REVIEW ARTICLE

Efficacy of Botulinum Toxin in Tension-Type

Headaches: A Systematic Review of the
Literature

Brin Freund, MD; Aruna Rao, MBBS, MD

The Department of Neurology, Johns Hopkins Hospital, Baltimore, Maryland U.S.A.

& Abstract Conclusion: This systematic review demonstrates variable

study designs contributing to the low quality of evidence
Background: Botulinum toxin is approved to treat chronic
available regarding botulinum toxin in TTH, but some data
migraine and has been shown to confer significant benefit in
suggest efficacy. There does not appear to be irrefutable
refractory cases. Due to its effect on pain by sensory
evidence of a lack of efficacy of botulinum toxin in TTH. Using
modulation, there may also be efficacy in its use in chronic
the paradigm for botulinum toxin in chronic migraine may
tension-type headache (CTTH).
prove fruitful in treating CTTH. Further studies are warranted
Methods: A systematic review of the literature was per-
to evaluate the utility of botulinum toxin in this common
formed using our predefined inclusion and exclusion criteria.
debilitating condition. &
We targeted prospective trials, randomized or nonrandom-
ized, studying botulinum toxin in tension-type headaches
Key Words: botulinum toxin, tension-type headache, head-
(TTHs) in adults.
ache, Botox
Results: Twenty-two studies were included, including 9
nonrandomized, uncontrolled studies, 8 randomized, pla-
cebo-controlled and double-blinded trials (RCTs), 3 RCTs with INTRODUCTION
a crossover, open-label period, 1 comparative, randomized,
single-blinded evaluation, and 1 retrospective study with Chronic headaches are disabling and significantly bur-
prospective evaluation of headache response to cosmetic den their sufferers and are common in the population.
botulinum toxin. Studies included 11 to 300 subjects, with One study noted that migraine headache was considered
duration typically less than 6 months and with only 1 among the top 10 diseases that cause disability.1 Recent
treatment period. Results were mixed, likely due to variable randomized, placebo-controlled trials have shown sig-
study design, including toxin dosing, injection paradigms,
nificant benefit in treating chronic migraine (CM) with
duration/frequency of treatment, and outcome measures.
botulinum toxin.2 This has led to a new era of migraine
There was moderate-quality evidence that botulinum toxin
improved VAS scoring, and some studies demonstrated treatment using modulation of sensory pathways.
efficacy based on improved frequency/severity. Tension-type headache (TTH) is another condition
with a very high socio-economic impact, hence the
importance of its study.3 TTH is common, occurring in
Address correspondence and reprint requests to: Brin Freund, MD,
Johns Hopkins Hospital, 1776 Emerald Lane, Middleburg, FL 32068, U.S.A.
up to 38% of adults, with up to 2% having near daily
E-mail: bfreund3@jhmi.edu. headaches, classifying them as chronic tension-type
Submitted: November 23, 2018; Revised January 21, 2019;
headaches (CTTHs).4 It has been theorized that TTH
Revision accepted: February 3, 2019
DOI. 10.1111/papr.12773 occurs due to sensitization of muscle afferents by local
mediators, which leads to central desensitization, and
© 2019 World Institute of Pain, 1530-7085/19/$15.00
if untreated results in CTTH.4,5 Botulinum toxin,
Pain Practice, Volume 19, Issue 5, 2019 541–551 which includes onabotulinumtoxin A (Botox; Allergan,
542  FREUND AND RAO
Madison, NJ, USA) and abobotulinumtoxin A (Dysport;
Ipsen US, Cambridge, MA, USA), targets the myofascial
sensory system, which theoretically should help abort
the pain pathway in TTH and prevent progression to
CTTH.5 There have been mixed results from prior
reviews and meta-analyses regarding the efficacy of
botulinum toxin in TTH.3,6 The most recent systematic
review included 11 trials,3 but did not include a number
of studies that were described in a previous meta-
analysis from 2012.6 The review by Jackson et al. also
did not include a number of trials that are described in
this review that were available at the time of their
publication,7–11 possibly related to their exclusion
criteria.6 In their review, a few studies in the CM group
also included patients with TTH,12,13 and evaluated
studies of patients with both chronic and episodic
TTH.14–16 For these reasons, an updated review on
botulinum toxin treatment in CTTH is warranted.
In this systematic review, the aim was to better
elucidate the efficacy of botulinum toxin in CTTH. We
discuss the shortcomings and strengths of prior analyses
to help guide future trials.
METHODS
Search Strategy and Study Selection
This systematic review was performed with adherence
to the Preferred Reporting Items for Systematic
Reviews and Meta-Analyses (PRISMA) guidelines.17
A literature search was performed in May 2018 using
MEDLINE, Embase, Ovid, and PubMed databases.
Separate searches were performed in each database
using “tension-type headache” and “botulinum toxin”
as well as “tension-type headache” and “Botox.”
Eligibility criteria were defined prior to performing
the literature search. These included studies with
prospective enrollment, nonrandomized or random-
ized, placebo controlled or comparative, with or
without blinding, and involving the use of botulinum
toxin in CTTH. Studies were excluded if they included
migraine headaches only, were single case reports or
retrospective case series, included pediatric patients,
were published in any language other than English,
included nonhuman subjects, lacked full text availabil-
ity for review, or were abstracts presented at confer-
ences without a published, comprehensive analysis
reported.
Using the above criteria, titles were reviewed in all
results, looking for duplicate studies. If the title
described a study that would clearly be excluded based
on our predefined criteria, it was removed. In all other
studies, abstracts were then reviewed to determine what
type of analysis was performed (case report, case series,
abstract presentation, review, etc.). The full text of the
papers remaining was then analyzed. This was per-
formed by 2 reviewers (B.F. and J.G.), and the results
were combined.
Prior reviews or meta-analyses3,6 were used as a
reference to ensure we did not miss any studies. Our
search resulted in all of the studies noted in these 2
papers. Any studies they included that we did not
studied migraineurs or pediatric patients only.
Data Extraction and Assessment of Quality of Studies
Data were extracted from the text of the articles thus
identified, relating to other treatment or placebo arms,
size of each group, type of botulinum toxin, dose and
frequency of treatment, location of injections, study
duration, and outcome measures, which were based on a
prior meta-analysis6 and International Headache Soci-
ety (IHS) recommendations.18 A quality assessment was
performed, based on the Grading of Recommendations
Assessment, Development and Evaluation (GRADE)
criteria from Cochrane.19 We chose headache-specific
outcome measures that were evaluated in more than 2
studies, and further analyzed them regarding the quality
of evidence supporting conclusions on the effects of
botulinum toxin. We separated these analyses by ran-
domized controlled trials (RCTs) and non-RCTs. RCT
analyses began with high-quality scores, and non-RCT
with low-quality grading, per GRADE.19 A meta-
analysis was not performed given the variable outcome
measures and study designs. See Tables S1 to S7 for
analyses of quality of evidence regarding outcome
measures.
RESULTS
Our search resulted in 473 studies. After removing
duplicates, 316 articles remained. Using the other
predefined exclusion criteria, we were left with 43
studies of which we reviewed the full text. Three were
excluded due to being case series20 or a cost-effective-
ness study,21 or lacking differentiation between
migraine and TTH when discussing patients with
chronic daily headache in their cohort.22 The other
excluded studies did not meet inclusion criteria as noted
above. In total, 22 analyses were included in this review

(Figure 1). Refer to Table 1 for more data on these
studies.4,7–16,23–33
Study Characteristics
Nine studies were prospective, nonrandomized, and
uncontrolled,7–12,25,32,33 8 were randomized, double
blinded, and placebo controlled,4,15,16,24,26,29–31 3 were
randomized, double blinded, and placebo controlled
with a crossover, open-label portion,13,27,28, and one
was a comparative, randomized, single-blinded evalua-
tion of botulinum toxin vs. methylprednisolone injec-
tions.14 One study was a retrospective evaluation of
patients in a dermatology clinic, which was included due
to prospective enrollment for wrinkle treatment, but
included headache response.23
Studies enrolled between 6 and 300 patients. Dosing
and injection paradigms varied, with some studies
having fixed, predetermined protocols used in all
patients, while others “followed the pain” as previously
described.34 Those analyses that used standardized
dosing9–13,15,16,27,29,30,32had mixed results, with some
showing benefit.9–13,27,28,32 The other studies differed in
dosing of toxin, with variable results as well. Even
Figure 1. Literature search.
Botulinum Toxin in TTH  543
among those with a standardized approach, no studies
had the same injection protocol. Multiple studies
showed positive outcomes, with toxin dosing ranging
from 30 to 200 units4,7–14,27,28,32though studies using
more than 200 units15,16,30 and less than 50 units23,29
did not demonstrate much benefit. Therefore, optimal
dosing is unclear.
Most studies included those with history of CTTH
diagnosed by IHS criteria,35 though 1 included episodic
TTH as well.14 Some did not note exclusion of other
headache syndromes,7,10,10–12,23,25,27,28statistically ana-
lyzed data from chronic migraineurs with CTTH,8,13 or
purposely included those with other chronic pain
conditions such as temporomandibular joint disor-
ders.9,32
Most of the studies were no more than 6 months in
duration, with only 2 reports following patients for at
least 1 year.11,28 Outcome measures were variable,
including subjective reports of headache severity and
frequency (either by number or using scales such as the
Clinical Global Impression Scale), use of analgesics or
abortives, headache-free days, duration of headache,
and objective scoring protocols for pain (Headache
Disability Inventory, Numeric Rating Scale, Headache
Table 1. Studies Included in Review
544 

Reference Study Type Comparison Sample Size Treatment Dose Study Duration Findings

4 Randomized, Placebo 300 Botulinum toxin type 50 to 150 units, 120 days No significant difference in
blinded, placebo- A “usub” patients reporting 50%
controlled decrease in headache frequency
at days 60 and 90
Significant difference in number
reporting 50% decrease in
headache frequency in the 100
FREUND AND RAO

unit, 100 “U subgroup”, and 86

“U subgroup” groups as
compared to placebo
7 Prospective, None 60 Botulinum toxin type 80 to 150 total units 3 months Improved headache frequency by
nonrandomized A 40% to 80% P = 0.0064
between all groups
8 Prospective, None 22 Botulinum toxin type 30 to 100 units 30 days Decrease in median headache
nonrandomized A frequency from 30 days per
month to 10 days per month
(P < 0.001)
9 Prospective, None 60 total subjects, 46 Botulinum toxin type Total 150 units 3 months 63% reported 50% improvement
nonrandomized met criteria for CTTH A in facial pain; all with CTTH
reported 50% improvement in
headache; headache-free days
increased from mean 11 to 19
10 Prospective, None 10 Unknown 80 units NA Decreased mean pain scores from
nonrandomized 7.1 to 0.6 out of 10, lasting 6 to
12 weeks
11 Prospective, None 28 Botox (Allergan), 50 units total 1 year Headache frequency decreased,
nonrandomized once with 25% achieving complete
resolution at 12 weeks, 64% at
1 year
12 Prospective, None 11 with TTH Botox (Allergan), q12 100 units total 27 weeks 4/11 responded with at least 50%
nonrandomized to 15 weeks reduction in headache
frequency
13 Randomized, Placebo 46 with CTTH and 14 Unknown, q12 weeks 200 units total 24 weeks (12 week Headache-free days improved
blinded, placebo- with chronic placebo- significantly from week 8 to 12
controlled with migraine enrolled at controlled, after treatment (P < 0.05) but
crossover open- beginning, 51 12 week open- this difference was not noted
label portion completed; all but 1 label crossover) when comparing baseline to
patient in the week 12 (P < 0.07); during
placebo group chose open-label phase those
to cross over and receiving 2 treatments vs. 1
receive botulinum treatment had significantly
toxin injections at fewer headache days (26 vs. 40,
week 12 P < 0.05)
14 Randomized, single- 40 mg MTP plus 10 Botox, 10 MTP Botox (Allergan), 5 to 15 units per site 60 days Significant difference in VAS
blinded, lidocaine once favoring Botox
comparative
15 Randomized, Placebo 10 placebo, 11 Dysport (Dysport; 200 total units, 20 12 weeks No significant difference in
blinded, placebo- Dysport Ipsen US, Cambridge, units per injection headache frequency
controlled MA, USA), once
Table 1. (Continued)

Reference Study Type Comparison Sample Size Treatment Dose Study Duration Findings

16 Randomized, Placebo 4 placebo, 4 Dysport Dysport (Speywood 500 total units 12 weeks No significant difference in
blinded Ltd), once (used EMG outcome measures
to confirm muscle
changes after
injections)
23 Retrospective None 8 Botox (Allergan) 12 to 40 units NA 2/8 had no headaches following
treatment
24 Randomized, Placebo 14 Botox, 14 placebo Botox (Allergan), 2 to 12 units per site, 3 months At 30 days, headache days per
blinded, placebo- once range of 30 to 80 month went from 19.93 to 15, at
controlled units total 90 days to 12.07 (Botox); at
30 days, headache days per
month went from 19.21 to 17.5,
at 90 days to 15.92 (placebo);
severity decreased from 6.21/10
to 3.5/10 by day 90 in Botox
group and 6.36/10 to 5.21/10 in
placebo group; headache’s
shorter duration and abortive
use decreased significantly by
days 30 and 90 with Botox
25 Prospective, None 17 Unknown Unknown 6 weeks 12/17 noted improvement in
nonrandomized, headache severity and
uncontrolled frequency; mean NRS 7 before
treatment and 0 after treatment
(P < 0.01) and mean HIT-6 went
from 55 to 44 after treatment
(P < 0.001)
26 Randomized, Placebo 19 Botox, 21 placebo Botox (Allergan), Maximum 100 units 12 weeks No significant difference in
blinded, placebo- once total, 10 to 20 units outcomes
controlled per muscle
27 Randomized, Placebo 10 Botox, 9 placebo Unknown 100 total units, 25 24 weeks (12 week Significant reduction in
blinded, placebo- units per site placebo- headache frequency during
controlled, controlled, double-blinded phase
followed by open- 12 week open- (P = 0.013), maximal at 5 to
label crossover label crossover) 8 weeks, also seen during open-
period label phase; no difference in
other outcome measures
28 Randomized, Placebo 16 in placebo- Unknown, q3 months 45 to 95 units 8 weeks placebo- Increase in headache-free days,
blinded, placebo- controlled period, 30 controlled period, and decrease in headache
controlled, in the crossover 18 months severity in the open-label
followed by open- period crossover period portion
label crossover
period
29 Randomized, Placebo 30 Botox, 29 placebo Botox (Allergan), 20 total units, 2.5 8 weeks Significantly lower WHYMPI and
blinded, placebo- once units per injection angry mood scores at 4 weeks,
controlled lost significance at 8 weeks; no
difference in VAS
30 Randomized, Placebo 53 Dysport, 54 Dysport once 500 total units 18 weeks No significant difference in
blinded, placebo- placebo outcome measures
controlled
Botulinum Toxin in TTH  545
 546 
FREUND AND RAO

Table 1. (Continued)

Reference Study Type Comparison Sample Size Treatment Dose Study Duration Findings

31 Randomized, Placebo, 2 different 33 received 210 units, Dysport once Varied 18 weeks (6 week Headache duration significantly
blinded, placebo- groups with similar 28 received 420 run-in phase, shorter and global assessment
controlled injection paradigm units, 64 in placebo 12 week post- score better in the 420 unit
at 210 and 420 total group treatment phase) group vs. placebo comparing
units baseline to the 8 to 12 week
period (P < 0.05); otherwise no
significant differences
32 Prospective, None 42 Botox (Allergan) 42 units 24 weeks VAS and VNRS decreased
nonrandomized, (P < 0.0001); mean headache
uncontrolled intensity decreased (P > 0.0001);
all other measures improved
with Botox (not statistically
reported)
33 Prospective, None 6 Botox (Allergan) ?30 to 40 units ?5 months At 1st follow up, 2 patients noted
nonrandomized, improvement in the algometric
uncontrolled measures on the treatment side,
3 noted improvement on the
contralateral side; reported
stable analgesic use; 3 noted
decreased VAS score after 1st
Botox which persisted in 2 after
2nd dosing

CTTH, chronic tension-type headache; EMG, electromyography; HIT-6, Headache Impact Test 6; MTP, methyl-prednisolone; NA, not applicable; TTH, tension-type headache; usub, ; VNRS, verbal numeric rating scale; WHYMPI, west
haven-yale multidimensional pain inventory.

Impact Test 6 [HIT-6], VAS, Total Tenderness Score,
West Haven-Yale Multidimensional Pain Inventory) and
psychiatric symptoms (Beck Depression Inventory, Psy-
chosocial Adjustment to Illness Scale).
Outcomes
In the nonrandomized, prospective studies, there were
significant benefits of botulinum toxin treatment seen in
reduced headache frequency,7,8,11,12 particularly in
patients with muscle allodynia,12 and up to 1 year after
treatment.11 These trials also noted improvement in
headache severity9,25,32 and decreased analgesic or
abortive use.11
Regarding the randomized, placebo-controlled,
blinded trials, results were mixed. Some showed
decreased headache frequency at 30 days,24 90 days,24
and 18 months with retreatment every 3 months,28 but
efficacy did not last past 8–12 weeks in 2 studies.13,27
One study noted that the difference in response to
onabotulinumtoxin A vs. placebo was not seen until day
90 of the trial, which occurred in different groups
receiving similar doses of onabotulinumtoxin A with
different injection paradigms but no correlation with
higher dosing.4 Decreased headache severity at 90 days
was described24, and there was a significant benefit of
onabotulinumtoxin A in headache duration and abortive
use.24 Headache duration decreased in 1 study and
appeared to correlate with higher dosing of abobo-
tulinumtoxin A.31 Subjective report of headache
improvement was significant in some analyses,13,31 while
others noted nonsignificant differences among placebo
and treatment groups26 or no subjective benefit.15,16,27,29
Some studies showed no improvement in pain, headache
frequency/severity,29,30 or psychological symptoms.30
There appeared to be a correlation between the absence
of medication overuse headache and response to botuli-
num toxin.13
Some of the randomized trials had a crossover, open-
label period. During this time, benefits were again noted
in those undergoing botulinum toxin therapy,13,27 and
headaches were less frequent in those who had been
randomized to receive botulinum during the first and
open-label periods when compared to those only
receiving the botulinum toxin during the second time
frame,13 suggesting repeated treatment with botulinum
toxin may have additive effects on improving headaches.
As noted above, injection paradigms differed among
trials. One nonrandomized study compared different
injection protocols and found a statistically significant
Botulinum Toxin in TTH  547
difference favoring fixed injection protocols over “fol-
low the pain models.”7
Quality of Evidence
We evaluated headache frequency, daily use of abor-
tives, VAS scores, and headache-free days in the RCTs,
and headache frequency, daily use of abortives, and VAS
scores in non-RCTs (see Tables S1 to S7). We found low
evidence supporting any conclusions from these studies
in every analysis except for the effect of botulinum toxin
on VAS scoring in non-RCTs, which showed moderate
evidence that there was benefit.
DISCUSSION
This systematic review of botulinum toxin in CTTH
shows that there is variability among the previous
studies regarding design, which makes interpreting the
outcomes of these studies collectively a difficult task.
Today, onabotulinumtoxin A is approved for CM
treatment. However, earlier studies of treatment of
CM showed mixed results,2 similar to the evidence that
has been presented in this review regarding studies of
botulinum toxin and CTTH. There were 2 studies in
200736,37 and 1 from 201138 that did not support a
benefit of onabotulinumtoxin A treatment in CM.
However, in 2010 the PREEMPT I and II studies—
which were 24-week double-blind, parallel-group,
placebo-controlled trials followed by a 32-week open-
label phase, providing treatments every 12 weeks at 31
fixed sites with 40 extra units being provided at the
investigator’s discretion—showed significant reduction
in headache and migraine days as a result of botulinum
toxin treatment.39,40 These findings were confirmed by
other prospective studies.41–45 Two others found botu-
linum toxin as effective as amitriptyline46 and topira-
mate.47 Another study noted incobotulinumtoxin A was
effective in treating CM.48 The difference in outcomes
between the earlier studies and those that came later
could be due to smaller sample sizes in the earlier trials,
the shorter follow-up period, lack of scheduled repeat
treatment with botulinum toxin, and differing injection
paradigms. These appear to be similar issues regarding
the current studies evaluating botulinum toxin in CTTH.
Study sizes were relatively small in most of the trials
on CTTH in this review. All but 1 prospective trial had
less than 50 total subjects, and only 1 randomized study
enrolled more than 125 patients. On the other hand, the
randomized, placebo-controlled studies on botulinum
548  FREUND AND RAO
toxin in CM enrolled over 600 patients.39,40 In prospec-
tive, post-marketing studies, which confirmed botuli-
num toxin efficacy in CM, 52 to 254 subjects were
evaluated.41–44 Therefore, future trials should include
larger sample sizes.
As described previously, most studies did not follow
patients out for more than 6 months, and some were as
brief as 6 weeks in duration. However, longer study
durations may be necessary to show benefit in treatment.
Only 2 randomized trials13,28 and 1 nonrandomized
prospective study12 retreated patients at regular inter-
vals of every 12 to 15 weeks. Currently, onabotulinum-
toxin A is approved by the U.S. Food and Drug
Administration for injection in CM every 12 weeks,
which is supported by the finding that peak responses to
botulinum toxin in migraine are at 8 to 12 weeks
postinjection.49 It is also noted that some patients may
need treatment to be repeated after the first cycle before
efficacy is seen.50 Studies also have shown that extend-
ing treatment to a longer duration shows cumulative
improvement in headache in those with CM due to
medication overuse.43,45 In the PREEMPT trials, studies
were 56 weeks in duration,39,40 and prospective studies
in CM mentioned previously were at least 1 year.41–44
Therefore, short duration and lack of repeat treatment
could contribute to lack of response to botulinum toxin
in those with CTTH. Interestingly, one study did not
note benefit until 3 months after treatment,4 while
another described continued improvement in headache
frequency and severity from day 30 to 90.24 Studies in
CTTH should have longer duration and repeated
injections over time to avoid the possibility of inaccu-
rately concluding lack of response due to inadequate
therapy.
Injection protocols varied drastically from study to
study, making it difficult to reach a reasonable conclu-
sion in order to comment. It has been suggested that the
injection sites themselves may have no bearing on
effectiveness of botulinum toxin in TTH,51 but this
was based on a small number of studies in the early
2000s. In our review, we also did not find a correlation
between outcomes and the injection paradigm selected
(prespecified vs. follow the pain), with only 1 study
showing benefit from a prespecified protocol as opposed
to following the pain.7 The studies that mirrored most
closely the protocol used in CM but at higher dosing30,31
or lower dosing11,12 showed mixed results. None of the
studies in CTTH followed the exact paradigm described
in migraine studies and in clinical practice. “Follow the
pain” has been advocated by some in the treatment of
CTTH with botulinum toxin,34 though only 2 studies in
this review tried to address any differences in these
protocols regarding efficacy.4,7 Some allowed the clin-
ician to choose from different muscle groups, which is
accepted in the CM treatment protocol as well.12–14,24
Others did try to set ground rules based on the choice of
muscles to be injected, such as tenderness or muscle tone
being increased,8,26–28 including targeting the muscles of
the primary pain-generating condition.9,25,32 Consider-
ation should be given to mimicking or adapting the
current CM treatment paradigm for use in CTTH trials.
Dosing and type of toxin were also variable. Some of
the studies in this review suggested that higher doses
may be more beneficial, but this was not evaluated in
multiple studies. In the PREEMPT trials, there was both
a standardized protocol dictating the use of most of the
botulinum toxin provided, with a smaller percentage
additionally provided to the investigators to use at their
discretion.39,40 It is difficult to conclude that a rigid
approach is necessary but should be considered in future
analyses to rule this out as a confounder, and as noted
above, investigators may want to try a similar approach
as that taken in CM.
Concurrent use of other preventives could affect
results of studies of botulinum toxin in headache
treatment, and most of the trials in this review did not
clearly report coincident prophylactic treatment. Trials
in CM were designed to account for this by excluding
patients with recent headache prophylactic medication
use39,40 due to possible confounding of results. Silber-
stein et al.4 noted that the lack of accounting for other
preventive treatment may have been a shortcoming in
their study. This needs to be addressed in future studies.
CONCLUSION
In this systematic review, we have updated the literature
regarding prospective studies on botulinum toxin and
CTTH. We found that there was variability in study
designs, including duration of the trials, frequency of
injections, injection paradigms used, toxin dosing,
concurrent prophylactic treatments, co-occurring head-
ache diagnoses, and outcome measures, making broad
conclusions difficult. However, while previous studies
questioned the efficacy of botulinum toxin in the
treatment of CTTH,52 we have found through our
review that there could be benefit to the use of botulinum
toxin in CTTH with careful patient selection, specific
injection paradigms, and clear goals of treatment. We
propose that further study is warranted given the impact

CTTH has on global morbidity. By addressing the
shortcomings in these trials and using botulinum toxin
therapy in CM as a model, with particular focus on
longer durations of study and testing multiple injection
paradigms with different dosing of toxin including the
PREEMPT protocol, a randomized, placebo-controlled
study could be designed to answer the question of
botulinum toxin utility in treating CTTH.
ACKNOWLEDGEMENTS
We thank Dr. James Gugger (Johns Hopkins Hospital)
for his efforts in reviewing the literature search and data
quality analysis as well as the manuscript itself.
CONFLICTS OF INTEREST
The authors have no conflicts of interest to declare.
Supporting Information
Additional supporting information may be found online
in the Supporting Information section at the end of the
article.
Table S1. Headache frequency in randomized
controlled trials.
Table S2. Daily use of abortives in randomized,
controlled trials.
Table S3. Visual analogue scale in randomized,
controlled trials.
Table S4. Headache-free days in randomized,
controlled trials.
Table S5. Visual analog scale/pain score in
nonrandomized, controlled trials.
Table S6. Headache frequency in nonrandomized,
controlled trials.
Table S7. Abortive use in nonrandomized, controlled
trials.
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