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Cisapride for Children with Intractable Constipation: An Interim Verdict!

1996; Lippincott Williams & Wilkins; Volume: 22; Issue: 1 Linguagem: Inglês

10.1097/00005176-199601000-00003

1536-4801

Vera Loening‐Baucke,

Congenital gastrointestinal and neural anomalies

Many children with chronic constipation and encopresis are referred to university medical centers because of poor response to conventional treatment. Conventional treatment usually includes disimpaction, prevention of reaccumulation of feces by increasing dietary fiber, treatment with laxatives, and altering behavior by toilet sitting. There are many refractory patients, children who comply with all aspects of the conventional treatment program and who experience a decrease in symptoms but continue to have constipation and/or encopresis; others are dependent on laxatives and have recurrence of symptoms when laxatives are withdrawn. Twelve-month follow-up studies of constipated children showed that 51% had recovered after receiving laxatives and behavior modification (1). Evaluation of the duration of laxative treatment in more than 300 children with functional constipation showed that 22% of the patients required regular laxatives for 12 months (2). Of 215 children at a mean follow-up of 4 years, 21% still used laxatives, 17% had fewer than three bowel movements per week, and 29% had more than two encopretic episodes per month (3). The article by Nurko et al. (4) in this issue deals with a group of children with intractable constipation who benefitted from cisapride treatment. These children, with normal defecation dynamics as assessed by anorectal manometry, had severe constipation and/or encopresis as documented by remaining symptomatic on conventional laxative treatment. Cisapride, 0.2 mg/kg/dose with a maximum of 10 mg/dose, was given three times daily for 12 weeks in an open label trial. The 27 children with intractable constipation were allowed to continue with the treatment regimen that they were using before the cisapride trial. This treatment consisted of daily laxatives, addition of senna if no bowel movement had occurred for 48 h, and a daily enema if no bowel movement had occurred after 2 days of taking senna. At the end of 12 weeks of cisapride administration, 14 (52%) patients had three or more bowel movements per week and no soiling and did not use enemas, stimulants, or laxatives. Four (15%) patients were symptom-free but used enemas, stimulants, or laxatives. These 18 patients became symptom-free after 6 ± 4 weeks. In addition, seven (26%) patients showed increased frequency of bowel movements and decreased frequency of soiling. Two (7%) patients showed no improvement with cisapride. Cisapride was well tolerated by the children, with mild side effects of abdominal pain, diarrhea, and headache in one patient each. Nurko et al. (4), the first to evaluate their patients 4 weeks after attempts to stop cisapride were initiated, found that 10 of the 18 symptom-free patients were able to successfully stop cisapride and laxatives. The 37% 4-month recovery rate in patients with intractable constipation and normal defecation dynamics is excellent. Twenty-month follow-up revealed that 37% had recovered, with three of the 10 patients having experienced an intermittent relapse. Cisapride, a prokinetic drug like metoclopramide and domperidone, acts on the myenteric plexus, enhancing motility of the gut. The action of cisapride appears to involve the facilitation of acetylcholine release in the intramural plexuses (5). Experiments suggest that cisapride induces gastrointestinal peristalsis by stimulation of 5-HT4-receptors in the myenteric plexus (6,7) and antagonizing 5-HT3-receptors (7,8). Side effects are either gastrointestinal (abdominal cramping, borygmi, and diarrhea) or central nervous system (headache) related. Cisapride promotes esophageal clearance of acid in patients with reflux disease; accelerates gastric emptying in patients with gastroparesis, especially in diabetic gastroparesis; and accelerates small bowel transit in patients with chronic intestinal pseudoobstruction. Cisapride appears to have prokinetic actions on the colon as well. It accelerates the transit of fecal material from the terminal ileum to the anus in healthy adult volunteers (9-12). The spectrum of motility disorders of the lower gastrointestinal tract for which cisapride may be clinically useful includes the treatment of constipation, irritable bowel syndrome, postoperative ileus, and colonic pseudoobstruction. One of the most promising uses of cisapride may be in the treatment of constipation. Several studies have suggested that cisapride may have a role in the management of chronic constipation in children and adults (13-16). Nurko et al. (4) reported that children with intractable constipation benefitted greatly from cisapride treatment. No other reports of cisapride in intractable constipation of childhood are available in the literature, but two studies deal with milder disease (13,14). Staiano et al. (13) evaluated cisapride, 0.2 mg/kg three times daily, in 17 children with functional constipation in a randomized, double-blind, placebo-controlled trial. These patients had constipation defined as fewer than four bowel movements per week and/or a total gastrointestinal transit time of >33 h, but their constipation was not determined to be refractory or intractable. After 12 weeks of cisapride treatment, stool frequency increased, laxative or suppository use decreased, and total gastrointestinal transit time decreased (but did not normalize) significantly in the nine children who were randomized to receive cisapride. Placebo significantly decreased laxative or suppository use but had no significant effect on stool frequency and transit time. Outcome after withdrawal of cisapride was not evaluated. Murray et al. (14) gave cisapride to children with refractory constipation in an open trial. In this study, two children with constipation and 10 with constipation and encopresis, refractory to or dependent on vigorous use of laxatives, were given cisapride, 0.14 to 0.3 mg/kg four times daily. At a single point in time, a mean of 61 ± 12 weeks on cisapride, a cross-sectional evaluation revealed that six children had increased stool frequency, three had no change, and three had decreased stool frequency. Mean stool frequency did not change significantly. Encopresis ceased in eight patients and improved in two. During cisapride administration, 67% of patients could discontinue and 25% could decrease other anticonstipation therapies. Outcome after withdrawal of cisapride was not evaluated. Two studies of the effect of cisapride on constipation in adults have been reported (15, 16). In a placebo-controlled trial in 126 adults with constipation, cisapride (20 mg twice daily) increased spontaneous stool frequency and decreased laxative consumption (15). In a double-blind, placebo-controlled, randomized crossover study cisapride accelerated colonic transit in the cecum and ascending colon in five constipated patients with slow transit constipation but did not increase stool frequency and had no effect on colonic transit parameters and frequency of bowel movements in four constipated patients with delay in rectosigmoid transit (16). The 37% 4-month and 20-month recovery rates, the 67% 3-month complete response rate, and the 93% 3-month improvement rate from cisapride in children in the study by Nurko et al. (4) suggest that cisapride is an effective agent for some of the children with intractable constipation and encopresis. Any new therapeutic advance requires clear proof of effectiveness from well-designed and well-conducted trials. All too often, initial reports of a new therapy are overly optimistic and confirmation is required for a proper perspective. An interim verdict on the beneficial value of cisapride in children with intractable constipation must suffice until the true contribution of cisapride to the treatment of intractable constipation in children is shown in a well-designed, double-blind, placebo-controlled trial.