The placebo response to citric acid-induced cough: pharmacodynamics and gender differences

Characteristics of the response to placebo in a citric acid-induced cough challenge were investigated as part of a randomized, double-blind crossover trial to assess the antitussive effect of dextromethorphan. Baseline cough responses were established on two occasions in 22 healthy subjects. They received 60 ml placebo antitussive syrup and cough frequency following five inhalations of 10% citric acid over 5 min was measured at regular intervals up to 12 h. Response-time models of varying complexity were used to describe the placebo cough suppression data. The cough response to placebo was also compared to that of the untreated state. The placebo cough response was best characterized by a non-linear increase in cough suppression up to a maximum reduction of 1.6 coughs from baseline at 4-4.5 h, followed by a non-linear return to baseline. The cough response in the untreated state was not different from that of placebo (P=0.99). Females coughed more frequently than males (median number of coughs=10.5 vs. 9.0, respectively P<0.001; Mann-Whitney U test), and adaptation to the cough stimulus was significantly more rapid in females (P<0.025). Accordingly, in trials that use citric acid-induced cough, gender should be considered in study design, particularly in relation to the timing of measurements.