Adam Fabisiak1, Marcin Włodarczyk2, Natalia Fabisiak3, Martin Storr4, Jakub Fichna5. 1. Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland; Department of Digestive Tract Diseases, Faculty of Medicine, Medical University of Lodz, Lodz, Poland. . adam.fabisiak@umed.lodz.pl. 2. Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland; Department of General and Colorectal Surgery, Faculty of Military Medicine, Medical University of Lodz, Poland. dr.mwlodarczyk@gmail.com. 3. Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland; Department of Gastroenterology, Faculty of Military Medicine, Medical University of Lodz, Poland. nat.fabisiak@gmail.com. 4. Center of Endoscopy, Starnberg, Germany; Department of Medicine II, Ludwig Maximilians University of Munich, Germany. gidoc@gmx.com. 5. Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland. jakub.fichna@umed.lodz.pl.
Abstract
BACKGROUND AND AIMS: Irritable bowel syndrome (IBS) is one of the most common functional gastrointestinal (GI) disorders characterized by pain and impaired bowel movements. Currently available drugs show limited efficacy. Cannabinoid 1 receptor (CB1) inverse agonists (CB1-RAN) cause diarrhea and may be candidates for the treatment of constipation-predominant IBS (IBS-C). We evaluated the effects of CB1-RAN in clinical trials for their potential use in IBS-C. METHODS: Database search identified all clinical trials published up to May 2018 that reported rimonabant and taranabant treatment for at least one month and detailed the GI adverse events (AEs). Categorical outcomes (subgroups of AEs) were analyzed using the odds ratio (OR). RESULTS: Eighteen trials met the inclusion criteria. Rimonabant 20 mg produced significantly more overall AEs (OR=1.35, CI: 1.19-1.52, p<0.0001), psychiatric events (OR=1.79, CI: 1.46-2.21, p<0.001) and GI AEs (OR=2.05, CI: 1.65-2.55, p<0.001) compared to placebo. Taranabant at doses ranging from 0.5 to 8 mg produced significantly more overall AEs (OR=1.36, CI: 1.13-1.64, p<0.002), psychiatric AEs (1.82, CI: 1.54-2.16, p<0.001) and GI AEs (OR=1.75, CI: 1.29-2.37, p<0.001) compared to placebo. CONCLUSIONS: The approach to target CB1 in the gut for the treatment of IBS-C or chronic constipation seems a promising therapeutic option. Prospective clinical trials on the possible targeting of CB1 and the endocannabinoid system are warranted.
BACKGROUND AND AIMS: Irritable bowel syndrome (IBS) is one of the most common functional gastrointestinal (GI) disorders characterized by pain and impaired bowel movements. Currently available drugs show limited efficacy. Cannabinoid 1 receptor (CB1) inverse agonists (CB1-RAN) cause diarrhea and may be candidates for the treatment of constipation-predominant IBS (IBS-C). We evaluated the effects of CB1-RAN in clinical trials for their potential use in IBS-C. METHODS: Database search identified all clinical trials published up to May 2018 that reported rimonabant and taranabant treatment for at least one month and detailed the GI adverse events (AEs). Categorical outcomes (subgroups of AEs) were analyzed using the odds ratio (OR). RESULTS: Eighteen trials met the inclusion criteria. Rimonabant 20 mg produced significantly more overall AEs (OR=1.35, CI: 1.19-1.52, p<0.0001), psychiatric events (OR=1.79, CI: 1.46-2.21, p<0.001) and GI AEs (OR=2.05, CI: 1.65-2.55, p<0.001) compared to placebo. Taranabant at doses ranging from 0.5 to 8 mg produced significantly more overall AEs (OR=1.36, CI: 1.13-1.64, p<0.002), psychiatric AEs (1.82, CI: 1.54-2.16, p<0.001) and GI AEs (OR=1.75, CI: 1.29-2.37, p<0.001) compared to placebo. CONCLUSIONS: The approach to target CB1 in the gut for the treatment of IBS-C or chronic constipation seems a promising therapeutic option. Prospective clinical trials on the possible targeting of CB1 and the endocannabinoid system are warranted.