Key messages
• There may be little to no difference between lubiprostone and placebo (dummy treatment) in achieving treatment success in children with intractable constipation. We also found that lubiprostone is probably as safe as placebo.
• There is probably little or no difference between prucalopride, also a laxative, and placebo in frequency of defecation per day, treatment success, and safety.
• It is unclear whether any of the other treatments we looked at are helpful. The evidence is uncertain because of the very low number of study participants and problems with how the research was reported.
• Currently, there is not an agreed-upon definition for intractable constipation. To develop further evidence on therapies for intractable constipation, researchers must use the same definition. We would encourage further work to come up with an agreed-upon definition.
What is intractable constipation?
Constipation in children is a common problem. If doctors cannot find an underlying cause for the symptoms, it is called functional constipation. The symptoms of constipation include lower frequency of defecation, bowel incontinence or soiling, and stomach pain. Constipation can be mild and respond well to standard treatments, such as behavioural changes or laxatives. However, it can also be more severe or last for a long time. We defined intractable constipation as constipation that persists despite standard treatments.
What did we want to find out?
We wanted to find out which treatments are helpful and safe for treating children (between 0 and 18 years of age) with constipation that has not responded to standard medical treatments (intractable constipation). This extreme level of constipation can impact a child's life in very negative ways, such as keeping them away from school and other daily activities; causing them pain, discomfort, and general distress; and requiring hospital visits for treatment. Consequently, there is a need to investigate if the tested therapies can help resolve the problem.
What did we do?
We considered any medication, surgical procedure, or therapy to help children with intractable constipation. Each study compared a specific treatment to placebo, no treatment, or another treatment. We were interested in whether the treatments increased the frequency of defecation, improved symptoms, or led to treatment success. We also wanted to know if the treatments were safe, so we looked at whether they caused side effects. We searched for randomised controlled trials (studies in which people are randomly assigned to one of two or more treatment groups) comparing any medical, surgical, or complementary therapy versus no treatment, placebo, or another treatment in children with intractable constipation.
What did we find?
We found 10 studies involving a total of 1278 children. The average age of study participants ranged from around 5 to 10 years. The studies were conducted in Iran, Brazil, Colombia, the USA, Canada, Australia, and several European countries. Studies lasted from one to six months.
The studies made the following comparisons:
• botox injection versus stool softeners;
• erythromycin versus placebo;
• lubiprostone versus placebo;
• rectal sodium dioctyl sulfosuccinate and sorbitol versus oral polyethylene glycol laxatives;
• biofeedback therapy versus no treatment;
• intrarectal electromotive botox injection versus a usual botox injection;
• botox injection versus myectomy of the internal anal sphincter;
• prucalopride versus placebo;
• transcutaneous electrical stimulation versus sham stimulation; and
• dietitian-prescribed Mediterranean diet with written instructions versus written instructions.
Main results
• There may be little to no difference between lubiprostone and placebo in achieving treatment success, and there is probably little to no difference in adverse events for this comparison.
• There is probably little or no difference between prucalopride and placebo in defecation frequency, treatment success, and adverse events.
• We do not know whether any of the other treatments looked at in this review are safer or more beneficial than others.
What are the limitations of the evidence?
The evidence is limited due to small participant numbers in the included studies, and because each study looked at a different comparison, both of which resulted in the evidence being imprecise. There were also issues with the way the studies were conducted, which led to concerns that study results might be biased.
How up-to-date is this evidence?
This review is current to June 2023.
We identified low to moderate certainty evidence that oral lubiprostone may result in little to no difference in treatment success and adverse events compared to placebo. Based on moderate certainty evidence, there is probably little or no difference between oral prucalopride and placebo in defecation frequency, treatment success, or adverse events. For all other comparisons, the certainty of the evidence for our predefined primary outcomes is very low due to serious concerns with study limitations and imprecision. Consequently, no robust conclusions could be drawn.
Constipation that is prolonged and does not resolve with conventional therapeutic measures is called intractable constipation. The treatment of intractable constipation is challenging, involving pharmacological or non-pharmacological therapies, as well as surgical approaches. Unresolved constipation can negatively impact quality of life, with additional implications for health systems. Consequently, there is an urgent need to identify treatments that are efficacious and safe.
To evaluate the efficacy and safety of treatments used for intractable constipation in children.
We searched CENTRAL, MEDLINE, Embase, and two trials registers up to 23 June 2023. We also searched reference lists of included studies for relevant studies.
We included randomised controlled trials (RCTs) comparing any pharmacological, non-pharmacological, or surgical treatment to placebo or another active comparator, in participants aged between 0 and 18 years with functional constipation who had not responded to conventional medical therapy.
We used standard Cochrane methods. Our primary outcomes were symptom resolution, frequency of defecation, treatment success, and adverse events; secondary outcomes were stool consistency, painful defecation, quality of life, faecal incontinence frequency, abdominal pain, hospital admission for disimpaction, and school absence. We used GRADE to assess the certainty of evidence for each primary outcome.
This review included 10 RCTs with 1278 children who had intractable constipation. We assessed one study as at low risk of bias across all domains. There were serious concerns about risk of bias in six studies.
One study compared the injection of 160 units botulinum toxin A (n = 44) to unspecified oral stool softeners (n = 44). We are very uncertain whether botulinum toxin A injection improves treatment success (risk ratio (RR) 37.00, 95% confidence interval (CI) 5.31 to 257.94; very low certainty evidence, downgraded due to serious concerns with risk of bias and imprecision). Frequency of defecation was reported only for the botulinum toxin A injection group (mean interval of 2.6 days). The study reported no data for the other primary outcomes.
One study compared erythromycin estolate (n = 6) to placebo (n = 8). The only primary outcome reported was adverse events, which were 0 in both groups. The evidence is of very low certainty due to concerns with risk of bias and serious imprecision.
One study compared 12 or 24 μg oral lubiprostone (n = 404) twice a day to placebo (n = 202) over 12 weeks. There may be little to no difference in treatment success (RR 1.29, 95% CI 0.87 to 1.92; low certainty evidence). We also found that lubiprostone probably results in little to no difference in adverse events (RR 1.05, 95% CI 0.91 to 1.21; moderate certainty evidence). The study reported no data for the other primary outcomes.
One study compared three-weekly rectal sodium dioctyl sulfosuccinate and sorbitol enemas (n = 51) to 0.5 g/kg/day polyethylene glycol laxatives (n = 51) over a 52-week period. We are very uncertain whether rectal sodium dioctyl sulfosuccinate and sorbitol enemas improve treatment success (RR 1.33, 95% CI 0.83 to 2.14; very low certainty evidence, downgraded due to serious concerns with risk of bias and imprecision). Results of defecation frequency per week was reported only as modelled means using a linear mixed model. The study reported no data for the other primary outcomes.
One study compared biofeedback therapy (n = 12) to no intervention (n = 12). We are very uncertain whether biofeedback therapy improves symptom resolution (RR 2.50, 95% CI 1.08 to 5.79; very low certainty evidence, downgraded due to serious concerns with risk of bias and imprecision). The study reported no data for the other primary outcomes.
One study compared 20 minutes of intrarectal electromotive botulinum toxin A using 2800 Hz frequency and botulinum toxin A dose 10 international units/kg (n = 30) to 10 international units/kg botulinum toxin A injection (n = 30). We are very uncertain whether intrarectal electromotive botulinum toxin A improves symptom resolution (RR 0.96, 95% CI 0.76 to 1.22; very low certainty evidence) or if it increases the frequency of defecation (mean difference (MD) 0.00, 95% CI −1.87 to 1.87; very low certainty evidence). We are also very uncertain whether intrarectal electromotive botulinum toxin A has an improved safety profile (RR 0.20, 95% CI 0.01 to 4.00; very low certainty evidence). The evidence for these results is of very low certainty due to serious concerns with risk of bias and imprecision. The study did not report data on treatment success.
One study compared the injection of 60 units botulinum toxin A (n = 21) to myectomy of the internal anal sphincter (n = 21). We are very uncertain whether botulinum toxin A injection improves treatment success (RR 1.00, 95% CI 0.75 to 1.34; very low certainty evidence). No adverse events were recorded. The study reported no data for the other primary outcomes.
One study compared 0.04 mg/kg oral prucalopride (n = 107) once daily to placebo (n = 108) over eight weeks. Oral prucalopride probably results in little or no difference in defecation frequency (MD 0.50, 95% CI −0.06 to 1.06; moderate certainty evidence); treatment success (RR 0.96, 95% CI 0.53 to 1.72; moderate certainty evidence); and adverse events (RR 1.15, 95% CI 0.94 to 1.39; moderate certainty evidence). The study did not report data on symptom resolution.
One study compared transcutaneous electrical stimulation to sham stimulation, and another study compared dietitian-prescribed Mediterranean diet with written instructions versus written instructions. These studies did not report any of our predefined primary outcomes.