percent CI, 1.11 to 1.57)
(p = 0.002) (Fig. 6). Statistical heterogeneity was
significant (I2 = 66 percent; p < 0.0001), which
prompted random-effect modeling. No severe side
effects were reported; any side effects were mild in
severity, transient, and resolved without sequelae.

242
Copyright © 2018 American Society of Plastic Surgeons. Unauthorized reproduction of this article is prohibited.
 Table 1.  Randomized Controlled Trials on Botulinum Toxin Type A and Migraine That Were Selected for the Meta-Analysis
FS and FTP
Maximum Double-Blind Sample Dropouts
Source Location Inclusion Criteria Dose Whole Study (P/B) (%)
Silberstein, 2000 12 headache centers EM: Subjects were eligible for this study FS: 25/75 90/120 123 (P = 41, B25 = 42, B75 = 40) 1 (1)
across the United if they had experienced an average of
States 2–8 moderate to severe migraines per
month over the previous 3 mo
Barrientos, 2002 1 Chilean center EM FS: 50 90/90 30 (P = 15, B = 15) 0 (0)
Evers, 2004 1 German center EM: average frequency of 2–8 attacks per FS: 16/100 90/90 60 (P = 20, B16 = 20, B100 = 20) 0 (0)
month in the preceding 3 mo
Elkind, 2006 16 North American EM: Eligible patients were to have an FS: 7.5/25/50 120/480 401 (P = 106, B7,5 = 105, 38 (9)
study centers average of 4–8 moderate to severe B25 = 101, B50 = 106)
migraines per month that occurred
with a stable frequency and severity
Aurora, 2007 20 North American EM: 4 moderate to severe migraine FTP: 110/260 270/330 369 PNR: 203 (P = 100, B = 103) 84 (23)
study centers episodes but ≤15 headache days per PR: 166 (P = 82, B = 84)
month (confirmed by a headache
diary)
Cady 2007 1 American center EM: Headache Impact Test (HIT)-6 FS: 139 90/180 59 (P = 19, B = 40) 5 (8%)
score greater than 56 were eligible to
participate
Rejla 2007 37 study centers in EM: 3 moderate to severe untreated or FS: 75/150/225 270/330 495 PNR = 322 (P = 72, B75 = 83, 80 (19)
nine countries treated migraine episodes per month B150 = 82, B225 = 85) PR = 173
(P = 46, B75 = 40, B150 = 43,
B225 = 44)
Saper, 2007 7 North American EM: average of 4–8 moderate to severe FS: Frontal, 10; 90/120 232 (P = 45, Bfrontal = 44, Btemporal = 7 (3)
study centers migraine headaches per month temporal, 6; 45, Bglabellar = 49, BFTG = 49)
glabellar: 9,
FTG, 25
Vo, 2007 1 American center CM: >5 times/mo FS: 205 90/120 32 (P = 17, B = 15) 11 (35)
Freitag, 2008 1 American center CM: 15 headache days during the FS: 100 120/160 36 (P = 18, B = 18) 5 (12)
prospective baseline phase
Volume 143, Number 1 • Botulinum Toxin Type A versus Placebo

Petri, 2009 16 German centers EM: 3–6 attacks per month FS: 80/210 90/120 122 (P = 62, B80 = 29, B210 = 31) 5 (4)
Aurora, 2010 56 North American CM: >15 headache days FS: 155 ± FTP: 40 180/450 679 (P = 338, B = 341) 88 (13)
sites
Diener, 2010 66 global sites CM: 15 days/4 wk FS: 155 ± FTP: 40 180/450 705 (P = 358, B = 347) 60 (9)
Chankrachang, 6 centers in Thailand EM: an average of 2–8 migraine attacks FS: 120/240 90/120 128 (P = 42, B120 = 43, B240 = 43) 9 (7)
2011 per month over the 3 mo before a
screening period
Sandrini, 2011 Italian centers CM: >15 headache days every 4 wk FS: 100 90/210 68 (P = 35, B = 33) 12 (17.7)
in the past 3 mo
Hollanda, 2014 1 Brazilian center CM FS: 96 90/90 38 (P = 18, B = 20) 0 (0)
Hou, 2015 1 Chinese center EM and CM: (35.3% chronic migraine) FS: 25 120/120 60 (P = 19, B = 41) 0 (0)
EM, episodic migraines; CM, chronic migraines; P, placebo group; B, botulinum toxin type A group; FS, fixed site; FTP, follow the pain; FTG, all three areas (frontal, temporal, and glabellar).

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 Plastic and Reconstructive Surgery • January 2019
Fig. 2. Risk of bias summary of the studies included, using the
Review Manager program: judgments for each risk-of-bias item
for each included study.
DISCUSSION
The Lancet Global Burden of Disease Study
201526 has ranked migraine as the seventh high-
est cause of disability worldwide. Since 2005, the
244
Copyright © 2018 American Society of Plastic Surgeons. Unauthorized reproduction of this article is prohibited.
prevalence of migraines has increased by 15.3
percent. Headache disorders, including migraine,
tension type headache, and medication overuse
headache, are third in the worldwide classifica-
tion of disabilities and are an extensive public
health problem.27 Disability caused by chronic
migraines has a significant impact on quality of
life and increases use of health resources.
The significant results of the two PREEMPT
trials7,8 regarding injectable botulinum toxin for
chronic migraines have led to the validation of
botulinum toxin as a prophylactic treatment for
chronic migraine by the U.S. Food and Drug
Administration in October of 2010. The primary
result of our meta-analysis is that botulinum toxin
type A is superior to placebo for chronic migraines
at month 3. Significant results were also apparent
at month 2. The analysis of intermediate results
shows that botulinum toxin type A is rapidly effec-
tive (within 2 months), which has not been high-
lighted previously.28,29 The toxin also tends to be
effective when taken for episodic migraines at
month 3. Previous studies had reported a stronger
effect of botulinum toxin when given for chronic
migraines,30 but our meta-analysis demonstrates
effectiveness against episodic migraines in accor-
dance with subgroup analysis results in a retro-
spective study by Janis et al.31
Concerning quality of life, our study shows
significant improvement in patient quality of life
at month 3 in the botulinum toxin type A group.
To date, this improvement has not been reported
in other meta-analyses.28,29 In accordance with
other studies, this amelioration is linked directly
to a reduction in depressive symptoms.32–34 It can
be explained by the reduced impact of headaches
and migraine-related disability, thus reducing
symptoms of depression and anxiety.
Our meta-analysis identified a greater inci-
dence of adverse events in botulinum toxin type
A groups than in placebo groups at month 3.
Treatment-related adverse events included muscle
weakness, diplopia, blepharoptosis, myalgia, dizzi-
ness, sedation, asthenia, dyskinesia, hypesthesia,
sinus infection, neck pain, dysphagia, and skin
tightness. No severe side effects were reported.
Botulinum toxin was shown to have a beneficial
safety and tolerability profile to treat migraines in
analyses by Naumann and Jankovic35 and Silber-
stein.,36 In contrast, prophylactic oral medications
have potentially troublesome systemic side effects
(e.g., weight gain, drowsiness, fatigue, dizziness,
and decreased libido); some are even dangerous
(e.g., allergy, anaphylactic shock).37 Moreover,
 Volume 143, Number 1 • Botulinum Toxin Type A versus Placebo

Fig. 3. Forest plot of changes in headache episodes per month between baseline and month 3. *Studies using changes in numbers
of headache days per month were also included in the meta-analysis to decrease heterogeneity. IV, inverse variance; NR, nonre-
sponders; R, responders.

incremental cost-effectiveness, too, favors the use
of botulinum toxin.38,39
Our results show a statistical tendency
(p = 0.18) for injections of botulinum toxin to
reduce the frequency of episodic migraines. These
findings were contradicted by Shuhendler et al.,29
who did not find a statistical difference between
botulinum toxin type A injection and placebo.
Their negative results led to acknowledgment
of the inefficacy of botulinum toxin for episodic
migraines by the American Academy of Neurol-
ogy in 2008.40 This lack of significance, particu-
larly for episodic migraines, could be explained
by a high response rate to placebo, which is often
encountered in trials that explore pain disorders
such as migraine.41,42
A recent study by et al. reported that placebo
response ranged from 14 to 50 percent in clinical tri-
als that analyzed preventive migraine treatments.43
The placebo effect is also closely dependent on the
desire to take part in a botulinum toxin type A trial
versus placebo. In this setting, the cosmetic bene-
fits of injecting botulinum toxin and its associated
low-risk side effects compare favorably with other
prophylactic migraine medications, thus increas-
ing patients’ willingness to enter such studies and

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 Plastic and Reconstructive Surgery • January 2019

Fig. 4. Forest plot of changes in numbers of headache episodes per month between baseline and month 2. *Studies that used
changes in numbers of headache days per month were included in the meta-analysis to decrease heterogeneity. IV, inverse vari-
ance; NR, nonresponders; R, responders

inflating the placebo effect. Indeed, open-label
studies emphasize a greater favorable association
between botulinum toxin type A and migraines.
The statistical tendency of botulinum toxin to
reduce the frequency of episodic migraines needs
to be assessed further in double-blind, placebo-
controlled, randomized trials.
Nonetheless, the cosmetic use of botulinum
toxin type A may have reduced efficacy in botuli-
num groups. The occurrence of muscular paralysis,
mainly in the frontalis, procerus, and corruga-
tors, can reveal—both to the blinded patient and
to the investigator—which treatment they are
receiving. This can thus increase the placebo effect
and reduce the response to botulinum toxin type
A. According to Solomon,44 the loss of treatment
blinding was highlighted in two randomized, dou-
ble-blind, placebo-controlled trials that evaluated
how many patients guessed which treatment they
had received. Mathew et al.45 reported that 85.1
percent of patients had correctly identified they
were receiving botulinum toxin. This clearly shows
the importance of blindness in randomized, dou-
ble-blinded, placebo-controlled trials that evaluate
the prophylactic effects of botulinum toxin.

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 Volume 143, Number 1 • Botulinum Toxin Type A versus Placebo

Fig. 5. Forest plot of quality of life at 3 months. Higher scores indicate a lower quality of life. Std, standardized; IV, inverse variance;
HIT-6, Headache Impact Test; MIDAS, Migraine Disability Assessment; BDI, Beck Depression Inventory–II; HDI, Headache Disability
Inventory. °Studies that used changes in quality of life from baseline to 3 months were included in the meta-analysis to decrease
heterogeneity.

Concomitant prophylaxis can also confound
the outcomes of migraine trials. In seven studies of
our meta-analysis, patients included were asked to
stop other prophylactic medications. The third edi-
tion of guidelines for controlled trials on migraine
drugs46 recommends stopping any prophylactic
medications for migraines. Other medications,
not taken for migraines, can be continued at doses
stable for the previous 3 months, but only if they
have few side effects and no clinical interactions
with migraines. Acute medications are permitted
for the duration of the study, but must be logged.46
The overuse of headache medications needs to
be considered. Sandrini et al. evaluated the effect of
botulinum toxin in reducing treatment consump-
tion for medication overuse headache.18 They found
a significant reduction in the consumption of drugs
for acute pain even though reduction in overall
headache days was not significant. Finally, a 2-year
prospective trial led by Negro et al.47 demonstrated
the efficiency and safety of long-term treatment with
botulinum toxin in patients affected by chronic
migraine and overuse of headache medications.
Other studies have evaluated responses to
botulinum toxin A. Lee et al.48 analyzed the ratio
of mean arterial blood flow between the internal
carotid artery and the homolateral middle cere-
bral artery using transcranial Doppler sonography.
The ratio was higher in botulinum toxin respond-
ers than in nonresponders (p = 0.027), even after
controlling for covariates (p = 0.025). Cernuda-
Morollón et al. measured interictal calcitonin
gene-related peptide and vasoactive intestinal
peptide levels in peripheral blood to predict the
response to botulinum toxin.49
In conclusion, a major strength of this updated
meta-analysis is the exhaustiveness of our research,
which includes three additional studies compared
to the meta-analysis of Jackson et al.28 Further-
more, analysis of intermediate results (starting at 2
months) shows that botulinum toxin had rapid effi-
cacy, which has not been previously highlighted.
We have, for the first time, included criteria
reflecting quality of life, which is significantly
improved at month 3 in the botulinum toxin type
A group for both chronic and episodic migraines.
However, our study has some limitations. First,
despite our attempts to contact the authors, we
were unable to obtain all patient-level data and had
to work using aggregate data; nevertheless, this
may have avoided discrepancies between the stud-
ies included (particularly for episodic migraines,
where statistical heterogeneity was significant).
Second, outcomes were various, such as the clus-
tering of migraine frequency when presented as
migraine-days per month and number of crises per

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 Plastic and Reconstructive Surgery • January 2019

Fig. 6. Forest plot of adverse events at 3 months. IV, inverse variance.

month. However, the data between groups were
clinically similar, and our inclusion of data from
all of the trials in the analyses reduced statistical
heterogeneity.
Finally, we did not include controlled trials
examining other prophylactic oral medications
in our meta-analysis. Other studies have com-
pared botulinum toxin injections to various pro-
phylactic oral medications, such as topiramate,14
amitriptyline,13 valproate,50 and methylpredniso-
lone.51 These studies do not demonstrate any
superiority of other oral treatments over botuli-
num toxin.
CONCLUSIONS
This meta-analysis reveals that botulinum
toxin type A was superior to placebo for chronic
migraines at 3 months, and was also significant at 2
months. There was also a tendency for botulinum
toxin type A to be effective for episodic migraines
at 3 months. This finding needs to be investigated
further to identify the causes of statistical hetero-
geneity between studies. For the first time, our
analysis highlights the significant (p < 0.00001)
improvement in patients’ quality of life at 3 months
in the botulinum toxin type A group, which exhib-
ited few and mild adverse events. Botulinum toxin
type A is a safe and well-tolerated treatment that
should be offered to patients with migraine.
Benoit Chaput, M.D.
Plastic and Reconstructive Surgery Unit
CHU Rangueil
1, Avenue Jean Poulhès
Toulouse, France
benoitchaput31@gmail.com
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