Background Rimegepant improves both headache pain and physical function in clinical studies for the acute treatment of migraine. It is not clear whether rimegepant has direct effects on physical function or if improvements in function are an indirect treatment effect mediated through reductions in headache pain. The objective of this study was to estimate the extent to which rimegepant-mediated reductions in headache pain intensity contribute to improvements in physical functioning during a migraine attack. Methods Data were pooled from four placebo-controlled trials of rimegepant 75 mg for acute treatment of migraine. Participants rated current headache pain and functional disability on four-point scales prior to dosing and from 15 min to 48 h post-dose. A cross-sectional mediation model including variables for pain, function, and treatment (rimegepant or placebo) was run separately at each timepoint. Based on results of cross-sectional modeling, a longitudinal pseudo-steady-state mediation model was constructed to estimate relationships between variables using all available data during the period when all processes in the model were considered to have achieved and maintained equilibrium. The pseudo-steady-state model assumed relationships between variables were the same at all timepoints. Results Across all studies and treatment groups, participants ( N = 3975) were mostly female (75.2–89.2%) and mean age was 40.0 to 41.9 years. Cross-sectional models ( N = 3441–3834 across timepoints) indicated that the period represented by measurements at 3, 4, 6, and 8 h can be considered a pseudo-steady-state period for a mediation model representing inter-relationships among headache pain, function, and treatment. The pseudo-steady-state model ( N = 3281) incorporated all available data from 3, 4, 6, and 8 h post-dose and estimated that 76.1% of the effect of treatment on function is mediated indirectly via improvements in headache pain, with 23.9% representing a direct effect (representing all other effects/mediators not included in the model). Conclusion The effect of rimegepant on functioning was largely mediated through reductions in headache pain intensity during the migraine attack. Approximately one-quarter of the improvement in functioning was mediated through factors other than pain intensity.
Abraham et al. (Sun,) studied this question.