Can knowledge of Placebo and Nocebo Mechanisms Help Improve Randomized Clinical Trials?

Over the last decade, there has been a substantial increase in negative results from randomized controlled trials (RCTs), which may be due to an increasing placebo response among other factors. Currently, identification and exclusion of placebo responders from trials are attempted to overcome this problem, but so far the success of these approaches has been limited. At the same time, the placebo-mechanism literature has highlighted how contextual factors, such as patients' expectations, interfere with the effect of drug administration, leading to a certain degree of uncertainty in RCTs. In this chapter, we review the current challenges of RCTs including the uncertainties of the active arm, the placebo arm, the additivity assumption, and the double-blind procedure. We use the placebo-mechanism literature to debate the strengths and weaknesses of attempts to identify and exclude placebo responders from trials. Finally, we illustrate how insights from the placebo-mechanism literature may point to new ways of improving RCTs.