Trimebutine maleate in the treatment of functional biliary disorders: TRIBUNE study results

Introduction. The term «functional disorders of the biliary tract and bile ducts» defines the conditions, which produce typical patterns of biliary pains in the absence of obvious signs of organic lesions of the gallbladder and bile ducts. The materials of the Rome IV consensus present the diagnostic criteria of their main types – functional disorders of the gall bladder and sphincter of Oddi. Vasilenko Clinic of Internal Diseases Propedeutics, Gastroenterology and Hepatology of the University Clinical Hospital No. 2 of Sechenov University carried out a noninterventional observational program to study the experience in using Trimedat® (trimebutine maleate) in the routine outpatient and inpatient practice in the treatment of patients with functional diseases of the biliary tract. Information partners of the program are the Russian Gastroenterological Association (RGA) and the Russian Society for the Study of the Liver (RSSL).

Materials and methods. The program included patients of both sexes aged 18 to 65 years with ICD-10 diagnoses «spasm of the sphincter of Oddi» (K 83.4), «postcholecystectomy syndrome» (K 91.5), «other specified diseases of the gallbladder» (K 82.8) , «other specified diseases of the bile ducts» (K 83.8), «disorders of gallbladder and biliary tract in diseases classified elsewhere» (K 87.0), if the clinical picture was consistent with functional biliary disorders according to the Rome IV criteria and in cases when the doctor decided to prescribe Trimedat® therapy. Patients were observed for 28 ± 1 days. The dynamics of biliary pain and discomfort, as well as other symptoms (in particular, nausea, flatulence) were evaluated on the background of the therapy, using the Gastrointestinal Symptom Score Scale, in which the severity of each symptom is estimated by 7 grades (Alekseev N.Yu., 2006) with adding a section to evaluate the biliary disorders. In the presence of criteria for functional disorders of the gallbladder, an ultrasound control of the fraction of its discharge was carried out before and after the therapy.

Results. 100 patients (33 (33%) men and 67 (67%) women, the average age 42.2 ± 13.2 years (18–65 years)) were enrolled in the program. In accordance with the Rome IV Consensus, the majority of patients (83 (83%)) had the functional disorders of GB; in 16 (16%) patients with the removed GB, the picture corresponded to the functional disorder of SO, one patient with kept GB was diagnosed with SO dysfunction. The treatment with Trimedate® at a standard dosage resulted in a decrease in the proportion of pain in the epigastric region (in the Scale section evaluating the biliary tract symptoms), the degree of nausea and bloating. Differences between the visits were estimated by the Friedman’s test, p <0.001. In addition, other sections of the scale also showed a decrease in indicators in scores. 79 patients underwent repeated ultrasound cholecystography at the end of treatment. It showed an increase in the fraction of GB emptying.

Conclusions. The use of Trimedate® in patients with functional disorders of the gall bladder and sphincter of Oddi resulted in the reduction of the severity of the main symptoms - the severity of biliary pain, nausea, bloating. The patients with GB dysfunction showed an increase in the fraction of GB emptying.

1. Cotton P.B., Elta G.H., Carter C.R., Pasricha P.J., Corazziar E.S. Gallbladder and Sphincter of Oddi. Disorders. 2016; 150(60): 1420–1429.e2 doi: 10.1053/j.gastro.2016.02.033.

2. Barthet M., Bouvier M., Pecout C., Berdah S., Viviand X., Mambrini P., Abou E., Salducci J., Grimaud J.C. Effects of trimebutine on sphincter of Oddi motility in patients with post-cholecystectomy pain. Aliment Pharmacol Ther, 1998, 12(7): 647-652.

3. Xu X., Li Q., Zhou L., Ru L.. Neurochemical mechanism of the gastrointestinal interdigestive migrating motor complex in rats with acute inflammatory stomach ache. Neural Regeneration Research. 2012; 7(27): 2136-2143. doi: 10.3969/j.issn.1673-5374.2012.27.008.

4. Seetharam P., Rodrigues G. Sphincter of Oddi and its Dysfunction. Saudi Journal of Gastroenterology : Official Journal of the Saudi Gastroenterology Association. 2008; 14(1): 1-6. doi: 10.4103/1319-3767.37793.

5. Wilcox C.M. Sphincter of Oddi dysfunction Type III: New studies suggest new approaches are needed. World Journal of Gastroenterology: WJG. 2015; 21(19): 5755-5761. doi: 10.3748/wjg.v21.i19.5755.

6. Vitton V., Delpy R., Gasmi M., et al. Is endoscopic sphincterotomy avoidable in patients with sphincter of Oddi dysfunction? Eur J Gastroenterol Hepatol. 2008; 20: 15–21.

7. Vitton V., Ezzedine S., Gonzalez J-M., Gasmi M., Grimaud J-C., Barthet M. Medical treatment for sphincter of oddi dysfunction: Can it replace endoscopic sphincterotomy? World Journal of Gastroenterology : WJG. 2012; 18(14): 1610- 1615. doi: 10.3748/wjg.v18.i14.1610.

8. Afghani E., Lo S.K., Covington P.S., Cash B.D., Pandol S.J.. Sphincter of Oddi Function and Risk Factors for Dysfunction. Frontiers in Nutrition. 2017; 4: 1. doi: 10.3389/fnut.2017.00001.

9. Ballal M.A., Sanford P.A.. Physiology of the sphincter of Oddi–the present and the future? Part 1. Saudi J Gastroenterol. 2000; Sep, 6(3): 129-46.

10. Yakovenko E.P., Agafonova N.A., Yakovenko A.V., Ivanov A.N., Kagramanova A.V. Opioid receptor agonist trimebutin in the treatment of functional disorders of the gallbladder and sphincter of Oddi. Lechashchy Vrach. 2014; 2: 56-60. (In Russ).

11. Alekseev N.Yu. Diagnosis and prognosis of the course of liver pathology under the influence of alphaamanitine: dissertation of PhD in medicine: 14.00.05. Voronezh, 2006; 141 p. (In Russ).

12. Blanquet F., Bouvier M., Gonella J. Action of trimebutine in cat and rabbit colon: evidence of an opioid-like effect. J Pharmacol Exp Ther. 1985; Sep, 234(3): 708-12.

13. Fioramonti, Bueno. Centrally acting agents and visceral sensitivity. Gut. 2002; 51(Suppl I): i91– i95. Rivière. Peripheral kappa-opioid agonists for visceral pain. Br J Pharmacol, 2004 April, 141(8): 1331–1334.

14. Roman et al. Pharmacological Properties of Trimebutine and N-Monodesmethyltrimebutine. JPET. 1999; 289: 1391–1397.

15. Pol O., Alameda F., Puig M.M. Inflammation enhances μ-opioid receptor transcription and expression in mice intestine. Mol Pharmacol. 2001; 60: 894–9.

16. Holzer P. Opioid receptors in the gastrointestinal tract. Regulatory peptides. 2009; 155(1-3): 11-17. doi: 10.1016/j.regpep.2009.03.012.

17. Collins S.M., Daniel E.E. Opiate modulation of gastrointestinal motility and the actions of trimebutine. Can J Gastroenterol. 1991; 5: 185-193.