The Placebo and Nocebo Responses in Clinical Trials in Inflammatory Bowel Diseases

Abstract

Placebo and nocebo responses are mostly discussed in clinical trials with functional bowel disorders. Much less has been investigated and is known in gastrointestinal diseases beyond irritable bowel syndrome (IBS), especially in inflammatory bowel diseases (IBD). For the purpose of this review, we screened the Journal of Interdisciplinary Placebo Studies (JIPS) database with approximately 4,500 genuine placebo research articles and identified nine meta-analyses covering more than 135 randomized and placebo-controlled trials (RCTs) with more than 10,000 patients with Crohn´s disease (CD) and another five meta-analyses with 150 RCTs and more than 10,000 patients with ulcerative colitis (UC). Only three discussed nocebo effects, especially in the context of clinical use of biosimilars to treat inflammation. The articles were critically analyzed with respect to the size of the placebo response in CD and UC, its effects on clinical improvement versus maintenance of remission, and mediators and moderators of the response identified. Finally, we discussed and compared the differences and similarities of the placebo responses in IBD and IBS and the nocebo effect in switching from biologics to biosimilars in IBD management.

Keywords: Crohn´s disease; clinical trial; inflammatory bowel disease; placebo and nocebo effects; systematic (literature) review; ulcerative colitis.

FIGURE 1

The conventional model of the placebo response in randomized, placebo-controlled trials (RCT): It is assumed that in the drug arm of the RCT, the placebo response is equal to its size in the placebo arm. In both, the effects of the spontaneous course of symptoms, methodological effects such as the “regression to the mean,” and responses biases contribute to its size, in addition to the placebo effect, which is the individual response of a patient towards placebo provision.

FIGURE 2

Dose-dependent function of the (pooled,%) placebo response in a meta-analysis of randomized and placebo-controlled trials (RCT) in ulcerative colitis (22): the number of doctor visits during the trial has an effect on all clinical outcome parameters, clinical benefit (improvement), endoscopically assessed remission, histologically assessed remission, and clinical remission measures.

FIGURE 3

Design scheme for a remission maintenance study in IBD that would allow including a “no-treatment” arm to assess the spontaneous course of the disease. The concept has been called “cohort multiple randomized and placebo-controlled trials (cmRCT)” (Relton et al., 2010); for a discussion see (Weimer and Enck 2014).