Efficacy and safety of propranolol for treatment of temporomandibular disorder pain: a randomized, placebo-controlled clinical trial

Abstract

Propranolol is a nonselective beta-adrenergic receptor antagonist. A multicenter, randomized, double-blind, placebo-controlled, 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 = 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 (-1.8, 95% CL: -6.2, 2.6; P = 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 = 0.03). Propranolol was likewise efficacious for a ≥50% reduction in FPI (number-needed-to-treat = 6.1, P = 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.

Trial registration: ClinicalTrials.gov NCT02437383.

Conflict of interest statement

Conflict of Interest Statement

All authors declare no financial relations that might represent a possible conflict of interest.

Figures

Figure 1.

Trial design.

Figure 2.

Flow diagram of participants in the trial.

Figure 3.

Regression-model estimates of four 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 prior to study visits at baseline (week 0) and up to three follow-up visits occurring 1, 5 and 9 weeks after initiating treatment with either propranolol 60 mg, BID () or placebo (). 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 x treatment group interaction, study site, gender, 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 were 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 two treatment groups.