Functional constipation is a common problem in children worldwide, with a reported prevalence ranging between 0.7% and 29.6% (1). Treatment consists of behavioral interventions (eg, education, toilet training, bowel diary) and laxatives (2). In many countries polyethylene glycol (PEG) is the laxative of first choice in the treatment of functional constipation in children, both for disimpaction and for maintenance treatment (3). Although PEG has only been used for the treatment of constipation for approximately 3 decades, it has rapidly become the most widely used laxative in both children and adults (4). The popularity of PEG is primarily based on its effectivity, safety profile, and administration route. This review describes the mechanism of action, published studies on effectivity, and safety and recent developments concerning PEG, specifically focusing on its role in the treatment of childhood functional constipation.
MECHANISM OF ACTION
PEG is a biologically inert, water-soluble polymer that is minimally absorbed in the gastrointestinal tract (5,6). It has no electrical charge and therefore does not influence the movement of other solutes. Because of these properties, PEG acts as an osmotic laxative. Moreover, PEG interacts with water molecules by forming hydrogen bonds, in a ratio of 100 water molecules per 1 PEG molecule, which leads to an additional increase in colonic water content. These properties render PEG a highly effective laxative drug. Its efficacy is dose dependent, meaning that higher doses of PEG lead to increasingly watery stools. After oral ingestion, it takes approximately 24 to 48 hours to observe an effect on stool consistency.
FORMULATIONS AND DOSAGES
PEG preparations are available in different formulations and dosages, which vary between manufacturers and countries. Two types of PEG, PEG 3350, and PEG 4000, are available, the numbers indicate the molecular weight of the molecule. Some PEG formulations contain added electrolytes, such as sodium chloride, potassium chloride, sodium bicarbonate, and sodium sulfate (7). These electrolytes are designed to minimize the risk for electrolyte imbalances. Only a few studies have investigated clinically relevant differences between PEG 3350 and PEG 4000. A 4-week trial comparing PEG 3350 with electrolytes and PEG 4000 in adults showed no differences in defecation frequency (8). For children, similar results have been presented (9), but not published in full manuscript form as yet. Recommended dosages for disimpaction and maintenance treatment are provided in Table 1.
Two randomized placebo-controlled trials have evaluated the efficacy of PEG in children with functional constipation (n = 101) (10,11). Both studies showed a significant increase in bowel movements compared to baseline, favoring PEG over placebo. A Cochrane meta-analysis showed a mean difference of 2.61 stools per week (95% confidence interval [CI] 1.15–4.08) (12). Both studies also described improvements for secondary outcomes such as stool consistency and straining (10,11).
The efficacy of PEG has also been compared to other laxatives (12). A meta-analysis, including 6 studies comparing the efficacy of PEG and lactulose, showed a significantly greater number of stools per week with PEG (mean difference 0.70, 95% CI 0.10–1.31) (12). Three studies compared PEG with milk of magnesia and showed that defecation frequency per week was significantly greater with PEG (mean difference 0.69, 95% CI 0.48–0.89), although this effect was considered small and the clinical relevance uncertain (12). Two studies compared liquid paraffin (mineral oil) with PEG, but showed no statistically significant difference in the number of stools per week (mean difference 0.35, 95% CI −0.24–0.95). A study comparing PEG and flixweed (Descurainia sophia L., a known commonly used medical herb in Traditional Persian Medicine) and 1 comparing PEG and dietary fiber also failed to show a significant difference in defecation frequency (13,14).
Reported adverse events in the aforementioned studies were generally minor and included flatulence, bloating, abdominal pain, nausea, vomiting, diarrhea, fecal incontinence, and headache. In the 2 randomized placebo-controlled trials, adverse events did not occur more frequently in patients receiving PEG compared to patients receiving placebo. These findings support a previous study on the long-term safety of PEG in children (15). One study reported a case of an allergic reaction to PEG; this seems to be the only serious adverse event directly related to the use of PEG reported (12). If PEG needs to be administrated via a nasogastric tube this can be safely done provided correct nasogastric tube placement is verified before infusion.
In children with constipation after repaired anorectal malformations, a recent randomized control trial has shown that stimulant laxatives (eg, senna) should be the laxative of choice as stool consistency modification by PEG may lead to fecal continence (16).
CONTRAINDICATIONS AND INTERACTIONS
PEG is contraindicated in patients allergic to it or those with known or suspected bowel obstruction. In patients predisposed to water and electrolyte balance disturbances (eg, patients with impaired hepatic or renal function, or patients taking diuretics), PEG should be prescribed prudently and with consideration given to regular monitoring of serum electrolytes.
PEG should be used cautiously in children with swallowing problems such as patients with severe neurologic impairment, because of risk of aspiration. PEG is a nonabsorbable material and its aspiration may cause pulmonary complications and even death, almost invariably after nasogastric administration (17).
Palatability of drugs is important to establish therapy adherence, especially in children. For PEG, an assortment of flavored formulations is available, including chocolate and orange flavored preparations. PEG without added electrolytes is fairly tasteless, whereas added electrolytes cause a more profound (salty) flavor, which may not be well accepted by all children (18). If the child is not predisposed to electrolyte disturbances and does not tolerate PEG with electrolytes, a formulation without added electrolytes can be prescribed.
FACTS AND MYTHS
Parents may express concerns against the use of PEG for the treatment of their child. In recent years, concerns may have been incited by stories parents have read on the Internet. In this section, we will discuss a few of these concerns.
One of the commonly expressed concerns is the fear of addiction to laxatives. Physical or psychological dependence have never been reported for the use of PEG, nor are they expected to occur based on its mechanism of action. It is, however, known that abrupt cessation of treatment with PEG can cause a relapse related to the underlying constipation. Therefore, after establishing a stable maintenance treatment period, it is recommended to slowly wean off PEG. This weaning process may mistakenly be confused as a sign of addiction. Another frequently expressed concern is the fear that the effect of PEG will wear off over time. Until now however, there is no published adult or pediatric evidence to support this fear.
Parents may also express their concern for the development of a “lazy bowel” or “lazy bowel syndrome.” These nonmedical terms refer to a decrease in colonic function as a result of laxative usage. This phenomenon has, however, not been described in the medical literature for patients using PEG. It is more likely that patients with severe functional constipation suffer from an underlying motility disorder, mistakenly attributed to the use of PEG.
Moreover, parents may be worried about the safety of PEG because it has not been approved for pediatric use by the Food and Drug Administration (FDA), as was also pointed out in a news article in The New York Times in 2012 (19). Off-label drug use is an important issue in pediatric healthcare, because a great number of medications still do not have labeling information for the use in pediatric patients (20). Therefore, many drugs are prescribed off-label to children. The term “off-label,” however, does not necessarily imply an improper or illegal use, in contrast, it refers to the process where practitioners use their professional judgment and experience to prescribe a drug, a decision process that should always rely on the best available evidence and the importance of the benefit for the individual patient (20).
FOOD AND DRUG ADMINISTRATION CONCERNS
Over the past years, the FDA has received reports of tremors, tics, and obsessive-compulsive behavior in children taking PEG 3350 (19). This has instigated an investigation into the potential relationship between PEG and these neuropsychiatric events. Whether there is a causal relationship between the use of PEG and these events is still under investigation, but the FDA has decided that no action is necessary at this time based on available information. In the literature, the co-occurrence of behavioral problems and childhood functional constipation has been described extensively (21–23). Therefore, the co-occurrence of these neuropsychiatric events and the use of PEG could potentially be related to the co-occurrence of behavioral problems and functional constipation in general. Current and future research will need to further elucidate this possible association.
In 2008 the FDA reported that traces of ethylene glycol and diethylene glycol (potential nephrotoxins and neurotoxins in case of high exposure) had been detected in batches of PEG 3350 formulations. This is, however, most likely due to impurities during the manufacturing process. The potential effects of such traces are currently under investigation. An article in the New York Times discussing this chain of events led to increased parental concerns (24). In response to these concerns, the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition published an online document with answers to frequently asked questions about PEG, to support patients and their caretakers (http://naspghn.informz.net/NASPGHN/data/images/PEG%203350%20FAQ.pdf).
Since its introduction in 2000, PEG has rapidly become the treatment of first choice for children with functional constipation globally. PEG is highly effective, has a good safety profile, and is well tolerated by children. Over recent years, concerns have arisen regarding potential neuropsychiatric events related to the use of PEG and the presence of smaller compounds such as ethylene glycol and diethylene glycol, which could result from the manufacturing process. The FDA is, however, currently investigating these concerns and to this date, no action is necessary based on available information.
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