New Treatment Options in Childhood Constipation?

To date, the worldwide prevalence of symptoms of constipation in children varies widely and is estimated to range between 0.3-28%. Childhood constipation is recognized by infrequent, hard stools and the involuntary loss of faeces in the underwear. It is a debilitating condition that is often associated with abdominal pain. It causes distress to the child and to the family and can result in severe emotional disturbance and family discord. Importantly, childhood constipation often continues into adulthood and it is suggested that longstanding faecal impaction from childhood-on may result in a more complex pathophysiological end-state later in life (1). This again emphasizes the significance of an effective therapeutic intervention in children. To date however, treatment modalities are mainly based on empiricism and have little evidence of long-term efficacy. Although many compounds have been tried, there are little data to support there use. Moreover, there is a huge lack of large double-blind randomised controlled trials in children with well defined outcome measures. As in many more other fields in the medical treatment of children only a minority of the drugs used to treat constipated children have been studied adequately in the population, have appropriate use information on the product label and the information regarding safety and efficacy for pediatric patients is insufficient or absent. Currently acute simple constipation is usually treated with a high fibre diet and sufficient fluid intake, filling out a diary and toilet training. Based on the American medical position statement the treatment of chronic constipation consists of 4 important phases: 1) education, 2) disimpaction, 3) prevention of re-accumulation of faeces and 4) follow up (2). In this paper firstly recent advances in the treatment of constipation in adults and children are discussed, such as the selective 5-HT4, agonist, tegaserod, pre- and probiotics and sacral nerve stimulation. The second part will cover the use of polyethylene glycol which has been described as an effective and well-tolerated treatment choice for pediatric constipation, especially as an adjunct to education and behavioural training. PEG 3350 and PEG 4000 have been proved an option for children with constipation who have failed or are intolerant of other pharmacotherapies. Serotonin plays a key role in mediating peristalsis and stimulating intestinal secretion via 5-HT4 receptors in the gut wall. Tegaserod, a selective agonist that acts at 5-HT4 receptors and increases small bowel transit, stimulates intestinal secretion and inhibits visceral afferent responses has proven effective in the treatment of chronic constipation in adults (3,4). Two randomized placebo controlled trials including more than 3000 patients with constipation showed a significant increase in spontaneous bowel movements per week and a significant reduction in straining, abdominal bloating/distension, and abdominal pain/discomfort. The most common adverse events, headache and abdominal pain, were more frequent with placebo than with tegaserod. In children with hard stools, caused by excessive straining, 5-HT4 agonist might benefit children with constipation and tendency to form hard stools, scybala and large rectal masses. This seems to be present more frequently in children.The role of this promising new agent in pediatric constipation has to be established in future studies. National and international collaboration to evaluate the efficacy of Tegaserod in children is of imminent importance to match similar quality and valuable results as described in adults with constipation. Researchers claim a positive effect on intestinal transit and stool consistency of pre- and probiotics. Non-digestible oligosaccharides consist mainly of fructo-oligosaccharides (FOS). FOS is a soluble dietary fibre, which reduces faecal pH, increases the water/holding capacity of stool and faecal weight and decreases intestinal transit time. Furthermore, it has prebiotic effects by selectively stimulating the growth of probiotic bacteria, such as bifidobacteria. A double-blind randomized controlled study in healthy infants comparing a fructo-oligosaccharide-supplemented cereal (0.75 g FOS per cereal serving) with placebo showed a significant increase in mean numbers of stool per infant and softer stools (5). The FOS supplemented cereal was well tolerated. In another study in healthy women, the probiotic strain Bifidobacterium animalis shortened both the total colonic transit time and the rectosigmoid transit time (6). However, the number of stools per week did not significantly change between the Bifidobacterium and controls. Surprisingly, faecal weight, bacterial mass and faecal excretion of secondary bile salts were not influenced significantly. In contrast to these latter studies a double-blind placebo controlled, randomized study showed no additional effect of the probiotic strain Lactobacillus GG to lactulose alone in children with constipation (7). The human flora seems to be mainly determined genetically in the intestine, dominated by a few genera. Permanent changes in this milieu can only be achieved by tailoring prebiotics individually. This probably explains the lack of effect of probiotics and the effects of cereal based FOS's, which contain soluble and non-soluble fibre (8). Further studies are needed to unravel the mechanism and also to assess the clinical efficacy of pre- and probiotics in children with defecation disorders. If conventional therapy (dietary advice, toilet training, oral- and rectal laxatives in combination with behavioural therapy) fails, surgery may then be considered, even in pediatrics. However, from the pediatric literature it is well known that a continent appendicostomy or a button cecostomy, to provide antegrade administration of enemas, or even sigmoid resection have significant associated morbidity. An alternative surgical approach to constipation might be sacral nerve stimulation (9). This technique established in the treatment of detrusor irritability and urinary retention, involves modifying the neural control of the lower bowel and pelvic floor through sacral nerve stimulation. So far only small studies have been published with encouraging results for the treatment of adult patients with outlet obstruction and slow transit constipation. The number of bowel movements increased significantly from 1.1 per week to 5.8 per week, whereas abdominal pain and bloating decreased significantly. A minority of patients complained of pain from the implant. One implant became infected. Studies have sought to unravel the mechanism of action of sacral nerve stimulation but this remains unclear. Larger studies in adults with constipation are necessary to confirm the earlier findings, before this new treatment option should be introduced in the treatment of children with treatment resistant constipation. PEG is a non-absorbable agent with high molecular mass, and is not metabolised by colonic bacteria. It has become the agent of choice in treating childhood constipation during both disimpaction and maintenance phases of treatment's use as a laxative has gained much interest in the last decade. There is evidence that PEG is of value in the treatment of constipation in infants, toddlers and children. Most data, however, come from uncontrolled studies (10). Only one large double blinded, randomised controlled trial has been performed showing that PEG and lactulose both significantly increase defecation frequency and decrease encopresis frequency (11). Success (defined as a defecation frequency of 3 or more/week together with an encopresis frequency of once per 2 weeks or less) was more present in the PEG group (56% vs. 29%) after 8 weeks. Abdominal pain, straining- and pain on defecation were reported significantly less, however more children on PEG (with electrolytes) complaint about the bad taste. Youssef et al showed in a double blind placebo controlled trial that PEG 3350 was safe and effective in the treatment of childhood faecal impaction (12). Multi-centre large randomised controlled trials have to confirm these observations. In conclusion, to better evaluate novel agents, large-scale multi-centre double-blind randomised controlled trials with well-defined outcome measures are required. These studies are necessary to compare the safety and efficacy of different laxative regimenns in children with mild and severe constipation.