Chronic constipation in children
А.Summary of findings
General tolerability and safety in children
The evidence is very poor quality and sparse. We found no studies on the general tolerability and safety of docusate calcium, docusate sodium, lactulose, lubiprostone, and psyllium that met our expanded eligibility criteria. All of the studies we found were rated poor quality for the assessment of adverse events and results should be interpreted with caution.
We found three poor quality studies that reported safety or tolerability information for PEG 3350 without a comparison group. All three had serious methodological problems. The most common adverse events reported were diarrhea in 10–13%, bloating/flatulence in 6–18%, and pain/cramping in 2–5%. They found no significant laboratory abnormalities and reported that PEG 3350 was well tolerated by children.
We found one RCT that reported on the tolerability and harms of tegaserod for the treatment of postpubertal adolescents with constipation predominant IBS. The study reported that no adverse events were observed in any patient and there were no dropouts.
Comparative tolerability and safety in children
The evidence was limited to one poor quality RCT comparing PEG 3350 with lactulose in children. It did not report any serious adverse events. This study reported more abdominal pain, pain at defecation, and straining at defecation in those treated with lactulose and worse palatability with PEG. The results should be interpreted cautiously due to the poor quality of the study.
B. Detailed assessment
General risk of harms
Table 26 summarizes the trials assessing the general harms of constipation drugs in children;
Summary of trials assessing the general safety and harms of constipation drugs in children.
Table 29 summarizes the evidence profile for the general tolerability and safety of individual drugs.
Evidence Profile of the general tolerability and harms of constipation drugs in children.
Docusate calcium, Docusate sodium, Lactulose, Lubiprostone, and Psyllium
We did not find any studies on the general harms of these medications in children that met our eligibility criteria.
We found no studies reporting the general safety of PEG that included a placebo comparison group. Three poor quality studies reported safety or tolerability information without a comparison group.67–69 Two studies67, 69 were funded by the makers of PEG without electrolytes. The other study68 did not report a source of funding or any conflicts of interest, but was by the same group of authors as the prospective cohort study. The most common adverse events reported were diarrhea in 10–13%, bloating/flatulence in 6–18%, and pain/cramping in 2–5%. They found no significant laboratory abnormalities. PEG 3350 was well tolerated by children. Results of these studies should be interpreted with caution due to the poor quality.
One prospective cohort study67 included 83 children over the age of 2 treated with PEG without electrolytes (mean required dose 0.75 g/kg/d) at pediatric clinics at a referral center for a mean of 8.7 months (range 3 to 30 months). The mean age of subjects was 7.4 (range 2.0–16.9). Previous therapies for constipation had been attempted in 82% of subjects prior to enrollment. For safety and adverse events, the study reported diarrhea in 10%, abdominal pain in 2%, bloating or flatulence in 6%, elevated alanine aminotransferase (ALT) in 11%, and elevated aspartate transaminase (AST) in 4%. No abnormalities in electrolytes were found. Of the 9 patients with abnormal ALTs during treatment, 8 had repeat values 8 weeks later. Seven of the 8 were still on PEG therapy. Seven of the 8 had normal repeat values; one subject had a level 1.2 x normal (28 U/L). The 3 elevated ASTs were <1.5 times normal and all had normal repeat values 8 weeks later while still receiving PEG. The duration and dose of PEG was not different between those with elevated liver function tests (LFTs) and those with normal labs. No major adverse events were reported in the study. For tolerability, PEG was liked by 93% of children. All children (n = 68, 82%) who had used other therapies in the past preferred PEG to other laxatives.
One retrospective chart review68 examined the safety of PEG without electrolytes in 75 infants and toddlers with functional constipation under the age of 2 over a 3.5 year period examined. Although they were not required to have chronic constipation, the mean duration of constipation was 10 months (range 0.5 to 23 months). Diarrhea was reported in 7% of 71 subjects followed for up to 4 months and in an additional 2% of 47 subjects followed for over 6 months. Parents did not report increased flatus, abdominal distention, vomiting, or new onset abdominal pain in any subjects. None stopped PEG due to adverse events. Lab tests (CBC, electrolytes, and LFTs) were occasionally done in some subjects and all those checked were normal. The study was rated poor quality for several reasons including: no comparison group, adverse events were not defined, adverse events were not clearly pre-specified, and high attrition.
One dose response study69 was a prospective, double-blind, parallel trial that randomized children aged 3 to 18 years with chronic constipation to 4 doses of PEG 3350 without electrolytes (Miralax®, 0.25 g/kg/d, 0.50 g/kg/d, 1 g/kg/d, or 1.5 g/kg/d). All groups were treated for 3 days and evaluated 5 days after beginning treatment. They enrolled forty-one subjects referred to a pediatric gastroenterology clinic for evaluation of chronic constipation with evidence of fecal impaction. For all subjects, the following adverse events were reported: diarrhea (13%), nausea (5%), vomiting (5%), bloating/flatulence (18%), and pain/cramping (5%). Diarrhea was more prevalent in the high dose groups than the low dose groups (25% vs. 10%; P < 0.02). No patients had clinically significant abnormal laboratory values after the use of PEG 3350. For tolerability, 95% of children took the medication on the first attempt. In addition, all children said that they would repeat a 3-day regimen of PEG 3350 to help treat a future fecal impaction. The results of the study should be interpreted with caution due to poor quality (no control group).
As described in the tegaserod section for general harms in adults (see above), the FDA issued a public health advisory to inform patients and health care professionals that the sponsor of tegaserod agreed to stop selling the medication because of cardiovascular adverse events.12 We found one RCT that reported on the safety and harms of tegaserod for the treatment of postpubertal adolescents with constipation predominant IBS.53 The study reported that no adverse events were observed in any patient, including diarrhea, dehydration, vomiting, rectal bleeding, weight loss, or headache. In addition there were no dropouts. This study is summarized in Table 27.
Summary of trials assessing the general safety and harms of tegaserod for the treatment of chronic constipation and IBS-C in children.
Comparative risk of harms
Table 28 summarizes the trial assessing the comparative harms of constipation drugs; Table 30 summarizes the evidence profile for the comparative tolerability and harms.
Summary of trials assessing the comparative harms of constipation drugs.
Evidence profile of the comparative tolerability and harms of constipation drugs in children.
PEG 3350 vs. lactulose
We found one poor quality RCT46 meeting our inclusion criteria that compared PEG 3350 with lactulose in children. This study did not report any serious adverse events; it reported more abdominal pain, pain at defecation, and straining at defecation in those treated with lactulose and worse palatability with PEG.46 The results should be interpreted cautiously due to the poor quality of this study.
The RCT46 was a multicenter head-to-head trial from the Netherlands that randomized 100 patients to PEG 3350 with electrolytes (Transipeg) (2.95–11.8 g/d) or lactulose (6–24 g/d) for 8 weeks of treatment. The trial enrolled children from the ages of 6 months to 15 years (mean 6.5 years) with constipation. Stimulant laxatives were prescribed during the treatment phase if the treatment they were randomized to was unsuccessful. The authors report that 20% of both groups required stimulant laxatives during the study. Adverse events were assessed on a 3 point scale by patients. There were more patients with a weekly score > 1 for abdominal pain, pain at defecation, and straining at defecation in the lactulose group (values not reported, P < 0.05), and more patients had a weekly score > 1 for bad palatability in the PEG group (values not reported, P < 0.05). There were nine premature withdrawals between the two groups, with 4 in the PEG group (2 lost to follow-up, 1 unknown reason, and 1 bad palatability) and 5 in the lactulose group (2 lost to follow-up, 2 helicobacter positive, and 1 unknown). There were no serious adverse events reported. However, the authors did not define serious adverse events or how these were assessed. For tolerability, more patients reported "bad palatability" in the PEG group (%s not reported, P < 0.05). The study was rated poor for several reasons including: lack of an ITT analysis and adverse events were not pre-specified and defined.