Racecadotril Efficacy in the Symptomatic Treatment of Adult Acute Diarrhoea: A Systematic Review and Meta-Analysis


The efficacy of racecadotril (RC), an intestinal antisecretory drug acting via an enkephalinase inhibition, was reviewed in paediatric acute diarrhoea but not yet in adults. Objective: To estimate the effectiveness of RC in the symptomatic treatment of acute diarrhoea in adults. Data Sources: A systematic review of MedLine, Cochrane Controlled Trials Register, DARE, and Embase (up to November 2013). Additional studies were identified by contacting clinical experts and the manufacturer. Study Selection and Appraisal: Randomized Controlled Trials performed in adults suffering from acute diarrhoea using RC in one treatment arm. Independent extraction of articles using predefined data fields, and methodological quality measurement assessment. All randomised trials performed in adults suffering from acute diarrhoea with RC as the studied group. Statistics: The main efficacy endpoint was diarrhoea duration defined as time to recovery compared between groups by survival techniques and converted into hazard ratio (HR). We exclusively used a random-effect meta-analytic model. Constipation proportion was the main safety endpoint, evaluated between treatments by the Relative Risks (RR). Results: Twelve randomised trials (2619 patients) met inclusion criteria. Duration of diarrhoea was much shorter in the RC group, the proportion of patients having recovered at any time of the treatment period was 65% higher in the RC group, compared with placebo (HR = 1.65 [1.38-1.97], p < 0.00001, n= 1001). Duration of diarrhoea was similar in the RC and loperamide groups (HR = 1.08 [0.95-1.22], p = 0.24, n = 1618). The proportions of constipated patients were similar in the RC and placebo groups 0.95 [0.24-3.68], p = 0.97), however, about 3 times more constipated patients were found in the loperamide group compared with the RC group (RR = 0.34 [0.22-0.51], p < 0.0001). Conclusions: Compared to placebo, RC is characterized by a clinically relevant earlier remission of diarrhoea. When compared to loperamide, diarrhoea duration was similar, however, significantly fewer secondary constipation adverse effects were observed.

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Vetel, J. , Hamza, H. , Coffin, B. and Lehert, P. (2014) Racecadotril Efficacy in the Symptomatic Treatment of Adult Acute Diarrhoea: A Systematic Review and Meta-Analysis. International Journal of Clinical Medicine, 5, 361-375. doi: 10.4236/ijcm.2014.57052.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Lew, J., Glass, R., Gangarosa, R., Cohen, I., Bern, C. and Moe, C (1991) Diarrheal Deaths in the United States, 1979 through 1987. JAMA, 265, 3280-3284.
[2] Garthright, W.E., Archer, D.L. and Kvenberg, J.E. (1988) Estimates of Incidence and Costs of Intestinal Infections Diseases in the United States. Public Health Reports, 103, 107-115.
[3] Baumer, P. and Joulin, Y. (2009) Pre-and Post-Parketing Safety Profiles of Racecadotril Sachets, a “New” Antidiarrhoeal Drug. Journal of Pediatric Gastroenterology and Nutrition, 48, E99.
[4] Baumer, P. and Joulin, Y. (2009) Pre-and Post-Marketing Safety Profiles of Racecadotril Capsules, a “New” Antidiarrhoeal Drug. Gut, 58, A114.
[5] Hinterleitner, T.A., Petritsch, W., Dimsity, G., Berard, H., Lecomte, J.M. and Krejs, G.J. (1997) Acetorphan Prevents Cholera-Toxin Induced Water and Electrolyte Secretion in the Human Jejunum. European Journal of Gastroenterology & Hepatology, 9, 887-891.
[6] Bergmann, J.F., Chaussade, S., Coututier, D., Baumer, P., Schwartz, J.C. and Lecomte, J.M. (1992) Effects of Acetorphan, an Antidiarrhoeal Enkephalinase Inhibitor on Oro-Caecal and Colonic Transit Times in Healthy Volunteers. Alimentary Pharmacology & Therapeutics, 6, 305-313. http://dx.doi.org/10.1111/j.1365-2036.1992.tb00052.x
[7] Lehert, P., Cheron, G., Alvarez Calatayud, G., Cezard, J.P., Gutierrez Castrellon, P., Melendez Garcia, J.M. and Savitha, M.R. (2011) Racecadotril for Childhood Gastroenteritis: An Individual Patient Data Meta-Analysis. Digestive and Liver Disease, 43, 707-713.
[8] Higgins, J.P.T. and Green, S. (2011) Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0. The Cochrane Collaboration. www.cochrane-handbook.org
[9] DerSimonian, R. and Laird, N. (1986) Meta-Analysis in Clinical Trials. Controlled Clinical Trials, 7, 177-188.
[10] Egger, M., Davey Smith, G., Schneider, M. and Minder, C. (1997) Bias in Meta-Analysis Detected by a Simple, Graphical Test. BMJ, 315, 629-634. http://dx.doi.org/10.1136/bmj.315.7109.629
[11] Fleiss, J.L. (1993) The Statistical Basis of Meta-Analysis. Statistical Methods in Medical Research, 2, 121-145.
[12] Higgins, J.P.T., Thompson, S.G., Deeks, J.J. and Altmann, D.G. (2003) Measuring Inconsistency in Meta-Analyses. BMJ, 327, 557-560. http://dx.doi.org/10.1136/bmj.327.7414.557
[13] Light, K.E. (1984) Analyzing Nonlinear Scatchard Plots. Science, 6, 76-78.
[14] Stern, J.M. and Simes, R.J (1997) Publication Bias: Evidence of Delayed Publication in a Cohort Study of Clinical Research Projects. BMJ, 13, 640-645. http://dx.doi.org/10.1136/bmj.315.7109.640
[15] Baumer, P., Danquechin-Dorval, E., Bertrand, J., Vetel, J.M., Schwartz, J.C. and Lecomte, J.M. (1992). Action of Acetorphan, an Enkephalinase Inhibitor, in Acute Diarrhea [Action de l’Acétorphan, Inhibiteur de l’Enképhalinase, sur la Diarrhée Aigue]. Annals of Gastroenterology & Hepatology, 28, 279-285.
[16] Ang, E.R., Flores, H.H., Estanislao, N.N. and Uy, M. (2009) Efficacy, Tolerability, and Safety of Racecadotril versus Loperamide in Acute Diarrhea among Adults—A Meta-Analysis. UEGW/WCOG, London, 21-25 November, Poster, P0778.
[17] Baldi, F., Bianco, M.A., Nardone, G., Pilotto, A. and Zamparo, E. (2009) Focus on Acute Diarrhoeal Disease. World Journal of Gastroenterology, 15, 3341-3348. http://dx.doi.org/10.3748/wjg.15.3341
[18] Eberlin, M., Mück, T. and Michel, M.C. (2012) Comprehensive Review of the Pharmacodynamics, Pharmacokinetics and Clinical Effects of the Neutral Endopeptidase Inhibitor Racecadotril. Frontiers in Pharmacology, 93, 1-16.
[19] Alam, N.H., Ashraf, H., Khan, W.A., Karim, M.M. and Fuchs, G.J. (2003) Efficacy and Tolerability of Racecadotril in the Treatment of Cholera in Adults: A Double Blind, Randomised, Controlled Clinical Trial. Gut, 52, 1419-1423.
[20] Beaugerie, L., Baumer, P., Chaussade, S., Berard, H., Rozenbaum, W., Pialoux, G., Le Quintrec, Y., Schwartz, J.C. and Lecomte, J.M. (1996) Treatment of Refractory Diarrhoea in AIDS with Acetorphan and Octreotide: A Randomized Crossover Study. European Journal of Gastroenterology & Hepatology, 8, 485-489.
[21] Baumer, P., Duvivier, C., Berard, H., Pialoux, G., Fretault, N., Rozenbaum, W., Schwartz, J.C. and Lecomte, J.M. (1995) HIV-Related Diarrhea: Efficacy of Acetorphan in a Randomized Controlled Trial. Gastroenterology, 108, A778.
[22] Dorval, E.D., Regimbeau, C., Gamelin, E., Picon, L. and Bérard, H. (1995) Treatment of Acute Chemically Induced Diarrhea by Inhibition of Enkephalinase. Results of a Pilot Study. Gastroentérologie Clinique et Biologique, 19, 27-30.
[23] Goncalves, E., Da Costa, L., Abigerges, D. and Armand, J.P. (1995) A New Enkephalinase Inhibitor as an Alternative to Loperamide in the Prevention of Diarrhea Induced by CPT-11. Journal of Clinical Oncology, 13, 2144-2146.
[24] Freyer, G., Rougier, P., Bugat, R., Droz, J.P., Marty, M., Bleiberg, H., Mignard, D., Awad, L., Herait, P., Culine, S., Trillet-Lenoir, V. and CPT-11 F205, F220, F221 and V222 Study Groups (2000) Prognostic Factors for Tumour Response, Progression-Free Survival and Toxicity in Metastatic Colorectal Cancer Patients Given Irinotecan (CPT-11) as Second-Line Chemotherapy after 5FU Failure. British Journal of Cancer, 83, 431-437.
[25] Ychou, M., Douillard, J.Y., Rougier, P., Adenis, A., Mousseau, M., Dufour, P., Wendling, J.L., Burki, F., Mignard, D. and Marty, M. (2000) Randomized Comparison of Prophylactic Antidiarrheal Treatment versus No Prophylactic Antidiarrheal Treatment in Patients Receiving CPT-11 (Irinotecan) for Advanced 5-FU-Resistant Colorectal Cancer: An Open-Label Multicenter Phase II Study. American Journal of Clinical Oncology, 23, 143-148.
[26] Saliba, F., Hagipantelli, R., Misset, J.L., Bastian, G., Vassal, G., Bonnay, M., Herait, P., Cote, C., Mahjoubi, M., Mignard, D. and Cvitkovic, E. (1998) Pathophysiology and Terapy of Irinotecan-Induced Delayed-Onset Diarrhea in Patients with Advanced Colorectal Cancer: A Prospective Assessment. Journal of Clinical Oncology, 16, 2745-2751.
[27] Lin, S. (2001) A Multicentric, Randomised, Double-blinded, Comparative, Paralleled Groups Study to Assess the Efficacy and Safety of Domestic Racecadotril 100mg tid po versus Imported Racecadotril 100mg tid po in the Treatment of Acute Diarrhea in Chinese Adults. GSK Report 52607/011.
[28] Gendre, J.P., Baumer, P., Fretault-Heurtebize, N., Schwartz, J.C. and Lecomte, J.M. (1999) Symptomatic Treatment of Adult Acute Diarrhoea: Clinical Equivalence of [R]acetorphan et [R,S]acetorphan. Gastroenterology, 116, G3735.
[29] Coffin, B. and Baumer, P. (2008) Effect of a New Bid Treatment by Racecadotril in Adult Patients with Acute Onset Diarrhea, a Non-Inferiority Study. Gastroenterology, 134, W1046.
[30] Bouhnik, Y., Baumer, P. and Hebuterne, X. (2008) Racecadotril 175 Mg Tablet Bid Is More Efficient than Racecadotril 100mg Capsule tid in the Treatment of Acute Diarrhea in Adults. Gastroenterology, 134, W1044.
[31] Coffin, B., Bouhnik, Y. and Baumer, P. (2008) Efficacy of a New 175 Mg Bid Treatment by Racecadotril in Patients with Acute Diarrhea. Meta-Analysis of 2 Randomized Prospective Studies. Gastroenterology, 134, W1045.
[32] Frexinos, J. and Sallenave, J.R. (1996) Comparison of Loperamide-Oxide and Acetorphan in Acute Diarrhoea. Gut, 39, A173.
[33] Yao, P. and Xi, L. (2011) Clinical Effect of Racecadotril Tablets for Acute Diarrhea in Adults. Chinese Journal of Clinical Pharmacology. http://en.cnki.com.cn/Article_en/CJFDTOTAL-GLYZ201108005.htm
[34] Mehta, S. (2012) A Novel Approach in the Treatment of Acute Infective Diarrhea. Medecine Update, 22, 430-434.
[35] Baumer, P., Danquechin-Dorval, E., Bertrand, J., Vetel, J.M., Schwartz, J.C. and Lecomte, J.M. (1992) Effects of Acetorphan, an Enkephalinase Inhibitor, on Experimental and Acute Diarrhoea. Gut, 33, 753-758.
[36] Hamza, H., Ben Khalifa, H., Baumer, P., Berard, H. and Lecomte, J.M. (1999) Racecadotril versus Placebo in the Treatment of Acute Diarrhoea in Adults. Alimentary Pharmacology & Therapeutics, 13, 15-19.
[37] Moraes, E., Chinzon, D., Coelho, L.G., Fernandes, T.F., Haddad, M.T. and the Brazilian Racecadotril Investigators Research Group. (2001) A Multicentric, Randomised, Investigator-Blind, Parallel Group Study to Assess the Efficacy, Safety and Tolerability of Racecadotril versus Saccharomyces boulardii in the Treatment of Acute Diarrhoea in Adults. [Estudo Multicentrico de Grupos Paralelos, Randomizado, Cego para o Investigator, para Avaliar a Eficacia, Seguranca e Tolerabilidade do Racecadotril versus Saccharomyces boulardii no tratamento da diarreia aguda em adultos]. Revista Brasileira de Medicina, 56, 65-74.
[38] Rogé, J., Baumer, P., Berard, H., Schwartz, J.C. and Lecomte, J.M. (1993) The Enkephalinase Inhibitor, Acetorphan, in Acute Diarrhoea: A Double-Blind, Controlled Clinical Trial versus Loperamide. Scandinavian Journal of Gastroenterology, 28, 352-354.
[39] Vetel, J.M., Berard, H., Fretault, N. and Lecomte, J.M. (1999) Comparison of Racecadotril and Loperamide in Adults with Acute Diarrhoea. Alimentary Pharmacology & Therapeutics, 13, 21-26.
[40] Prado, D. (2002) A Multinational Comparison of Racecadotril and Loperamide in the Treatment of Acute Watery Diarrhoea in Adults. Scandinavian Journal of Gastroenterology, 37, 656-661.
[41] Wang, H.H., Shieh, M.J. and Liao, K.F. (2005) A Blind, Randomized Comparison of Racecadotril and Loperamide for Stopping Acute Diarrhea in Adults. World Journal of Gastroenterology, 11, 1540-1543.
[42] Gallelli, L., Colosimo, M., Tolotta, G.A., Falcone, D., Luberto, L., Curto, L.S., Rende, P., Mazzei, F., Marigliano, N.M., De Sarro, G. and Cucchiara, S. (2010) Prospective Randomized Double-Blind Trial of Racecadotril Compared with Loperamide in Elderly People with Gastroenteritis Living in Nursing Homes. European Journal of Clinical Pharmacology, 66, 137-144.
[43] Schuermans, V., Vancommel, R., Dom, J. and Brugmans, J. (1974) Loperamide (R 18 553), a Novel Type of Antidiarrhoeal Agent. Placebo-Controlled Comparison of the Constipating Activity and Safety of Loperamide, Diphenoxylate and Codeine in Normal Volunteers. Arzneimittel-Forschung, 24, 1653-1657.
[44] Basilisco, G., Bozzani, A., Camboni, G., Recchia, M., Quatrini, M., Conte, D., Penagini, R. and Bianchi, P.A. (1985) Effect of Loperamide and Naloxone on Mouth-to-Caecum Transit Time Evaluated by Lactulose Hydrogen Breath Test. Gut, 26, 700-703. http://dx.doi.org/10.1136/gut.26.7.700
[45] Sninsky, C.A., Davis, R.H., Clench, M.H., Thomas, K.D. and Mathias, J.R. (1986) Effect of Lidaminine Hydrochloride and Loperamide on Gastric Emptying and Transit of the Small Intestine. A Double-Blind Study. Gastroenterology, 90, 68-73.
[46] World Health Organization (1990) Loperamide. In: The Rational Use of Drugs in the Management of Acute Diarrhoea in Children, WHO, Geneva, 17-22.
[47] Brown, J.W. (1979) Toxic Megacolon Associated with Loperamide Therapy. JAMA, 241, 501-502.
[48] Garrett, J.M., Sauer, W.G. and Moertel, C.G. (1967) Colonic Motility in Ulcerative Colitis after Opiate Administration. Gastroenterology, 53, 93-100.
[49] Walley, T. and Milson, D. (1990) Loperamide Related Toxic Megacolon in Clostridium difficile Colitis. Postgraduate Medical Journal, 66, 582-584. http://dx.doi.org/10.1136/pgmj.66.777.582-a
[50] Lelouch, S., Cadranel, J.F., Moussali, J., Benhamou, Y., Gerosa, Y., Gargot, D. and Opolon, P. (1991) Ogilvie’s Syndrome Associated with Treatment by Loperamide and Nifedipine. Gastroentérologie Clinique et Biologique, 15, 455-456.
[51] Petit, R., Bouziane, A., Calès, P., Ruget, O. and Boyer, J. (1993) Toxic Megacolon Caused by Loperamide-Myorelaxants Combination. Gastroentérologie Clinique et Biologique, 17, 62-63.
[52] McFarland, L.V. (2010) Systematic Review and Meta-Analysis of Saccharomyces boulardii in Adult Patients. World Journal of Gastroenterology, 16, 2202-2022. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2868213/
[53] Allen, S.J., Martinez, E.G., Gregorio, G.V. and Dans, L.F. (2010) Probiotics for Treating Acute Infectious Diarrhoea. Cochrane Database of Systematic Reviews, 10, Article ID: CD003048.
[54] Gregorio, G.V., Gonzales, M.L., Dans, L.F. and Martinez, E.G. (2009) Polymer-Based Oral Rehydration Solution for Treating Acute Watery Diarrhoea. Cochrane Database of Systematic Reviews, 15, Article ID: CD006519.
[55] Musekiwa, A. and Volmink, J. (2011) Oral Rehydration Salt Solution for Treating Cholera: ≤ 270 mOsm/L Solutions vs ≥ 310 mOsm/L Solutions. Cochrane Database of Systematic Reviews, 7, Article ID: CD003754.
[56] Castillo, L.A. (2013) In Adults with Acute Diarrhoea, which Treatment Is More Effective between Loperamide and Racecadotril? PCOM Physician Assistant Studies Student Scholarship, Paper 150.

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