Pathogenesis of Functional Biliary Pain and Pharmacology of Trimebutin

Aim: to provide data on the pathogenesis of functional biliary pain and provide rationale for the use of trimebutine for this indication.

Key points. Biliary pain is one of the most frequent reasons for patients to see a doctor. The diagnosis of functional disorder of the gallbladder and Oddi's sphincter is legitimate only after the exclusion of organic causes from both the gastrointestinal tract and other organs and systems. The initial appeal to surgeons with a complaint of pain in the epigastrium or right hypochondrium may lead to unjustified surgical intervention that does not bring relief to the patient's suffering. The consequences of cholecystectomy also have an anatomical and physiological justification for the occurrence or preservation of biliary pain. Currently, two main hypotheses are being considered to explain its cause: increased intraluminal pressure due to morphological and functional obstacles to bile outflow and visceral hypersensitivity. In the multilevel system of regulation of the gallbladder and sphincter apparatus, the opioid system occupies a special place. The agonist of peripheral receptors of the enkephalinergic system, trimebutine, in clinical studies led to the relief of biliary pain in more than 80 % of patients with functional biliary disorders, while a significant decrease in the severity of diarrhea, dyspeptic, and constipation syndromes was revealed.

Conclusion. The prescription of the peripheral receptor agonist of the enkephalinergic system, trimebutine, is pathogenetically justified for functional biliary pain.

1. Ivashkin V.T., Mayev I.V., Shulpekova Yu.O., Baranskaya E.K., Okhlobystin A.V., Trukhmanov A.S., et al. Diagnostics and treatment of biliary dyskinesia: Clinical guidelines of the Russian gastroenterological Association. Russian Journal of Gastroenterology, Hepatology, Coloproctology. 2018;28(3):63–80. (In Russ.). DOI: 10.22416/1382-4376-2018-28-3-63-80

2. Cotton P.B., Elta G.H., Carter C.R., Pasricha P.J., Corazziari E.S. Rome IV. Gallbladder and sphincter of Oddi disorders. Gastroenterology. 2016;S0016– 5085(16)00224-9. (Online ahead of print). DOI: 10.1053/j.gastro.2016.02.033

3. Rose J., Fields R., Strasberg S. Poor reproducibility of gallbladder ejection fraction by biliary scintigraphy for diagnosis of biliary dyskinesia. J Am Coll Surg. 2018;226(2):155–9. DOI: 10.1016/j.jamcollsurg.2017.10.025

4. Osipenko M.F., But-Gusaim V.I., Voloshina N.B., Bicbulatova E.A. “Overlap syndrome” irritable bowel syndrome and functional gallbladder and sphincter of Oddi disorders. Baikal Medical Journal. 2008;80(5):21–6. (In Russ.).

5. Latenstein C.S.S., Wennmacker S.Z., de Jong J.J., van Laarhoven C.J.H.M., Drenth J.P.H., de Reuver P.R. Etiologies of long-term postcholecystectomy symptoms: A systematic review. Gastroenterol Res Pract. 2019;2019:4278373. DOI: 10.1155/2019/4278373

6. Shulpekova Yu.O., Nechaev V.M., Ivashkin V.T. Biliary pain in the structure of episodes of right upper abdominal pain. Pediatric Nutrition. 2020;18(6):42–52. (In Russ.). DOI: 10.20953/1727-5784-2020-6-42-52

7. Drossman D.A. Functional gastrointestinal disorders: History, pathophysiology, clinical features, and Rome IV. Gastroenterology. 2016;150(6):1262–79.e2. DOI: 10.1053/j.gastro.2016.02.032

8. Sheptulin A.A., Kardasheva S.S. Controversial issues of gallbladder and sphincter Oddi disorders: Analysis of Rome IV criteria (2016). Clinical Medicine. Russian Journal. 2018;96(1):84–7. (In Russ.). DOI: 10.18821/0023-2149-2018-96-1-84-87

9. Lavoie B., Nausch B., Zane E.A., Leonard M.R., Balemba O.B., Bartoo A.C., et al. Disruption of gallbladder smooth muscle function is an early feature in the development of cholesterol gallstone disease. Neurogastroenterol Motil. 2012;24(7):e313–24. DOI: 10.1111/j.1365-2982.2012.01935.x

10. Svistunov A.A., Butorova L.I., Osadchuk M.A., Kireeva N.V., Tokmulina G.M., Ardatskaya M.D. The biliary pain syndrome in the context of Rome IV criteria: The rational approach to the choice of spasmolytic therapy in the clinical practice. Russian Journal of Evidence-Based Gastroenterology. 2018;7(2):59– 69. (In Russ.). DOI: 10.17116/dokgastro20187259

11. Huang Z.-P., Qiu H., Yu B.-P. Distribution changes of interstitial cells of Cajal during cholesterol gallstone formation in guinea pigs fed a high cholesterol diet. Int J Clin Exp Pathol. 2018;11(3):1653–9.

12. McCabe 4th M.E., Dilly C.K. New causes for the old problem of bile reflux gastritis. Clin Gastroenterol Hepatol. 2018;16(9):1389–92. DOI: 10.1016/j.cgh.2018.02.034

13. Yi S.-Q., Ohta T., Tsuchida A., Terayama H., Naito M., Li J., et al. Surgical anatomy of innervation of the gallbladder in humans and Suncus murinus with special reference to morphological understanding of gallstone formation after gastrectomy. World J Gastroenterol. 2007;13(14):2066–71. DOI: 10.3748/wjg.v13.i14.2066

14. Ivashkin V.T., Pavlov Ch.S., Popova I.R., Shulpekova Yu.O. Trimebutine maleate in the treatment of functional biliary disorders: TRIBUNE study results. Meditsinsky Sovet. 2018;21:117–25. (In Russ.). DOI: 10.21518/2079-701X-2018-21-117-125

15. Tropskaya N.S., Popova T.S. Mechanism of trimebutine affect in the functional gastrointestinal disorders. Klinicheskaya gastroenterologiya i gepatologiya. Russkoe izdanie. 2008;1(4):1–4. (In Russ.).

16. Holzer P. Opioids and opioid receptors in the enteric nervous system: From a problem in opioid analgesia to a possible new prokinetic therapy in humans. Neuroscience Letters. 2004;361(1–3):192–5. DOI: 10.1016/j.neulet.2003.12.004

17. 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 J Gastroenterol. 2012;18(14):1610–5. DOI: 10.3748/wjg.v18.i14.1610

18. Ogawa N., Nakajima S., Tamada K., Yokoue N., Tachibana H., Okazawa M., et al. Trimebutine suppresses Toll-like receptor 2/4/7/8/9 signaling pathways in macrophages. Arch Biochem Biophys. 2021;711:109029. DOI: 10.1016/j.abb.2021.109029