Efficacy and Safety of Clidinium/Chlordiazepoxide as an Add-on Therapy in Functional Dyspepsia: A Randomized, Controlled, Trial

Abstract

Background/Aims The treatment of refractory functional dyspepsia (FD) is a challenge. Clidinium/chlordiazepoxide is a combination of antispasmodic and anxiolytic drugs that has been used as an adjunct treatment for FD in clinical practice with limited supporting evidence of efficacy. The aim of the study is to assess the efficacy and safety of clidinium/chlordiazepoxide as an adjunct treatment to a proton pump inhibitor (PPI) in refractory dyspepsia. Methods We performed a study of patients who met the Rome IV criteria for FD who failed to respond to PPIs. Patients were randomly assigned to groups that received clidinium/chlordiazepoxide or placebo as an add-on treatment to PPI for 4 weeks. The primary outcome was the rate of responders, which was defined as a > 50% reduction in dyspepsia symptom score after 4 weeks of treatment. The secondary outcomes were an improvement in the quality of life and the safety profile. Results Between March 2017 and February 2018, 78 patients were enrolled. The rates of responders in the clidinium/chlordiazepoxide group and placebo groups were 41.03 % and 5.13% at week 4 (P < 0.001). The clidinium/chlordiazepoxide group also showed significant improvement in overall quality of life over placebo. However, the clidinium/chlordiazepoxide group had more frequent drowsiness than the placebo group (30.27% vs 6.52%, P = 0.034). There were no major adverse events in either group. Conclusions Clidinium/chlordiazepoxide significantly improved dyspeptic symptoms and quality of life. This combination may be used as an add-on therapy in FD patients without major adverse events.

British Society of Gastroenterology guidelines on the management of functional dyspepsia

“… 273 The anti-cholinergic clidinium, combined with the anxiolytic chlordiazepoxide, as add-on therapy improved dyspeptic symptoms and quality of life significantly in one trial conducted in 78 patients, but its availability is limited. 274 A combination preparation of the anxiolytic flupenthixol and the antidepressant melitracen showed potential efficacy in a crossover RCT of 25 patients with refractory FD. 275 As previously discussed, one trial used a multimodal approach in 100 patients with refractory FD, which involved intensified medical management testing for and targeting of abnormalities of sensory and motor function including gastric emptying, a standardised nutrient challenge and, if clinically indicated, 24-hour pH monitoring, manometry and breath tests.…”

“…In another RCT, recruiting 95 patients, a duodenal-release formulation of a spasmolytic combination of caraway oil and l-menthol improved epigastric pain and early satiation within 24 hours in 75% of patients with more severe symptoms, compared with usual treatment alone 273. The anti-cholinergic clidinium, combined with the anxiolytic chlordiazepoxide, as add-on therapy improved dyspeptic symptoms and quality of life significantly in one trial conducted in 78 patients, but its availability is limited 274. A combination preparation of the anxiolytic flupenthixol and the antidepressant melitracen showed potential efficacy in a crossover RCT of 25 patients with refractory FD 275.…”

Randomised clinical trial: the effects of pregabalin vs placebo on functional dyspepsia

“…Therefore, alternative treatments for patients who fail to respond to PPI are needed and are currently under‐investigated. These treatments include prokinetics, 9,10 neuromodulators 11,12 or anxiolytics 13,14 …”

The devil is in the detail: a critique of nine editorials published by the International Task Force on Benzodiazepines

“…The section briefly reviews six studies from the 1970s, five of which are small and none of which have influenced recent gastroenterology clinical practice guidelines in support of benzodiazepines in routinely supplanting commonly used medication classes such as antispasmodics, antidepressants or proton pump inhibitors (Kamada 2021; Lacy 2021). Although not specifically addressed, the unique but antiquated combination of chlordiazepoxide and clidinium bromide was recently evaluated with positive results as an add-on therapy for functional dyspepsia but it is unclear how much benefit is clearly derived from the antimuscarinic compared with the benzodiazepine, as they have not been evaluated separably (Puasripun 2020). The authors of this trial recommend short-term use of this combination solely as an adjunct to standard pharmacotherapy such as proton pump inhibitors (Puasripun 2020).…”

“…Although not specifically addressed, the unique but antiquated combination of chlordiazepoxide and clidinium bromide was recently evaluated with positive results as an add-on therapy for functional dyspepsia but it is unclear how much benefit is clearly derived from the antimuscarinic compared with the benzodiazepine, as they have not been evaluated separably (Puasripun 2020). The authors of this trial recommend short-term use of this combination solely as an adjunct to standard pharmacotherapy such as proton pump inhibitors (Puasripun 2020).…”