The hidden effects of blinded, placebo-controlled randomized trials: an experimental investigation

The knowledge of having only a 50% chance of receiving an active drug can result in reduced efficacy in blinded randomized clinical trials (RCTs) compared to clinical practice (reduced external validity). Moreover, minor onset sensations associated with the drug (but not with an inert placebo) can further challenge the attribution of group differences to drug-specific efficacy (internal validity). We used a randomized experimental study with inert placebos (inert substance) vs active placebos (inducing minor sensations), and different instructions about group allocation (probability of receiving drug: 0%, 50%, 100%). One hundred forty-four healthy volunteers were informed that a new application method for a well-known painkiller would be tested. Pain thresholds were assessed before and after receiving nasal spray. Half of the nasal sprays were inert placebos (sesame oil), while the other half were active placebos inducing prickling nasal sensations (sesame oil with 0.014% capsaicin). The major outcome was pain threshold after placebo application. A substantial expectation effect was found for the inert placebo condition, with participants who believed they had received an active drug reporting the highest pain thresholds. Active placebos show substantial differences to passive placebos in the 50% chance group. Therefore, patient expectations are significantly different in placebo-controlled clinical trials (50% chance) vs clinical practice (100% chance). Moreover, minor drug onset sensations can challenge internal validity. Effect sizes for these mechanisms are medium, and can substantially compete with specific drug effects. For clinical trials, new study designs are needed that better control for these effects.