This review discusses how the placebo effect related to treatment side effects may confound clinical trials on antitussives and specifically looks at the implications for trials on ATP antagonists. These new antitussives have distinctive side effects on the sensation of taste, and investigators have expressed concerns that this may unblind the clinical trials. Blinding is an essential component of trial design, but the degree of blinding in trials is rarely assessed. The assumptions of additivity and balance in clinical trials are discussed as important factors that allow assessment of the pharmacological activity of an antitussive. How side effects unbalance a clinical trial by amplifying the placebo effect of active treatments is discussed. The point is made that unblinding of trials invalidates any assessment of efficacy but that there is little interest or discussion about this fundamental aspect of trials. Proposals are discussed which may improve the blinding of trials and control placebo effects by changes to participant information, trial design, patient selection and use of active placebos. The issue of unblinding of clinical trials is not a new issue, but if real progress is to be made in developing new antitussives, then it is an issue that needs to be urgently addressed.
Keywords: ATP antagonist; Additivity; Blinding; Cough; Placebo effect; Side effects.
© 2021. The Author(s).