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What Is the Role of Prokinetic Agents for Constipation?

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What Is the Role of Prokinetic Agents for Constipation? Evidence Based Answers CLINICAL INQUIRIES from the Family Physicians Inquiries Network ONLINE EXCLUSIVE Ginger Boyle, MD Spartanburg Family Medicine What is the role of prokinetic Residency Program, Spartanburg, SC agents for constipation? Anne Mounsey, MD University of North Carolina, Chapel Hill Evidence-based answer Karen Crowell, MLIS University of North Carolina, Erythromycin has a limited role in available for constipated adults (SOR: A, Chapel Hill treating pediatric patients (strength of consistent, good-quality, patient-oriented recommendation [SOR]: B, limited-quality, evidence for tegaserod; SOR: B, for patient-oriented evidence). Tegaserod and cisapride), but cardiovascular risk restricts cisapride are the only prokinetic agents prescribing of both medications. z Evidence summary and death have occurred when erythro- Prokinetic agents promote transit of in- mycin is given to adults and children at testinal contents by increasing the fre- the usual antibiotic doses.4 quency or strength of small intestine contractions. Available prokinetics in- Adult constipation: clude erythromycin and metoclopramide. The options are limited FAST TRACK Metoclopramide has been tested only for One RCT of cisapride for constipation Erythromycin upper gastrointestinal mobility. The only showed that it improved symptoms,5 randomized controlled trials (RCTs) of whereas another demonstrated no sig- has a limited erythromycin for constipation have been nificant difference between cisapride and role in treating conducted in children. Cisapride and tega- placebo in constipation-predominant pediatric patients serod have been withdrawn from general irritable bowel syndrome.6 Reports of with constipation. use because of adverse side effects. The fatal arrhythmias have prompted restric- TABLE summarizes the available data. tions on the use of the drug. In 2 RCTs of tegaserod for consti- Pediatric constipation: pation, patients exhibited improved ab- Erythromycin helps; watch dosage dominal symptoms and increased spon- A small RCT of 14 children between 4 taneous bowel movements (NNT=6 for and 13 years of age showed that erythro- 2 mg and 5 for 6 mg in the first study; mycin improved symptoms of constipa- NNT=11 for 2 mg and 7 for 6 mg in the tion and decreased laxative use (number second study).7,8 A pooled analysis of needed to treat [NNT]=10).1 Two RCTs RCTs of tegaserod revealed an increase in neonates demonstrated that erythro- in cardiovascular events, prompting mycin shortened intestinal transit time withdrawal of the drug from the market and improved feeding tolerance.2,3 (number needed to harm=1000).9 Tegas- The erythromycin dose used in these erod is available only for emergency and studies was lower than the dosage for an- investigational use. tibiotic purposes; no adverse effects were Renzapride, a newer prokinetic simi- reported. However, cardiac arrhythmias lar to cisapride, is under investigation. It 220d VOL 58, No 4 / APRIL 2009 THE JOURNAL OF FaMILY PRACTICE Prokinetics for constipation TABLE Prokinetics for constipation: What the research tells us DRUG DESIGN (N) DOSE OUTCOME NNT Erythromycin Crossover 20 mg/kg/day †Constipation 10 estolate1 children divided qid and laxative use (14) Cisapride5 RCT adults 5-10 mg tid ü Spontaneous 4 (69) BM † Abdominal pain Cisapride6 RCT adults 5-10 mg tid Abdominal N/A (82) pain and constipation, drug=placebo Tegaserod7 RCT adults 2 mg or 6 mg bid † Constipation 6 (2 mg) (1348) ü Spontaneous 5 (6 mg) BM Tegaserod8 RCT adults 2 mg or 6 mg bid † Constipation 11 (2 mg) (1264) and abdominal 7 (6 mg) pain Renzapride11 Pilot study adults Escalating dose: † Abdominal Not enough (17) 2 mg daily pain and information to 2 mg bid bloating to calculate Renzapride12 Parallel group adults 1, 2, or 4 mg daily ü Colonic transit; N/A (48) stool form and ease of passage, drug=placebo BM, bowel movement; N/A, not available; NNT, number needed to treat; RCT, randomized controlled trial. is one tenth the strength of cisapride and chronic constipation in children. Braz J Med Biol FAST TRACK carries a lower potential risk of cardiac Res. 2003;36:1391-1396. Renzapride is a complications.10 Two small placebo-con- 2. Costalos C, Gounaris A, Varhalama E, et al. Eryth- romycin as a prokinetic agent in preterm infants. J newer prokinetic trolled trials demonstrated improved ab- Pediatr Gastroenterol Nutr. 2002;34:23-25. dominal pain and stool consistency, but 3. Costalos C, Gavrili V, Skouteri V, et al. The effect that is one-tenth only 1 showed statistically significant re- of low-dose erythromycin on whole gastrointesti- nal transit time of preterm infants. Early Hum Dev. the strength of sults compared with placebo.11,12 2001;65:91-96. cisapride and has 4. Ray WA, Murray KT, Meredith S, et al. Oral eryth- Recommendations romycin and the risk of sudden death from cardiac a lower potential causes. N Engl J Med. 2004;351:1089-1096. The North American Society for Pediat- 5. Van Outryve M, Milo R, Toussaint J, et al. “Proki- risk of cardiac ric Gastroenterology, Hepatology, and netic” treatment of constipation-predominant irri- complications. Nutrition states that the benefits of cis- table bowel syndrome: a placebo-controlled study of cisapride. J Clin Gastroenterol. 1991;13:49-57. 13 apride do not outweigh the risks. The 6. Ziegenhagen DJ, Kruis W. Cisapride treatment of American College of Gastroenterology’s constipation-predominant irritable bowel syndrome Chronic Constipation Task Force states is not superior to placebo. J Gastroenterol Hepatol. 2004;19:744-749. that tegaserod effectively treats chronic 7. Johanson JF, Wald A, Tougas G, et al. Effect of constipation.14 Neither guideline includes tegaserod in chronic constipation: a randomized, recommendations regarding other proki- double-blind, controlled trial. Clin Gastroenterol Hepatol. 2004;2:796-805. netic agents. n 8. Kamm MA, Müller-Lissner S, Talley NJ, et al. Tegas- erod for the treatment of chronic constipation: a ran- References domized, double-blind, placebo-controlled multina- tional study. Am J Gastroenterol. 2005;100:362-372. 1. Bellomo-Brandao MA, Collares EF, da-Costa-Pinto EA. Use of erythromycin for the treatment of severe 9. US Food and Drug Administration, Center for Drug Evaluation and Research. FDA Public Health Advi- www.jfponline.com VOL 58, No 4 / APRIL 2009 220e ES I R I sory: tegaserod maleate. March 30, 2007. Available table bowel syndrome. Clin Gastroenterol Hepatol. INQU at: www.fda.gov/cder/drug/advisory/tegaserod. 2004;2:895-904. htm. Accessed November 17, 2007. 13. North American Society for Pediatric Gastroenterol- AL 10. Galligan JJ, Vanner S. Basic and clinical pharma- ogy, Hepatology and Nutrition. Evaluation and treat- C cology of new motility promoting agents. Neuro- ment of constipation in children: summary of updated gastroenterol Motil. 2005;17:643-653. recommendations of the North American Society for 11. Tack J, Middleton SJ, Horne MC, et al. Pilot study Pediatric Gastroenterology, Hepatology and Nutri- CLINI of the efficacy of renzapride on gastrointestinal tion. J Pediatr Gastroenterol Nutr. 2006;43:405-407. motility and symptoms in patients with constipa- 14. American College of Gastroenterology Chronic tion-predominant irritable bowel syndrome. Ali- Constipation Task Force. An evidence-based ment Pharmacol Ther. 2006;23:1655-1665. approach to the management of chronic con- 12. Camilleri M, McKinzie S, Fox J, et al. Effect of ren- stipation in North America. Am J Gastroenterol. zapride on transit in constipation-predominant irri- 2005;100(suppl 1):S1-S4. 220f VOL 58, No 4 / APRIL 2009 THE JOURNAL OF FaMILY PRACTICE.
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