Examining the Nocebo Effect in Trials of Neuromodulators for Use in Disorders of Gut-Brain Interaction

INTRODUCTION: Nocebo effects are believed to influence the rate of reported adverse events (AE) and subject withdrawal in both the treatment and placebo groups of randomized clinical trials (RCT). Neuromodulators are commonly prescribed to treat disorders of gut-brain interaction (DGBI), but adherence to these medications is often limited by side effects such as headache, dry mouth, fatigue, and altered bowel habits. We performed a systematic review and meta-analysis to assess the proportion and risk difference of patients who experienced side effects leading to withdrawal in the placebo arm vs the treatment arm of RCT of neuromodulators for DGBI. We also sought to estimate the risk of developing any AE in the placebo arm of these studies and the rate of specific individual AEs. METHODS: We searched MEDLINE, Embase, Web of Science Core Collection, and the Cochrane Central Register of Controlled Trials Searches to identify RCT that included terms for DGBI and for commonly prescribed neuromodulators. We calculated pooled proportions of patients experiencing an AE leading to withdrawal in the active treatment group vs the placebo group with 95% confidence intervals (CI), the pooled proportions of patients experiencing any AE, the pooled proportions of patients experiencing specific AE such as dizziness and headache, the pooled proportions of patients experiencing severe AE, and corresponding pooled risk differences with 95% CI. RESULTS: There were 30 RCT included representing 2,284 patients with DGBI. Twenty-seven RCT reported data on AE leading to withdrawal. The pooled proportion of total patients with AE leading to withdrawal in the placebo group was 4% (95% CI 0.02–0.04). The pooled proportion of patients with AE leading to withdrawal who received neuromodulators was 9% (95% CI 0.06–0.13). In the 12 studies reporting data on patients experiencing at least 1 AE, the pooled proportion of patients experiencing any AE in the placebo group was 18% (95% CI 0.08–0.30), compared with 43% (95% CI 0.24–0.63) in the neuromodulator group. Thus, approximately 44% of the rate of withdrawal (0.04/0.09) and 42% of the rate reporting any side effects (0.18/0.43) in the neuromodulator group may be attributed to nocebo effects in the right context. Subgroup analysis by sex, medication class, risk of bias, and specific DGBI revealed differing withdrawal rates. There was no statistically significant difference in patients experiencing individual AE of dizziness, headache, or diarrhea. Rates of dry mouth, fatigue, and constipation were higher in treatment groups compared with those in placebo groups. DISCUSSION: Patients with DGBI in RCT randomized to placebo groups frequently experience AE and AE that lead to withdrawal consistent with a strong nocebo effect. Nonspecific AE such as dizziness, headaches, and diarrhea occurred similarly in patients receiving placebo compared with those receiving neuromodulators.