Am J Gastroenterol. 2022 Dec 22. doi: 10.14309/ajg.0000000000002108. Online ahead of print.
BACKGROUND AND AIMS: Nocebo effects are thought to influence the rate of reported adverse events (AEs) and subject withdrawal in both the treatment and placebo groups of randomized clinical trials (RCTs). Neuromodulators are commonly prescribed to treat disorders of gut-brain interaction (DGBIs), 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 versus the treatment arm of RCTs of neuromodulators for DGBIs. We also sought to estimate the risk of developing any AE in the placebo arm of these studies as well as the rate of specific individual adverse events.
METHODS: We searched MEDLINE, Embase, Web of Science Core Collection, and the Cochrane Central Register of Controlled Trials Searches to identify RCTs that included terms for DGBIs and for commonly prescribed neuromodulators. We calculated pooled proportions of patients experiencing an AE leading to withdrawal in the active treatment group versus the placebo group with 95% confidence intervals (CI), the pooled proportions of patients experiencing any adverse event, the pooled proportions of patients experiencing specific adverse events such as dizziness and headache, the pooled proportions of patients experiencing severe adverse events and corresponding pooled risk differences with 95% CIs.
RESULTS: There were 30 RCTs included representing 2284 DGBI patients. 27 RCTs reported data on AEs leading to withdrawal. The pooled proportion of total patients with AEs leading to withdrawal in the placebo group was 4% (95% CI 0.02 – 0.04). The pooled proportion of patients with AEs 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 one AE, the pooled proportion of patients experiencing any adverse event in the placebo group was 18% (95% CI 0.08 – 0.30), compared to 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 DGBIs revealed differing withdrawal rates. There was no statistically significant difference in patients experiencing individual AEs of dizziness, headache or diarrhea. Rates of dry mouth, fatigue and constipation were higher in treatment groups compared to placebo groups.
CONCLUSION: Patients with DGBIs in RCTs randomized to placebo groups frequently experience AEs and AEs that lead to withdrawal consistent with a strong nocebo effect. Non-specific AEs such as dizziness, headaches and diarrhea occurred similarly in patients receiving placebo compared to those receiving neuromodulators.