Placebo Response in Clinical Trials: Taming the Human Brain
The use of placebo in comparative clinical trials has exposed another lesser known side of the placebo, i.e., the placebo response. The placebo response is now being increasingly discussed, not only to adjust for the true clinical efficacy of a drug but also to understand the basis of psychological therapy, and benefits in therapeutic areas such as neurological disorders, especially pain. The mechanism of placebo action is multifaceted and works on the levels of brain and biochemical signaling, stimulated by priming and expectations. The imaging data show that certain areas of the brain are hyperactive while some are hypoactive during the placebo‑mediated response, and trigger a biochemical pathway that relieves the symptoms. The data also suggest that the extent of benefit, i.e., the effect size of placebo response is directly proportional to positive expectations associated with the treatment, trust on the treating doctor, and certain beliefs associated with previous treatment. Although placebos incite a positive response, these might compromise or artifact the true efficacy of the drugs, thereby necessitating the need of addressing or minimizing the placebo response. Furthermore, it is important to identify the factors that modulate the placebo response, such as severity and natural burning out of the disease. Therefore, it is important to take a two‑pronged approach‑first, placebo as a treatment, for example, in neurological diseases, and second, adequately designed studies that minimize the placebo response. In this article, we discuss the placebo response, the mechanism behind it, its implications in clinical trials, and how to address the same.