693013

research-article2017
AORXXX10.1177/0003489417693013Annals of Otology, Rhinology & LaryngologyPatel et al

Original Article
Annals of Otology, Rhinology & Laryngology

IncobotulinumtoxinA Injection for

1­–6
© The Author(s) 2017
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DOI: 10.1177/0003489417693013
https://doi.org/10.1177/0003489417693013

A Randomized Controlled Pilot Study journals.sagepub.com/home/aor

Amit A. Patel, MD1, Michael Z. Lerner, MD1,

and Andrew Blitzer, MD, DDS, FACS1

Abstract
Objectives: Temporomandibular disorder (TMD) involves dysfunction of the temporomandibular joint and associated
muscles of mastication causing pain with chewing, limitation of jaw movement, and pain. While the exact pathophysiology
of TMD is not completely understood, it is thought that hyperfunction of the muscles of mastication places stress on
the temporomandibular joint, leading to degeneration of the joint and associated symptoms. We hypothesize that
chemodenervation of the muscles of mastication with IncobotulinumtoxinA (Xeomin) will decrease the stress on the
temporomandibular joint and improve pain associated with temporomandibular joint and muscle disorder (TMJD).
Methods: Twenty patients were randomized to IncobotulinumtoxinA (170 units) or saline injection of the masticatory
muscles. Patient-reported pain scale (0-10) was recorded at 4-week intervals following injection for 16 weeks. Patients
who received saline injection initially were assessed for reduction in pain at the first 4-week interval and if still had
significant pain were rolled over into the IncobotulinumtoxinA arm.
Results: Preinjection pain scores were similar between patients. While there was a statistically significant reduction in pain
score in the placebo group one month, there was an overall larger drop in average pain scores in those patients injected
with IncobotulinumtoxinA initially. All patients initially injected with placebo crossed over into the IncobotulinumtoxinA
group. Similar results were seen when examining the composite masticatory muscle tenderness scores. There was no
significant change in usage of pain medication.
Conclusions: We demonstrate utility of IncobotulinumtoxinA in treating patients with TMD with pain despite pain
medication usage and other conventional treatments.

Keywords
IncobotulinumtoxinA, temporomandibular disorder

Temporomandibular disorder (TMD) is a nonspecific term
used to describe joint and muscle disorders that affect the
masticatory system. It has been reported that about 5% to
12% of the US population is affected by TMD, and the
annual cost of managing TMD, excluding cost related to
imaging, is about $4 billion.1 Plesh and colleagues2 reported
that in the 2000-2005 US National Health Interview Survey
(NHIS), which included a total of 189 977 people, 4.6% (n
= 58 964) of people had experienced temporomandibular
joint and muscle disorder (TMJD).
Symptoms are commonly related to pain surrounding
the joint and may include referred ear pain, headache,
transmitted neck pain, decreased jaw mobility, difficulty
and/or pain while chewing, and crepitus or other noise
within the joint with movement. In general, TMD is divided
into myofascial TMD or arthrogenic TMD. Myofascial
TMD is associated with the pain from hyperfunctioning
muscles of mastication leading to chronic myositis. In con-
trast, arthrogenic TMD is associated with intracapsular
pathology, with pain at the level of the joint itself, often
confused with ear pain.3
Temporomandibular disorder encompasses many clini-
cal abnormalities, which may include spasm of the masse-
ter, temporalis, and/or pterygoid musculature. Pain
associated with TMD may be muscular or joint in origin.
Current treatments for TMD include measures such as exer-
cise and massage; systemic anti-inflammatory medications
1
New York Center for Voice and Swallowing Disorders, New York,
New York, USA
Corresponding Author:
Amit A. Patel, New York Center for Voice and Swallowing Disorders,
425 West 59th Street Floor 10, New York, NY 10019, USA.
Email: ameker@gmail.com
2 Annals of Otology, Rhinology & Laryngology 
such as NSAIDs, muscle relaxants, and tranquilizers; and
various types of occlusal devices to offset the strain on the
muscles and joint. However, there is a lack of evidence that
any one treatment is more effective than another. For exam-
ple, a systematic review performed on orthodontics for
treating TMD was unable to find a single article to match
their inclusion criteria.4 Another systematic review compar-
ing interventions for TMD showed equivalent pain reduc-
tion with splints versus diclofenac sodium and that
glucosamine was as effective as ibuprofen for pain manage-
ment; however, the review did comment on the lack of high
level evidence.5
IncobotulinumtoxinA (brand name: Xeomin, manufac-
tured by Merz North America Inc, Raleigh, North Carolina,
USA) is a neurotoxin that blocks presynaptic acetylcho-
line release. Local injections of IncobotulinumtoxinA
have been FDA approved for therapy for blepharospasm
and cervical dystonia and the management of frown lines.
Botulinum toxin has also been used for other types of
focal dystonia such as spasmodic dysphonia, oromandibu-
lar dystonia, and occupational writer’s cramp and
spasticity.6-11
We hypothesize that a major factor leading to pain
associated with TMD is related to excess strain placed on
the temporomandibular joint by hyperfunction and
spasms of the masseter, temporalis, and pterygoid muscu-
lature. In theory, weakening these muscles with botutli-
num toxin injection should lead to relief of symptoms.
There is also evidence that the botulinum toxins also
decrease pain by the effect on the afferent nerves and
decrease the release of inflammatory mediators (Substance
P, CGRP, Glutamate).12 This study is intended to examine
the effectiveness and safety of IncobotulinumtoxinA in
relieving the subject’s muscle spasm and pain associated
with TMD.
Study Design
The study was monitored and approved by the Western
Institutional Review Board (WIRB) in Seattle,
Washington, USA. The study duration was 4 months.
Subjects were recruited from a variety of dental and oto-
laryngology practices where patients had failed standard
treatments. Those who volunteered for the study were
screened for specific inclusion and exclusion criteria
(described in the following). Approximately 50% of the
subjects who volunteered were recruited for the study.
Subjects who completed the study attended a total of 5
study visits 1 month apart and 1 telephone interview at 1
week after injection. At the initial visit (day 0), patients
were screened, reviewed informed consent, and answered
a questionnaire. Females who met inclusion criteria were
screened with a pregnancy test. Subjects who met all
inclusion criteria were then randomized via random
computer generated number to 1 of the 2 double-blinded
treatment groups, placebo versus IncobotulinumtoxinA
injection. Patients receiving IncobotulinumtoxinA were
injected under EMG control with 50 units into each mas-
seter muscle, 25 units into each temporalis muscle, and 10
units into each external pterygoid muscle using a 27-gauge
monopolar electrode injection needle. Patients receiving
placebo received an equal volume of normal saline into
each muscle injected with the same needle. Patients were
then sent home with a pain diary and at 1 week completed
a telephone interview. Patients were also asked for
adverse event occurrence such as pain at the injection
site, local reaction to the injection, and difficulty chew-
ing. Patients returned at 1 month. In those patients who
did not have at least a 50% reduction in pain, an unblinded
nurse reviewed which injection they had initially received.
Those who were injected with placebo initially and did
not report at least a 50% reduction in pain received
IncobotulinumtoxinA injection, and those initially
injected with Incobotulinumtoxin A were injected with
saline (placebo). Patients then returned each month for
review of their diary and examination (a total of 4 months
after the blinded second injection).
Objective/purpose of study
The primary objective of the trial is to examine the efficacy
of IncobotulinumtoxinA at a total of 170 units (50 units to
each masseter, 25 units to each temporalis, 10 units to each
external pterygoid) compared to placebo in the treatment of
TMD in a double-blind trial measured by a decrease in pain
on a 1 to 10 scale.
Primary objective
Evaluate for decrease in pain related to TMD with
IncobotulinumtoxinA injection compared to placebo.
Secondary objectives
1. Evaluate for decrease in pain medication usage rela-
tive to placebo via a 0 to 10 pain scale.
2. Assess the safety of treatment with
IncobotulinumtoxinA relative to placebo (incidence
of adverse events).
3. Evaluate for a decrease in tenderness to palpation of
the temporalis, masseter, and external pterygoid
muscles via a composite pain scale (1 = no pain on
palpation, 4 = maximal pain on palpation, scale
range, 6-24).
Inclusion and Exclusion Criteria
Please see Table 1.
Patel et al 3

Table 1.  Inclusion and Exclusion Criteria.

Inclusion Criteria Exclusion Criteria

TMD pain assessment >3 on a 0-10 ordinal scale
Pain at least 10 days per month
TMD signs/symptoms for at least 3 months prior to initial visit
TMD symptoms refractory to conventional therapy
(medications or oral devices)
Females who are pregnant, breast feeding, not practicing birth control
Treatment of other conditions with botulinum toxin
TMJ surgery within 6 months of initial visit
Patients anticipating hospitalization or change in the current regimen
of treatment for TMD pain (including change in medication or other
procedures)

Abbreviations: TMD, temporomandibular disorder; TMJ, temporomandibular joint.

Table 2.  Average Reduction in Pain Scores:

IncobotulinumtoxinA Versus Placebo.

Placebo IncobotulinumtoxinA
Months n=9 n = 10
Post-
injection Δ Pain Score P Value Δ Pain Score P Value
1 1.7a .01 4.5 .0002
2 4.43 .0003 4.1 .0014
3 3.54 .004 4.4 .004
4 1.54 .2 2.9 .009

Note. Δ pain score = average reduction in pain score (initial pre-injection

pain score – pain score at timepoint x); paired Student t test used to
calculate P values assessing statistical significance between the change in
pre- and post-injection pain scores.
a
Indicates that all placebo patients at this point received
IncobotulinumtoxinA injection.
Results
Data were available for 19 of 20 patients (1 patient dropped
out due to a family illness and moved out of state). Placebo
group refers to those patients who received a saline as their
first injection, while Incobotulinumtoxin A group refers to
those patients who received IncobotulinumtoxinA as their
first injection. No adverse events were noted. Initial pain
scores were similar between the 2 groups (placebo group =
5.43 ± 2.6 vs IncobotulinumtoxinA group = 5.4 ± 2.1, P =
.976; see Table 1). Four weeks after initial injection, change
in average pain scores between each group showed statisti-
cally different decrease (placebo = 1.7, P = .01,
IncobotulinumtoxinA = 4.5, P = .0002; see Table 2), with
the IncobotulinumtoxinA group showing a larger drop in
value than the placebo group. Despite a drop in average
pain scores in the placebo group, all patients in the placebo
group subjectively reported minimal to no relief and were
therefore crossed over to the IncobotulinumtoxinA treat-
ment group at 4 weeks. Average pain scores for the
IncobotulinumtoxinA group at 4 weeks was statistically sig-
nificantly less than the placebo group (placebo = 3.72 ± 2.5
vs IncobotulinumtoxinA = 0.9 ± 1.7, P = .009). At 2, 3, and
4 months following injection, pain scores between the 2
groups (now both active toxin) remained similar (Table 1,
Figure 1.  Average pain scores: IncobotulinumtoxinA versus
placebo.
Note. Circle and diamonds represent average pain score at each
timepoint. Dashed line shows placebo effect alone. Note that all patients
in placebo group rolled over to IncobotulinumtoxinA at 1 month to
receive IncobotulinumtoxinA (dashed line overlapping solid line).
Figure 1). Average change in pain score also remained sta-
tistically significantly lower at 2, 3, and 4 months following
injection when compared to baseline. Table 3 shows a com-
parison between the 2 groups with the timepoints shifted to
reflect months after IncobotulinumtoxinA injection. Patients
started out with no statistical difference between pain scores
and showed similar decreases in pain scores at 1 and 2
months following injection with IncobotulinumtoxinA. At 3
months after IncobotulinumtoxinA injection, the placebo
group had a statistically higher pain score than the injection
group.
In terms of composite masticatory muscle pain to palpa-
tion score, initial pain scores were also similar between the
2 groups (placebo = 15.9 ± 3.3 vs IncobotulinumtoxinA =
14.9 ± 3.9, P = .566). At 1 month, there was a statistically
significant difference in the groups in terms of composite
pain score (placebo = 13.8 ± 3.7, IncobotulinumtoxinA =
8.6 ± 2.8, P = .003). After crossover, at 2, 3, and 4 months,
similar composite scores were noted between the two 2
(Table 4, Figure 2).
4 Annals of Otology, Rhinology & Laryngology 

Table 3.  Average Pain Scores: Incobotulinumtoxin A Versus Table 5.  Pain Medication Usage: IncobotulinumtoxinA Versus
Placebo. Placebo.

Months Post Placebo IncobotulinumtoxinA Months Post Placebo IncobotulinumtoxinA

Toxin Injection n=9 n = 10 P Value Injection n=9 n = 10 P Value
–1 5.43 ± 2.6   Pre-injection 11.2 ± 12.7 10.4 ± 10.1 .902
0 3.72 ± 2.5 5.4 ± 2.1 .13 1 17.2 ± 13.3a 8.7 ± 9.4 .211
1 1.0 ± 1.3 0.9 ± 1.7 .89 2 5.3 ± 4.6 1.7 ± 4.6 .157
2 1.89 ± 2.2 1.3 ± 2.5 .59 3 2.8 ± 6.0 0.6 ± 1.3 .398
3 3.89 ± 2.0 1.0 ± 1.7 .003 4 4.8 ± 7.8 3.8 ± 9.9 .821
4 2.5 ± 2.7  
Note. Pain medication use refers to average numbers of days per month
Note. ± precedes standard deviation values. P values calculated using for each group. ± precedes standard deviation values. P values calculated
unpaired t test comparing IncobotulinumtoxinA and placebo groups. –1 using unpaired t test.
a
month represents timepoint for pre-placebo pain score; the placebo pain Indicates that all placebo patients at this point received
score at 0 month represents 1 month post placebo injection prior to all IncobotulinumtoxinA injection.
subjects crossing over to IncobotulonumtoxinA injection.

Table 4.  Composite Masticatory Muscle Tenderness Scores:

IncobotulinumtoxinA Versus Placebo.

Months Post Placebo IncobotulinumtoxinA

Injection n=9 n = 10 P Value
Pre-injection 15.9 ± 3.3 14.9 ± 3.9 .566
1 13.8 ± 3.7a 8.6 ± 2.8 .003
2 9.4 ± 2.7 8.3 ± 2.3 .333
3 9.7 ± 4.3 9.0 ± 3.5 .716
4 12.7 ± 3.8 12.5 ± 5.1 .909

Note. ± precedes standard deviation values. P values calculated using

unpaired t test comparing IncobotulinumtoxinA and placebo groups.
a
Indicates that all placebo patients at this point received
IncobotulinumtoxinA injection.

Figure 3.  Pain medication use: IncobotulinumtoxinA versus

placebo.
Note. Initial circle and diamond represent average days of pain
medication use during the 3 months prior to start of the trial.
Each subsequent circle/diamond represents average days of pain
medication use during the previous month. Dashed line shows placebo
effect alone. Note that all patients in placebo group rolled over to
IncobotulinumtoxinA at 1 month to receive IncobotulinumtoxinA
(dashed line overlapping solid line).

Regarding pain medication usage, no difference was

Figure 2.  Average composite muscle tenderness scores:
IncobotulinumtoxinA versus placebo.
Note. Circle and diamonds represent composite muscle tenderness
score at each timepoint. Dashed line shows placebo effect alone. Note
that all patients in placebo group rolled over to IncobotulinumtoxinA at
1 month to receive IncobotulinumtoxinA (dashed line overlapping solid
line).
noted at baseline in terms of days of pain medication usage
between the 2 groups. Interestingly, an increase in days of
pain medication usage was noted in the placebo group after
initial injection (17.2 ± 13.3 days of use compared with 11.2
± 12.7 days of use in the IncobotulinumtoxinA group; Table
5, Figure 3), although this was not statistically significant.
For the remainder of the study, no difference in days of pain
medication use was noted at any timepoint.
Discussion
Temporomandibular disorder describes a spectrum of disor-
ders causing pain of the temporomandibular joint and
Patel et al 5
surrounding structures due to hyperfunction of the muscles
of mastication, specifically the masseters and external pter-
ygoids. Previous study of injecting the muscles of mastica-
tion with botulinum toxin suggested a role in the treatment
of TMD.13 In this study, we sought to answer whether che-
modenervation of these muscles with incobotulinumtoxinA
(IncobotulinumtoxinA) would lead to relief of pain associ-
ated with TMD in comparison with placebo. When compar-
ing overall pain score at 1 month after injection of placebo
versus IncobotulinumtoxinA, both groups showed statisti-
cally significant drops in average pain score. It should be
noted however that both groups started with a similar pain
scores, and the IncobotulinumtoxinA group showed a larger
drop in pain scores. While there may be a significant pla-
cebo effect, the perceived effect may be due to small sample
size. Two other results from this study also argue against a
placebo effect. First, when examining the composite masti-
catory muscle tenderness score (each muscle rated on an
increasing pain scale 1-4, maximum composite score of
16), both groups started with similar composite scores. At 1
month, the placebo group showed almost no effect of injec-
tion while there was statistically significant drop in com-
posite score in the IncobotulinumtoxinA group. Second,
and perhaps even more telling, is all patients in the placebo
group reported little relief from injection and were crossed
over into the IncobotulinumtoxinA group.
We also examined change in days of pain medication
usage. Both groups had similar rates of pain medication
usage in the 3 months prior to the study commencement.
Interestingly, the placebo group showed a slight uptick in
days of pain medication use in the 1 month following initial
injection while the IncobotulinumtoxinA group showed a
slight decrease, although the difference between the 2
groups was not significant. For the other timepoints, at 2, 3,
and 4 months, the number of days of pain medication use
was decreased from baseline between the 2 groups, although
the difference between the groups was not statistically
significant.
Limitations of this study include small study size. It is
possible that a truly significant drop in pain scores might be
seen with a larger sample size, which is definitely suggested
by the change in the composite muscle pain score.
Additionally, as a pilot study, the results cannot be abso-
lutely applied to larger generalized groups. The results are
encouraging however and suggest that this may be a new
way of helping patients, but a larger, multicenter study
should be performed. Additionally, although validated for
pain studies, there is a certain subjectivity to a 0 to 10 pain
scale for overall pain as well as determining degree of mus-
cle tenderness on a 0 to 4 pain scale. There was a suggestion
of decrease in pain medication usage, although no result
approached significance. This may be related to the fact that
patients may have used different type of pain medications
(NSAIDs vs opiates, etc) or different preparations within
the same class (naproxen vs. ibuprofen, etc) or that the same
dose of the same medication between different people leads
to different degrees of relief.
Conclusions
We demonstrate in this trial the utility of IncobotulinumtoxinA
injection in the treatment of TMD refractory to pain medi-
cation and other conventional treatments in comparison to
placebo. Patients noted no adverse events during the study
and reported significant reduction in pain. Use of
IncobotulinumtoxinA for TMD could be considered when
weighing treatment options in patients who have failed con-
servative management.
Authors’ Note
The principal investigator Andrew Blitzer had full access to all the
data in the study and takes full responsibility for the integrity of
the data and the accuracy of the data analysis. Presented at the
2016 Triological Association in Chicago, Illinois, USA, May
2016, as a poster presentation by Amit A. Patel, MD.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with
respect to the research, authorship, and/or publication of this
article.
Funding
The author(s) disclosed receipt of the following financial support
for the research, authorship, and/or publication of this article: This
study was supported by an unrestricted research Grant from Merz
North America.
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