Methodological considerations for designing and conducting open-label placebo trials

Abstract

In pain and other research fields, placebos have traditionally been associated with deception, although harnessing placebo effects does not necessarily require deception. Open-label placebos (OLPs) represent a novel approach in which inert treatments are administered openly and transparently, allowing patients to knowingly receive an inert treatment while still experiencing therapeutic benefits (eg, pain relief). As OLP research grows, concerns have been raised regarding methodological rigor and the unique challenges posed by unblinded designs in both experimental and clinical contexts. Given the inherent transparency regarding treatment group allocation in OLP trials, particular attention is needed when defining appropriate control groups, implementing feasible blinding strategies, and providing a treatment rationale to adequately explain OLPs. Addressing these challenges is crucial to advancing both the scientific understanding of the psychoneurobiological mechanisms underlying OLP effects and their clinical relevance in pain. In this review, we outline key methodological considerations for designing and conducting OLP studies in pain research and beyond, providing guidance on control group selection, blinding strategies, and reporting standards. In addition, we integrate insights from the patient advisory board of the transregional Collaborative Research Center (CRC/TRR) 289 “Treatment Expectation” to incorporate patient perspectives on the feasibility and acceptability of OLPs. Aligning study designs with patient needs and expectations may foster a more meaningful, patient-centered approach to OLP research. By combining methodological guidance and emphasizing patient-centered insights, this review aims to enhance the quality, relevance, and clinical translation of OLP research in pain.