Evaluation of tolerance of polyethylene glycol 4000 (PEG 4000) versus lactulose in constipated children

The Rome IV diagnostic criteria define chronic idiopathic, or functional, constipation as the presence of two or more of the following for at least 12 weeks (which need not be consecutive) in the preceding 12 months: (1) Straining for more than 25% of defecation attempts; (2) Lumpy or hard stools for at least 25% of defecation attempts.(3) The sensation of anorectal obstruction or blockage for at least 25% of defecation attempts.(2)

Use of osmotic laxatives like lactulose and polyethylene glycol (PEG) are among the first step in the pharmacological treatment of Functional constipation.(3)

Until now, lactulose had been the more common osmotic laxative used for children.Although lactulose is often prescribed to children with functional constipation, evidence supporting the use of lactulose in clinical practice is scarce. Moreover, lactulose has been demonstrated to be less effective than liquid paraffin or PEG in outcomes of stool frequency per week, consistency, relief of abdominal pain, and need for additional medication. (4,5)These adverse effects of lactulose have led to the rise of PEG as the most preferred laxative for constipation in children. (6)

PEG (or macrogol) is a linear polymer, in which water molecules are retained using hydrogen connections, causing an intraluminal fluid volume increase. It is not metabolized and is minimally (<1 %) absorbed in the intestine. (3)

Different types of PEG are commonly used particularly PEG 3350 and PEG 4000, with molecular weights of 3.350 and 4.000 g/mol, respectively. To minimize the risk of disturbing the electrolyte balance by osmosis, a combination of PEG with electrolytes can be used, which is iso-osmotic instead of hypo-osmotic.(7)

In 1997, A Staiano et al reviewed the use of high dose polyethylene glycol solution in the treatment of functional constipation and encopresis in children. They concluded that polyethylene glycol caused a significant increase in bowel frequency and a decrease in gastrointestinal transit time. Side-effects, consisting of nausea, vomiting, and irritability, have limited the use of this treatment in a few children. (8)

With the treatment of functional constipation often requiring long term interventions, it becomes important to ascertain the long term safety of the options including their clinical and biological tolerance.

With this background,, Christophe Dupont et al, from the department of Neonatology-Pediatrics, Hospital Cochin-Saint Vincent-de-Paul, France, carried out a study to assess the safety of polyethylene glycol (PEG) 4000 laxative without additional salts in pediatric patients, comparing the same to that of Lactulose.

The findings were published in the Journal of Pediatric Gastroenterology and Nutrition.

The Study Design was a 3-month multicenter, randomized, double-blind, double-dummy, lactulose-controlled, parallel study.

The study population included 96 ambulatory children, aged 6 months to 3 years with constipation despite the usual dietary treatment for at least 1 month. Constipation was defined as less than 1 stool per day for more than 1 month in children 6 to 12 months old and less than 3 stools per week for more than 3 months in children aged 13 months to 3 years (9).

Children having a history of intractable fecaloma or organic gastrointestinal disease such as Hirschsprung disease, neurologic, endocrine or metabolic disorders, allergic diseaseor allergies were excluded from the study.

Investigators randomly allocated either PEG 4000 or lactulose treatment to the children for 3 months, with the same strategy for dose adaptation. Starting dose was one pair of sachets, one containing the active drug (PEG 4000 4 g/sachet or lactulose 3.33 g/sachet) and the other a placebo to be taken at breakfast.

At baseline and on day 42 (D42) and 84 (D84), a physical examination was performed, including a rectal examination. Stool frequency and consistency, bloating, flatulence, abdominal pain, vomiting, and nausea were recorded on a Self-Diary Evaluation Booklet.

Laboratory tests performed at baseline and D84 included total protein, serum albumin, serum iron, plasma electrolytes (Na1, 1, K1, Cl2, HCO32, and serum vitamins B9 (folates, A and 25hydroxy D3.

Clinical efficacy was measured by stool frequency and consistency, the disappearance of abdominal pain and bloating, appetite (visual analog scale), impaction, use of enemas, and amount of PEG 4000 or lactulose consumption.

The primary endpoint was based on the percentage of children per group of treatment with at least one value ONR at D84 among all tested biologic parameters, to their baseline status; i.e., with or without at least one value ONR. Biological secondary endpoints comprised- 1) the percentage of children per group with an ONR value on D84 taking into account the baseline status, and 2) a quantitative analysis of each laboratory parameter.

After accounting for dropouts, the intention to treat population included 51children (10 babies and 41 toddlers) in the PEG 4000group and 45 (12 babies and 33 toddlers) in the lactulosegroup

1. The percentage of children with at least one value out of normal range at day 84 to baseline status (with or without at least one value out of normal range), i.e. the primary endpoint, was 87% and 90% in the PEG and lactulose groups, respectively, without any difference between groups.

2. The whole blood parameters showed no qualitative or quantitative treatment-related changes. Vitamin A values were above the normal range in 56% and 41% of children at baseline versus 33% and 36% at day 84 in the PEG and lactulose groups, respectively.

3. Iron values were similarly under the normal range of 47% and 51% at baseline versus 42% and 51% at day 84.

4. Clinical tolerance was similar for both treatments except for vomiting and flatulence, which were significantly higher with lactulose.

5. Significantly higher improvements were evidenced with PEG regarding stool consistency, appetite, fecaloma, and use of additional laxatives.

6. A significant and permanent improvement in appetite score was observed at D42 in the PEG 4000 group (119%) compared with lactulose 42 (24%) (P, 0.003).

With these results, the researchers noted some important observations.

1. This study highlighted the efficacy of PEG 4000 on childhood constipation as it showed that PEG 4000 without added salts at 4g to 8g did not induce any change in blood electrolytes, total protein, serum albumin, iron, folates and vitamins A and D, that could be related to the 3-month treatment.

2. Efficacy analysis revealed that PEG 4000 and lactulose are both effective in their effect on constipation and associated symptoms. Nevertheless, stool consistency, appetite, new- onset fecal impaction, and enema use were all significantly better in the PEG group.

3. The study also addressed clinical tolerance and thus allowed to establish the events accompanying the onset and the long-term use of laxatives in children.

"This 3-month study in 96 constipated children aged 6 months to 3 years confirms the long-term tolerance of PEG 4000 in pediatrics and indicates a PEG efficacy similar to or greater than that of lactulose" the authors confirmed.

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