Treating Constipation With Prucalopride: One Size Does Not Fit All
2014; Elsevier BV; Volume: 147; Issue: 6 Linguagem: Inglês
10.1053/j.gastro.2014.10.024
ISSN1528-0012
Autores Tópico(s)Congenital gastrointestinal and neural anomalies
ResumoSee “Prucalopride is no more effective than placebo for children with functional constipation,” by Mugie SM, Korczowski B, Bodi P, et al, on page 1285. See “Prucalopride is no more effective than placebo for children with functional constipation,” by Mugie SM, Korczowski B, Bodi P, et al, on page 1285. Functional constipation (FC) is among the most common functional gastrointestinal (GI) disorders in children. Epidemiologic studies conducted throughout the world cite a prevalence as high as 29.6%.1Tabbers M.M. DiLorenzo C. Berger M.Y. et al.Evaluation and treatment of functional constipation in infants and children: evidence-based recommendations from ESPGHAN and NASPGHAN.J Pediatr Gastroenterol Nutr. 2014; 58: 265-281Crossref Scopus (497) Google Scholar, 2van den Berg M.M. Benninga M.A. Di Lorenzo C. Epidemiology of childhood constipation: a systematic review.Am J Gastroenterol. 2006; 101: 2401-2409Crossref PubMed Scopus (437) Google Scholar FC is associated with poor school functioning,3Rajindrajith S. Devanarayana N.M. Weerasooriya L. et al.Quality of life and somatic symptoms in children with constipation: a school-based study.J Pediatr. 2013; 163: 1069-1072 e1Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar poor quality of life,1Tabbers M.M. DiLorenzo C. Berger M.Y. et al.Evaluation and treatment of functional constipation in infants and children: evidence-based recommendations from ESPGHAN and NASPGHAN.J Pediatr Gastroenterol Nutr. 2014; 58: 265-281Crossref Scopus (497) Google Scholar and a significant economic burden.4Liem O. Harman J. Benninga M. et al.Health utilization and cost impact of childhood constipation in the United States.J Pediatr. 2009; 154: 258-262Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar The results of treatment in children are suboptimal, and ≤30% continue to require treatment after 8 years.5van Ginkel R. Reitsma J.B. Büller H.A. et al.Childhood constipation: longitudinal follow-up beyond puberty.Gastroenterology. 2003; 125: 357-363Abstract Full Text Full Text PDF PubMed Scopus (279) Google Scholar The magnitude of the problem in combination with the poor outcomes of treatment stresses the need for new therapies for FC in children.6Mugie S.M. Korczowski B. Bodi P. et al.Prucalopride is no more effective than placebo for children with functional constipation.Gastroenterology. 2014; 147: 1285-1295Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar The results found with the use of prucalopride in placebo controlled trials in adults,7Camilleri M. Kerstens R. Rykx A. et al.A placebo-controlled trial of prucalopride for severe chronic constipation.N Engl J Med. 2008; 358: 2344-2354Crossref PubMed Scopus (440) Google Scholar, 8Quigley E.M. Vandeplassche L. Kerstens R. et al.Clinical trial: the efficacy, impact on quality of life, and safety and tolerability of prucalopride in severe chronic constipation—a 12-week, randomized, double-blind, placebo-controlled study.Aliment Pharmacol Ther. 2009; 29: 315-328Crossref PubMed Scopus (253) Google Scholar, 9Tack J. van Outryve M. Beyens G. et al.Prucalopride (Resolor) in the treatment of severe chronic constipation in patients dissatisfied with laxatives.Gut. 2009; 58: 357-365Crossref PubMed Scopus (266) Google Scholar as well as a small, open-label trial in children10Winter H.S. Di Lorenzo C. Benninga M.A. et al.Oral prucalopride in children with functional constipation.J Pediatr Gastroenterol Nutr. 2013; 57: 197-203Crossref PubMed Scopus (37) Google Scholar raised great expectations on the possible use of this novel drug for the treatment of FC in children. Prucalopride is a selective, high-affinity, 5-hydroxytryptamine receptor-4 (5HT4) agonist with GI prokinetic properties.11Frampton J.E. Prucalopride.Drugs. 2009; 69: 2463-2476Crossref PubMed Scopus (47) Google Scholar It has been shown to accelerate colonic transit, and it facilitates colonic motility with the release of acetylcholine after the activation of 5-HT4 receptors on cholinergic neurons.11Frampton J.E. Prucalopride.Drugs. 2009; 69: 2463-2476Crossref PubMed Scopus (47) Google Scholar Previous studies of other nonselective 5HT4 agonists like cisapride12Nurko S. Garcia-Aranda J.A. Worona L.B. et al.Cisapride for the treatment of constipation in children: a double-blind study.J Pediatr. 2000; 136: 35-40Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar and tegaserod13Liem O. Mousa H.M. Benninga M.A. et al.Tegaserod use in children: a single-center experience.J Pediatr Gastroenterol Nutr. 2008; 46: 54-58Crossref PubMed Scopus (13) Google Scholar in children have also shown significant benefit with their use. Unfortunately these nonselective 5HT4 agonists were associated with adverse, life-threatening cardiovascular side effects because of their affinity for the hERG-encoding potassium channel, 5-HT1 or 5-HT2 receptors, something that has not been seen with prucalopride. In this issue of Gastroenterology, Mugie et al6Mugie S.M. Korczowski B. Bodi P. et al.Prucalopride is no more effective than placebo for children with functional constipation.Gastroenterology. 2014; 147: 1285-1295Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar report the data from a large, multicenter, placebo-controlled trial of prucalopride in children with FC. They found, using response criteria that included >3 spontaneous bowel movements per week and 3 spontaneous bowel movements per week was 29.2% on prucalopride. Therefore, the overall response rate based only on bowel movements after prucalopride in children is similar to the adults. However, the results of the placebo arm (35.5%) in the pediatric study stand in contrast with the results of adult trials (9%–12%).7Camilleri M. Kerstens R. Rykx A. et al.A placebo-controlled trial of prucalopride for severe chronic constipation.N Engl J Med. 2008; 358: 2344-2354Crossref PubMed Scopus (440) Google Scholar, 8Quigley E.M. Vandeplassche L. Kerstens R. et al.Clinical trial: the efficacy, impact on quality of life, and safety and tolerability of prucalopride in severe chronic constipation—a 12-week, randomized, double-blind, placebo-controlled study.Aliment Pharmacol Ther. 2009; 29: 315-328Crossref PubMed Scopus (253) Google Scholar, 9Tack J. van Outryve M. Beyens G. et al.Prucalopride (Resolor) in the treatment of severe chronic constipation in patients dissatisfied with laxatives.Gut. 2009; 58: 357-365Crossref PubMed Scopus (266) Google Scholar Although this could be viewed only as another example of differences in placebo responses explaining the sometimes contradictory results of trials in adults and children, because it also occurred with the amitriptyline trial for functional abdominal pain in children,14Saps M. Youssef N. Miranda A. et al.Multicenter, randomized, placebo-controlled trial of amitriptyline in children with functional gastrointestinal disorders.Gastroenterology. 2009; 137: 1261-1269Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar there are additional reasons to explain these differences. The definitions of FC, pathophysiologic mechanisms, and primary endpoints differ between pediatric and adult trials. For example, the presence of FI is not part of the adult definition of FC, whereas it constitutes an important criterion in children, because daytime FI is present in ≤77%.1Tabbers M.M. DiLorenzo C. Berger M.Y. et al.Evaluation and treatment of functional constipation in infants and children: evidence-based recommendations from ESPGHAN and NASPGHAN.J Pediatr Gastroenterol Nutr. 2014; 58: 265-281Crossref Scopus (497) Google Scholar That prucalopride had such a limited response in the treatment of children confirms that FC in children is an heterogeneous disorder with a complex pathophysiology that is not necessarily related to an abnormal transit. In fact, the prevalence of slow transit constipation in children is lower than adults and it has been reported in only 13%–25%1Tabbers M.M. DiLorenzo C. Berger M.Y. et al.Evaluation and treatment of functional constipation in infants and children: evidence-based recommendations from ESPGHAN and NASPGHAN.J Pediatr Gastroenterol Nutr. 2014; 58: 265-281Crossref Scopus (497) Google Scholar of cases. This contrasts with adult studies that found slow transit constipation in 60%–71% of patients with intractable constipation.15Travaglio E. Lemma M. Cuccia F. et al.Prevalence of constipation in a tertiary referral Italian Colorectal Unit.Ann Ital Chir. 2014; 85: 287-291PubMed Google Scholar Therefore, given the prokinetic nature of prucalopride, it could have been predicted that, given that slow transit constipation is less common in children, there would be lower responses to prucalopride in children than in adults. In the present pediatric study, no colonic transit was performed, so it is not possible to know if the medication was more successful in those patients with slow transit, or if responders were those in which the colonic transit improved. A second common pathophysiologic feature in FC in children is withholding behavior, which is not as important in adults. In the trial by Mugie et al,6Mugie S.M. Korczowski B. Bodi P. et al.Prucalopride is no more effective than placebo for children with functional constipation.Gastroenterology. 2014; 147: 1285-1295Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar 61% of children had history of excessive volitional stool retention. In experimental studies in adults, it has been shown that the chronic voluntary suppression of defecation produced a lesser frequency of defecations associated with increase in total transit times. This shows that defecation habits induce changes in colonic function,16Klauser A.G.1 Voderholzer W.A. Heinrich C.A. et al.Behavioral modification of colonic function. Can constipation be learned?.Dig Dis Sci. 1990; 35: 1271-1275Crossref PubMed Scopus (118) Google Scholar which in part explains the effects of withholding. In children, withholding behavior leads to stool retention and secondary FI that results from overflow, mainly in the presence of fecal impaction or as a result of stool leakage from the rectum when stools approach the anus. Therefore, the influence of behavioral factors may also explain some of the differences found among studies in children and adults. Another dissimilarity between pediatric and adult trials is that primary endpoints differ as mentioned.6Mugie S.M. Korczowski B. Bodi P. et al.Prucalopride is no more effective than placebo for children with functional constipation.Gastroenterology. 2014; 147: 1285-1295Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar FI has been used as endpoint in most trials in FC in children. In the current study, there was a decrease in FI from baseline, but there was no difference in the final FI episodes between groups. This result is similar to other studies comparing laxatives with placebo.12Nurko S. Garcia-Aranda J.A. Worona L.B. et al.Cisapride for the treatment of constipation in children: a double-blind study.J Pediatr. 2000; 136: 35-40Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar, 17Nurko S. Youssef N.N. Sabri M. et al.PEG3350 in the treatment of childhood constipation: a multicenter, double-blinded, placebo-controlled trial.J Pediatr. 2008; 153 (261 e1): 254-261Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar, 18Thomson M.A. Jenkins H.R. Bisset W.M. et al.Polyethylene glycol 3350 plus electrolytes for chronic constipation in children: a double blind, placebo controlled, crossover study.Arch Dis Child. 2007; 92: 996-1000Crossref PubMed Scopus (66) Google Scholar In the present study there were more responders in the prucalopride arm among children ≥12 years of age,6Mugie S.M. Korczowski B. Bodi P. et al.Prucalopride is no more effective than placebo for children with functional constipation.Gastroenterology. 2014; 147: 1285-1295Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar which indicates that age can have an important influence in the incidence of FI. It is possible that as children get older the mechanisms involved in FC may be similar to adults. Prucalopride is not the first type of therapy for FC where there have been different outcomes between adults and children. There are multiple controlled studies of biofeedback in children with defecation abnormalities that showed no beneficial effect. Moreover, the studies found no relationship between attaining normal defecation dynamics and response to therapy.1Tabbers M.M. DiLorenzo C. Berger M.Y. et al.Evaluation and treatment of functional constipation in infants and children: evidence-based recommendations from ESPGHAN and NASPGHAN.J Pediatr Gastroenterol Nutr. 2014; 58: 265-281Crossref Scopus (497) Google Scholar These findings markedly contrast with the experience in adults, in which biofeedback has been shown to be highly effective in patients with dyssynergic defecation.19Bharucha A.E. Pemberton J.H. Locke 3rd, G.R. American Gastroenterological Association technical review on constipation.Gastroenterology. 2013; 144: 218-238Abstract Full Text Full Text PDF PubMed Scopus (455) Google Scholar Other laxatives have been shown to be effective for the treatment of FC in children. The use of polyethylene glycol (PEG) is the mainstay of treatment. If changes in behavior are thought to be an important pathway to solve a large proportion of cases of FC in children, the use of osmotic laxatives may be a more rational approach. Children who soften their stools lose the fear to defecate over time. The occurrence of looser stools avoids large fecal masses and perianal pain that would not be the case with the use of a stimulant laxative. Placebo-controlled studies, and studies comparing PEG-based solution with other laxatives, have consistently shown that PEG is more effective.1Tabbers M.M. DiLorenzo C. Berger M.Y. et al.Evaluation and treatment of functional constipation in infants and children: evidence-based recommendations from ESPGHAN and NASPGHAN.J Pediatr Gastroenterol Nutr. 2014; 58: 265-281Crossref Scopus (497) Google Scholar In a long-term, randomized trial of PEG versus lactulose,20Voskuijl W. de Lorijn F. Verwijs W. et al.PEG 3350 (Transipeg) versus lactulose in the treatment of childhood functional constipation: a double blind, randomised, controlled, multicentre trial.Gut. 2004; 53: 1590-1594Crossref PubMed Scopus (150) Google Scholar using the same endpoints as Mugie et al,6Mugie S.M. Korczowski B. Bodi P. et al.Prucalopride is no more effective than placebo for children with functional constipation.Gastroenterology. 2014; 147: 1285-1295Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar PEG-based solutions achieved a successful outcome in 56% of participants compared with 29% in the lactulose group. These results are much higher than those seen with prucalopride. In fact, recent guidelines for the evaluation and treatment of FC in children of NASPGHAN and ESPGHAN recommend PEG as the first line of treatment.1Tabbers M.M. DiLorenzo C. Berger M.Y. et al.Evaluation and treatment of functional constipation in infants and children: evidence-based recommendations from ESPGHAN and NASPGHAN.J Pediatr Gastroenterol Nutr. 2014; 58: 265-281Crossref Scopus (497) Google Scholar The guidelines also recommend a minimum treatment of 2 months. The study by Muggie et al6Mugie S.M. Korczowski B. Bodi P. et al.Prucalopride is no more effective than placebo for children with functional constipation.Gastroenterology. 2014; 147: 1285-1295Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar assessed the primary efficacy endpoint over weeks 5–8 of the study, which implies a shorter period of treatment. Given that children in the study had a mean duration of symptoms of 4.4 years and a mean age of 4.5 years, it may be unrealistic to expect substantial changes in a large proportion of children who had FC for most of their life in such a short period of time. This observation leads to the question on whether the short length of the trial could explain the negative results. Although, we are not able to respond fully to this question owing to the design of the study, the results of the open label re-randomization that followed the double-blind period (PEG or prucalopride) can give some insights. At the end of the open-label period, significantly more children who received prucalopride (40.2%) rated their constipation as severe to very severe compared with children who received PEG (28.0%). This suggests that a longer period of treatment would have probably not changed the overall conclusions of the study, and that even though the long-term phase was not a blind comparison, the response associated with PEG was better. Therefore, this study does not provide new data to justify a change in the indication of PEG as first line of treatment for FC in children. Future head-to-head comparisons between prucalopride and other laxatives are needed in both adults and children. The advent of new molecules like the kind of oral secretagogues, or the use of ileal bile acid transporter inhibitors (that may have both a prokinetic and a secretory effect) may represent new alternatives that need to be studied further in children. In summary, the authors have shown that there is no beneficial effect of the use of prucalopride alone if compared with placebo in children. Despite the disappointing results of this clinical trial, the study may help to provide further insight to the differences in mechanisms underlying FC in adults and children and the optimal design of randomized, controlled trials in children. Prucalopride Is No More Effective Than Placebo for Children With Functional ConstipationGastroenterologyVol. 147Issue 6PreviewPrucalopride is a selective, high-affinity agonist of the 5-hydroxytryptamine (serotonin) receptor 4 that enhances motility in the gastrointestinal tract. We performed a multicenter, randomized, placebo-controlled, double-blind, phase 3 trial to evaluate the efficacy and safety of prucalopride in children (6 months to 18 years old) with functional constipation. Full-Text PDF
Referência(s)