Nocebo effects and influencing factors in the randomized clinical trials of chronic constipation: A systematic review and meta-analysis

Background: Nocebo effects are unavoidable in randomized clinical trials. We aimed to assess the magnitude of nocebo effects and explore the influencing factors in chronic constipation. Methods: We searched the PubMed, Embase, and Cochrane Library databases up to July 2022. Randomized, placebo-controlled trials investigating interventions in chronic constipation were included. We conducted a random effects meta-analysis of the proportion of adverse events (AEs) in placebo-treated participants and evaluated the effect of trial characteristics on nocebo effects. Key Results: We identified 20,204 studies from the databases, of which 61 were included in the final analysis. The pooled placebo AE rate was 30.41%, and AE-related withdrawal rate was 1.53%. The most commonly reported AEs were headache (5.67%), diarrhea (4.45%), abdominal pain (3.98%), nasopharyngitis (3.39%), nausea (3.36%), and flatulence (2.95%). The placebo AE rate was lower in trials conducted in Asia compared to those in Europe, North America, and international trials. It was also lower in trials diagnosed by Rome III compared to clinician's opinion and Rome II. Additionally, the placebo AE rate was lower in single-center trials compared to multicenter trials, lower in 5-8 weeks therapy compared to 9-12 weeks therapy, lower in participants with FC compared to those with IBS-C and CC, lower in trials with 2 arms compared to 3 arms, and higher in trials with prokinetic drugs compared to secretagogues and laxatives. Conclusions & Inferences: The placebo AE rate was 30.41% in patients with chronic constipation. Based on our findings, we recommend that researchers take the nocebo effects into consideration when designing and conducting clinical trials and adopt specific measures to mitigate the negative influence of nocebo effects.