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Review
. 2021 Aug;199(4):319-326.
doi: 10.1007/s00408-021-00458-2. Epub 2021 Jul 19.

Placebo and Side Effects Confound Clinical Trials on New Antitussives

Ronald Eccles  1
Affiliations
Review

Placebo and Side Effects Confound Clinical Trials on New Antitussives

Ronald Eccles. Lung. 2021 Aug.

Abstract

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.

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Conflict of interest statement

None to declare. The author acts as a consultant on occasion to the pharmaceutical industry.

Figures

Fig. 1
Fig. 1
Efficacy of an antitussive medicine consists of a pharmacological effect and a placebo effect. The placebo effects of both arms of the study are balanced, and subtraction of the efficacy of the placebo from the efficacy of the active arm allows measurement of pharmacological antitussive efficacy. This is the principle of additivity in clinical trials
Fig. 2
Fig. 2
Factors influencing the magnitude of the placebo effect in a cough medicine. The perceived placebo effect of a medicine consists of a true placebo effect and non-specific effects. Note that the efficacy of the medicine and any side effects may contribute to the placebo effect of the active medicine and may also influence the placebo arm of the study if patients expect side effects
Fig. 3
Fig. 3
The active medicine has side effects which unblind the study and amplify the placebo effect in the active treatment arm of the study. In the placebo arm of the study, the placebo effect may be decreased because patients are unblinded because they do not suffer from expected side effects. Unblinding due to side effects causes an unbalancing of the study and the principle of additivity, used to determine the pharmacological effect of the medicine, is invalid
Fig. 4
Fig. 4
Magnitude of placebo effects in a properly blinded clinical trial. The magnitude of the antitussive efficacy is shown by the height of the column. The trial consists of 200 patients. 100 allocated to placebo and 100 allocated to an active medicine. The patients are asked at the end of the study to guess which treatment they were taking. Because the study is properly blinded in each arm of the study, the patient’s guesses as regards their treatment are no better than one would expect by chance with 50 patients in each of the four groups. This means that the mean antitussive efficacy for the two treatment groups is balanced
Fig. 5
Fig. 5
Magnitude of the placebo effects in a clinical trial where there is some unblinding of the treatments, perhaps due to incidence of side effects in the active medicine. The magnitude of the antitussive efficacy is shown by the height of the column. The trial consists of 200 patients. 100 allocated to take placebo and 100 allocated to take an active medicine. The patients are asked at the end of the study to guess which treatment they were taking. Because the study is partially unblinded, the patient’s guesses as regards their treatment are better than one would expect by chance. In the placebo treatment arm of 100 patients, 80 patients receiving placebo correctly guess their placebo treatment and only 20 patients receiving placebo incorrectly guess they are taking an active medicine. Similarly, in the active treatment arm, 80 patients receiving the active medicine correctly guess they are taking an active medicine and 20 patients incorrectly guess they are taking placebo. This means that the mean antitussive efficacy for the 100 patients in the active treatment arm is greater than the mean antitussive efficacy in the placebo treatment arm and this could be mis-interpreted as supporting the efficacy of the active medicine
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