Effect of comorbid migraine on propranolol efficacy for painful TMD in a randomized controlled trial

Inna E Tchivileva, Richard Ohrbach, Roger B Fillingim, Pei Feng Lim, Massimiliano Di Giosia, Margarete Ribeiro-Dasilva, John H Campbell, Holly Hadgraft, Janet Willis, Samuel J Arbes Jr, Gary D Slade, Inna E Tchivileva, Richard Ohrbach, Roger B Fillingim, Pei Feng Lim, Massimiliano Di Giosia, Margarete Ribeiro-Dasilva, John H Campbell, Holly Hadgraft, Janet Willis, Samuel J Arbes Jr, Gary D Slade

Abstract

Introduction: The migraine-preventive drug propranolol is efficacious in reducing pain from temporomandibular disorder, suggesting potential modifying or mediating effects of comorbid migraine.

Methods: In this randomized controlled trial, myofascial temporomandibular disorder patients were treated with propranolol or placebo for 9 weeks. The primary endpoint was change in a facial pain index derived from daily symptom diaries. Linear and logistic regression models tested for a migraine × treatment-group interaction in reducing facial pain index. Counterfactual models explored changes in headache impact and heart rate as mediators of propranolol's efficacy.

Results: Propranolol's efficacy in reducing facial pain index was greater among the 104 migraineurs than the 95 non-migraineurs: For example, for the binary ≥ 30% reduction in facial pain index, odds ratios were 3.3 (95% confidence limits: 1.4, 8.1) versus 1.3 (0.5, 3.2), respectively, although the interaction was statistically non-significant (p = 0.139). Cumulative response curves confirmed greater efficacy for migraineurs than non-migraineurs (differences in area under the curve 26% and 6%, respectively; p = 0.081). While 9% of the treatment effect was mediated by reduced headache impact, 46% was mediated by reduced heart rate.

Conclusions: Propranolol was more efficacious in reducing temporomandibular disorder pain among migraineurs than non-migraineurs, with more of the effect mediated by reduced heart rate than by reduced headache impact.

Study identification and registration: SOPPRANO; NCT02437383; https://ichgcp.net/clinical-trials-registry/NCT02437383.

Keywords: Adrenergic beta-antagonists; autonomic nervous system; chronic pain; facial pain; headache; sympathetic nervous system.

Conflict of interest statement

Declaration of conflicting interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Figures

Figure 1.
Figure 1.
Change in three endpoints at three follow-up visits for participants in two treatment groups stratified according to the baseline migraine status. Endpoints were estimated for propranolol () and placebo (O) groups in regression models (ITT population). Endpoints are: percentage of participants with a ≥ 30% reduction in FPI plotted for (a) non-migraineurs and (b) migraineurs; percentage of participants with a ≥ 50% reduction in FPI plotted for (c) non-migraineurs and (d) migraineurs; and percentage of participants reporting a reduction of ≥ 6 points in the HIT-6 scale plotted for (e) non-migraineurs and (f) migraineurs. FPI endpoints were recorded at up to three follow-up visits that occurred 1, 5 and 9 weeks after initiating treatment. Percentage reductions in FPI were calculated relative to baseline and dichotomized to signify the percentage of participants with ≥ 30% and ≥ 50% reductions. The HIT-6 score was reported at weeks 5 and 9 and dichotomized to signify the percentage of participants with a ≥ 6-point post-baseline reduction considered a clinically meaningful improvement. Adjusted percentages were estimated from binomial logistic generalized estimating equation models with predictor variables of the baseline migraine status, treatment group, visit, and all two-way and three-way interactions. Covariates were study site, sex, and race/ethnicity (and for the FPI models, the baseline value of FPI). Estimate statements for each model were used to calculate adjusted odds ratios and 95% confidence limits at week 9.
Figure 2.
Figure 2.
Cumulative proportion of FPI responders at week 9 for two treatment groups analyzed by migraine status (ITT population): (a) migraineurs and (b) non-migraineurs. FPI endpoints were recorded at up to three follow-up visits occurring 1, 5 and 9 weeks after initiating treatment with either propranolol () or placebo (O). Adjusted percentages of participants responding, plotted on the vertical axis, were calculated by dichotomizing relative reductions at week 9 compared to week 0. Thresholds for dichotomization are shown on the horizontal axis. Adjusted percentages were estimated with binary logistic regression models using the generalized estimating equation method allowing for repeated visits by study participants. Numbers above plotted values represent a number needed to treat. Area under the curve (AUC) was calculated using the trapezoid rule and expressed as the percentage of maximum response within the range of 20% to 70% reduction (shaded rectangle).
Figure 3.
Figure 3.
Causal mediation of propranolol effect on proportion of FPI responders at week 9. The mediation model is adjusted for study site, sex, race/ethnicity, and baseline FPI. (a) Mediation model with change in the HIT-6 score (continuous variable) as a potential mediator of the total effect of treatment group on a ≥ 50% reduction in FPI. (b) Mediation model with change in heart rate (continuous variable) as a potential mediator of the total effect of treatment group on a ≥ 50% reduction in FPI. Values are covariate-adjusted odds ratios (ORs) and 95% confidence limits.

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