Key messages
1. We found no clear difference in effect between active and standard placebos, but we are very uncertain about the results.
2. We suggest that researchers carefully consider the type of placebo when investigating medicines with clear side effects.
What are standard placebos and active placebos?
Blinding (or masking) is an important part of randomised trials and ensures that participants and healthcare providers are not influenced by knowing whether the participant is receiving the experimental treatment. If they had this knowledge, they might unintentionally overestimate (or underestimate) the effect of the treatment. One method of blinding is to give the non-treated group of participants a placebo, which looks like the medicine (e.g. a tablet of similar shape, colour, smell, taste, and texture) but does not contain its active ingredients.
Blinding with a placebo may not always be successful. The treatment may have side effects that distinguish it from the placebo so that the treatment effect is still not measured accurately. For this reason, some trials use active placebos, which mimic some of the side effects of the experimental medicine. However, it is unclear whether the choice of placebo type actually makes a difference to the treatment effects.
What did we want to find out?
We wanted to find out whether treatment effects in randomised trials differ when using active placebos compared to standard placebos.
What did we do?
We collected and analysed trials that directly compared the two types of placebo, or that compared both placebos with an experimental medicine. If people receiving active placebo experience better results than those receiving standard placebo, this difference might be due to them believing that they are receiving the experimental medicine. It would also mean that in trials that compare a medicine with standard placebo, the beneficial effect of the medicine is exaggerated. This is important if the measured benefits of the treatment are small or moderate and thus especially sensitive to changes in the methods used for the trial.
What did we find?
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.
We did not find a statistically significant difference between active and standard placebo control interventions in our primary analysis, but the result was imprecise and the CI compatible with a difference ranging from important to irrelevant. Furthermore, the result was not robust, because two sensitivity analyses produced a more pronounced and statistically significant difference. We suggest that trialists and users of information from trials carefully consider the type of placebo control intervention in trials with high risk of unblinding, such as those with pronounced non-therapeutic effects and participant-reported outcomes.
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.
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.
We 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.
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 extracted data, assessed risk of bias, scored active placebos for adequacy and risk of unintended therapeutic effect, and categorised active placebos as unpleasant, neutral, or pleasant. We requested individual participant data from the authors of four cross-over trials published after 1990 and one unpublished trial registered after 1990. Our primary inverse-variance, random-effects meta-analysis used standardised mean differences (SMDs) of active versus standard placebo for participant-reported outcomes at earliest post-treatment assessment. A negative SMD favoured the active placebo. We stratified analyses by trial type (clinical or preclinical) and supplemented with sensitivity and subgroup analyses and meta-regression. In secondary analyses, we investigated observer-reported outcomes, harms, attrition, and co-intervention outcomes.
We included 21 trials (1462 participants). We obtained individual participant data from four trials. Our primary analysis of participant-reported outcomes at earliest post-treatment assessment resulted in a pooled SMD of −0.08 (95% confidence interval (CI) −0.20 to 0.04; I2 = 31%; 14 trials), with no clear difference between clinical and preclinical trials. Individual participant data contributed 43% of the weight of this analysis. Two of seven sensitivity analyses found more pronounced and statistically significant differences; for example, in the five trials with low overall risk of bias, the pooled SMD was −0.24 (95% CI −0.34 to −0.13). The pooled SMD of observer-reported outcomes was similar to the primary analysis. The pooled odds ratio (OR) for harms was 3.08 (95% CI 1.56 to 6.07), and for attrition, 1.22 (95% CI 0.74 to 2.03). Co-intervention data were limited. Meta-regression found no statistically significant association with adequacy of the active placebo or risk of unintended therapeutic effect.