Botulinum Toxin Versus Placebo Injections to Temporalis and Masseter Muscles

Myofascial pain is classically used to describe pain experienced in the masticatory muscles
and its associated structures (Freund 1999). It afflicts nearly 10% of Americans (Freund
2000). There have been many described treatments such as the use of oral appliances,
non-steroidal anti-inflammatory medications, physiotherapy, behavioral therapy and
counseling, acupuncture, and botulinum toxin injections (Freund 2000). However, no single
treatment has been found to be significantly superior to the others (Freund 2000).

This is a randomized, double-blind, placebo-controlled multicenter study. Subjects will be
recruited from the divisions of Oral and Maxillofacial Surgery from all sites. Patients aged
18-65 years with myofascial pain involving the temporalis and masseters are eligible to enter
the study. A complete history and physical examination will be performed for all patients in
order to make an accurate diagnosis. The research diagnostic criteria (RDC/TMD) will be used
to assign a diagnosis of myofascial pain of the masticatory region. All investigators and
site-specific data collectors will be trained and calibrated in physical examination
techniques and data collection to ensure uniformity between sites. Patients will complete a
visual analog scale regarding pain during their screening appointment. To participate in the
study, the subject must have greater than or equal to 3.5/10 on the visual analog scale of
pain. Informed written consent will be obtained from all patients. Any patient lacking the
capacity to make medical decisions will be excluded from the study, although they will be
treated as deemed medically necessary. Consent will be written at the sixth grade level, and
all potential subjects will be asked to verbally repeat the purpose, methods, and required
follow-up to ensure adequate understanding.

The site specific PI will educate fellow faculty and referring departments that the study is
enrolling new subjects, advertising is anticipated, and referring physicians will not receive
any financial compensation. The intent is to enroll a total of 110 subjects from all sites.
The study participants will be reimbursed $25 per treatment visit for their participation.

Previous studies have demonstrated a reduction of pain as indicated on the visual analogue
scale of 45% and 32% with the use of intramuscular botulinum toxin A injections into masseter
and temporalis (Freund 1999, Guarda-Nardini 2012). Von Lindern et. al. found a mean reduction
of 3.2 points on a visual analog scale in the verum group. Based on the preliminary data and
the sample size calculations estimating a difference in mean pre-post VAS change between
groups of 1 point or greater (on a scale of 1-10), we plan to enroll a total of 110 subjects.
With 50 patients in the botulinum toxin A injection group and 50 patients in the placebo
group (N=100), the study will have more than 90% power to detect a difference in mean in
pre-post change between groups of 1.0 point or greater on VAS, using a two-sided t-test and
assuming a standard deviation of 1.5 for the mean difference. This calculation allows for 10%
attrition rate. An intent-to-treat design will be followed and all subjects will have
scheduled outcome evaluations until the end of the study, death of the subject, or subject
refusal. Subjects will be withdrawn from their randomly assigned treatment for considerations
of subject safety only.

Descriptive statistics including mean, standard deviation, median, range, frequency, and
percent will be calculated for the entire cohort as well as by the study arm (botulinum toxin
A and unpreserved 0.9% sodium chloride) to assess the results of randomization and identify
potential confounders. The primary analyses of the data will be performed according to
subjects' original treatment assignment (i.e., intention-to-treat analyses) and the inclusion
of all data from all subjects randomized in the final analysis. To assess the primary
endpoint of improvement of pain on a visual analog scale (VAS) between pre-op, 1, 2, and
month post-op, and 3 months post-op, a repeated measure of analysis of variance will be
performed with one between subject factor (botulinum toxin A versus placebo) and one within
subject factor (time). This analysis will also be used for the secondary endpoints: function
(MIO/jaw limitation scale) and quality of life (SF12). In the event of significant loss to
follow-up, we will explore the use of a linear mixed model to assess the independent effect
of the study group on VAS over the study visits. The paired t-test, or the signed-rank test
as appropriate, will be used to assess change in pain, function, and QOL between pairs of
relevant time points for both study arms. To assess the difference in proportion of adverse
events between the botulinum toxin A and placebo groups, either the chi-square or Fisher's
exact test will be used, as appropriate. All p-values will be two-sided with statistical
significance evaluated at the 0.05 alpha level. Ninety-five percent confidence intervals (95%
CI) will be calculated to assess the precision of the obtained estimates. All analyses will
be performed in SAS Version 9.4 (SAS Institute Inc., Cary, NC). Note: This section was
drafted in conjunction with Dr. Paul Christos and Gulce Askin, MPH in the Division of
Biostatistics and Epidemiology, Department of Healthcare Policy and Research. They will be
aiding in protocol design and development, data management, study implementation, study
monitoring, and data analysis and reporting.

Adverse events will be reported to the Data and Safety Monitoring Board every six months. The
participants will be provided with the phone number of the primary investigator and
co-investigators for use in reporting any adverse events. The study participants will also be
questioned at one, two, and and three months post-treatment for the occurrence of any adverse
events. The report of any such events will provide details including severity, relationship
to treatment, onset, duration, and outcome. The Data and Safety Monitoring Board will
regularly review these reports, and should any trend develop that suggests significant
adverse outcomes, the study will be discontinued. If any serious adverse events occur (death,
life-threatening, those involving prolonged hospitalization or disability), the independent
study monitor, other study sites, IRBs, and DSMB will be notified with 24 hours in the case
of death or 72 hours in the event of other serious adverse events.

IRB approval for this study is currently in process (assigned protocol number 1607017383).
Pending approval from the IRB for each involved site, research investigators will honor their
responsibility to safeguard the rights and welfare of individuals who are or may become
subjects of research. Investigators will also maintain compliance with Department of Health
and Human Services regulations. All requirements and determinations made by the IRB will be
followed to minimize unnecessary risks to subjects. The investigators will abide by
procedures consistent with sound research design. Botulinum toxin A is currently not FDA
approved for use in myofascial pain disorder of the masticatory region. If the IRB deems its
use a "subject risk," an application for investigational new drug (IND) will be submitted to
the FDA under the research or noncommercial category. This requirement is not anticipated
given the routine use of botulinum toxin A, previous studies demonstrating benefit with
minimal risk, and its existing FDA approval for use in the masseter and temporalis muscles
for orofacial dystonia/dyskinesia.

Inclusion Criteria:

- 18-65 years of age

- Ability to give informed consent

- Myofascial pain of masticatory muscles as defined according to the RDC/TMD criteria

- Baseline pain measured by the subject ≥3.5/10 on visual analog scale

Exclusion Criteria:

- Baseline pain measured by the subject <3.5/10 on visual analog scale

- Central/Neuropathic pain disorder affecting the masticatory muscles

- Temporomandibular Joint Arthralgia that is more severe than the myofascial pain
disorder affecting the masticatory muscles

- Previous Temporomandibular Joint Surgery

- Systemic arthropathies

- Fibromyalgia

- Allergy to study medications

- Traumatic injury of masticatory muscles or temporomandibular joint within last 12
months

- Mandibular fracture within last 12 months

- Pregnancy or breast feeding

- Cervical radiculopathy or surgery

- Prior botox injection in the masticatory muscles

- Initiation of additional treatment of MPD within the past 3 months