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What is the role of prokinetic agents for constipation?
Erythromycin has a limited role in treating pediatric patients (strength of recommendation [SOR]: B, limited-quality, patient-oriented evidence). Tegaserod and cisapride are the only prokinetic agents available for constipated adults (SOR: A, consistent, good-quality, patient-oriented evidence for tegaserod; SOR: B, for cisapride), but cardiovascular risk restricts prescribing of both medications.
Evidence summary
Prokinetic agents promote transit of intestinal contents by increasing the frequency or strength of small intestine contractions. Available prokinetics include erythromycin and metoclopramide. Metoclopramide has been tested only for upper gastrointestinal mobility. The only randomized controlled trials (RCTs) of erythromycin for constipation have been conducted in children. Cisapride and tegaserod have been withdrawn from general use because of adverse side effects. The TABLE summarizes the available data.
TABLE
Prokinetics for constipation: What the research tells us
| DRUG | DESIGN (N) | DOSE | OUTCOME | NNT |
|---|---|---|---|---|
| Erythromycin estolate1 | Crossover children (14) | 20 mg/kg/day divided qid | †Constipation and laxative use | 10 |
| Cisapride5 | RCT adults (69) | 5-10 mg tid | ü Spontaneous BM † Abdominal pain | 4 |
| Cisapride6 | RCT adults (82) | 5-10 mg tid | Abdominal pain and constipation, drug=placebo | N/A |
| Tegaserod7 | RCT adults (1348) | 2 mg or 6 mg bid | † Constipation ü Spontaneous BM | 6 (2 mg) 5 (6 mg) |
| Tegaserod8 | RCT adults (1264) | 2 mg or 6 mg bid | † Constipation and abdominal pain | 11 (2 mg) 7 (6 mg) |
| Renzapride11 | Pilot study adults (17) | Escalating dose: 2 mg daily to 2 mg bid | † Abdominal pain and bloating | Not enough information to calculate |
| Renzapride12 | Parallel group adults (48) | 1, 2, or 4 mg daily | ü Colonic transit; stool form and ease of passage, drug=placebo | N/A |
| BM, bowel movement; N/A, not available; NNT, number needed to treat; RCT, randomized controlled trial. | ||||
Pediatric constipation: Erythromycin helps; watch dosage
A small RCT of 14 children between 4 and 13 years of age showed that erythromycin improved symptoms of constipation and decreased laxative use (number needed to treat [NNT]=10).1 Two RCTs in neonates demonstrated that erythromycin shortened intestinal transit time and improved feeding tolerance.2,3
The erythromycin dose used in these studies was lower than the dosage for antibiotic purposes; no adverse effects were reported. However, cardiac arrhythmias and death have occurred when erythromycin is given to adults and children at the usual antibiotic doses.4
Adult constipation: The options are limited
One RCT of cisapride for constipation showed that it improved symptoms,5 whereas another demonstrated no significant difference between cisapride and placebo in constipation-predominant irritable bowel syndrome.6 Reports of fatal arrhythmias have prompted restrictions on the use of the drug.
In 2 RCTs of tegaserod for constipation, patients exhibited improved abdominal symptoms and increased spontaneous bowel movements (NNT=6 for 2 mg and 5 for 6 mg in the first study; NNT=11 for 2 mg and 7 for 6 mg in the second study).7,8 A pooled analysis of RCTs of tegaserod revealed an increase in cardiovascular events, prompting withdrawal of the drug from the market (number needed to harm=1000).9 Tegaserod is available only for emergency and investigational use.
Renzapride, a newer prokinetic similar to cisapride, is under investigation. It is one tenth the strength of cisapride and carries a lower potential risk of cardiac complications.10 Two small placebo-controlled trials demonstrated improved abdominal pain and stool consistency, but only 1 showed statistically significant results compared with placebo.11,12
Recommendations
The North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition states that the benefits of cisapride do not outweigh the risks.13 The American College of Gastroenterology’s Chronic Constipation Task Force states that tegaserod effectively treats chronic constipation.14 Neither guideline includes recommendations regarding other prokinetic agents.
1. Bellomo-Brandao MA, Collares EF, da-Costa-Pinto EA. Use of erythromycin for the treatment of severe chronic constipation in children. Braz J Med Biol Res. 2003;36:1391-1396.
2. Costalos C, Gounaris A, Varhalama E, et al. Erythromycin as a prokinetic agent in preterm infants. J Pediatr Gastroenterol Nutr. 2002;34:23-25.
3. Costalos C, Gavrili V, Skouteri V, et al. The effect of low-dose erythromycin on whole gastrointestinal transit time of preterm infants. Early Hum Dev. 2001;65:91-96.
4. Ray WA, Murray KT, Meredith S, et al. Oral erythromycin and the risk of sudden death from cardiac causes. N Engl J Med. 2004;351:1089-1096.
5. Van Outryve M, Milo R, Toussaint J, et al. “Prokinetic” treatment of constipation-predominant irritable bowel syndrome: a placebo-controlled study of cisapride. J Clin Gastroenterol. 1991;13:49-57.
6. Ziegenhagen DJ, Kruis W. Cisapride treatment of constipation-predominant irritable bowel syndrome is not superior to placebo. J Gastroenterol Hepatol. 2004;19:744-749.
7. Johanson JF, Wald A, Tougas G, et al. Effect of tegaserod in chronic constipation: a randomized, double-blind, controlled trial. Clin Gastroenterol Hepatol. 2004;2:796-805.
8. Kamm MA, Müller-Lissner S, Talley NJ, et al. Tegaserod for the treatment of chronic constipation: a randomized, double-blind, placebo-controlled multinational study. Am J Gastroenterol. 2005;100:362-372.
9. US Food and Drug Administration, Center for Drug Evaluation and Research. FDA Public Health Advisory: tegaserod maleate. March 30, 2007. Available at: www.fda.gov/cder/drug/advisory/tegaserod.htm. Accessed November 17, 2007.
10. Galligan JJ, Vanner S. Basic and clinical pharmacology of new motility promoting agents. Neurogastroenterol Motil. 2005;17:643-653.
11. Tack J, Middleton SJ, Horne MC, et al. Pilot study of the efficacy of renzapride on gastrointestinal motility and symptoms in patients with constipation-predominant irritable bowel syndrome. Aliment Pharmacol Ther. 2006;23:1655-1665.
12. Camilleri M, McKinzie S, Fox J, et al. Effect of renzapride on transit in constipation-predominant irritable bowel syndrome. Clin Gastroenterol Hepatol. 2004;2:895-904.
13. North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. Evaluation and treatment of constipation in children: summary of updated recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr. 2006;43:405-407.
14. American College of Gastroenterology Chronic Constipation Task Force. An evidence-based approach to the management of chronic constipation in North America. Am J Gastroenterol. 2005;100(suppl 1):S1-S4.
Erythromycin has a limited role in treating pediatric patients (strength of recommendation [SOR]: B, limited-quality, patient-oriented evidence). Tegaserod and cisapride are the only prokinetic agents available for constipated adults (SOR: A, consistent, good-quality, patient-oriented evidence for tegaserod; SOR: B, for cisapride), but cardiovascular risk restricts prescribing of both medications.
Evidence summary
Prokinetic agents promote transit of intestinal contents by increasing the frequency or strength of small intestine contractions. Available prokinetics include erythromycin and metoclopramide. Metoclopramide has been tested only for upper gastrointestinal mobility. The only randomized controlled trials (RCTs) of erythromycin for constipation have been conducted in children. Cisapride and tegaserod have been withdrawn from general use because of adverse side effects. The TABLE summarizes the available data.
TABLE
Prokinetics for constipation: What the research tells us
| DRUG | DESIGN (N) | DOSE | OUTCOME | NNT |
|---|---|---|---|---|
| Erythromycin estolate1 | Crossover children (14) | 20 mg/kg/day divided qid | †Constipation and laxative use | 10 |
| Cisapride5 | RCT adults (69) | 5-10 mg tid | ü Spontaneous BM † Abdominal pain | 4 |
| Cisapride6 | RCT adults (82) | 5-10 mg tid | Abdominal pain and constipation, drug=placebo | N/A |
| Tegaserod7 | RCT adults (1348) | 2 mg or 6 mg bid | † Constipation ü Spontaneous BM | 6 (2 mg) 5 (6 mg) |
| Tegaserod8 | RCT adults (1264) | 2 mg or 6 mg bid | † Constipation and abdominal pain | 11 (2 mg) 7 (6 mg) |
| Renzapride11 | Pilot study adults (17) | Escalating dose: 2 mg daily to 2 mg bid | † Abdominal pain and bloating | Not enough information to calculate |
| Renzapride12 | Parallel group adults (48) | 1, 2, or 4 mg daily | ü Colonic transit; stool form and ease of passage, drug=placebo | N/A |
| BM, bowel movement; N/A, not available; NNT, number needed to treat; RCT, randomized controlled trial. | ||||
Pediatric constipation: Erythromycin helps; watch dosage
A small RCT of 14 children between 4 and 13 years of age showed that erythromycin improved symptoms of constipation and decreased laxative use (number needed to treat [NNT]=10).1 Two RCTs in neonates demonstrated that erythromycin shortened intestinal transit time and improved feeding tolerance.2,3
The erythromycin dose used in these studies was lower than the dosage for antibiotic purposes; no adverse effects were reported. However, cardiac arrhythmias and death have occurred when erythromycin is given to adults and children at the usual antibiotic doses.4
Adult constipation: The options are limited
One RCT of cisapride for constipation showed that it improved symptoms,5 whereas another demonstrated no significant difference between cisapride and placebo in constipation-predominant irritable bowel syndrome.6 Reports of fatal arrhythmias have prompted restrictions on the use of the drug.
In 2 RCTs of tegaserod for constipation, patients exhibited improved abdominal symptoms and increased spontaneous bowel movements (NNT=6 for 2 mg and 5 for 6 mg in the first study; NNT=11 for 2 mg and 7 for 6 mg in the second study).7,8 A pooled analysis of RCTs of tegaserod revealed an increase in cardiovascular events, prompting withdrawal of the drug from the market (number needed to harm=1000).9 Tegaserod is available only for emergency and investigational use.
Renzapride, a newer prokinetic similar to cisapride, is under investigation. It is one tenth the strength of cisapride and carries a lower potential risk of cardiac complications.10 Two small placebo-controlled trials demonstrated improved abdominal pain and stool consistency, but only 1 showed statistically significant results compared with placebo.11,12
Recommendations
The North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition states that the benefits of cisapride do not outweigh the risks.13 The American College of Gastroenterology’s Chronic Constipation Task Force states that tegaserod effectively treats chronic constipation.14 Neither guideline includes recommendations regarding other prokinetic agents.
Erythromycin has a limited role in treating pediatric patients (strength of recommendation [SOR]: B, limited-quality, patient-oriented evidence). Tegaserod and cisapride are the only prokinetic agents available for constipated adults (SOR: A, consistent, good-quality, patient-oriented evidence for tegaserod; SOR: B, for cisapride), but cardiovascular risk restricts prescribing of both medications.
Evidence summary
Prokinetic agents promote transit of intestinal contents by increasing the frequency or strength of small intestine contractions. Available prokinetics include erythromycin and metoclopramide. Metoclopramide has been tested only for upper gastrointestinal mobility. The only randomized controlled trials (RCTs) of erythromycin for constipation have been conducted in children. Cisapride and tegaserod have been withdrawn from general use because of adverse side effects. The TABLE summarizes the available data.
TABLE
Prokinetics for constipation: What the research tells us
| DRUG | DESIGN (N) | DOSE | OUTCOME | NNT |
|---|---|---|---|---|
| Erythromycin estolate1 | Crossover children (14) | 20 mg/kg/day divided qid | †Constipation and laxative use | 10 |
| Cisapride5 | RCT adults (69) | 5-10 mg tid | ü Spontaneous BM † Abdominal pain | 4 |
| Cisapride6 | RCT adults (82) | 5-10 mg tid | Abdominal pain and constipation, drug=placebo | N/A |
| Tegaserod7 | RCT adults (1348) | 2 mg or 6 mg bid | † Constipation ü Spontaneous BM | 6 (2 mg) 5 (6 mg) |
| Tegaserod8 | RCT adults (1264) | 2 mg or 6 mg bid | † Constipation and abdominal pain | 11 (2 mg) 7 (6 mg) |
| Renzapride11 | Pilot study adults (17) | Escalating dose: 2 mg daily to 2 mg bid | † Abdominal pain and bloating | Not enough information to calculate |
| Renzapride12 | Parallel group adults (48) | 1, 2, or 4 mg daily | ü Colonic transit; stool form and ease of passage, drug=placebo | N/A |
| BM, bowel movement; N/A, not available; NNT, number needed to treat; RCT, randomized controlled trial. | ||||
Pediatric constipation: Erythromycin helps; watch dosage
A small RCT of 14 children between 4 and 13 years of age showed that erythromycin improved symptoms of constipation and decreased laxative use (number needed to treat [NNT]=10).1 Two RCTs in neonates demonstrated that erythromycin shortened intestinal transit time and improved feeding tolerance.2,3
The erythromycin dose used in these studies was lower than the dosage for antibiotic purposes; no adverse effects were reported. However, cardiac arrhythmias and death have occurred when erythromycin is given to adults and children at the usual antibiotic doses.4
Adult constipation: The options are limited
One RCT of cisapride for constipation showed that it improved symptoms,5 whereas another demonstrated no significant difference between cisapride and placebo in constipation-predominant irritable bowel syndrome.6 Reports of fatal arrhythmias have prompted restrictions on the use of the drug.
In 2 RCTs of tegaserod for constipation, patients exhibited improved abdominal symptoms and increased spontaneous bowel movements (NNT=6 for 2 mg and 5 for 6 mg in the first study; NNT=11 for 2 mg and 7 for 6 mg in the second study).7,8 A pooled analysis of RCTs of tegaserod revealed an increase in cardiovascular events, prompting withdrawal of the drug from the market (number needed to harm=1000).9 Tegaserod is available only for emergency and investigational use.
Renzapride, a newer prokinetic similar to cisapride, is under investigation. It is one tenth the strength of cisapride and carries a lower potential risk of cardiac complications.10 Two small placebo-controlled trials demonstrated improved abdominal pain and stool consistency, but only 1 showed statistically significant results compared with placebo.11,12
Recommendations
The North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition states that the benefits of cisapride do not outweigh the risks.13 The American College of Gastroenterology’s Chronic Constipation Task Force states that tegaserod effectively treats chronic constipation.14 Neither guideline includes recommendations regarding other prokinetic agents.
1. Bellomo-Brandao MA, Collares EF, da-Costa-Pinto EA. Use of erythromycin for the treatment of severe chronic constipation in children. Braz J Med Biol Res. 2003;36:1391-1396.
2. Costalos C, Gounaris A, Varhalama E, et al. Erythromycin as a prokinetic agent in preterm infants. J Pediatr Gastroenterol Nutr. 2002;34:23-25.
3. Costalos C, Gavrili V, Skouteri V, et al. The effect of low-dose erythromycin on whole gastrointestinal transit time of preterm infants. Early Hum Dev. 2001;65:91-96.
4. Ray WA, Murray KT, Meredith S, et al. Oral erythromycin and the risk of sudden death from cardiac causes. N Engl J Med. 2004;351:1089-1096.
5. Van Outryve M, Milo R, Toussaint J, et al. “Prokinetic” treatment of constipation-predominant irritable bowel syndrome: a placebo-controlled study of cisapride. J Clin Gastroenterol. 1991;13:49-57.
6. Ziegenhagen DJ, Kruis W. Cisapride treatment of constipation-predominant irritable bowel syndrome is not superior to placebo. J Gastroenterol Hepatol. 2004;19:744-749.
7. Johanson JF, Wald A, Tougas G, et al. Effect of tegaserod in chronic constipation: a randomized, double-blind, controlled trial. Clin Gastroenterol Hepatol. 2004;2:796-805.
8. Kamm MA, Müller-Lissner S, Talley NJ, et al. Tegaserod for the treatment of chronic constipation: a randomized, double-blind, placebo-controlled multinational study. Am J Gastroenterol. 2005;100:362-372.
9. US Food and Drug Administration, Center for Drug Evaluation and Research. FDA Public Health Advisory: tegaserod maleate. March 30, 2007. Available at: www.fda.gov/cder/drug/advisory/tegaserod.htm. Accessed November 17, 2007.
10. Galligan JJ, Vanner S. Basic and clinical pharmacology of new motility promoting agents. Neurogastroenterol Motil. 2005;17:643-653.
11. Tack J, Middleton SJ, Horne MC, et al. Pilot study of the efficacy of renzapride on gastrointestinal motility and symptoms in patients with constipation-predominant irritable bowel syndrome. Aliment Pharmacol Ther. 2006;23:1655-1665.
12. Camilleri M, McKinzie S, Fox J, et al. Effect of renzapride on transit in constipation-predominant irritable bowel syndrome. Clin Gastroenterol Hepatol. 2004;2:895-904.
13. North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. Evaluation and treatment of constipation in children: summary of updated recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr. 2006;43:405-407.
14. American College of Gastroenterology Chronic Constipation Task Force. An evidence-based approach to the management of chronic constipation in North America. Am J Gastroenterol. 2005;100(suppl 1):S1-S4.
1. Bellomo-Brandao MA, Collares EF, da-Costa-Pinto EA. Use of erythromycin for the treatment of severe chronic constipation in children. Braz J Med Biol Res. 2003;36:1391-1396.
2. Costalos C, Gounaris A, Varhalama E, et al. Erythromycin as a prokinetic agent in preterm infants. J Pediatr Gastroenterol Nutr. 2002;34:23-25.
3. Costalos C, Gavrili V, Skouteri V, et al. The effect of low-dose erythromycin on whole gastrointestinal transit time of preterm infants. Early Hum Dev. 2001;65:91-96.
4. Ray WA, Murray KT, Meredith S, et al. Oral erythromycin and the risk of sudden death from cardiac causes. N Engl J Med. 2004;351:1089-1096.
5. Van Outryve M, Milo R, Toussaint J, et al. “Prokinetic” treatment of constipation-predominant irritable bowel syndrome: a placebo-controlled study of cisapride. J Clin Gastroenterol. 1991;13:49-57.
6. Ziegenhagen DJ, Kruis W. Cisapride treatment of constipation-predominant irritable bowel syndrome is not superior to placebo. J Gastroenterol Hepatol. 2004;19:744-749.
7. Johanson JF, Wald A, Tougas G, et al. Effect of tegaserod in chronic constipation: a randomized, double-blind, controlled trial. Clin Gastroenterol Hepatol. 2004;2:796-805.
8. Kamm MA, Müller-Lissner S, Talley NJ, et al. Tegaserod for the treatment of chronic constipation: a randomized, double-blind, placebo-controlled multinational study. Am J Gastroenterol. 2005;100:362-372.
9. US Food and Drug Administration, Center for Drug Evaluation and Research. FDA Public Health Advisory: tegaserod maleate. March 30, 2007. Available at: www.fda.gov/cder/drug/advisory/tegaserod.htm. Accessed November 17, 2007.
10. Galligan JJ, Vanner S. Basic and clinical pharmacology of new motility promoting agents. Neurogastroenterol Motil. 2005;17:643-653.
11. Tack J, Middleton SJ, Horne MC, et al. Pilot study of the efficacy of renzapride on gastrointestinal motility and symptoms in patients with constipation-predominant irritable bowel syndrome. Aliment Pharmacol Ther. 2006;23:1655-1665.
12. Camilleri M, McKinzie S, Fox J, et al. Effect of renzapride on transit in constipation-predominant irritable bowel syndrome. Clin Gastroenterol Hepatol. 2004;2:895-904.
13. North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. Evaluation and treatment of constipation in children: summary of updated recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr. 2006;43:405-407.
14. American College of Gastroenterology Chronic Constipation Task Force. An evidence-based approach to the management of chronic constipation in North America. Am J Gastroenterol. 2005;100(suppl 1):S1-S4.
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