A randomized placebo controlled trial to evaluate the effects of butamirate and dextromethorphan on capsaicin induced cough in healthy volunteers

Abstract

Aims: The examination of cough reflex sensitivity through inhalational challenge can be utilized to demonstrate pharmacological end points. Here we compare the effect of butamirate, dextromethorphan and placebo on capsaicin-induced cough in healthy volunteers.

Methods: In this randomized, placebo-controlled, six way crossover study the effect of dextromethrophan 30 mg, four doses of butamirate and placebo was evaluated on incremental capsaicin challenges performed at baseline and 2, 4, 6, 8, 12 and 24 h following dosing. The primary end point was the area under the curve (AUC(0,12h)) of log10 C5 from pre-dose to 12 h after dosing. Plasma butamirate metabolites were analyzed to evaluate pharmacokinetic and pharmacodynamic relationships.

Results: Thirty-four subjects (13 males, median age 25 years) completed the study. Cough sensitivity decreased from baseline in all arms of the study. Dextromethorphan was superior to placebo (P = 0.01) but butamirate failed to show significant activity with maximum attenuation at the 45 mg dose. There was no apparent relationship between pharmacokinetic and pharmacodynamic parameters for butamirate.

Conclusions: We have demonstrated for the first time that dextromethorphan attenuates capsaicin challenge confirming its broad activity on the cough reflex. The lack of efficacy of butamirate could be due to formulation issues at higher doses.

Keywords: butamirate; capsaicin; cough sensitivity; dextromethorphan.

© 2014 The British Pharmacological Society.

Figures

Figure 1

Figure 1 demonstrates how the pharmacodynamic parameters were determined. Log10C5 is on the y axis and time on the x axis

Figure 2

Consort diagram demonstrating progress through this randomized, placebo controlled, six way crossover clinical study. The six study medications were butamirate citrate 1.5 mg ml−1 oral syrup 22.5 mg (15 ml), butamirate citrate 1.5 mg ml−1 45 mg (30 ml), butamirate citrate 1.5 mg ml−1 67.5 mg (45 ml), butamirate citrate 1.5 mg ml−1 90 mg (60 ml), dextromethorphan 1.5 mg ml−1 (Benylin® dry coughs non-drowsy syrup) 30 mg (20 ml) and matched placebo for butamirate syrup 30 ml. The sequence of administration of medications was determined by computer generated block randomization. Period 1 comprises those subjects who received the first randomized medication. Period 2 comprises those subjects who received the first and second medications and accordingly for the other periods of the study. Period 6 comprises those who received all the six study medications

Figure 3

Temporal profile of log10C5 over a period of 24 h (PP population) for dextromethorphan, the different doses of butamirate and placebo is demonstrated. Dextromethorphan was superior to placebo (P = 0.01). The effect of butamirate failed to reach significance, the maximal effect being observed with the 45 mg dose. , butamirate 22.5 mg; , butamirate 45 mg; , butamirate 67.5 mg; , butamirate 90 mg; , dextromethorphan 30; , placebo