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Available online at www.sciencedirect.com

ScienceDirect

British Journal of Oral and Maxillofacial Surgery xxx (2020) xxx–xxx

Review
Botulinum toxin in the management of temporomandibular
disorders: a systematic review
S. Thambar a,b,c,∗ , S. Kulkarni c , S. Armstrong a , D. Nikolarakos a
a Dept. of Oral & Maxillofacial Surgery, Gold Coast University Hospital, 1 Hospital Boulevard, Southport, QLD, 4215, Australia
b Griffith University, School of Medicine, Griffith Health Centre (G40), Gold Coast Campus, Cnr Parklands Drive and Olsen Avenue, Southport, QLD,
4215, Australia
c Griffith University, School of Dentistry, Griffith Health Centre (G40), Gold Coast Campus, Cnr Parklands Drive and Olsen Avenue, Southport, QLD,

4215

Accepted 10 February 2020

Abstract

The aim of this review was to critically investigate and assess the evidence relating to the use and efficacy of botulinum toxin (BTX) in
the management of temporomandibular joint disorders (TMD) and masticatory myofascial pain. A comprehensive search was conducted of
PubMed, Scopus, Embase, and Cochrane CENTRAL, to find relevant studies from the last 30 years up to the end of July 2018. Seven were
identified. Three showed a significant reduction in pain between the BTX and placebo groups and one showed a clinical, but not a significant,
difference. In one that compared BTX with another novel treatment, myofascial pain reduced equally in both groups, and in the remaining two
there was no significant difference in pain reduction between the BTX and control groups. Of the four studies that assessed mouth opening,
two reported that BTX had resulted in a slight improvement; one reported no improvement, and the other a worsening of the condition. A
meta-analysis was not possible because of the considerable variation in the studies’ designs, the heterogeneity between the groups, and the
different assessment tools used. Despite showing benefits, consensus on the therapeutic benefit of BTX in the management of myofascial
TMD is lacking. Further randomised controlled trials with larger sample sizes, minimal bias, and longer follow-up periods are now needed.
© 2020 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.

Keywords: Temporomandibular Joint Disorders; Myofacial Masticatory Muscle Pain; Botulinum Toxin

Introduction
Temporomandibular disorders (TMD) refer to a group of
debilitating masticatory conditions that are often associated
with considerable morbidity and a reduction in a person’s
quality of life. They are a leading cause of orofacial pain,
and affect the temporomandibular joint (TMJ), masticatory
muscles, and surrounding structures. Approximately 44% of
∗ Corresponding author at: Dept. of Oral & Maxillofacial Surgery, Gold
Coast University Hospital, 1 Hospital Boulevard, Southport, QLD, 4215,
Australia.
E-mail address: s.thambar@gmail.com (S. Thambar).
the population are affected, but only a quarter of them seek
professional help.1 Patients can often present with a combina-
tion of specific and non-specific signs and symptoms, such as
pain in and around the jaw on movement, neck pain, reduced
jaw excursion, crepitus, trismus, tinnitus, earache, periorbital
pain, and headache.2,3
Given its multifactorial aetiological nature, the diagnosis
of TMD is often complex and based on specific history and
physical examination findings. Parafunctional habits such as
night-time bruxism have a key role and can result in morn-
ing headaches, occlusal attrition, or masseteric hypertrophy.4
Unconscious clenching of the jaw (usually secondary to
social stress, anxiety, or depression) is another contributory

https://doi.org/10.1016/j.bjoms.2020.02.007
0266-4356/© 2020 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.

Please cite this article in press as: Thambar S, et al. Botulinum toxin in the management of temporomandibular disorders: a systematic
review. Br J Oral Maxillofac Surg (2020), https://doi.org/10.1016/j.bjoms.2020.02.007
YBJOM-5922; No. of Pages 12
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factor. A history of tinnitus, aural fullness, or otalgia is also
common given that the TMJ and important muscles of the ear
share innervation by branches of the trigeminal nerve.5 Pre-
vious orthodontic treatment, malocclusion of the jaw, trauma,
and loss of the posterior dental arch, should be investigated
in the history. Imaging studies are organised to assess the
integrity of the joint, the dentition, and to look for contributing
trauma and rheumatological disorders such as osteoarthritis
and rheumatoid arthritis. Plain-film closed and open views of
the joint, as well as orthopantomograms (OPG) are effective
methods for initial investigation. In selected patients, mag-
netic resonance imaging (MRI) can be done to assess the
integrity of the joint, the articular disc, and its surrounding
structures.6
The management of TMD ranges from non-
pharmacological conservative treatment to invasive surgical
procedures. Initial management includes the avoidance of
triggers, jaw rest through a soft diet, physiotherapy, warm
compresses, dental review for an occlusal splint, and simple
analgesia.7,8
Botulinum toxin (BTX) has increasingly been used as
an adjuvant treatment for head and neck pain over the past
20 years.9 It is a 150 kDa exotoxin produced by Clostrid-
ium botulinum, a gram-negative, anaerobic spore-forming
bacterium.10 Seven serotypes exist, ordered from A to G,
with serotype A (BTX-A) being the most readily available.
Its action is mediated through receptor-mediated endocyto-
sis in the synapse and the subsequent cleavage of SNAP-25
(synaptosomal-associated protein 25) docking proteins. This
inhibits the release of acetylcholine at the neuromuscular
junction, and ultimately leads to muscle weakness.11,12 These
effects are temporary and last between three to six months.9
BTX inhibits the release of mediators from the salivary glands
and sweat glands.13 It also has a direct effect on peripheral
nociceptors and can be used to treat neuropathic pain as it
regulates the release of inflammatory mediators such as glu-
tamate, calcitonin gene-related peptide, and substance P.14 It
has been hypothesised that it reduces both central pain sen-
sitisation and chronic pain, but does not interfere with acute
pain or local anaesthesia, as it does not affect A-delta sensory
fibres.15
In the head and neck, BTX is currently indicated for the
management of post-herpetic neuralgia, migraine headaches,
masseteric hypertrophy, sialorrhoea, Frey syndrome, and
hemifacial spasm.16 Its analgesic effects and its ability to
reduce parafunctional oral habits that involve the mastica-
tory muscles mean that it has increasing benefits for the
management of TMD.
In this systematic review we have attempted to answer the
following PICO question: Compared with other conservative
treatments or placebo, does intramuscular injection of BTX
reduce pain in adult patients with TMD?
The participants (P) were adult patients (over 16 years of
age) with clinically diagnosed TMD, which includes mastica-
tory myofascial pain. The intervention (I) was intramuscular
injection of BTX, irrespective of dose, timing, or subtype
Please cite this article in press as: Thambar S, et al. Botulinum toxin in the management of temporomandibular disorders: a systematic
review. Br J Oral Maxillofac Surg (2020), https://doi.org/10.1016/j.bjoms.2020.02.007
(A–G), into the muscles of mastication, irrespective of which
ones were injected. The comparator/control (C) was any alter-
native conservative treatment such as physiotherapy, use of
an occlusal splint, or placebo alone.
The primary outcome (O) was subjective assessment
based on a visual analogue scale (VAS) for pain, or question-
naires assessed by the patients. Secondary outcomes were
maximal mouth opening (assessed by maximal incisal open-
ing) and adverse events that were associated with BTX.
Methods
This study was done according to the PRISMA (Preferred
Reporting Items for Systematic Reviews and Meta-Analyses)
statement.17 Four electronic databases: PubMed, EMBASE,
Scopus, and the Cochrane Central Register of Controlled Tri-
als (CENTRAL) were searched up to the end of February
2018 using the following MeSH terms: Botulinum Toxins,
Type A, Temporomandibular Joint Disorders, Masticatory
Muscles, Pain, Arthritis AND Temporomandibular Joint. As
an example, the search terms used in each electronic database
were “Botulinum Toxins, Type A AND [Temporomandibu-
lar Joint Disorders OR (Masticatory Muscles AND Pain) OR
(Temporomandibular Joint AND Pain) OR (Arthritis AND
Temporomandibular joint)]”.
Full texts of in vivo human studies (randomised controlled
clinical trials (RCT), or quasi-randomised controlled trials,
including single or double-blind crossover studies) that were
published in the last 30 years in the English language were
included. Studies were excluded if the patients had previously
had operations for TMD, or the condition had been caused
by rheumatoid arthritis, ankylosing spondylitis, or psoriatic
arthritis. Those that included patients with dislocations of the
joint, congenital disorders, or neoplasia, were also excluded.
The Cochrane risk-of-bias tool for randomised controlled
trials was used to assess each study. For each one, all seven
elements in the tool were assessed and judged as “low risk”,
“high-risk”, or “unclear risk”. Based on the results of each of
these elements, the overall risk was assessed.
The Jadad score was used to assess the quality of the dou-
ble blinding, randomisation, and flow of patients. Seven items
were scored for each study, the last two of which were nega-
tive, so the scores ranged from 0 (bad) to 5 (good). Based on
these, the overall quality of the methods was assessed.
The data that were tabulated included the study design,
diagnostic criteria, duration of symptoms before the interven-
tion, mean age, sex, sample size, dropouts, and intervention;
also BTX brand, method used to identify the target muscle,
muscles and the points injected, frequency, total dose, and
duration of follow up.
Data on the outcome measures were also tabulated to com-
pare pain intensity (primary outcome), maximal jaw opening
(secondary outcome), and adverse events (secondary out-
come) between groups.
 Table 1

YBJOM-5922;
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Please cite this article in press as: Thambar S, et al. Botulinum toxin in the management of temporomandibular disorders: a systematic

Characteristics of the studies related to the participants.

First author, year, and Study design Diagnostic criteria for Duration of symptoms Age (years) Sex Sample size Dropouts
reference TMD before intervention
(months)
Single-centre, Myofascial pain with ≥ 6 months of 15 F Group 1: 15 5 (3 with pain

No. of Pages 12
Nixdorf 200218 placebo-controlled, or without disc moderate to severe Age range 18-45 escalation took
Group 2: 15
double-blinded, displacement pain analgesia, prohibited
crossover RCT by study design, 2 had
unilateral
zygomaticus major

S. Thambar et al. / British Journal of Oral and Maxillofacial Surgery xxx (2020) xxx–xxx
paralysis
Multicentre, Chronic facial pain ≥3 months, having Group 1: 60 Group 1: 0
von Lindern 200319 placebo-controlled, caused by had appropriate Not available Not available
Group 2: 30 Group 2: 0
single-blinded RCT hyperactivity of the conservative treatment
masticatory muscles,

ARTICLE IN PRESS
parafunctional
movement and
hypermobility
disorders
Single-centre, Myofascial pain and Group 1: 10 Group 1: 0
Guarda-Nardini 20084 placebo-controlled, clinical diagnosis of ≥6 months Age range 25-45 10 M and 10 F
Group 2: 10 Group 2: 0
double-blinded RCT bruxism

Single-centre, Myofascial pain with Time not specified, 20 F and 4 M (equally Group 1: 12 Group 1: 0
Kurtoglu 200820 placebo-controlled, or without disc but had to have “had Mean 26.5 assigned to both Group 2: 12 Group 2: 0
double-blinded RCT displacement undergone groups)
conservative TMD
treatment without
complete relief of
symptoms”
Multicentre, ≥6 months despite Group 1: 21 1
Ernberg 20119 placebo-controlled, Myofascial pain Mean 38 21 F
conservative treatment Group 2: 21
double-blinded,
crossover RCT

Guarda-Nardini Single-centre, Myofascial pain with 22 F and 8 M (equally Group 1: 15 Group 1: 0

controlled, or without disc ≥ 6 months Mean 45 assigned to both
201221 Group 2: 15 Group 2: 0
single-blinded RCT displacement groups)

Double-blinded, TMD pain >3 on a ≥3 months refractory Group 1: 10 Group 1: 1

Patel 201722 placebo-controlled 0–10 ordinal scale, at to conventional Not available Not available Group 2: 10 Group 2: 0
RCT with selective least 10 days/month treatment NB all patients in
crossover Group 1 rolled over
into the treatment
group (Group 2) at the
1-month review

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Variations in the study methods, the assessment tools used
to evaluate pain and the groups, made meta-analysis not pos-
sible.
Results
Search outcome
The selection process is shown in Fig. 1. Seven randomised
controlled trials met the inclusion criteria, two of which were
crossover studies.
Study characteristics
Tables 1 and 2 show the relevant characteristics of the studies
(published between 2002 and 2017).4,9,18–22 They included a
total of 220 patients, of whom 143 were treated by injection of
BTX-A. Considerably more women were included than men,
reflecting the demographics of the condition, and two studies
included women only. All the patients had been diagnosed
with TMD according to specific diagnostic criteria, and had
had symptoms for at least three months.
Treatment
Five studies reported the use of onabotulinumtoxinA (Botox,
Allergan),4,9,18–20 Guarda-Nardini et al21 reported the use
of abobotulinumtoxin-A (Dysport, Ipsen), and Patel et al22
incobotulinum toxin A (Xeomin, Merz Pharmaceuticals). All
patients had injections into the masseter, and in four studies,
both the masseter and temporalis were injected (Table 2).
Only Patel et al22 reported injection into the masseter, tem-
poralis, and lateral pterygoid muscle in all patients. Palpation
with electromyographic confirmation was done to identify
the target muscle in four studies.9,18,20,22 Von Lindern et
al19 used palpation in accordance with the muscle’s predeter-
mined topography; Guarda-Nardini et al used it with potential
ultrasonographic guidance in 2008,4 but palpation only in
2012.21 The total dose varied from 70U to 300U. Injections
were given bilaterally in a single session in all the studies,
and patients were followed up one month later. Three studies
reported additional long-term follow-up appointments.9,21,22
Assessment of bias
Table 3 shows the domains of the Cochrane risk-of-bias tool
with an assessment of bias for each study. Guarda-Nardini
et al in 201221 did not conceal allocation because the patients
in the control group had had multiple fascial manipulations
and it was not possible to blind the patients or practitioners.
A 30% dropout rate in the crossover study by Nixdorf et
al18 resulted in a high level of attrition bias. The study by
Patel et al22 also had a high level of attrition bias because
every patient in the control arm crossed over to the BTX-A
arm because of the poor improvement in pain at one-month
Please cite this article in press as: Thambar S, et al. Botulinum toxin in the management of temporomandibular disorders: a systematic
review. Br J Oral Maxillofac Surg (2020), https://doi.org/10.1016/j.bjoms.2020.02.007
review (in accordance with the study design). This meant that
data were missing from the control arm. The small sample
size in all the studies was a further source of bias. Finally, as
only three studies9,21,22 had a three-monthly follow up, the
short follow up in the remaining four4,18,19,20 constituted a
source of reporting bias.
Assessment of quality of methods
Table 4 shows the individual items used to calculate the Jadad
score, and scores for the methods used in each study.
Primary outcome: efficacy of BTX-A for pain
The summary outcomes of the studies are shown in Table 5.
The study by Nixdorf et al18 was a placebo-controlled,
double-blind, crossover RCT with crossover at 16 weeks to
allow for a four-week washout period. Pain was recorded on a
100-point left-to-right horizontal VAS. Even though the mean
(SD) reduction in pain was 19 (31) mm in the BTX-A group
and 1 (16) mm in the placebo group, it was not significant
(p = 0.10). Four patients in the study, however, improved with
a 20 mm reduction in pain.18 Only 10 completed the entire
study: five dropped out, and three took analgesia for the pain,
which had been prohibited in the study design.
The study by von Lindern et al19 was a placebo-controlled,
single-blind trial that assessed subjective pain scores on a
10-point VAS (0: no pain to 10: worst pain imaginable). In
91% of cases (55 patients) pain had improved by 3.2 points,
which was significant (p < 0.01). Nevertheless, the baseline
mean (SD) pain had not been reported. In a similar study
in 2008, Guarda-Nardini et al4 used a 10-point VAS, which
showed that pain at rest and on chewing had lessened in
the BTX-A group but had remained constant in the placebo
group. Kurtoglu et al20 used the research diagnostic criteria
for temporomandibular disorders (RDC/TMD) Axis II biobe-
havioural questionnaire and showed no significant difference
between the BTX-A and control groups. Similarly, in their
double-blind crossover RCT that assessed pain on a 100 mm
VAS, Ernberg et al9 showed no significant difference in pain
reduction between BTX-A and saline injections into the mas-
seter. However, the dropout rate was lower than that in the
study by Nixdorf et al,18 and there was an appreciable clinical
reduction in pain in the BTX-A group at the one-month and
three-month follow ups (Table 6).
The 2012 trial by Guarda-Nardini et al21 used a 10-point
VAS to compare BTX-A with fascial manipulation. The mean
(SD) pain score decreased to 5.2 (2.1) immediately after
injection and to 4.8 (2.0) at the three-month follow up. Finally,
Patel et al22 conducted a placebo-controlled, double-blind
RCT in which a patient-reported 10-point pain scale was
recorded at monthly intervals after injection. While there
was a significant reduction in the scores in the placebo group
after one month (p = 0.01), the overall reduction in mean pain
scores in the BTX-A group was larger. All patients in the
placebo group subsequently crossed over into the BTX-A
 YBJOM-5922;
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Table 2
Characteristics of the studies related to the interventions.
First author, year, and Intervention BTX brand Methods to identify target Target muscles injected Points injected, frequency Total dose Total follow
reference muscle up (months)

No. of Pages 12
Group 1: BTX-A Botox Palpation with Both groups: masseter Both groups: 50U masseter, 150U 2
Nixdorf 200218 electromyographic
Injection and temporalis 25U temporalis. (single
confirmation session, bilaterally)
Group 2: placebo NB: 0.6 ml for each dose
(normal saline) divided over 3 injection sites
injection in each muscle.

S. Thambar et al. / British Journal of Oral and Maxillofacial Surgery xxx (2020) xxx–xxx
Group 1: BTX-A Botox Palpation in accordance to Both groups: masseter, Both groups: dependant on Mean 70U 1
von Lindern 200319 pre-determined topography of temporalis or medial areas with pain, (single
injection
Group 2: placebo the corresponding muscle pterygoid muscle depending session, bilaterally)
(normal saline) on areas of maximal
injection tenderness and pain.

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Group 1: BTX-A Botox Palpation under Both groups: masseter and Both groups: four 100U 6
Guarda-Nardini 20084 anatomo-topographic and/or intramuscular injections
injection anterior temporalis
Group 2: placebo ultrasonographic control within the masseter (30U)
(normal saline) and three intramuscular
injection injections within the anterior
temporalis (20U) (single
session, bilaterally)

Group 1: BTX-A Botox Palpation with Both groups: masseter and Both groups: three injections 100U 0.5 and 1
Kurtoglu 200820 electromyographic within the masseter (30U)
injection temporalis
Group 2: placebo confirmation and two injections within the
(normal saline) temporalis (20U) (single
injection session, bilaterally)
Group 1: BTX-A Botox Palpation with Both groups: 3 standard 50U or 100U 1 and 3
Ernberg 20119 electromyographic Both groups: masseter points on each masseter–
injection
Group 2: placebo confirmation deep portion 0.1 ml (10U)
(normal saline) ×1, superficial portion 0.2 ml
injection (20U) ×2. (single session,
bilaterally)

Group 1: BTX-A Group 1: masseter and Both groups bilaterally 300U 1 and 3
Guarda-Nardini
injection Dysport Palpation only temporalis
201221 Group 2: fascial Group 1: single session,
manipulation Group 2: not applicable
dosing not specified
technique Group 2: weekly
Group 1: placebo Xeomin Palpation with Both groups: Group 1: 50U to each 170U 4
Patel 201722 electromyographic masseter, temporalis
(normal saline) masseter, 25U to each
injection confirmation and lateral pterygoid temporalis, 10U to each
muscle lateral pterygoid in a
Bilateral. Single session
Group 2: BTX-A Group 2: same volume NS
injection

5
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Table 3
Assessment of bias in the studies with the Cochrane risk-of-bias tool.

No. of Pages 12
First author, year, and Selection bias Selection bias Reporting bias Other sources of Performance Detection bias Attrition bias Overall bias
reference (random (allocation (selective bias bias (blinding of (blinding of (incomplete
sequence concealment) reporting) participants and outcome outcome data)
generation) personnel) assessment)

S. Thambar et al. / British Journal of Oral and Maxillofacial Surgery xxx (2020) xxx–xxx
Nixdorf 200218 Low Low High Low Unclear Unclear High Moderate
von Lindern 200319 Unclear Unclear Low High Low High Low Moderate
Guarda-Nardini 20084 High High High Low High High High High
Kurtoglu 20084 Low Low Low Unclear Low Low Low Low
Ernberg 20119 Low Low High High Low Low Low Moderate

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Guarda-Nardini 201221 High Low High High High High Low High
Patel 201722 Low Low Unclear High Low High Low Moderate

Table 4
Assessment of the quality of the study’s methods with the Jadad score.
First author, year, and Was the study Method of Double-blinded Method of Description of Deduct 1 point if Deduct 1 point if Overall score
reference randomised? randomisation study (+1) double blinding withdrawals and method of study was
(+1) described and described and dropouts (+1) randomisation double blinded
appropriate (+1) appropriate (+1) described and but method of
inappropriate binding
(−1) inappropriate
(−1)
Nixdorf 200218 Yes Yes Yes Yes Yes – – 5
von Lindern 200319 Yes No No No No – N/A 1
Guarda-Nardini 20084 Yes No Yes No Yes N/A – 3
Kurtoglu 200820 Yes Yes Yes Yes Yes – – 5
Ernberg 20119 Yes Yes Yes Yes Yes – – 5
Guarda-Nardini 201221 Yes Yes No No Yes −1 N/A 2
Patel 201722 Yes Yes No No Yes – N/A 3
 YBJOM-5922;
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Table 5
Summary outcomes of the studies at initial follow-up appointment.
First author, Intervention No. of Initial follow up Primary Mean (SD) pain intensity Mean (SD) maximal incisal opening (mm) Adverse effects

No. of Pages 12
year, and participants (months after outcome
reference injection) assessment tool
Before treatment After treatment Before treatment After treatment
Group 1: 10 – included in 2 100-point pain Group 1: −19 Group 1: 0 Group 1:
Nixdorf 200218 both groups 56 (SD N/A) 43 (SD N/A)
BTX-A VAS (31) asymmetrical

S. Thambar et al. / British Journal of Oral and Maxillofacial Surgery xxx (2020) xxx–xxx
injection (crossover trial) smile as a result
of paralysis of
zygomaticus
major (2
patients),

ARTICLE IN PRESS
escalation of
pain (1 patient)
Group 2: normal Group 2: −1 Group 2: +10 (9) Group 2:
saline injection (16) escalation of
pain (2 patients)
von Lindern Group 1: Group 1: 12 1 10-point pain N/A Group 1: −3.2 N/A N/A Group 1: 1
200319 BTX-A VAS (N/A) patient with
injection temporary
swallowing
difficulty or
localised
paralysis of
muscle of facial
expression
(specific
symptom not
specified in
article)
Group 2: normal Group 2: 12 Group 2: −0.4 Group 2: none
saline injection (N/A)
Guarda-Nardini Group 1: Group 1: 21 1 10-point pain Group 1: 5 Group 1: 2.5 Group 1: 46.3 Group 1: 46.6 None
20084 BTX-A VAS (3.62) (2.72) (8.74) (9.61)
injection
Group 2: normal Group 2: 21 Group 2: 3.9 Group 2: 3.7 Group 2: 43.8 Group 2: 43.9
saline injection (2.92) (2.67) (9.4) (9.15)
Group 1: Group 1: 15 1 RDC/TMD Group 1: 56.1 Group 1: 43.9 N/A N/A None
Kurtoglu 200820 questionnaire
BTX-A (17.1) (25.2)
injection (characteristic
Group 2: normal Group 2: 15 pain intensity) Group 2: 58.9 Group 2: 51.4
saline injection (14.7) (23.0)

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First author, Intervention No. of Initial follow up Primary Mean (SD) pain intensity Mean (SD) maximal incisal opening (mm) Adverse effects
year, and participants (months after outcome
reference injection) assessment tool
Before treatment After treatment Before treatment After treatment

No. of Pages 12
Group 1: Group 1: 10 1 RDC/TMD Group 1: 69 (11) Group 1: 61 (15) Group 1: 42.7 Group 1: 44.3 Group 1:
Ernberg 20119 BTX-A questionnaire (11.3) (7.2) headache (7),
injection (characteristic muscle
pain intensity) weakness (2),
increased pain

S. Thambar et al. / British Journal of Oral and Maxillofacial Surgery xxx (2020) xxx–xxx
(3),
influenza-like
symptoms (2)
Group 2: normal Group 2: 10 Group 2: 67 (14) Group 2: 65 (15) Group 2: 43.4 Group 2: 44.3 Group 2:
saline injection (7.3) (7.3) headache (9),

ARTICLE IN PRESS
muscle
weakness (4),
increased pain
(1),
influenza-like
symptoms (1)
NB: all side
effects had
resolved at the
1-month follow
up
Guarda-Nardini Group 1: Group 1: 15 1 10-point pain Group 1: 7.3 Group 1: 5.2 Group 1: 48.7 N/A (recorded at Group 1: minor
201221 BTX-A VAS (1.1) (2.1) (8.3) 3 month discomfort
injection follow-up) during chewing
in the first two to
three weeks
after treatment
Group 2: fascial Group 2: 15 Group 2: 6.0 Group 2: 2.1 Group 2: 52 Group 2: some
manipulation (2.0) (1.4) (9.5) pain with digital
pressure on
manipulation
(four patients)
Group 1: normal Group 1: 12 1 10-point patient Group 1: 5.43 Group 1: 3.71 N/A N/A None
Patel 201722 -reported pain
saline injection (2.6) (2.5)
Group 2: Group 2: 12 scale Group 2: 5.4 Group 2: 0.9
BTX-A NB: all Groups (2.1) (1.7)
injection 1 patient rolled
over into the
treatment group
at 1 month

VAS: visual analogue scale; RDC/TMD: research diagnostic criteria for temporomandibular disorders.
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Fig. 1. Flow chart of the article search and selection.

group. Pain scores remained lower than baseline at long-
term follow-up appointments, and the results were significant
(p = 0.004).22
In summary, BTX-A injection reduced pain in the short-
term in the studies by Kurtoglu et al,20 von Lindern et al,19
Guarda-Nardini et al,21 and Patel et al,22 but those by Nixdorf
et al18 and Ernberg et al9 showed no significant improvement.
Ernberg et al,9 however, showed clinically appreciable short-
term and long-term improvements.
Secondary outcome: efficacy of BTX-A on maximal
mouth opening
that five patients had dropped out of the study because of
adverse effects. Pain had increased in three and they had
started taking analgesics, which was prohibited by the study
design, although two were in the placebo group. The other
adverse effect, which was experienced by two patients in
the BTX-A group, was unilateral paralysis of the zygomati-
cus major. In their 2012 study, Guarda-Nardini et al reported
that one patient had had minor discomfort for a few weeks
while chewing.21 Ernberg et al9 reported seven patients with
headache, two with weakness, three with increased pain, and
two with influenza-like symptoms, all of which resolved.

The efficacy of BTX-A injection on maximal mouth opening Discussion

was assessed in both studies by Guarda-Nardini et al,4,21 and
the two crossover studies.9,18 Descriptive analysis from the
2008 study by Guarda-Nardini et al4 showed a slight increase
in the maximum non-assisted mouth opening in the BTX
group but no change in the placebo group. Their 2012 study21
showed that at the three-month follow-up, mouth opening had
improved slightly in the BTX-A group. In contrast, Nixdorf
et al18 found that maximum mouth opening had improved by
5 mm in the placebo group but worsened by 3 mm in the BTX-
A group. Their study, however, had a high risk of attrition bias
because a large number of patients dropped out, affecting
its internal and external validity. Ernberg et al9 showed no
change in the BTX-A or placebo group at the short-term and
long-term follow-up appointments.
Secondary outcome: adverse effects
All the reported adverse effects were temporary and were
known side-effects of BTX-A. Nixdorf et al18 reported
BTX has been approved for many conditions including
cervical dystonia, overactivity of the bladder, and chronic
migraine,16 but it has not been firmly approved for TMD
because reported findings have varied. To address this, we
have incorporated evidence from a wider search of the
databases than was done previously.
The benefits of the muscle-relaxing properties of BTX
were first shown by Schwartz and Freund who reported
that 90% of patients with muscular and autogenous pain
showed improvements in pain and function after topical
application.23 Several subsequent case series and cohort stud-
ies that reported varying techniques and dosages of BTX,
also showed an improvement in the symptoms of TMD. A
trial concluded that after injection into the masseter and tem-
poralis, BTX-A also indirectly reduced inflammation in the
articular structures.19
There is consensus that mechanisms of the peripheral
and central nervous systems are responsible for the pain in

Please cite this article in press as: Thambar S, et al. Botulinum toxin in the management of temporomandibular disorders: a systematic
review. Br J Oral Maxillofac Surg (2020), https://doi.org/10.1016/j.bjoms.2020.02.007
YBJOM-5922; No. of Pages 12
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TMD,19 and it has been postulated that injection of BTX

leads to the direct attenuation of muscle contractions through

Group 1: 44.3 (7.3)

Group 2: 44.2 (8.7)

chemical denervation.24 It also has a direct analgesic effect

Group 1: 51.4 (SD

Group 2: 52.4 (SD

Mean (SD) maximal incisal opening (mm)

After treatment
on sensory nociceptive symptoms, as it partially antagonises
the release of substance P, glutamate, and calcitonin gene-
regulated peptide.24 This reduction in pain typically occurs

N/A)

N/A)
N/A
a few days after injection and also occurs in neighbouring
muscle groups.4
BTX is available in four different formulations and
Group 1: 42.7 (11.3)

Group 2: 43.4 (7.3)

Group 1: 48.7 (8.3)

potencies: abobotulinumtoxinA (Dysport, Ipsen), incobo-
Group 2: 52 (9.5)
Before treatment

tulinumtoxinA (Xeomin, Merz Pharmaceuticals), onabo-

tulinumtoxinA (Botox, Allergan), and rimabotulinumtoxinB
N/A (Myobloc, Solstice Neurosciences). Botox was used in most
of the studies, but Xeomin and Dysport were used in one study
each.21,22 Each product has an individual potency and is not
interchangeable with any other, so further trials are needed
to compare the different formulations.25 BTX was diluted
Group 1: 4.8 (2.0)

Group 2: 2.5 (2.2)

Group 1: N/A (no

group 2: 1.0 (1.7)

Group 1: 58 (14)

Group 2: 65 (11)

longer receiving
After treatment

with normal saline in all the studies, but published data have
shown that local anaesthesia can also be used as a vehicle
control)

without altering its clinical effects.26 This would minimise

the discomfort after the injection and could be considered in
future trials.
Mean (SD) pain intensity

This review has highlighted the importance of consistent

Group 1: 5.43 (2.6)

diagnostic criteria for TMD, with six of the studies using

Group 1: 7.3 (1.1)

Group 2: 6.0 (2.0)

Group 2: 5.4 (2.1)

Before treatment
Group 1: 69 (11)

Group 2: 67 (14)

the RDC/TMD, and only one study using its own criteria.19
Most studies used a VAS to assess pain, whereas others used
a behavioural scale. Given that no verbal descriptors were
assigned to individual numbers in these scales, the interpreta-
tion of the values by patients is ambiguous, as is the reporting
VAS: visual analogue scale; RDC/TMD: research diagnostic criteria for temporomandibular disorders.

of statistical analyses.27 In their comparison of the validity

patient-reported pain
(characteristic pain

10-point pain VAS

and reliability of a VAS, a numerical scale, and a behavioural

Primary outcome
assessment tool

scale, Conti et al28 reported that a numerical scale was the best
questionnaire
RDC/TMD

way to score pain reproducibly. They concluded that although

intensity)

10-point

it was more accurate, caution was needed when analysing the

scale

results because of the lack of a gold standard for comparison,

as well as the subjective aspect of measurements of pain,
and the normal fluctuations of TMD symptoms.28 For this
Long-term follow up

group by this stage)

patients rolled over
3 (NB: all Group 1

reason, a standard numerical scale should be considered in

into the treatment
Summary outcomes of the studies that reported long-term follow up.

subsequent trials.
(months after

The review has also highlighted two problems associated

injection)

with the secondary outcome of maximum mouth opening.

Limited mouth opening is most often a presenting com-
3

plaint for three categories of diagnoses: disc displacement

with or without reduction, and myofascial pain. This, how-
ever, was not reported as part of the diagnosis in any of
Group 1: BTX-A

Group 1: BTX-A

Group 2: BTX-A
Group 2: normal

Group 1: normal
Group 2:fascial
saline injection

saline injection

the studies. Although Guarda-Nardini et al4 and Nixdorf et

manipulation
Intervention

al18 reported conflicting results, and Ernberg et al9 found

injection

injection

injection

no significant change, all three studies reported initial mea-

surements between 43.0 mm and 46.3 mm. Understanding
that the mean (SD) mouth opening in men is 51.3 (8.3) mm
First author, year, and

and in women is 44.3 (6.7) mm, and that this reduces with
age, a significant increase from the initial measurement may
Guarda-Nardini
Ernberg 20119

not be possible (although it may still improve), as was the

Patel 201722

case in the study by Ernberg et al.9 Definite conclusions as

reference
Table 6

201221

to whether BTX-A injections would improve mouth open-

Please cite this article in press as: Thambar S, et al. Botulinum toxin in the management of temporomandibular disorders: a systematic
review. Br J Oral Maxillofac Surg (2020), https://doi.org/10.1016/j.bjoms.2020.02.007
YBJOM-5922; No. of Pages 12
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S. Thambar et al. / British Journal of Oral and Maxillofacial Surgery xxx (2020) xxx–xxx
ing cannot be made based on current evidence. Studies to
compare the outcomes of BTX-A injections and placebo in
patients with a primary complaint of limited mouth opening
would be helpful.
There was considerable variation in the masticatory mus-
cles injected and doses of BTX used. All the studies reported
injection into the masseter, but Ernberg et al9 treated this
muscle alone, possibly limiting the effect. The other stud-
ies reported injection into the temporalis and masseter as
a minimum, with von Lindern et al19 including the medial
pterygoid, and Patel et al22 the lateral pterygoid. The total
dose varied from 50U9 unilaterally to 300U bilaterally.21
However, Dysport, which was used in the latter study, has
an efficacy of 0.4:1 compared with Botox, and would have
been equivalent to 60U Botox. Most of the studies reported
electromyographic evaluation to confirm the target mus-
cle. It must be noted that definitive evidence is limited on
which muscles to inject, but as six reported injection into
the masseter and temporalis, this could at least be considered
anecdotal evidence.
Despite a total of 220 participants being included across
the seven studies, most had small sample sizes (around
14/group), which has ultimately reduced the quality of the
evidence. A sample size for future studies (at 5% Type 1 error)
has been estimated to be 21/group. This was calculated from
the required change in VAS scores (approximately 30%) and
the existing SD in the results.
The high dropout rate in the study by Nixdorf et al18
resulted in incomplete outcome data and a high risk of attri-
tion bias.29 Attrition bias is always difficult to manage for a
chronic condition like TMD in which a patient may think that
the treatment is not having an effect, nevertheless this was the
only trial affected.29 The study was a crossover trial, and these
often have the added issue of patient bias, which results from
expectations of the treatment effect. For example, a patient
whose pain is reduced after the first injection, may expect the
second injective to be less effective. Those who experienced
changes in facial expression may have assumed they had been
treated with BTX and may not have wanted to continue the
placebo injections because of post-injection pain. This was
encountered by Nixdorf et al18 and it ultimately affected the
analysis of the results.
Future studies would benefit from longer follow-up peri-
ods. Freund and Schwartz30 found that maximum voluntary
clenching decreases after two weeks and reverts to baseline
levels as a result of axonal sprouting and reinnervation, which
occurs in eight weeks.30 Kurtoglu et al20 found that 28 days
of follow up was adequate given the differences in measure-
ments between the groups. As the effect of BTX can last up
to six months, this would be the most suitable period for fol-
low up, but only one study reported it for this period. There is
also great variation among patients regarding the optimal fre-
quency of dosing and duration of effect, which supports the
importance of patient-directed treatment.23 This should be
considered in future trials to ensure an appropriate duration
of follow up.
Please cite this article in press as: Thambar S, et al. Botulinum toxin in the management of temporomandibular disorders: a systematic
review. Br J Oral Maxillofac Surg (2020), https://doi.org/10.1016/j.bjoms.2020.02.007
11
Finally, all the patients were screened for the known con-
traindications to BTX: inflammation at the proposed injection
site, breast-feeding, pregnancy, chronic degenerative neu-
romuscular disorders, and treatment with aminoglycoside
antibiotics.12 All the adverse effects experienced by the
patients were temporary and included localised pain, diffi-
culty chewing, and focal muscle weakness. Paralysis of the
zygomaticus major that resulted in an asymmetrical smile was
common and is thought to be the result of local diffusion of the
BTX-A from the masseter, or direct trauma to the muscle.18
It is important to consider that this local diffusion of BTX-
A may depend on the dose and volume, and may increase
around areas of compromised fascial integrity; another point
that should be considered to minimise side effects in future
studies.31,32
The high costs of treatment with BTX compared with other
conservative measures also needs consideration. In a pilot
study that looked at the osteopenic consequences of BTX
injections into the masticatory muscles, Raphael et al33 found
reduced density in all patients who had been exposed to BTX,
and normal density in those who had not.
Conclusion
We have found variation in the study designs, inconsis-
tent reporting on assessment tools, and heterogeneous study
groups. Overall, the level of bias was moderate to high, mak-
ing the evidence moderate to low. Despite showing benefits,
clear consensus is lacking on the therapeutic benefit of BTX
in the management of myofascial TMD. Further RCT with
minimal bias, larger sample sizes, and longer follow-up peri-
ods are now needed. We must find the optimal target site and
dose, conduct feasibility tests for the cost of BTX, and find out
whether the benefit:cost ratio is clinically acceptable. Never-
theless, this review has shown that in patients with myofascial
TMD who have had at least three months’ appropriate con-
servative management, BTX can improve outcomes.
Conflict of interest
We have no conflicts of interest.
Ethics statement/confirmation of patients’ permission
Not applicable.
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