Impact of active placebo controls on estimated drug effects in randomised trials: a systematic review of trials with both active placebo and standard placebo

Background An estimated 60% of pharmacological randomised trials use placebo control interventions to blind (i.e. mask) participants. However, standard placebos do not control for perceptible non-therapeutic effects (i.e. side effects) of the experimental drug, which may unblind participants. Trials rarely use active placebo controls, which contain pharmacological compounds designed to mimic the non-therapeutic experimental drug effects in order to reduce the risk of unblinding. A relevant improvement in the estimated effects of active placebo compared with standard placebo would imply that trials with standard placebo may overestimate experimental drug effects. Objectives We aimed to estimate the difference in drug effects when an experimental drug is compared with an active placebo versus a standard placebo control intervention, and to explore causes for heterogeneity. In the context of a randomised trial, this difference in drug effects can be estimated by directly comparing the effect difference between the active placebo and standard placebo intervention. Search methods searched PubMed, CENTRAL, Embase, two other databases, and two trial registries up to October 2020. We also searched reference lists and citations and contacted trial authors. Selection criteria We included randomised trials that compared an active placebo versus a standard placebo intervention. We considered trials both with and without a matching experimental drug arm. We included 21 trials in this review, covering subjects such as pain and psychiatry. We found no clear difference between the two types of placebo in participant-reported outcomes (such as pain intensity). However, because the result was uncertain, the possible range of this result included both no difference and a potentially important difference in favour of active placebo. When we limited our analysis to higher-quality trials, active placebos were more beneficial than standard placebos, but these trials were not typical clinical trials and might not be applicable to clinical scenarios.