Open-label placebo clinical trials: is it the rationale, the interaction or the pill?

National surveys of primary care physicians demonstrate that placebo use is prevalent. Against their widespread use, until recently, it was assumed among researchers that placebos must be deceptively prescribed for beneficial effects to be elicited. However, a new programme of research in placebo studies indicates that it may be possible to harness placebo effects in clinical practice via ethical, non-deceptively prescribed 'open label placebos' ('OLPs'). To date, there have been 14 small scale clinical and experimental trials into OLPs. Results suggest therapeutic potential of these treatments for a range of conditions and symptoms. In this evidence-based Analysis we identify conceptual issues that, if not given due consideration, risk undermining research methodologies in OLP trials. Counterintuitively, owing to the nuances posed by placebo terminology, and the difficulties of designing placebos controls in OLP trials, we suggest that experimentalists reflect more deeply when formulating adequate comparison groups. Further research is needed to disentangle which specific components of OLPs are effective, such as: the rationale provided to participants; the quality of provider interaction; and/or the action of taking the pills. We conclude with recommendations for how researchers might take up the significant challenge of devising optimal placebo controls for OLP clinical trials. Although these issues are intricate, they are not merely academic: without due diligence to conceptual, and as a consequence, methodological considerations, OLP effect sizes may be over- or underestimated. We conclude that there may yet be potential to use OLPs in medical practice but clinical translation depends on rigorously controlled research. © Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.