Research Paper

Efficacy and safety of propranolol for treatment of

temporomandibular disorder pain: a randomized,
placebo-controlled clinical trial
Inna E. Tchivilevaa,b,*, Holly Hadgraftc, Pei Feng Lima,d, Massimiliano Di Giosiaa,d, Margarete Ribeiro-Dasilvae,
John H. Campbellf, Janet Willisc, Robert Jamesc, Marcus Herman-Giddensc, Roger B. Fillingime, Richard Ohrbachg,
Samuel J. Arbes Jrc, Gary D. Sladea,h

Abstract
Propranolol is a nonselective beta-adrenergic receptor antagonist. A multicenter, randomized, double-blind, placebo-controlled,
Downloaded from http://journals.lww.com/pain by BhDMf5ePHKbH4TTImqenVL3xadaqxR5nAvs5/UGXp0TPMLk7e5srmC3Jw3cMq8TRwbjcrBL0vyU= on 07/26/2020

parallel-group, phase 2b trial enrolled participants aged 18 to 65 years with temporomandibular disorder myalgia to evaluate efficacy
and safety of propranolol compared with placebo in reducing facial pain. Participants were randomized 1:1 to either extended-release
propranolol hydrochloride (60 mg, BID) or placebo. The primary endpoint was change in facial pain index (FPI 5 facial pain intensity
multiplied by facial pain duration, divided by 100). Efficacy was analyzed as a mean change in FPI from randomization to week 9 and as
the proportion of participants with $30% or $50% reductions in FPI at week 9. Regression models tested for treatment-group
differences adjusting for study site, sex, race, and FPI at randomization. Of 299 participants screened, 200 were randomized; 199 had
at least one postrandomization FPI measurement and were included in intention-to-treat analysis. At week 9, model-adjusted
reductions in mean FPI did not differ significantly between treatment groups (21.8, 95% CL: 26.2, 2.6; P 5 0.41). However, the
proportion with a $30% reduction in FPI was significantly greater for propranolol (69.0%) than placebo (52.6%), and the associated
number-needed-to-treat was 6.1 (P 5 0.03). Propranolol was likewise efficacious for a $50% reduction in FPI (number-needed-to-
treat 5 6.1, P 5 0.03). Adverse event rates were similar between treatment groups, except for more frequent fatigue, dizziness, and
sleep disorder in the propranolol group. Propranolol was not different from placebo in reducing mean FPI but was efficacious in
achieving $30% and $50% FPI reductions after 9 weeks of treatment among temporomandibular disorder participants.
Keywords: Temporomandibular joint disorder, Orofacial pain, Beta-blocker, Analgesia, Chronic pain, Migraine, SOPPRANO,
TMD, Myofascial pain

1. Introduction temporomandibular joints. In 2002, symptoms affected 6.3%

Painful temporomandibular disorder (TMD) is a common
musculoskeletal condition most often caused by myalgia
of masticatory muscles and/or arthralgia of the
Sponsorships or competing interests that may be relevant to content are disclosed
at the end of this article.
a
Center for Pain Research and Innovation, Adams School of Dentistry, University of
North Carolina at Chapel Hill, Chapel Hill, NC, United States, b Division of Oral and
Craniofacial Health Sciences, Adams School of Dentistry, University of North Carolina at
Chapel Hill, Chapel Hill, NC, United States, c Rho Inc, Durham, NC, United States,
d
Division of Diagnostic Sciences, Adams School of Dentistry, University of North Carolina
at Chapel Hill, Chapel Hill, NC, United States, e Department of Community Dentistry &
Behavioral Science, University of Florida, Gainesville, FL, United States, Departments of
f
Oral and Maxillofacial Surgery and, g Oral Diagnostic Sciences, University at Buffalo,
State University of New York, Buffalo, NY, United States, h Division of Pediatric and
Population Health, Adams School of Dentistry, University of North Carolina at Chapel Hill,
Chapel Hill, NC, United States
*Corresponding author. Address: Center for Pain Research and Innovation, Adams
School of Dentistry, University of North Carolina at Chapel Hill, CB #7455, Chapel
Hill, NC 27599, United States. Tel.: 11 919 537 3291; fax: 11 919 966 5339. E-mail
address: inna@unc.edu (I.E. Tchivileva).
Supplemental digital content is available for this article. Direct URL citations appear
in the printed text and are provided in the HTML and PDF versions of this article on
the journal’s Web site (www.painjournalonline.com).
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© 2020 International Association for the Study of Pain
http://dx.doi.org/10.1097/j.pain.0000000000001882
of females and 2.8% of males in the U.S. adult population,35
and prevalence has not changed appreciably.46,58 Chronic
TMD is associated with substantial disability and suffering, and
it diminishes quality of life.13 Jaw pain is the most common
symptom that compels patients to seek treatment. One study
reported an average TMD pain intensity rating of 4.3 on an 11-
point scale, similar to the averages reported for chest pain and
back pain.75 In addition to facial pain, patients with TMD
frequently report various comorbid idiopathic pain conditions
such as headache, low back pain, and fibromyalgia.8,58
The current pharmacological approaches to treat painful TMD
comprise nonsteroidal anti-inflammatory drugs (NSAIDs), corti-
costeroids, benzodiazepines, sedative hypnotics, muscle relax-
ants, opioids, antidepressants, and anticonvulsants.31,32,43
However, the 2010 Cochrane review of pharmacological
interventions for TMD concluded that there is insufficient
evidence to support the effectiveness of the reported drugs and
it emphasized a need for high-quality randomized controlled trials
for this condition.49
Temporomandibular disorder–associated pain has a significant
sympathetic component supported by the ample sympathetic
innervation of the TMJ.38,78 In rodent models of TMD, the
depletion of norepinephrine or the blockade of b-adrenergic
receptor reduced carrageenan-induced TMJ hyperalgesia61 and
formalin-induced TMJ nociception.25 A recent report found that

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the analgesic effect of a nonselective b-adrenergic receptor
antagonist propranolol in the carrageenan-induced TMJ hyper-
algesia in female rats was associated with reduction in joint
inflammation.80 In addition, intramuscular injection of propranolol
in rats also reduced carrageenan-induced pain of the gastroc-
nemius muscle.41 Although these studies used animal models of
inflammatory pain, it should be noted that subclinical muscle
inflammation in humans is one of the plausible causes for chronic
TMD myalgia.44
In humans, injection of propranolol into the masseter muscle of
healthy volunteers decreased pain induced by local administra-
tion of serotonin,20 but not of hypertonic saline.3 Human studies
exploring adrenergic blockade for treatment of TMD-related pain
are scarce: one study demonstrated pain relief after a single-dose
injection of propranolol41 and our pilot study found a decrease in
pain rating after 1-week treatment with propranolol.70 Currently,
extended-release propranolol is indicated for treatment of
hypertension, angina pectoris due to coronary atherosclerosis,
migraine, and hypertrophic subaortic stenosis.36
To further investigate propranolol as a novel drug for
management of TMD-associated pain, we conducted a phase
2b randomized controlled trial (SOPPRANO: Study of Orofacial
Pain and PropRANOlol). The primary objective of the trial was to
evaluate efficacy of propranolol compared to placebo in reducing
a composite index of facial pain intensity and duration after 9
weeks of treatment among participants with TMD. Secondary
objectives were to assess participant safety and to evaluate
efficacy using secondary endpoints measuring other aspects of
facial pain, physical and emotional functioning, and participant
ratings of improvement.
2. Methods
2.1. Trial oversight
The trial protocol was approved by the institutional review boards
at each trial site. Written informed consent was obtained from
each participant before any study assessments or procedures
were conducted. Twice a year, the trial was reviewed by the
independent Data Safety Monitoring Board, and 100% of critical
trial data were externally monitored.
2.2. Trial participants and inclusion/exclusion criteria
Participants were recruited from communities at 3 sites in the
United States: the University of North Carolina at Chapel Hill
(UNC), Chapel Hill, North Carolina; the University of Florida (UF),
Gainesville, Florida; and the University at Buffalo (UB), Buffalo,
New York. The recruitment continued from August 2015 to
January 2018, and the follow-up of the last participant was
finished in April 2018. The UB site started enrollment in January
2017. Eligible participants were women and men aged 18 to 65
years who had TMD myalgia (with or without arthralgia) when
assessed at the baseline visit by study examiners who used the
Diagnostic Criteria for Temporomandibular Disorders (DC/
TMD).64 Details of the DC/TMD examination are described
below. Participants also had to report having experienced facial
pain for at least 3 months, and had at least 10 days with facial pain
in the 30 days before the examination. Another inclusion criterion
was based on facial pain intensity reported on a “0” to “100”
numerical rating scale in a daily symptom diary (DSD). Specifi-
cally, during the week before randomization, participants had to
report a pain rating of $30 on at least 3 days, or their weekly
average rating was $30. The former criterion was added to the
Copyright © 2020 by the International Association for the Study of Pain. Unauthorized reproduction of this article is prohibited.
PAIN®
protocol in March 2016 to complement the existing pain intensity
criterion with a modification that assessed frequency of painful
days.
As rescue medication, participants were allowed to take over-
the-counter (OTC) NSAIDs, acetaminophen or aspirin, episodi-
cally, where the episodic use was defined as no more than 3
consecutive days and no more than 18 total days of NSAIDs from
baseline to treatment week 9. Concomitant use of prescription
pain medications was allowed only if the medication was taken
daily for at least 30 days before a baseline phase and continued to
be taken daily during the trial. Orofacial appliances for facial pain
could be used during the trial if their use was initiated at least 30
days before a screening visit and maintained for the duration of
the trial.
Exclusion criteria were congestive heart failure, a clinically
significant abnormal 12-lead electrocardiogram, sinus bradycar-
dia, uncontrolled hypertension or hypotension, bronchial asthma,
nonallergic bronchospasm, renal failure or dialysis, diabetes
mellitus, hyperthyroidism, fibromyalgia, or uncontrolled seizures;
used opioids, b-blockers, or medications that could interact with
propranolol; had facial trauma or orofacial surgery within 6 weeks
before a screening visit; had major psychiatric disorders requiring
hospitalization within the last 6 months before a screening visit;
had treatment for drug or alcohol abuse within the last year; or
were pregnant or nursing. The detailed list of inclusion/exclusion
criteria is provided in the Supplementary Materials (available at
http://links.lww.com/PAIN/A988).
2.3. Trial design and intervention
This multisite, randomized, double-blind, placebo-controlled,
parallel-group, phase 2b trial consisted of a telephone or visit
prescreening (conducted up to 28 days before a screening visit),
a baseline period (1-3 weeks), a treatment period (10 weeks
including a 1-week titration, an 8-week maintenance period, and
a 1-week taper), and a follow-up period (1 week). A diagram of the
trial is presented in Figure 1. After signing informed consent at the
screening visit, participants were evaluated for eligibility during
a subsequent baseline period. Eligible participants were ran-
domized to receive propranolol hydrochloride extended release
60 mg twice daily (BID) or placebo. In both treatment arms, the
study drug was titrated starting with one capsule per day (QD) in
the evening and increasing after one week to 2 capsules per day
(in the morning and in the evening). After reaching the target dose,
participants stayed on this dose for 8 weeks and then were
tapered down to one capsule per day (in the evening) for 1 week
before terminating the use of the study drug. Dose adjustment
and drug discontinuation were allowed in case of adverse events
(AEs). For protocol-specified evaluations, participants completed
6 scheduled visits: screening, randomization (propranolol 60 mg
QD), week 1 (propranolol 60 mg BID), week 5 (propranolol 60 mg
BID), week 9 (propranolol 60 mg QD), and week 11 (follow-up).
2.4. Randomization and masking
Randomization was initiated by study coordinators through an
electronic web response system. The randomization list was
generated centrally by randomization staff at the Data Co-
ordinating Center (DCC; Rho Inc, Durham, NC), who remained
independent from other DCC staff throughout the trial. The
randomization sequence was created with Proc Plan in SAS
statistical software (SAS v9.2, SAS Institute Inc, Cary, NC) and
was stratified by study site with a 1:1 allocation using fixed
permutated blocks of 4. The DCC sent randomization
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Figure 1. Trial design.
assignment directly to site pharmacies that prepared bottles with
investigational product for participants.
An independent pharmacy (Triangle Compounding Pharmacy,
Cary, NC) provided 60-mg extended release propranolol over-
encapsulated in a blue, oblong capsule and matching placebo. The
placebo was matched to the study drug for color, size, and weight,
and contained microcrystalline cellulose. The matched drug and
placebo were shipped to site pharmacies for distribution to study
coordinators. Site staff, investigators, participants, monitors, and
a statistician analyzing a primary endpoint were blinded to the
allocation. The blinding was tested by asking participants to report
their perceived group allocation at weeks 5 and 9 of treatment.
2.5. Trial endpoints and procedures
We followed recommendations of the Initiative on Methods,
Measurement, and Pain Assessment in Clinical Trials (IMMPACT)16
by measuring 6 core domains: (1) pain, (2) physical functioning, (3)
emotional functioning, (4) participant ratings of improvement, (5)
symptoms and AEs, and (6) participant disposition. As further
recommended by IMMPACT,18 we conducted thermal and
mechanical quantitative sensory testing. The endpoints were
collected at baseline and weeks 5 and 9 of treatment, if not
otherwise specified.
2.5.1. Primary endpoint
As specified a priori in the study protocol, the primary endpoint
was change in a weekly mean facial pain index (FPI) after 9 weeks
of treatment. The pain index was selected as the primary
endpoint based on findings from the pilot study,70 where the
composite index was sufficient in capturing changes seen
separately using endpoints of pain intensity and pain duration,
each of which represents an important component of the pain
experience. The weekly mean FPI was computed as the
arithmetic mean of a daily FPI calculated during the week before
randomization and for the week before each study visit. The daily
FPI was computed as daily facial pain intensity multiplied by daily
facial pain duration and divided by 100. The daily facial pain
Copyright © 2020 by the International Association for the Study of Pain. Unauthorized reproduction of this article is prohibited.
www.painjournalonline.com 1757
intensity was rated on a standard numerical rating scale from 0 5
“no pain” to 100 5 “worst pain imaginable,” whereas the daily
facial pain duration was measured as percentage of waking day
when participant had pain. The weekly mean FPI was calculated if
a participant completed at least 4 of the 7 daily reports of pain
intensity and duration per week; otherwise, it was considered
missing. The component scores of pain intensity and pain
duration were analyzed as secondary endpoints. To prevent
potential spillover of headache pain into ratings of facial pain,
separate DSD items asked about intensity and duration of
tension-type and migraine headache. All targeted types of pain
for the DSD were anchored through explicit instructions to each
participant. For example, facial pain was described to partic-
ipants as “pain in your jaws, temples, ears, or in front of your ears.”
2.5.2. Temporomandibular disorder examination
examination and pain-related secondary endpoints
Chronic TMD myalgia and arthralgia were classified according to
the DC/TMD specifications.64 To summarize: examiners
assessed masticatory muscles and the TMJ, noting any sites at
which pain was elicited either by palpation or upon jaw maneuver
(jaw opening or lateral excursion). When pain was elicited,
examiners asked participants to report if the pain was familiar to
any facial pain symptoms experienced in the preceding 30 days.
At the end of the examination, participants were asked if jaw
function during the previous 30 days had altered (made better or
made worse) any of the familiar evoked pain from the
examination. Temporomandibular disorder myalgia and arthral-
gia were classified separately, when there were: (1) evoked,
familiar pain in either the temporalis or masseter muscles
(myalgia) or in the TM joints (arthralgia), and (2) a positive history
of the evoked familiar pain having been modified by jaw function.
An examiner calibration session conducted before the enrollment
demonstrated excellent interexaminer agreement (kappa for
pairwise comparisons ranged from 0.82 to 1.00).
In addition to TMD classification, 3 examination findings are
presented in this article as secondary endpoints: pain-free,
maximum unassisted, and maximum assisted jaw openings.
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Temporomandibular disorder–related disability and interfer-
ence in functioning were assessed using the Graded Chronic
Pain Scale (GCPS).75 The GCPS grade is derived from several
variables: (1) the characteristic pain intensity computed as the
mean, multiplied by 10, of the 3 pain items; (2) the pain
interference score, computed as the mean, multiplied by 10, of
3 pain interference items; and (3) pain disability days. Based on
these 3 variables, participants were classified into 6 chronic pain
grades: 0 5 no pain, I 5 low pain intensity and low pain-related
disability, IIa 5 high pain intensity and low pain-related disability,
IIb 5 high pain intensity and high activity interference, III 5
moderate pain-related disability, and IV 5 severe pain-related
disability. For analyses, the GCPS endpoint was dichotomized
into a low-grade category including grades from 0 to IIa and
a high-grade category including grades from IIb to IV.
Limitations of jaw function were assessed with the Jaw
Functional Limitation Scale (JFLS),51,52 a validated questionnaire
that measures limitations on 3 subscales: mastication (6 items),
vertical jaw mobility (4 items), and verbal and emotional
expression (8 items). Each item is rated on an 11-point scale
from 0 5 “no limitation” to 10 5 “severe limitation.” The subscales
are computed as a mean response for all items in the subscale,
whereas the total score is the mean of all 18 items.
2.5.3. Physical functioning
Short Form-12 Health Survey version 2 (SF-12 v2)76 was used to
assess overall physical functioning. The SF-12 v2 is a briefer
measure of health-related quality of life derived by using 12 items
from the original Short Form 36 instrument. This questionnaire
produces 2 scores: a mental health composite score and
a physical health composite score.
Sleep was assessed with Pittsburgh Sleep Quality Index.7 This
19-item instrument assesses sleep quality during the previous
month across several domains: subjective sleep quality, sleep
latency, sleep duration, habitual sleep efficiency, sleep distur-
bances, use of sleep medication, and daytime dysfunction.
As propranolol is used for migraine prophylaxis, participant
migraine status was assessed using a structured headache
interview,71 based on the International Classification of Headache
Disorders, third edition beta version (ICHD-3 beta).30 In addition,
to evaluate headache-related disability, we used the Headache
Impact Test (HIT-6) that consists of 6 items: pain, social
functioning, role functioning, vitality, cognitive functioning, and
psychological distress.39 The participant answered each ques-
tion using responses ranging from “never” to “always.” These
responses were summed to produce a total HIT-6 score, with
higher scores indicating a greater degree of headache-related
burden.
Alcohol consumption was assessed at screening using the
Alcohol Use Disorders Identification Test (AUDIT)63 and was
monitored throughout the duration of the trial. Smoking habits
were evaluated at screening and at the end of the trial through
a questionnaire, based on National Health and Nutrition
Examination Survey (NHANES) smoking-related items.
2.5.4. Emotional functioning
The SF-12 v2 mental health composite score76 was used to
assess overall emotional functioning. The Hospital Anxiety and
Depression Scale evaluated anxiety and depression.82 Symptom
Checklist 90-Revised (SCL-90R) somatization subscale
assessed a degree of somatic symptoms experienced by
participants.40 The Perceived Stress Scale evaluated 14 sources
Copyright © 2020 by the International Association for the Study of Pain. Unauthorized reproduction of this article is prohibited.
PAIN®
of stress to produce an overall perceived stress rating.10 The
Coping Strategies Questionnaire Revised (CSQ-R)62 was used at
screening to measure the frequency with which participants
engaged in specific coping activities when experiencing pain,
using a 7-point numerical scale ranging from 0 5 “never do that”
to 6 5 “always do that”. The data for the catastrophizing subscale
are presented.
2.5.5. Participant ratings of improvement
Participants’ ratings of global improvement were evaluated after 5
and 9 weeks by asking “Since beginning treatment at this study,
how would you describe the change (if any) in activity limitations,
symptoms, emotions, and overall quality of life related to your
painful condition?” Response options were from the 7-point
Patient Global Impression of Change (PGIC) scale33 (1 5 “no
change or worse,” 2 5 “almost the same,” 3 5 “a little better,” 4 5
“somewhat better,” 5 5 “moderately better,” 6 5 “better, and
a definite improvement,”, and 7 5 “a great deal better”). For
analyses, this endpoint was dichotomized by combining scores
from 1 to 4 in one category of “No improvement” and scores from
5 to 7 in another category of “Moderate or greater improvement.”
2.5.6. Safety, concomitant medication coding, and
compliance
Safety endpoints were collected at each visit and included
adverse events (AEs), vital signs (systolic and diastolic blood
pressure and heart rate), and concomitant/rescue medication
use. The AEs were surveyed through a semistructured review of
organ systems. In addition, 8 AEs, commonly associated with the
use of propranolol, were systematically assessed through
a structured questionnaire. These AEs included dizziness,
unusual fatigue, nausea, diarrhea, constipation, hands numb or
tingling, sleep problems, and depression. The Common Termi-
nology Criteria for Adverse Events version 4.0 were used for
grading of AEs, and the Medical Dictionary for Regulatory
Activities (MedDRA) version 18.0 was used for coding of AEs.
At screening, a 12-lead electrocardiogram was reviewed by
site cardiologists for exclusion of clinically significant cardiovas-
cular abnormality. Vital signs were measured with the Accutorr
Plus (Datascope Corp, Montvale, NJ) and computed at each visit
as a mean of 3 measurements taken at 2-minute intervals after
a participant rested in a seated position for 10 minutes.
At each visit, participants reported their use of all medications,
including the study drug. Nonstudy medications were coded
using the World Health Organization Drug Dictionary (WHODrug)
version 2015.01. Study drug compliance was primarily assessed
through counts of the returned capsules at each visit and through
participant daily entries of drug usage in the DSDs as a backup.
2.5.7. Quantitative sensory testing
Heat pain threshold and tolerance were assessed on the ventral
forearm using commercially available thermal stimulators (Path-
way or TSA-II; Medoc, Ramat Yishai, Israel) accessorized with
a 16 3 16-mm thermode. Heat pain threshold was defined as the
temperature at which the participant first perceived heat pain,
whereas heat pain tolerance was defined as the temperature at
which the participant could no longer tolerate the pain. The
temperature increased from a baseline of 32˚C with a 0.5˚C/
second rate of rise until the participant responded by pressing the
button. The cutoff temperature for both measurements was 50˚C.
Average thermal threshold and tolerance were calculated from 4
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assessments conducted with a 5-second interstimulus interval at
different sites of the ventral forearm. For all heat tests, participants
were first given practice runs on a site distant from subsequent
testing to verify the participant’s understanding of the procedure.
Pressure pain thresholds were assessed bilaterally over
temporalis, masseter, and trapezius muscles, TMJs, and
lateral epicondyles with a pressure algometer (FDX-10;
Wagner Instruments, Riverside, CT). The PPTs were defined
as the amount of pressure at which the participant first
perceived the stimulus to be painful. One pretrial assessment
was performed at each site, followed by additional assess-
ments until 2 measures differing by less than 0.2 kg were
obtained, or 5 assessments were administered. In either case,
the mean of the 2 closest values was recorded as the threshold
estimate. Pressure stimuli were delivered at an approximate
rate of 1 kg/second. The cutoff pressure for all body sites was
5 kg. The values from the right and left sides were averaged to
obtain a single PPT value per anatomical site.
2.6. Statistical analysis
The main goal of the statistical analysis was to estimate change in
study endpoints and evaluate efficacy of propranolol by testing
a priori hypotheses concerning treatment group differences.
Descriptive statistics for safety measures were also generated.
Statistical analysis was performed using SAS v9.4 (SAS Institute Inc).
2.6.1. Intention-to-treat, per-protocol, and safety samples
The primary and secondary analyses applied the intention-to-treat
(ITT) principle by analyzing all available data from all randomized
participants according to their treatment allocation. Specifically, the
ITT sample comprised data from all postrandomization visits
through week 9, in which there was a valid measurement of the
primary endpoint, namely, the FPI. By necessity, the ITT sample
excluded any postrandomization visits in which there was no valid
value for the primary endpoint. Because mixed models do not
require imputation for missing data, individuals with some missing
endpoints were retained in the analyses.
Primary efficacy analysis was repeated in the per-protocol
sample, defined as the subset of the ITT sample after excluding:
(1) assessments from any visits made at or after a major protocol
deviation, and (2) participants whose compliance with study
medication was less than 60% over all study visits.
The safety analysis used data from all randomized participants
who received at least one dose of study medication, and the
treatment group was based on the study drug used, regardless of
the allocated treatment.
2.6.2. Evaluation of efficacy hypotheses
The null hypothesis for the primary test of efficacy was that the
mean change in the FPI at week 9 did not differ between
treatment groups. Because there was only one test, the threshold
to judge statistical significance was set at P , 0.05 using a 2-
tailed test. It was evaluated with a mixed model for repeated
measures using the MIXED procedure in SAS. The dependent
variable was the change in the mean FPI, and independent
variables were fixed effects for study site (2 dummy variables to
account for the 3 study sites), sex (binary variable), race
(dichotomized as White or non-White), the mean FPI at
randomization (a continuous covariate), visit (the 2 dummy
variables to account for the repeated visits at weeks 1, 5, and
9), allocated treatment group (binary variable), and a visit 3
Copyright © 2020 by the International Association for the Study of Pain. Unauthorized reproduction of this article is prohibited.
www.painjournalonline.com 1759
treatment interaction. Participants were included as a random
effect in the model, which used an unstructured variance–
covariance pattern, and the denominator degrees of freedom for
any sample imbalances were adjusted using Kenward Roger
method. An LSMESTIMATE statement calculated the adjusted
mean, standard error, and 95% confidence limits (95% CLs) for
the difference between treatment groups at week 9, and the
t statistic was calculated for inferences.
Additional analysis of the FPI dichotomized the endpoint using
established definitions of a clinically meaningful pain reduc-
tion,17,22 namely, a reduction in the mean FPI of $30% or $50%
relative to the participant’s mean FPI at randomization. Each
binary endpoint was modeled with a log-binomial model that
used the generalized estimating equations (GEE) approach in
SAS’s GENMOD procedure. This is analogous to the mixed
model used for the continuous variable, except that GEE fits
a marginal model to longitudinal data, and hence regression
parameters are population averages of the treatment effect. For
the GEE model, participants were the repeated effect, and
covariates were the same terms as used in mixed models,
including a visit 3 treatment interaction. The identity link for the
binomial distribution was specified, meaning that parameter
estimates represent the adjusted net difference in probability of
responding. Estimates, standard errors, and 95% CLs were
calculated and the F-statistic was used to calculate P-value. The
number needed to treat (NNT) was also calculated as the inverse
of each parameter estimate and its 95% CLs. For comparison
with other studies, odds ratios (ORs) and 95% CLs were also
calculated by specifying the logit distribution for the binary
distribution for the same GEE model. Consistent with the a priori
statistical analysis plan, no critical threshold was nominated for P-
values, and no adjustment was made for multiple statistical tests.
Secondary endpoints were modeled according to their scale of
measurement: either mixed model for repeated measures for
continuous variables (eg, pain intensity) or GEE models for binary
variables (eg, PGIC and all other dichotomized response
analyses).
2.6.3. Safety evaluation
For the safety analysis, AEs were aggregated across visits and the
data were analyzed per participant. The proportion of participants
with each category of AE was calculated, and P-values for
treatment group differences were computed using exact tests for
binary logistic regression in SAS’s LOGISTIC procedure.
2.6.4. Sample size justification
The target sample size of 200 randomized participants was
selected after calculating that it would provide 90% power to
detect a 27% difference between treatment groups in the primary
endpoint (ie, mean reduction in FPI of 8.1 in the propranolol group
vs 2.7 in the placebo group), assuming standard deviation of
11.9. Those estimates were deemed to be clinically meaningful
and credible, based on results from our pilot study that used
a randomized cross-over design to test efficacy of propranolol vs
placebo.70
3. Results
3.1. Study participants
A total of 200 participants were randomized in a 1:1 ratio to the
propranolol (n 5 100) and placebo (n 5 100) treatment groups
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(Fig. 2). Overall, 174 participants (87%) completed the study, with
equal percentage of completers in each group (87%). Main
reasons for the trial discontinuation were withdrawal of consent
(n 5 14) and loss to follow-up (n 5 6). One participant did not
provide any postbaseline data and was excluded from the ITT
population. The per-protocol sample comprised 143 participants
(71.5%). The most frequent protocol deviations leading to
participant exclusion from the per-protocol analyses were: (1)
use of OTC analgesics that exceeded the protocol definition of
episodic use (n 5 15 and n 5 21 in the propranolol and placebo
groups, respectively); (2) noncompliance with the study drug
(n 5 11 and n 5 10 in the propranolol and placebo groups,
respectively); and (3) inability to reach maintenance dose (n 5 9
and n 5 5 in the propranolol and placebo groups, respectively).
The safety sample comprised all 200 randomized participants
who received at least one dose of the study drug.
The participant baseline demographic and clinical character-
istics in the ITT sample were similar among treatment groups
(Table 1; and Table S1 in the Supplementary Materials, available
at http://links.lww.com/PAIN/A988). Most participants were
middle-age, white females. The mean time since onset of the
TMD pain was 11 years, and almost all participants suffered
from both myalgia and arthralgia (93.0%). The mean weekly FPI
was 30.6 (on the 0-100 scale) with a mean weekly facial pain
Figure 2. Flow diagram of participants in the trial.
Copyright © 2020 by the International Association for the Study of Pain. Unauthorized reproduction of this article is prohibited.
PAIN®
intensity of 47.6 (on the 0-100 scale) and a mean weekly facial
pain duration of 58.3% of waking day. On average, the
participants reported 24 days with facial pain in the last 30
days and 41.7% of them had TMD GCPS grades from IIb to IV,
signifying high pain intensity and moderate/severe disability.
Based on an established definition of jaw opening lesser than
40 mm as limited,64 the participants’ mean pain-free jaw
opening was restricted (29.8 mm), whereas no limitation was
found in their mean maximum unassisted or assisted opening
(44.2 and 48.2 mm, respectively), indicating no structural TMJ
limitation for opening in most cases. By contrast, the reported
mean limitation in jaw function measured by the JFLS was 2.6
(on the 0-10 scale), which is typical for a chronic painful TMD
sample.53
At baseline, 104 participants (52.3%) met criteria for definite
or probable migraine and reported a mean HIT-6 score of 54.8,
consistent with substantial headache-related disability. The
mean baseline values for physical/emotional functioning and
vital signs were within normal limits. For TMD treatment,
orofacial appliances were used at night by 17.1% of
participants and NSAIDs by 7.5%. In addition, 12.6% of
participants used NSAIDs for other pain conditions. A sub-
stantial proportion of participants were taking antidepressant
medications (20.1%).
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Table 1 point used, we present a cumulative distribution function curve

Baseline demographic and clinical characteristics of and NNTs across the entire range of the response, as was
participants (ITT population).* recommended by Farrar and colleagues.23,24 As shown in Figure
S1A in the Supplementary Materials, available at http://links.lww.
Characteristics Placebo Propranolol
(n 5 99) (n 5 100) com/PAIN/A988, the proportion of responders for FPI is
consistently higher in the propranolol group compared with
Age, y 34.2 (13.29) 33.9 (12.19)
placebo across all cutoffs, and the area under the curve (AUC) for
Sex, female 78 (78.8%) 77 (77.0%) propranolol is 18.3% greater than for placebo over a therapeu-
Race tically important range of response, such as 20% to 70%.
White 71 (71.7%) 79 (79.0%) The effect of propranolol on the mean weekly pain intensity
Black 18 (18.2%) 12 (12.0%) (difference vs placebo: 23.5%; 95% CL: 28.6, 1.7) and the mean
Asian 6 (6.1%) 5 (5.0%) weekly pain duration (difference vs placebo: 21.4%; 95% CL:
Other 4 (4.0%) 4 (4.0%) 27.6, 4.9) was not significant (Table 2). The correlation between
Study site pain intensity and pain duration was moderate to large, with Pearson
University of North Carolina 45 (45.5%) 45 (45.0%) correlation coefficients ranging from 0.49 at baseline to 0.71 at week
University of Florida 30 (30.3%) 31 (31.0%) 9. For the purpose of comparison with other studies that have used
University at Buffalo 24 (24.2%) 24 (24.0%) pain intensity as a primary endpoint, we also present results from
BMI, kg/m2 29.5 (11.00) 29.1 (14.40) a responder analysis and a cumulative distribution function curve
using the pain intensity endpoint (Table S2 and Fig. S1B in the
Facial pain
Time since onset, years 10.5 (9.43) 11.3 (9.85)
Supplementary Materials, available at http://links.lww.com/PAIN/
TMD myalgia and arthralgia 92 (92.9%) 93 (93.0%) A988). For a given threshold within a given treatment group, the pain
Weekly pain index, 0-100 scale 31.2 (18.94) 30.0 (19.96) intensity endpoint yielded a lower percentage of responders than the
Weekly pain intensity, 0-100 scale 47.4 (15.58) 47.9 (15.23) pain index. However, differences between treatment groups (ie, the
Weekly pain duration, 0-100 scale 60.1 (24.61) 56.6 (26.57) measures of treatment efficacy in a randomized clinical trial) were
Painful days in the last 30 d, n 24.0 (6.64) 23.7 (7.21) fairly consistent for the 2 endpoints, as were treatment-group
Pain-free jaw opening, mm 29.6 (11.58) 30.0 (10.79) differences in the AUCs. Across the clinically important threshold
Maximum unassisted jaw opening, mm 44.5 (10.08) 43.9 (8.44) range from 20% to 70%, the 17.7% treatment-group difference in
GCPS grade, IIb-IV 41 (41.4%) 42 (42.0%) AUC values for pain intensity was comparable with the 18.3%
Physical functioning difference for pain index. Compared with pain index, pain intensity
Migraine 53 (53.5%) 51 (51.0%) displayed a greater degree of variation in threshold-specific NNTs.
HIT-6, 36-78 scale 55.2 (8.70) 54.4 (9.10) The NNT of 20.1 at the 50% threshold seemed to be an outlier,
AUDIT, 0-40 scale 2.3 (1.73) 2.5 (2.08) primarily due to a threshold-specific spike in the proportion of
Current smokers 18 (18.2%) 14 (14.0%)
placebo responders.
Emotional functioning The analysis of the dichotomized PGIC at week 9 showed that
HADS anxiety, 0-21 scale 7.5 (4.59) 6.9 (4.19) a greater proportion of participants reported a moderate or
HADS depression. 0-21 scale 3.3 (3.14) 3.7 (3.54) greater global improvement in the propranolol group compared
Concomitant therapy with placebo (43.4% vs 27.7%; OR 5 2.0, 95% CL: 1.1, 3.7) with
Oral appliances 19 (19.2%) 15 (15.0%) a NNT 5 6.4 (95% CL: 3.3, 68.1) (Table 2 and Fig. 3D). The
TMD-specific NSAIDs 6 (6.1%) 9 (9.0%) percentages of patients endorsing any of 7 response options in
Non-TMD specific NSAIDs 12 (12.1%) 13 (13.0%) each treatment group are presented in Table S3 in the
Antidepressants 17 (17.2%) 23 (23.0%) Supplementary Materials, available at http://links.lww.com/
Benzodiazepines 4 (4.0%) 9 (9.0%)
PAIN/A988. The PGIC ratings at week 9 were significantly greater
Muscle relaxants 2 (2.0%) 3 (3.0%)
in the propranolol group (difference vs placebo: 0.82%, 95% CL:
* Data are means (SD) or numbers (%).
AUDIT, Alcohol Use Disorders Identification Test; BMI, body mass index; GCPS, Graded Chronic Pain Scale;
0.28, 1.37, P 5 0.003), indicating a nearly 1-point improvement
HADS, Hospital Anxiety and Depression Scale; HIT-6, Headache Impact Test-6; ITT, intention to treat; on the 7-point PGIC ordinal scale.
NSAIDs, nonsteroidal anti-inflammatory drugs; TMD, temporomandibular disorder. The results of the analyses for other secondary endpoints at
week 9 are shown in Table 2 and Table S2 in the Supplementary
Materials, available at http://links.lww.com/PAIN/A988. Among
3.2. Efficacy
other facial pain-related secondary endpoints, there was a signif-
The reduction in a mean weekly FPI was slightly greater in the icant improvement in pain-free jaw opening (difference vs placebo:
propranolol group compared with the placebo group at week 9, 3.2 mm; 95% CL: 1.0, 5.4), although no significant difference in
although the difference was marginal and not statistically maximum unassisted or assisted jaw openings or in a JFLS score
significant (difference vs placebo: 21.8%, 95% CL: 26.2, 2.6) emerged. Among endpoints associated with physical or emotional
(Table 2 and Fig. 3A). The primary endpoint in the per-protocol functioning, headache-related disability as measured by the HIT-6
sample also did not differ between treatment groups (difference questionnaire was the only endpoint with a significant reduction
vs placebo: 20.5%; 95% CL: 25.1, 4.1). However, the $30% after propranolol treatment (mean group difference vs placebo:
responder rate for the propranolol group at week 9 was greater 21.9; 95% CL: 23.7, 20.2). Among quantitative sensory testing
compared with placebo (69.0% vs 52.6%; OR 5 2.1, 95% CL: endpoints, a significant difference was observed only for the heat
1.1, 3.9) with an NNT 5 6.1 (95% CL: 3.2, 55.3) (Table 2 and Fig. threshold (difference vs placebo: 0.7; 95% CL: 0.0, 1.5).
3B). Likewise, the $50% responder rate at week 9 was greater in
the propranolol group than in the placebo group (55.5% vs
3.3. Adverse events, compliance, and masking
39.2%; OR 5 2.0, 95% CL: 1.1, 3.7) with an NNT 5 6.1 (95% CL:
3.2, 69.7) (Table 2 and Fig. 3C). Because the responder rate and At least one adverse event was reported for 86% participants
NNTs can vary substantially depending on the response cutoff receiving propranolol and 75% of those receiving placebo

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Table 2
Summary of primary and secondary endpoints (ITT population).
Endpoints Placebo (n 5 99) Propranolol (n 5 100) P
Primary endpoint
Mean weekly pain index, baseline to week 9
Change from baseline, mean (95% CL)* 212.1 (215.5, 28.7) 213.9 (217.4, 210.5)
Difference vs placebo, mean (95% CL) 21.8 (26.2, 2.6) 0.414
$30% reduction in mean weekly pain index, baseline to week 9
Subjects achieving response, % (95% CL)† 52.6 (41.4, 63.8) 69.0 (57.8, 80.2)
Odds ratio (95% CL)‡ 2.1 (1.1, 3.9) 0.028
Number needed to treat (95% CL)† 6.1 (3.2, 55.3) 0.028
$50% reduction in mean weekly pain index, baseline to week 9
Subjects achieving response, % (95% CL)† 39.2 (28.5, 49.8) 55.5 (43.9, 67.1)
Odds ratio (95% CL)‡ 2.0 (1.1, 3.7) 0.032
Number needed to treat (95% CL)† 6.1 (3.2, 69.7) 0.031
Secondary endpoints
Mean weekly pain intensity, baseline to week 9
Change from baseline, mean (95% CL)* 213.6 (217.6, 29.7) 217.1 (221.1, 213.1)
Difference vs placebo, mean (95% CL) 23.5 (28.6, 1.7) 0.187
Mean weekly pain duration, baseline to week 9
Change from baseline, mean (95% CL)* 216.6 (221.3, 211.8) 217.9 (222.8, 213.0)
Difference vs placebo, mean (95% CL) 21.4 (27.6, 4.9) 0.665
PGIC score dichotomized, baseline to week 9
Subjects achieving response, % (95% CL)† 27.7 (16.8, 38.6) 43.4 (31.5, 55.3)
Odds ratio (95% CL)‡ 2.0 (1.1, 3.7) 0.032
Number needed to treat (95% CL)† 6.4 (3.3, 68.1) 0.031
Pain-free jaw opening, baseline to week 9
Change from baseline, mean (95% CL), mm* 2.3 (0.6, 4.1) 5.5 (3.7, 7.4)
Difference vs placebo, mean (95% CL), mm 3.2 (1.0, 5.4) 0.005
Maximum unassisted jaw opening, baseline to week 9
Change from baseline, mean (95% CL), mm* 0.3 (21.0, 1.7) 0.8 (20.6, 2.2)
Difference vs placebo, mean (95% CL), mm 0.4 (21.2, 2.1) 0.584
HIT-6 score, baseline to week 9
Change from baseline, mean (95% CL)* 23.1 (24.6, 21.7) 25.1 (26.6, 23.6)
Difference vs placebo, mean (95% CL) 21.9 (23.7, 20.2) 0.034
* Estimates from a mixed-model repeated-measures (MMRM) analysis adjusted for treatment, visit, treatment-by-visit interaction, study site, sex, and race as fixed effects, with a baseline value of the endpoint as a covariate
and unstructured covariance matrix. Participant was a random effect. No adjustment for multiple comparisons was made.
† Estimates from generalized estimating equations for log-binomial models adjusted for treatment, visit, treatment-by-visit interaction, study site, sex, and race as fixed effects, with a baseline value of the endpoint as
a covariate.
‡ Estimates from generalized estimating equations for logistic models adjusted for treatment, visit, treatment-by-visit interaction, study site, sex, and race as fixed effects, with a baseline value of the endpoint as a covariate.
95% CL, 95% confidence limits; HIT-6, Headache Impact Test-6; ITT, intention to treat; PGIC, Patient Global Impression of Change.

(Table 3). Serious AEs (SAEs), severe AEs, and AEs leading to
discontinuation were infrequent. SAEs occurred in 1% of
participants given placebo and in 4% of those given propranolol,
including 1% of participants in the propranolol group who
reported an SAE before the treatment period (Table S4 in the
Supplemental Materials, available at http://links.lww.com/
PAIN/A988). Each specific SAE occurred in no more than one
participant. One death due to metastatic breast cancer
occurred in the propranolol group. Except for the events in
a participant with fatal breast cancer, all SAEs were resolved by
the end of the trial.
Most of the treatment-emergent AEs were mild to moderate in
severity and had similar incidence in both groups, with the
exception of fatigue, dizziness, and sleep disorder, which were
more frequent in the propranolol group (Table 3). As expected,
propranolol reduced the values of vital signs, but the absolute
reductions were small (Table S2, http://links.lww.com/PAIN/
A988) and well tolerated.
Participant compliance with the study drug was very good: only
11% of participants receiving propranolol and 10% of those
receiving placebo took , 60% of the study drug, specified in the
study protocol as noncompliance. On average, participants in the
propranolol group used 88% of the study drug, whereas
participants in the placebo group used 89%. Rescue medication
(OTC analgesics) was taken by 24% of participants receiving
propranolol and 19% of those receiving placebo. Only 8% of
participants exceeded the protocol definition of episodic use of
rescue medication in each group. During the treatment period,
the mean number of days with the rescue medication per
participant was low: 3.7 days (5.6% of the treatment days) and
1.1 day (1.9% of the treatment days) in the propranolol and
placebo groups, respectively.
At week 9, 168 (84.4%) participants provided information
about their perceived treatment allocation: 48 (55.8%) and 54
(65.9%) participants in the placebo and propranolol groups,
respectively, correctly identified their treatment. The participant
agreement in guessing their allocation was poor (kappa 5 0.22,
95% CL: 0.07, 0.36), indicating successful participant masking.
4. Discussion
Among participants with painful TMD, there was no significant
treatment group difference in the primary endpoint of FPI after 9
weeks of treatment. Yet, when the same endpoint was
dichotomized, proportions of responders were greater in the
propranolol group than the placebo group across the entire
clinically important range of 20% - 70% response. Cumulative
response curves for the more traditional endpoint, pain intensity,

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Figure 3. Regression-model estimates of 4 endpoints: (A) mean pain index; (B) percentage of participants with at least 30% reduction in pain index; (C) percentage
of participants with at least 50% reduction in pain index; (D) percentage of participants reporting overall improvement in their pain condition. The pain index
represents the product of pain intensity (0-100 numerical rating scale) multiplied by pain duration (0%-100% of day), divided by 100. It was recorded using daily
symptom diaries completed before study visits at baseline (week 0) and up to 3 follow-up visits occurring 1, 5, and 9 weeks after initiating treatment with either
propranolol 60 mg, BID ( ) or placebo (s). Percentage reductions in pain index were calculated relative to baseline and dichotomized to signify the percentage of
participants with $30% reduction and $50% reduction. Global impression of change was reported on a 7-point scale at visits 3 and 4, and dichotomized to signify
the percentage of participants with either “moderate,” “definite,” or “a great deal” of improvement. Adjusted means were estimated using mixed model for
repeated measures with covariates baseline pain index, study visit, treatment group, visit 3 treatment group interaction, study site, sex, and race/ethnicity.
Adjusted percentages and their 95% confidence limits were estimated with a log-binomial regression model using the generalized estimating equation method
allowing for repeated visits by study participants. Covariates were as described for the mixed model. For all models, treatment-group difference in means or
percentage at week 9 was computed with custom estimates of predicted population margins based on parameters in the model. Differences in percentages were
used to compute a number-needed-to-treat (NNT) and its 95% confidence limits. P-values tested the null hypothesis that the means or percentages at week 9 are
equivalent in the 2 treatment groups.

yielded a similar treatment group difference favoring propranolol,
although in the propranolol group there was a higher probability of
response for the FPI than for pain intensity. For example, among
participants receiving propranolol, 59% had a $50% reduction in
FPI but only 36% reported a $50% reduction in pain intensity.
The difference between these endpoints is important to un-
derstand for interpretation of the trial results. In addition, the
proportion of participants who reported a moderate or greater
global improvement in their TMD was also greater for propranolol.
Hence, the overall findings are consistent with a clinically
meaningful benefit of propranolol in reducing facial pain. Like-
wise, nominally significant results (ie, P , 0.05) were obtained in
secondary analyses comparing the treatment groups with
respect to pain-free jaw opening, headache-related disability,
and sensitivity to heat stimulation.
The apparent paradox in treatment effect estimates of pain index
(or intensity) analyzed as a continuous variable (ie, analysis of
a mean change) vs a dichotomized variable (ie, responder analysis)
stems from a group difference in distributions of a change (Fig. S2
in the Supplementary Materials, available at http://links.lww.com/
PAIN/A988). In both treatment groups, a critical mass of responses
was concentrated around thresholds of 30% and 50% reductions.
However, noticeably more participants in the placebo group
compared to the propranolol group fell short of these thresholds. In
contrast to the usual situation where responder analysis is
associated with less statistical power, the distribution led to more
statistical power for the responder analysis.66 FDA and IMMPACT
guidelines encourage responder analysis because it estimates
a clinically meaningful change in the endpoint at the individual level,
which is not the case for analysis of group means.17,47
A summary statistic for evaluating the difference between
groups and comparing it between studies is the NNT.11 The
observed NNT values for standard 30%/50% thresholds of FPI,
30% threshold of pain intensity, and PGIC were approximately 6,
implying that 6 patients need to be treated with propranolol in
order for one of them to benefit because of the drug. Because the
NNT is calculated relative to the control group, it relates
specifically to improvement because of the drug and not because
of other reasons, such as placebo response or spontaneous
remission. Regrettably, NNTs have not been widely reported for

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Table 3
Adverse events in the safety population.*
Adverse events No. (%) of participants
Placebo (n 5 100) Propranolol (n 5 100) P†
All events
Adverse events 75 (75.0%) 86 (86.0%)
Treatment-emergent adverse events‡ 70 (70.0%) 84 (84.0%)
Serious adverse events 1 (1.0%) 4 (4.0%)
Adverse events leading to study discontinuation 0 (0.0%) 1 (1.0%)
Severe treatment-emergent adverse events 4 (4.0%) 6 (6.0%)
Death 0 (0.0%) 1 (1.0%)
Treatment-emergent adverse events by type§
Gastrointestinal disorders
Diarrhea‖ 16 (16.0%) 18 (18.0%) 0.851
Nausea‖ 6 (6.0%) 14 (14.0%) 0.097
Constipation‖ 9 (9.0%) 10 (10.0%) 1.000
General disorders
Fatigue‖ 16 (16.0%) 29 (29.0%) 0.041
Infections and infestations
Nasopharyngitis 10 (10.0%) 12 (12.0%) 0.822
Upper respiratory tract infection 4 (4.0%) 7 (7.0%) 0.537
Nervous system disorders
Dizziness‖ 6 (6.0%) 21 (21.0%) 0.003
Paraesthesia‖ 9 (9.0%) 5 (5.0%) 0.407
Hypoesthesia‖ 5 (5.0%) 4 (4.0%) 1.000
Headache 1 (1.0%) 5 (5.0%) 0.212
Psychiatric disorders
Insomnia‖ 10 (10.0%) 13 (13.0%) 0.658
Depression‖ 9 (9.0%) 7 (7.0%) 0.795
Sleep disorder‖ 0 (0.0%) 6 (6.0%) 0.029
Musculoskeletal and connective tissue disorders
Back pain 5 (5.0%) 2 (2.0%) 0.445
Ear and labyrinth disorders
Vertigo 7 (7.0%) 5 (5.0%) 0.767
* The safety population included all participants who were randomized and received at least 1 dose of the study drug. If a participant had multiple types of adverse events, he/she was counted once for each type. If a participant
had multiple events of the same type, he/she was counted once for that type.
† P values were computed using exact logistic regression with adverse event incidence as the dependent variable and treatment group as the independent variable.
‡ Treatment-emergent adverse events were defined as adverse events occurring during a treatment period and included adverse events considered to be related as well as those not considered to be related to the study treatment.
§ Data are presented for treatment-emergent adverse events reported by $5% of participants in any treatment group and coded by System Organ Class and Preferred Term from the MedDRA v18.0.
‖ Expected adverse events systematically surveyed through the symptom questionnaire.

studies of TMD pharmacotherapy: the Cochrane review sum-
marized efficacy only in terms of average pain reductions.49
However, in clinical trials of patients with another muscle pain
disorder, fibromyalgia, the average NNT for a $30% pain
reduction was 10 for serotonin–norepinephrine reuptake inhib-
itors (SNRIs) duloxetine and milnacipran, 7.2 for pregabalin, and
4.9 for tricyclic antidepressants, whereas the NNTs for a $50%
reduction were even higher.14,29,77 The average NNT for
a moderate benefit in the PGIC ranged from 5 for SNRIs to 11
for pregabalin.14,77 Therefore, the NNT estimates in this study
represent a clinically important outcome.
One downside of an NNT is its reliance on specific thresholds of
a continuous measure and sensitivity to arbitrary deviations at
these thresholds. As seen in the cumulative response curves for
pain intensity, the 50% threshold yielded a higher NNT than other
NNTs across nearby thresholds of 40% to 60% because of the
threshold-specific surge in the number of placebo responders. To
monitor for such aberrations, it is important to review NNTs across
an entire range of clinically relevant thresholds.
As with previous trials of propranolol, the most common AEs
were diarrhea, fatigue, dizziness, and insomnia.67 Most were mild
to moderate in severity and their rates were similar between
treatment groups, except for fatigue, dizziness, and sleep
disorder, which were more frequent in the propranolol group.
The higher rates of AEs, compared with previous trials,42 can be
attributed to this study’s active surveillance of harms, which yields
more AEs than passive surveillance.4,34
Propranolol is a nonselective b-adrenergic receptor antagonist
with similar affinity for b1- and b2-adrenoreceptors and lower
affinity for b3-adrenoreceptors.2 It is used for treatment of
hypertension, ischemic heart disease, arrhythmias, migraine,
and anxiety.1,36 Analgesic effect of propranolol in musculoskel-
etal pain is plausible, given evidence for an enhanced adrenergic
tone in chronic pain states. For example, increased levels of
epinephrine and norepinephrine are found in patients with TMD
and fibromyalgia,21,72 and sympathetic dominance (parasympa-
thetic suppression) is reported in patients with TMD, fibromyalgia,
and arthritis.45,56,73 Stimulation of the cervical sympathetic nerve
leads to development of tension in jaw muscles in animal models,
also implicating sympathetic input in development of TMD
myalgia.54 Therefore, b-adrenergic blockade could exert an
analgesic effect by attenuating this adrenergic dysregulation.
Indeed, in various animal models, propranolol produced anti-
nociception, although different studies identified various b-adre-
noreceptor subtypes responsible for the effect.25,37,50,61
Potential mechanisms may include a direct action on peripheral
nociceptors9,37,61 and interactions with immune19,28,68,69,80,81
and cardiovascular systems.3,6,41,57
Because propranolol crosses the blood–brain barrier, it can
influence pain processing centrally. In migraine animal models,

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propranolol inhibits trigeminal nociception through antagonism of
b1-adrenergic receptors on thalamocortical neurons65 and
blocks chronic sensitization of descending pain pathways from
higher brain regions to the trigeminocervical complex.5
Propranolol can also alter affective modulation of pain by
reducing anxiety.59,60 In rodents, b-adrenergic blockade pre-
vents anxiety-like behavior and reduces negative affective
components of pain.15,79 In humans, propranolol is used to treat
anxiety,36,48,55 and anxiety is associated with increased odds of
TMD.26 Although baseline levels of anxiety in this study were quite
low, there was a trend toward greater reduction in anxiety for the
propranolol group compared with the placebo group (P 5 0.111).
To the best of our knowledge, only 3 studies have assessed
propranolol’s effect in patients with TMD. Consistent with our
findings, Light et al.41 noted lower ratings of TMD pain after
intravenous administration of a single low dose of propranolol,
compared with placebo. In our pilot trial70 with a cross-over design,
we found a significant reduction in FPI after one week of oral
administration of 40 mg of propranolol, although the magnitude of
effect was modest. In a placebo-controlled trial with a factorial
design, Gonçalves et al.27 used 90 mg of short-acting propranolol
with and without an oral appliance for 3-month treatment of
migraine patients with concomitant TMD. It is difficult to compare
our primary result with the analyses of TMD endpoints from that trial
because Gonçalves et al.27 focused on migraine-related endpoints
and their exploratory TMD-related endpoints did not include weekly
TMD pain ratings. The TMD endpoints, comparable to our trial,
were PPTs and maximum unassisted opening, for which neither
trial found significant group differences.
The strengths of the study are: (1) use of validated DC/TMD
examination for selecting participants with TMD myalgia and
arthralgia and for monitoring diagnostic status; (2) use of daily
diaries for facial pain assessment; (3) relatively low dropout rate;
(4) thorough assessments of rescue and concomitant medica-
tions; (5) active surveillance of harms; and (6) participants’
excellent compliance with the daily diaries and study drug.
This study has several limitations. First, this phase 2b trial was
not powered for assessments of all secondary endpoints. To
better characterize our patient population and understand
treatment effects, we collected many secondary endpoints
encompassing several categories for exploratory analysis, as
described by D’Agostino12 and endorsed in IMMPACT recom-
mendations.74 Specifically, the secondary endpoints (1) provided
background information, (2) served as components of the
composite primary endpoint, (3) could aid in understanding the
mechanisms of action of the treatment, (4) were related to
secondary hypotheses that were not major objectives of the
treatment, and (5) were intended for exploratory analyses. Given
the variety of secondary endpoints and a limited study size, no
adjustment for multiplicity was performed. Therefore, results for
these secondary endpoints should be interpreted with caution.
Second, this trial was limited to evaluation of endpoints at
a follow-up of 9 weeks after randomization and a longer follow-up
could be beneficial. Third, this study did not include certain
patient populations, such as patients with comorbid hyperten-
sion, fibromyalgia, hyperthyroidism, or opioid medication use.
Further studies are needed to inform the use of propranolol in
these populations.
To achieve results generalizable to clinical care settings, we
enrolled participants of any sex, race, and ethnicity, and they were
allowed to maintain preexisting treatments during the trial. The
exclusion criteria were limited to propranolol’s contraindications and
health conditions that could have affected pain ratings, for example,
comorbid hypertension, fibromyalgia, or hyperthyroidism.
Copyright © 2020 by the International Association for the Study of Pain. Unauthorized reproduction of this article is prohibited.
www.painjournalonline.com 1765
In conclusion, among patients with chronic painful TMD,
propranolol had a statistically nonsignificant effect, compared
with placebo, on mean change in FPI but propranolol was
efficacious in achieving $30% and $50% FPI reductions and in
improving participants’ ratings of global change after 9 weeks of
treatment. The drug was safe and well tolerated. These results
provide sufficient evidence to justify further investigation of
propranolol for TMD management.
Conflict of interest statement
The authors have no conflicts of interest to declare.
Acknowledgements
The authors thank the SOPPRANO research staff and patients
who participated in the trial. The authors also thank cardiologists
Drs. Alan Hinderliter (UNC at Chapel Hill), David Sheps (University
of Florida), and Thomas Cimato (University at Buffalo) for
monitoring participants’ safety. Funding for this study was
provided by the National Institutes of Health (NIH)/National
Institute of Dental and Craniofacial Research (NIDCR) R34-
DE022088 and U01-DE024169 grants. The trial is registered at
ClinicalTrials.gov, number NCT02437383. Full details of the trial
protocol are available at ClinicalTrials.gov.
Appendix A. Supplemental digital content
Supplemental digital content associated with this article can be
found online at http://links.lww.com/PAIN/A988.
Article history:
Received 7 August 2019
Received in revised form 23 March 2020
Accepted 24 March 2020
Available online 27 March 2020
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