Pharmacological management of childhood constipation: Bridging today’s gaps with tomorrow’s therapies

Abstract

Childhood constipation is a prevalent yet frequently underestimated global health concern, affecting approximately 10% of children across diverse populations. Its impact extends well beyond bowel-related symptoms, with affected children often experiencing extraintestinal manifestations such as pain in multiple sites, behavioral disturbances, and a markedly diminished quality of life. The burden is further compounded in low- and middle-income countries, where financial and logistical constraints limit access to effective treatment. The impact is intensified in developing countries due to limited healthcare resources and the unavailability of pharmacological agents. When left untreated or poorly managed, functional constipation (FC) can lead to significant long-term consequences, including persistent bowel dysfunction, psychological disorders, and progression to chronic constipation and other disorders of gut-brain interaction later in life. Pathophysiology of FC is multifactorial, involving factors such as stool withholding behavior, dietary habits, anorectal dysfunction, and psychological factors. Hence, management of FC is multifaceted, including both pharmacological and non-pharmacological interventions. Pharmacological management remains central to treatment, aimed at relieving symptoms and preventing adverse outcomes. However, current therapeutic strategies rely predominantly on a narrow range of osmotic and stimulant laxatives. Introducing new drugs that have often been shown to be effective in adults, have been found to have limited efficacy in children, with some performing no more effectively than a placebo in clinical trials. This highlights a substantial gap in pediatric pharmacotherapy and emphasizes the pressing need for new, evidence-based interventions tailored to the unique physiological and developmental characteristics of children. In this review, we critically examine the current pharmacologic options for managing childhood constipation, assess their limitations, and explore future directions of these drugs and other novel interventions for the development of more effective, accessible, and child-appropriate treatments for this common yet impactful condition.

Key Words: Child; Constipation; Drugs; Management; Pediatric; Pharmacological management; Therapies

Core Tip: Functional constipation ranks among the most common disorders associated with gut-brain interactions in children. Despite the existence of well-documented guidelines featuring structured pharmacological management algorithms, long-term outcomes remain unsatisfactory. To bridge the gap, we must consider the following questions: Why is it necessary to change how we approach childhood constipation? Why have most new pharmacological treatments not proven their effectiveness? What new adjustments are needed in clinical trials related to childhood constipation? What alternative strategies can pediatricians and researchers use to implement novel drugs in children? This review highlights current pharmacological treatments for childhood constipation, including osmotic laxatives, stimulant laxatives, lubricants, and enemas, and aims to bridge the therapeutic gap with novel agents such as prucalopride, lubiprostone, and botulinum toxin. Furthermore, pediatric use of medications emerging in adult studies, such as prosecretory drugs like linaclotide and tenapanor, is discussed.

INTRODUCTION

Functional constipation (FC) is a widely prevalent and often underestimated problem in pediatric clinical practice. The challenges posed by childhood FC collectively amount to a widespread, cross-border public health challenge due to several reasons. Firstly, around 9.5% of children around the globe are suffering from FC[1]. However, in some countries, both in the developing and developed world, the burden may be as high as 30%[2,3]. Secondly, the clinical and financial burden of FC is sizable. FC is one of the gastrointestinal disorders leading to emergency room visits, even using ambulance services, and emergency room bed occupancy for disimpaction[4,5]. In addition, the outpatient gastroenterology clinics are also inundated with children with constipation[6]. The medical costs associated with FC are substantially higher compared to healthy children and those with other common childhood diseases across the world[7-9]. Finally, FC has an impact on health-related quality of life (HRQL), impairing physical, social, educational, and psychological functioning[10]. In addition, when poorly managed, constipation causes serious repercussions in affected children (e.g. long-term psychological consequences and persistent bowel dysfunction) and progresses into adulthood as constipation and/or other disorders of gut-brain interactions[11,12].

The clinical management of FC is multifaceted and includes both pharmacological and non-pharmacological interventions. Non-pharmacological interventions for FC in children include toilet training, behavioral modification, reward-based systems, dietary management, and psychological support for both children and parents. These strategies are integral to the comprehensive, day-to-day management of the condition. Nevertheless, as the present review focuses specifically on pharmacological approaches, non-pharmacological interventions will not be discussed in detail.

Pharmacological intervention remains the cornerstone of treatment, essential for alleviating symptoms and averting serious repercussions. Yet, current therapeutic strategies are primarily confined to a limited arsenal of osmotic and stimulant laxatives- agents that offer only modest efficacy for many patients. Although several pharmacological treatments have proven effective for adults with FC, their use in children has been largely disappointing, with most clinical trials showing little to no benefit over placebo[13,14]. The limited benefits of these agents are secondary to differences in pathophysiology between children and adults, deficiencies in trial design, and including children with refractory constipation in some pediatric trials. Therefore, most evidence-based guidelines recommend only a handful of pharmacological interventions for children with FC[15,16].

In this review, we aimed not only to critically evaluate current pharmacological treatments for childhood constipation, with a focus on their limitations, but also to explore future directions for developing more effective, accessible, and child-appropriate therapies for this prevalent and impactful condition.

CURRENT MANAGEMENT OF FUNCTIONAL CONSTIPATION

FC is diagnosed using the Rome IV criteria[17] (Supplementary Table 1). In a child with uncomplicated FC, routine investigations provide no additional advantage during the management. Investigations are only recommended when the child is proven to have therapy-resistant constipation.

The standard pharmacological interventions for pediatric FC focus on three main aspects: Disimpaction, maintenance, and tapering off and stopping drugs. Table 1 summarizes the current pharmacological agents recommended by the up-to-date management guidelines from the NHS-United Kingdom, European and North American Societies of Pediatric Gastroenterology, Hepatology, and Nutrition, Indian Academy of Pediatrics, and Saudi Experts Consensus on FC[15,16,18,19]. Figure 1 shows the management of FC in children, highlighting the pharmacological interventions.

Figure 1  Pharmacological management of childhood functional constipation.

Table 1 Comparison of pharmacological interventions in guidelines.

Guideline
Pharmacological agents	NICE (2017)	ESPGHAN/NASPGHAN (2014)	IAP (2018)	Saudi experts (2022)
Osmotic laxatives
High-dose PEG for dis impaction	√	√	√	√
Low-dose PEG for maintenance phase	√	√	√	√
Lactulose for maintenance when PEG is not available	√	√	√	√
Stimulant laxatives as adjunct therapy with PEG during maintenance. e.g. Bisacodyl, Senna, Sodium Picosulfate	√	√	×	√
Enemas for disimpaction when PEG is not available. e.g. Sodium lauryl sulfoacetate, Sodium docusate, Sodium phosphate	√	√	√	×
Lubricants. e.g. Mineral oil, Liquid paraffin	×	√	×	×
Novel agents
Prucalopride	×	×	×	×
Lubiprostone	×	×	×	×
Linaclotide	×	×	×	×

NICE: National Institute for Clinical Excellence UK; ESPGHAN: European Society of Pediatric Gastroenterology, Hepatology and Nutrition; NASPGHAN: North American Society of Pediatric Gastroenterology, Hepatology and Nutrition; IAP: Indian Academy of Pediatrics; PEG: Polyethylene glycol.

Osmotic laxatives

Osmotic laxatives are considered the first-line pharmacological intervention for childhood FC. These agents are poorly absorbed in the gastrointestinal tract and exert a strong osmotic effect, drawing water into the intestinal lumen. This softens stools and exaggerated peristalsis through bowel distension, facilitate the passage of soft stools. All guidelines recommend polyethylene glycol (PEG) and lactulose to initiate therapy.

PEG

PEG comprises repeated ethylene glycol units [-(CH₂CH₂O)_n]. It is minimally absorbable (< 1%) and not degraded by intestinal microflora, hence increasing intraluminal fluid volume through its osmotic activity[20]. In addition, PEG interacts with water molecules by forming hydrogen bonds, in a ratio of 100 water molecules per PEG molecule, thereby increasing the water content of the colon. PEG 3350 and 4000 represent different molecular weights of 3.350 and 4.000 g/mol, respectively, sharing similar pharmacological action[21]. It is a tasteless, grit-free powder and has been approved by the FDA since 1999 to be prescribed for FC[22]. There are two types of PEG preparations: Namely, with and without electrolytes. A meta-analysis found no difference in the efficacy of PEG with and without electrolytes in maintenance therapy for children from 6 months to 16 years[23].

PEG is considered the first-line treatment for FC in children in terms of both dis impaction and maintenance in all current guidelines. It is proven to be more effective than lactulose, the other commonly used osmotic laxative, in terms of stool output per week, both in high and low doses. Children using PEG during the maintenance phase are less likely to receive additional stimulant laxatives[24]. Similarly, PEG is also shown to be more effective than milk of magnesia (MOM). A meta-analysis of 3 studies indicates that PEG is superior to increasing weekly stool output compared to MOM[24]. Therefore, PEG is currently the most used laxative in managing children with FC. Higher doses are necessary for disimpaction of the rectum and the colon, and a lower dose is being used for maintenance. Maintenance therapy should be given for a longer duration, a minimum of three months, until children fully recover from symptoms. However, the optimal doses within the safety margins for younger children (< 2 years) are still not precise due to insufficient data[25].

PEG should be used with caution in children with hepatic or renal dysfunction due to potential electrolyte imbalances. Furthermore, PEG is not recommended for children with swallowing problems and severe neurological impairment with a high risk of aspiration due to life-threatening lipoid pneumonia[26]. Common adverse effects include abdominal bloating and distension, flatulence, diarrhea, abdominal cramps, and nausea.

Lactulose

Lactulose is a synthetic disaccharide that is fermented in the large intestine by colonic microflora, leading to a decrease in colonic pH, which helps in the acceleration of colonic transit. In addition, the osmotic nature of the drug increases stool volume. Both actions help to increase stool output in children with FC[27]. There are no placebo-controlled randomized controlled trials (RCTs) for this time-tested old drug. However, a 2016 Cochrane review analyzed six studies comparing lactulose with PEG and reported a greater number of stools per week with PEG. In addition, children who received PEG were less likely to receive additional therapies compared to those who received lactulose[24]. The same review also reported that lactulose is less effective when compared to liquid paraffin and Senna[24]. Therefore, it is likely that lactulose is less often used in the management of constipation compared to PEG in the modern era. However, it is still commonly used in infants and young children. In addition, lactulose can be recommended as the second-line drug in the maintenance therapy when PEG is not available[15]. The adverse effect profile of lactulose is minimal and includes bloating, cramps, and gaseous distension.

Magnesium hydroxide

Magnesium hydroxide (MOM) and magnesium citrate are osmotic laxatives. Magnesium laxatives are inorganic salts. Their mechanism of action involves generating an osmotic gradient that leads to water retention in the bowel lumen[28]. Magnesium hydroxide may also act by inducing the release of cholecystokinin, leading to an increase in motility and intestinal secretion[29], or by activating nitric oxide synthase[30].

Loening-Baucke and Pashankar[31] evaluated the efficacy of PEG without electrolytes (0.7 g/kg/day) and MOM (2 mL/kg) in children with FC. Clinical outcomes were evaluated at 3-, 6-, 9-, and 12-month intervals. They found that PEG 3350 and MOM are equally effective in relieving symptoms, with neither leading to clinically significant side effects[31]. A more recent study also confirmed that there is no difference in treatment success between MOM and PEG[32]. Both studies found that MOM is less palatable. The 2016 Cochrane review, which included three clinical trials, noted that PEG showed higher clinical efficacy compared to MOM[24]. Common adverse reactions include diarrhea, abdominal pain, and bloating. It is best to avoid using MOM in children with renal insufficiency due to the likelihood of hypermagnesemia. MOM is rarely used in current practice for managing constipation in children and is replaced mainly by PEG.

Stimulant laxative

Stimulant laxatives, irrespective of their classification, act by stimulating the enteric nervous system of the colon and enhancing the peristaltic movements. This, in turn, propels the fecal matter towards the rectum, facilitating the elimination. In addition, they are known to promote intestinal secretions[33]. Based on their chemical structure, the stimulant laxatives are classified into two classes: Diphenylmethanes (bisacodyl and sodium picosulphate) and anthraquinones (senna). Both groups are said to be effective and safe, despite the limited availability of RCTs involving children.

In contrast to adults, stimulant laxatives are considered to be a second-line therapeutic option in the management of constipation in children. It is primarily because most children with constipation do not suffer from motility disorders that are commonly seen among adults. The current recommendation is to combine stimulant laxatives with osmotic laxatives when the latter alone is not achieving the desirable defecation frequency or the nature of stools[15,18]. Despite the common belief that long-term use of stimulant laxatives leads to structural alterations in the enteric nervous system and smooth muscles, and carcinogenicity, there is no evidence to prove these harmful effects[34].

Diphenylmethanes

Two pharmacological agents, namely, bisacodyl and sodium picosulphate, belong to this group. Diphenylmethanes, once metabolized by colonic bacteria or intestinal brush border enzymes, release their pharmacologically active metabolites. These metabolites induce peristalsis and increase intestinal secretions, improving bowel frequency[27]. The pharmacological action is confirmed by several studies that used intraluminal bisacodyl during colonic manometry and serial magnetic resonance imaging studies. Administration of bisacodyl induces high-amplitude, propagatory contractions in the colon and increases the intraluminal water content[35,36].

RCTs in adults have shown the clinical efficacy and safety of bisacodyl in adults with constipation[37,38]. The recent guideline issued by the American College of Gastroenterology strongly recommends the use of bisacodyl and sodium picosulphate as short-term or rescue therapy[39]. Despite clear evidence from physiological studies, as well as studies in adults, high-quality RCTs are not available to prove the efficacy of bisacodyl and sodium picosulphate in children. However, in clinical practice, bisacodyl is administered orally or rectally to treat children with constipation.

Anthraquinones

Senna is a plant-derived natural stimulant laxative. Its active ingredients are sennoside A and B, which are metabolized in a stepwise manner by the intestinal microflora, into the pharmacologically active rheinanthrone and rhein. These metabolites exert their laxative effect by stimulating the production of prostaglandin E2, which enhances the secretion of chloride ions. The ionic shift promotes both water retention and augments peristalsis, facilitating bowel motion. Pharmacokinetic studies show that over 90% of the administered sennosides and their metabolites are excreted in feces, indicating the limited systemic absorption and primary local action within the gastrointestinal tract[39].

A trial involving 37 children comparing the efficacy of senna and mineral oil in treating children with constipation showed that senna was less effective compared to mineral oil[40]. A crossover trial comparing senna with lactulose in children showed no difference in stool frequency between the two laxatives[41]. Adverse effects include diarrhea, abdominal pain, nausea, flatulence, and blistering skin rash in the diaper area[42]. Therefore, the certainty of evidence is low to recommend senna as a treatment modality for children with constipation.

Lubricants

Lubricant laxatives are tasteless, odorless, oily liquids composed of hydrocarbons derived from petroleum, such as liquid paraffin (mineral oil). Liquid paraffin acts primarily by coating the stool and intestinal mucosa, reducing water absorption from the fecal mass and thereby softening the hard stools. In addition, the lubrication facilitates easier passage of stools through the colon and rectum. It is generally considered helpful in managing mild to moderate symptoms of constipation on a short-term basis. The side effects include abdominal pain, nausea, vomiting, flatulence, and leakage of chemicals through the anus, irritating perianal skin[24]. Liquid paraffin mustn't be prescribed to children who are neurologically handicapped and children having swallowing difficulties who are at a high risk of developing life-threatening lipoid pneumonia when aspirated[43]. Liquid paraffin also has a minor risk of interfering with the absorption of fat-soluble vitamins[44]. Clinical trials have shown that mineral oil is as effective as PEG in treating children with FC, and mineral oil is superior to both lactulose and senna. However, the quality of the studies is low, and there is a high risk of bias[40,45,46]. Therefore, liquid paraffin is rarely used in modern-day clinical practice.

Enemas

An enema is a liquid solution instilled into the rectum through the anal canal. Ingredients in the enema help evacuate the impacted rectum by softening the impacted stools, lubricating the stools, or stimulating the motility of the rectum, depending on their chemical nature. In addition, some enemas are hyperosmolar and can exert an osmotic effect at the level of the rectum, facilitating the passage of stools. The most crucial advantage of enemas is their rapid action, which occurs within minutes. The primary indication of using an enema is to relieve fecal impaction. However, young children do not like to have enemas simply due to the pain associated with the therapy, which could precipitate stool withholding. A 2015 meta-analysis included two studies comparing enemas (dioctyl sulfosuccinate sodium and milk and molasse) with PEG on fecal disimpaction in children of 1-17 years. The two studies had two different outcome measures. In the meta-analysis, there was no clinically meaningful difference between the two agents in disimpaction[47].

Several pharmacological agents are being used as enemas (Table 2). One study reported no difference in stool output between enemas[48]. A Japanese retrospective analysis of 118 children with chronic constipation due to surgically corrected anatomical lesions (e.g. repaired anorectal malformations and Hirschsprung disease) and FC who were treated with olive oil enemas showed that the intervention was effective in disimpaction[49]. A RCT comparing conventional therapy (PEG, education, behavioral strategies) with conventional treatment with regular enemas found no additional therapeutic benefits of enemas in the maintenance phase[50]. Therefore, it is evident that enemas are not a very useful therapeutic intervention in the modern-day clinical management of childhood FC except for instances where a quick relief is necessary in a child with severe fecal impaction. The ESPGHAN/NASPGHAN guideline recommends using enemas during the disimpaction phase when PEG is not available[15]. There is no place for enemas in the maintenance phase.

Table 2 Types of enemas used in children with constipation.

Type of enema	Mechanism of action	Adverse effects
Mineral oil	Reduce the water absorption	Staining of underwear with leakage
	And soften stools
	Lubricate hard fecal masses to facilitate expulsion
Soap suds enema	Hypertonic solution	Rectal mucosal irritation
	It leads to detergent-based mucosal irritation to stimulate defecation	Colitis
		Bleeding
		Rarely strictures
Milk and molasses	Sugary nature of the enema affects the intestinal lining and produces gas, leading to abdominal distension, increased intra-abdominal pressure and the generation of peristalsis	Hemodynamic instability due to the shift of fluid
	Fat in the milk lubricates the fecal mass	Cramping and abdominal pain
		Nausea and vomiting
		Rectal irritation
Olive oil	Lubricate the stool mass, facilitating excretion	Mild rectal irritation leading to discomfort
	Soften the stool bolus by retaining water and partially breaking down the fecal mass	Leakage causing discomfort
	Subtle enhancement of local peristalsis	Hypersensitivity reactions
		Abdominal cramps
Phosphate	Highly osmotic and draws water into the rectal lumen, softening stools	Rectal irritation leading to rectal pain and burning sensation
	Rapid rectal distension triggers peristalsis	Hyperphosphatemia
		Hypocalcemia
		Other electrolyte imbalances
Sodium lauryl sulfoacetate	Lowers surface tension between fecal mass and intestinal fluid, and allows water and lipids to penetrate hard fecal mass, softening it	Rectal irritation and burning sensation
		Abdominal cramps and discomfort
		Nausea
Sodium docusate	It reduces the surface tension of stool and allows water and fat to penetrate the fecal mass, making it softer	Rectal irritation
		Abdominal cramps and discomfort
		Nausea

NOVEL PHARMACOLOGICAL AGENTS

In recent years, advances in the understanding of gastrointestinal physiology and receptor pharmacology have led to the development of novel agents targeting more specific mechanisms of action. Drugs such as prosecretory agents, serotonin receptor agonists, and chloride channel modulators, initially developed and approved for use in adults with chronic constipation or irritable bowel syndrome with constipation, have shown potential benefits in pediatric populations. The translation of these therapies into pediatric clinical trials has been driven by both clinical demand and regulatory encouragement to extend adult-approved therapies to children. Early-phase trials have shed light on their safety, tolerability, and efficacy in younger age groups. This section explores these emerging pharmacological agents and their evolving role in addressing FC.

Prucalopride

Prucalopride is a new generation of highly selective, high-affinity, 5-HT4 receptor agonist. The 5-HT4 receptor, which is found in enteric neurons and smooth muscles, when adequately stimulated, releases acetylcholine from cholinergic neurons that can induce intestinal motility, propagatory contractions, and colonic propulsion[51]. These 5-HT4 receptors are distributed throughout the gastrointestinal tract, including the colon and are found mainly on smooth muscle cells, enterochromaffin cells and within the myenteric plexus. The G-protein-coupled receptors, when activated by serotonin agonists, stimulate the production of cyclic adenosine monophosphate. This activation influences various neurotransmitters, most notably enhancing the release of acetylcholine, the primary excitatory neurotransmitter in the gastrointestinal system. This is considered the key mechanism behind the prokinetic effects of 5-HT4 receptor agonists[52]. It is chemically a benzofuran carboxamide, a highly selective 5-HT4 receptor agonist[53]. Unlike its predecessors (cisapride and tegaserod, which were withdrawn from the market due to cardiac arrhythmias and cardiac ischemic events), prucalopride has high selectivity and affinity, thereby eliminating the possibility of cardiovascular events and arrhythmias.

Phase 1 studies have shown the efficacy of prucalopride in improving stool consistency and frequency, accelerating colonic transit time, and increasing number of both high amplitude propagatory contractions and segmental nonpropagatory contractions[54-56]. Phase II trials in adults noted improvement in stool frequency and consistency[57-59]. Three phase III studies among adults have proved the clinical efficacy of prucalopride in relieving symptoms of severe constipation in adults and improving their HRQL[60-62]. Thereafter, many clinical trials and several meta-analyses have confirmed the efficacy of prucalopride as an effective therapeutic modality for the treatment of severe constipation in adults[63,64].

However, only two clinical trials have been published reporting the efficacy of prucalopride in childhood FC. One open-label, phase I study involving 38 children with FC to receive a single dose of oral prucalopride at a dose of 0.03 mg/kg to study the basic pharmacokinetics and pharmacodynamics over 72 hours. Out of them, 37 children were included in an 8-week extension study to receive a single dose of prucalopride at a dose of 0.02 mg/kg. Depending on the child’s response, the dose was permitted to be adjusted within the range of 0.01 to 0.03 mg/kg with additional laxatives and rescue therapy[65]. Prucalopride was noted to be rapidly absorbed with a limited inter-patient variability. During the 8 weeks, 94.3% achieved an average of ≥ 3/week motions. The overall mean stool frequency in the toilet during the 8 weeks was 6.8 per week. There was also a reduction in the average number of fecal incontinence (FI) episodes per week (5.6 in week 1 to 3.4 in week 8). In addition, it was also reported that there was normalization of stool consistency and improvement of the subjective feeling of the caregivers with regard to the general disease condition of the child. It is important to note that 57% of these children were on a number of other laxatives (including simple oral laxatives to phosphate enemas). Therefore, the reported clinical improvement cannot solely be attributed to prucalopride. Only 7 (19%) children were considered to have adverse reactions related to the drug, and those included abdominal pain, headache, and FI; however, no one discontinued the drug due to adverse events. No cardiovascular-related adverse reactions were noted, despite careful monitoring[65]. This study cleared doubts about possible serious cardiac-related adverse events in children. However, the open-label nature of the design, concomitant use of several other laxatives, and the small number of children involved in the study did not allow for drawing firm conclusions regarding the efficacy of prucalopride for childhood FC.

A well-designed, phase III multicenter trial was conducted to evaluate the usefulness and the safety of prucalopride in treating children (6 months to 18 years) with FC. They used 0.04 mg/kg oral solution for children weighing less than 50 kg and 2 mg for children weighing over 50 kg as a single dose. FC was diagnosed using standard Rome III criteria, and their primary efficacy endpoint was a mean spontaneous bowel movement (SBM) frequency of > 3/week and a mean fecal incontinence frequency of < 1/2 weeks during weeks 5-8 of the double-blind period. In addition, there were several secondary endpoints (SBM frequency, frequency of FI, retentive posturing, pain during defecation, stool consistency, abdominal pain, use of rescue medication, and quality of life)[13]. The majority of children randomized had severe or very severe FC, and the duration of symptoms was 4.4 years in the prucalopride group and 4.2 years in the placebo group. More than half (63.4%) had not been toilet-trained.

The proportions of children who achieved the primary efficacy endpoint at the end of the 8 weeks were similar between groups (17.0% in the prucalopride group and 17.8% in the placebo group; P = 0.90). Furthermore, there was no significant difference between groups in the improvement in the number of SBMs, FI episodes, pain during defecation, abdominal pain, use of rescue medication, and HRQL[13]. Treatment-emergent adverse events (TEAEs) were reported by 69.8% of patients in the prucalopride group and 60.7% of patients in the placebo group. On day 1, a higher percentage of patients in the prucalopride group (21.7%) experienced TEAEs compared to the placebo group (3.7%). The most frequently reported TEAE in both groups was headache, occurring in 13.2% of prucalopride-treated patients versus 0.9% in the placebo group. During the open-label phase, the most frequently reported TEAEs included vomiting, diarrhea and abdominal pain.

Failure of this much-anticipated trial may be due to several reasons. Firstly, most of the children who were included had long-standing severe FC who may not be responding to an eight-week course of a stimulant laxative. The majority of young children in the trial were not toilet-trained. Although parents were advised to train their children during the 8 weeks of the trial, this may not be enough to achieve satisfactory training. It is also important to note that the trial has included a lot of young children with FC, where the pathophysiology mainly revolves around fecal withholding. In such a scenario, a stimulant laxative is not able to address the pathophysiology, although it has similar population pharmacokinetics compared to adults[66].

Lubiprostone

Lubiprostone is a bicyclic fatty acid derived from prostaglandin E1. It is a high-affinity activator of the ClC-2. These channels are located close to the tight junctions on the apical cell membrane of the villus enterocytes[67]. When activated by lubiprostone, these channels secrete chloride-rich fluid into both the small and large intestinal lumen without altering the serum chloride level[68]. In physiological studies using a radiolabeled meal, it was shown that lubiprostone accelerates small intestinal and colonic transit[69]. This activation leads to the active transport of chloride ions into the intestinal lumen, followed by the passive movement of water and electrolytes, thereby increasing the fluid content within the intestinal lumen. The resulting luminal distension enhances gastrointestinal motility, which subsequently accelerates both intestinal and colonic transit. Several randomized clinical trials using lubiprostone in adults with chronic constipation showed clinical improvement and resolution of symptoms[70-72].

A phase III, multicenter, open-label safety trial was conducted from April 2016 to November 2016. Children between 6-18 years with FC according to Rome III criteria were prescribed either 12 mg or 24 mg twice a day for 24 weeks, depending on the child’s weight (< 50 kg-12 mg, > 50 kg-24 mg). It was reported that the drug was well-tolerated and safe. The standard treatment-related adverse events include diarrhea, nausea, upper abdominal pain, dyspepsia, and headache. Most of the adverse events were mild in intensity, and no safety concerns have been reported regarding vital signs and laboratory parameters[73].

An open-label, multicenter study on the safety and efficacy of lubiprostone in FC in children. One hundred nine children with FC according to Rome III criteria (age ranged between 3-17 years) completed the study. They were treated with lubiprostone 12 mg once a day, 12 mg twice a day, or 24 mg twice daily, depending on age and body weight. The researchers noted a statistically significant increase in SBM frequency at 1 week after starting treatment compared to baseline (3.1 vs 1.5, P < 0.0001) across all doses except the 12 mg once daily group. The most significant improvement in bowel frequency was observed in adolescents who were on 24 mg twice a day. Overall, stool frequency, stool consistency, straining, and pain at bowel movement were reported to improve significantly from baseline after starting treatment with lubiprostone. Standard treatment-related adverse events noted include nausea, vomiting, and diarrhea[74].

A phase III 12-week multicenter RCT and follow-up 36-week open-label trial was conducted, including children 6-17 years old, to test the efficacy and safety of lubiprostone for children who fulfill Rome III criteria for FC. Children who fulfilled an average of less than 3/week spontaneous bowel movements with > 25% of SBM involving at least some straining and/or stool form of 1 or 2 in the modified Bristol Stool Form Scale were randomized to receive lubiprostone (12 or 24 mg twice a day, depending on the age) or placebo. It is imperative to note that 72% of these children had a history of previous treatment failure and hence could be considered as refractory FC. They were allowed to have rescue medications when there was no bowel movement for 3 days, except for the first 24 hours after the first dose. The primary efficacy endpoint of the RCT was the overall SBM response defined as an increase of ≥ 1 SBM/week compared with baseline and ≥ 3 SBM/week for at least 9 weeks, including 3 of the final 4 weeks. A total of 147 in the lubiprostone group and 297 in the placebo group completed the study. Following a 12-week intervention, the authors found there was no statistically significant difference in the primary efficacy endpoint of overall SBM response rate between the lubiprostone and placebo groups (18.5% for the lubiprostone and 14.4% for the placebo, P = 0.22), even after both intention-to-treat and per-protocol analyses. Both phases of the study showed that lubiprostone was safe with minimal side effects such as nausea, vomiting, diarrhea, and abdominal pain[14].

Several factors led to the failure of this trial to show the efficacy of lubiprostone for FC in children compared to studies among adults. Like in the prucalopride trial, authors have included children with severe constipation (72% had previous treatment failure) into this trial as well. Additional factors contributing to the failure, as observed in the prucalopride study, include the inclusion of young children in whom the predominant pathophysiologic mechanism stool withholding is unlikely to change with lubiprostone, with another factor being a notably high placebo response.

Linaclotide

Linaclotide is a small, synthetic peptide that acts as an agonist to Guanylyl cyclase C. Guanylyl cyclase C is a single membrane-spanning enzyme that converts guanosine triphosphate to cyclic guanosine monophosphate (cGMP). In the gastrointestinal system, guanylate cyclase C receptors are expressed on the brush border membranes of the intestinal epithelial cells from the duodenum to the rectum[75]. When stimulated, it leads to the activation of the apical chloride channel, cystic fibrosis transmembrane conductance regulator through cGMP, increasing fluid secretion, accelerating intestinal transit, and also reducing the activity of visceral nociceptive neurons[76-78]. The pH-independent nature of linaclotide stimulates the receptors in both the small and large intestine, and therefore, it is therapeutically valuable for treating FC.

It is absorbed minimally and undergoes proteolytic digestion in the gastrointestinal tract to peptides and amino acids. Less than 1% of the orally administered dose is recovered in the feces after 24 hours[79]. Preclinical studies in rats have shown a significant increase in gastrointestinal transit[80,81]. Phase I study with 48 healthy subjects using multiple ascending oral doses noted improved stool consistency, easier passage of stools, and increased stool frequency. In addition, the study also reported that the drug is well-tolerated with no severe adverse reactions[80]. A phase II trial on adults with chronic constipation also showed the efficacy of linaclotide in improving complete SBM, stool consistency, and bloating, and reducing straining and abdominal discomfort[82]. Several randomized trials conducted in adults with idiopathic constipation and irritable bowel syndrome with constipation have shown an apparent efficacy of linaclotide (at doses of 145 micrograms and 290 micrograms daily) in improving stool frequency and consistency[83-85]. Several meta-analyses also reported the efficacy of linaclotide in treating adults with chronic constipation[86,87].

Two pediatric studies, including 2-5 years and 6-17 years, have reported the safety of the drug in both age groups[88,89]. The only significant adverse event reported was mild diarrhea. The only randomized, double-blind, placebo-controlled pediatric trial recruited 173 children (157 included in the intention-to-treat analysis) and randomized them to receive either a placebo or escalating doses of linaclotide according to body weight. The researchers reported only a numerical improvement of mean SBM frequency with increasing doses [1.90 in 6-11 year olds (in 36 or 72 micrograms) and 2.86 in 12-17 year olds (in 72 micrograms)] without a statistically significant difference. Similarly, none of the linaclotide groups showed statistically significant improvement of secondary end points (straining severity, stool consistency, daytime FI, daytime abdominal pain, bloating and overall complete SBM frequency rate)[89]. The lack of a statistically significant difference could be due to several reasons, including a small sample size, high placebo response and notable outliers in the placebo group. However, the finding of numerical improvement of spontaneous bowel frequency is encouraging and paves the way to an adequately powered phase III trial to confirm the efficacy of linaclotide for FC in children.

Botulinum toxin

Local injection of botulinum toxin inhibits the release of acetylcholine from presynaptic cholinergic nerves with an accompanying loss of junctional acetylcholine receptors, which would result in loss of excitatory sympathetic input to internal sphincter tone[90]. The toxin also reduces the contraction of striated and smooth muscles in a focal and transient fashion. It can be used repeatedly if necessary, and it may provide the same effect as internal sphincter myotomy without complications. The impact of the toxin lasts approximately 3 months, and it is expected that children learn to pass stools normally through the relaxed anal sphincter, leading to the resolution of symptoms. When compared to standard medical management, botulinum toxin was shown to be effective in reducing symptoms of FC, pain during defecation, fecal incontinence, and improving stool consistency[91]. However, this study had significant bias, including blinding of participants and outcome assessors, and selective reporting. A randomized double-blind trial compared the effectiveness of botulinum toxin and internal anal sphincter myectomy in children with constipation and FI. In this study, the authors reported improvement of predefined symptom scores of the botulinum toxin group without any statistically significant difference to that of the myectomy group (P < 0.87 at 3 months and P < 0.88 at 12 months), indicating the intersphincteric injection of the toxin is as effective as the time-tested surgical procedure. The secondary outcomes were not reported. The authors found no significant adverse effects of the intervention[92]. Both studies were conducted on children with refractory constipation, and therefore, the applicability of findings for children with non-refractory FC cannot be determined. The potential adverse reactions include urinary incontinence, paresis of the pelvic floor muscles, perianal abscess, pruritus ani, and rectal prolapse[93]. Furthermore, the therapeutic modality is expensive, needs general anesthesia, and may require repeated injections in some children. Further studies are necessary before recommending intersphincteric injection of botulinum toxin for children with FC.

DRUGS EMERGING FROM ADULT STUDIES

Several other novel pharmacological agents have been tested for the treatment of FC in adults. Although pediatric trials on these drugs have yet to be conducted, the adult studies show promising results (Table 3).

Table 3 Current clinical utility of novel pharmacological agents.

Name of drug	Mechanism of action	Adult trials	Pediatric trials
Plecanatide	Selective guanylate cyclase-C receptor agonist, which finally helps to increase secretion of chloride ions and water into the intestine, facilitating the passage of stools. Plecanatide is more active in acidic pH, hence the drug is more active in the upper small intestine	Phase III clinical trial has shown that the drug was able to increase the frequency of complete, spontaneous bowel movement compared to placebo	No pediatric trials
Tenapanor	Selective sodium/hydrogen exchanger isoform 3 inhibitor. The increased luminal sodium leads to retention of the fluid in the intestine, resulting in softening of stools and increased spontaneous bowel motions	Phase III clinical trials have shown a significant increase frequency of spontaneous bowel movements in adults with IBS-C	No pediatric data
Mizagliflozin	Selective sodium glucose co-transporter inhibitor in the small intestinal epithelium. The process helps to increase luminal water content and soften stool, and facilitate its passage	One trial including Japanese adults with IBS-C shows efficacy in improving spontaneous bowel motion compared to a placebo	No pediatric data
Elobixibat	Inhibits the reabsorption of bile acids in the terminal ileum. The non-absorbed bile acids stimulate the secretion of chloride and water into the colon and also enhance smooth muscle activity in the colon. Both activities contribute to the passage of soft stools	Although showing good safety and reducing colonic transit time, the improvement of clinical parameters related to constipation is limited and not convincing	No pediatric data

IBS-C: Irritable bowel syndrome with constipation.

Plecanatide

Plecanatide is another guanylyl cyclase C receptor agonist with a similar mechanism of action as linaclotide. It is a uroguanylin analogue that shows high affinity binding at acidic pH. Therefore, its main pharmacological action is in the upper small intestine. One published Phase I study enrolling 72 healthy volunteers administered nine doses of plecanatide (0.1, 0.3, 0.9, 2.7, 5.4, 8.1, 16.2, 24.3, and 48.6 mg). Plasma concentration check detected no plecanatide from 0.5-48 hours, indicating that the drug does not get absorbed into the body and metabolized in the gastrointestinal tract to amino acids and smaller peptides[94]. A phase III multicenter RCT involving 1394 patients was conducted to assess the efficacy of plecanatide for chronic constipation in adults. In this study, plecanatide was used in 3 mg or 6 mg once daily for 12 weeks. At each dose, plecanatide (2.5 and 2.2/week, respectively) was able to increase mean weekly complete SBM frequency from baseline compared to placebo (1.2/week; P < 0.001 for both doses). The most common treatment-related adverse event was diarrhea[95]. No pediatric trials have been conducted to assess the efficacy of plecanatide in children.

Tenapanor

Tenapanor is a small-molecule inhibitor that selectively targets the sodium/hydrogen exchanger isoform 3 (NHE-3), which is predominantly expressed on the apical surface of enterocytes. Physiologically, NHE-3 facilitates the absorption of sodium and phosphate in the gastrointestinal tract. By inhibiting the transporter, tenapanor reduces sodium uptake, leading to increased luminal sodium concentration and retention of fluid in the colon, resulting in softer stools and increased bowel motions[96]. Phase I and Phase II studies have concluded that tenapanor is safe and effective in treating IBS-C in adults[97,98]. Several phase III trials have shown that tenapanor increases spontaneous bowel motions compared to a placebo in adult patients with IBS-C[99,100].

Mizagliflozin

Mizagliflozin is a selective sodium glucose co-transporter 1 inhibitor that acts on the small intestinal epithelial cells[101]. It was initially developed as an anti-diabetic drug, but it was later noted that patients developed softer stools. The drug exerts its effect primarily by inhibiting intestinal glucose absorption, which is accompanied by a reduction in water reabsorption from the intestinal lumen. This mechanism is believed to contribute to increased luminal water content, thereby softening the stool and facilitating bowel movements. Phase I trial in healthy males has shown promising results of improving soft bowel motions in a dose-dependent manner, with good tolerability and safety[101]. An adult double blind RCT conducted in 2018 involving Japanese patients with constipation and IBS-C reported significant improvement in SBM in mizagliflozin compared to placebo. The commonest adverse event reported was diarrhea, and there had been no clinically meaningful change in blood sugar levels[102].

Elobixibat

Endogenous deconjugated bile salts activate specific bile acid receptors, such as G protein-coupled bile acid receptor-1(GPBAR-1/TGR-5), which are expressed on enteric neurons and epithelial cells in the colon. Activation results in the secretion of chloride and water into the intestinal lumen and enhances smooth muscle activity in the colon, softening stool consistency and improving bowel transit[103]. Elobixibat is a novel drug that inhibits the reabsorption of bile acids in the small intestine, resulting in higher concentrations of bile acids in the colon. Several trials have been conducted to assess the efficacy of elobixibat in adults with constipation, with variable success[104,105]. No pediatric trials have been undertaken to evaluate the effectiveness of elobixibat in FC.

BRINGING THE FUTURE TO TODAY

Why do we need to change the way we treat FC?

As stated previously, FC is one of the most prevalent disorders of the gut-brain interactions[1]. Despite the availability of well-documented guidelines with structured pharmacological management algorithms, the long-term outcomes remain unsatisfactory[15,16]. Prospective cohort studies have shown that at least one-third of these children progress to adulthood without resolution of their symptoms, suggesting that current pharmacological interventions are not entirely effective in achieving durable remission[11,106]. The persistence of symptoms reflects incomplete targeting of the pathophysiological mechanisms, including complex behavioral problems, altered gastrointestinal motility, visceral sensitivity problems, altered microbiome, and central neurocognitive pathways. Therefore, we need to bring together all available knowledge of advances in molecular gastroenterology, gut-brain interactions, and the cutting-edge knowledge of intestinal microbiome to open new avenues for future drug development aiming to improve both short- and long-term clinical outcomes.

Underlying pathophysiological mechanisms should be the primary therapeutic targets for managing FC. The peak is usually around the time of toilet training, and the withholding behavior related to fear of defecation plays a pivotal role in pathophysiology[107,108]. The process ultimately leads to the development of a rock-hard, large fecal mass in the rectosigmoid area, which is extremely difficult to evacuate, requiring the liquefaction of stools. The evacuation of the hard and large fecal mass leads to excruciating pain. The child avoids passing stools by tightening the gluteal muscles. The process goes as a vicious cycle leading to chronic constipation. Other pathophysiological mechanisms, such as slow transit constipation and dyssynergic defecation, are rare in younger children with constipation compared to adolescents and adults[109]. Although stress-related enteric dysfunction, altered microbiome, and altered visceral sensitivity, especially rectal hyposensitivity, may play at least a part in propagating symptoms of constipation, their role is yet to be uncovered.

Behavioral problems, poor toilet training, and related stool withholding play a significant role in developing FC. It is challenging to address all these complex issues as part of standard medical care in a complex clinical trial. Although it is possible to improve peristaltic movement using promotility drugs such as prucalopride and soften the stools using prosecretory drugs like lubiprostone, a child may still withhold without passing stools unless the initial issues of stool withholding are addressed and sorted. However, it is crucial to understand that regular toilet training and alleviating withholding behavior take time (sometimes more than the duration of the trial).

When designing drugs for children with constipation and performing clinical trials of pharmacological agents that are mainly developed for adults, it is imperative to understand this primary pathophysiological mechanism in children, what behavioral problems lead to stool withholding, and what therapeutic interventions are needed to overcome it.

Why have most novel pharmacological interventions failed to confirm their efficacy?

Old, time-tested pharmacological agents such as lactulose and bisacodyl have not gone through formal randomized, double blind controlled trials. Most of the comparative trials between drugs such as lactulose and bisacodyl, mineral oil with lactulose or bisacodyl have included a small number of children with mild symptoms of constipation. Most of these drugs have shown some efficacy in relieving symptoms of constipation despite methodological flaws in designing trials. Trials testing novel pharmacological agents such as prucalopride and lubiprostone have failed to show any beneficial effects over the placebo despite their methodological rigor. The possible reasons for the failure of these trials are given in Supplementary Table 2.

What is the role of novel laxatives?

Currently, the first-line therapy for FC in children is osmotic laxatives, namely PEG. When polyethylene glycol is not available, lactulose is used as the therapeutic agent. The current role of the stimulant laxative is as an adjunct therapy for osmotic laxatives[15]. One of the ways forward into the future is to combine novel stimulant laxatives with PEG. Therefore, it is essential to perform clinical trials to evaluate the usefulness of prucalopride combined with PEG and PEG alone in the management of FC in children. Similarly, PEG can be combined with secretagogues such as lubiprostone and compared with the standard first-line treatment, PEG. A singlecenter, prospective, doubleblind, randomized, placebocontrolled trial in adult outpatients undergoing colonoscopy demonstrated that a single dose of lubiprostone given before PEG significantly improves colon cleansing quality compared to PEG alone[110]. A meta-analysis of randomized controlled studies demonstrated that lubiprostone potentially mitigates the need for a high volume of liquid associated with PEG alone for bowel preparation prior to colonoscopy[111]. This approach will provide a higher response rate with mechanical synergism, faster time to first SBM, and reduce the need for rescue medications. It will also reduce the dose of either drug, enhance tolerability, and minimize dose-dependent side effects. It will help children who have a refractory type of constipation.

What novel changes are needed for the clinical trials for functional constipation?

It is important to design randomized, double-blind, placebo-controlled, parallel-group clinical trials to assess the efficacy of the newer drugs for the treatment of functional constipation in children. However, the design of the clinical trials may have at least partly led to the failure of most of the novel pharmacological agents. Therefore, clinicians designing clinical trials must think of novel and innovative ways of designing trials involving children with FC.

Phenotyping children included in the study: It is crucial to stratify children according to the primary pathophysiological mechanisms, such as children with withholding behavior, outlet obstruction, and slow transit constipation, using a simple standard protocol. Although adults’ guidelines lump the management of constipation and IBS-C together, it is vital to exclude children with IBS-C from drug trials for FC.

Include children from various strata of clinical care: Most trials have included children from tertiary care research centers, possibly having severe/therapy-resistant constipation. Constipation is a common problem in gastroenterology clinics in primary and secondary care centers, and most of these children present early with milder symptoms fulfilling the Rome IV criteria. Children with different severities may respond favorably to novel drugs.

Ensure relevant endpoints for pediatric practice: It is vital to redesign the endpoints for constipation trials in children. A 2016 systematic review of outcome measures in clinical trials of FC showed that a significant number of papers have used treatment success as the primary endpoint. Twelve out of 30 trials used defecation frequency and eight used frequency of FI as primary endpoints[112]. This inconsistency showed that a more precise definition is needed to define clinical endpoints for children.

Kuizenga-Wessel et al[113] have published a core outcome set for assessing the efficacy of interventions in children with FC. They include defecation frequency, stool consistency, painful defecation, fecal incontinence frequency, quality of life, side effects, and school absenteeism. However, the practicality of using this outcome set is questionable in a clinical trial in real life. The Rome subcommittee on clinical trials has provided a more pragmatic definition for defining treatment success. The subcommittee defines treatment success as not fulfilling Rome criteria for FC (less than two out of the six criteria) during 3 of the last 4 weeks of the trial, including the previous week[114]. This definition provides a more real-life outcome measure rather than bowel frequency per week (which could be misleading in children sometimes). However, the failed clinical trials have not used this clinical endpoint as their primary outcome measure.

Control the placebo effect: Since pediatric drug trials show a significant placebo effect, it is crucial to control the placebo effect[115]. Table 4 shows steps to minimize the placebo effect in trials related to pediatric FC.

Table 4 Methods to control the placebo effect.

Method	Description
Trial design	Rigorous randomization and concealment
	Careful selection of the placebo with matching taste, color, texture, and packaging
	Standardized co-interventions such as toilet training and education
	Bowel cleanout before randomization
Endpoint measurement	Encourage the use of sustained responses
	Use objective measurements (e.g., Bristol stool chart to assess stool consistency)
	Use electronic time-stamped diaries
Rescue therapy	Precise instructions and exact threshold for administration, with strict record maintenance
Data quality	Minimize missing data
Multicenter studies	Site training to ensure uniformity
	Monitor site-level placebo response
Statistical analysis	Mixed-effect models to minimize the amplification of the placebo effect
	Calculating adequate power to reduce placebo response
	Use sensitivity analysis for different responder thresholds

Integrate nonpharmacological interventions into both intervention and placebo groups rigorously: Toilet training is an integral part of the management of FC, especially in younger children. In addition, a diet with adequate fiber is also an essential step in the management, as a low fiber diet is a known risk factor for FC[116]. In addition to the fiber, it is essential to standardize the diet with a written guideline and record protein, carbohydrates, and fluid with a weekly checklist. Physical activity, although it does not have a clear causal relationship, is believed to play a role in predisposing children to develop FC[117].

All these factors could interfere with the results of an otherwise well-designed trial and therefore need to be controlled equally in both the intervention and placebo groups from the run-in period to the end of the follow-up.

Include children from countries other than the Western world in clinical trials: Most novel trials on pharmacological agents have included children only from Europe, the United States, and Canada[13,14]. Constipation is a significant challenge in countries outside the Western world, and in certain Asian, African, and Latin American countries, about 20%-30% of children suffer from FC[1]. Including children from other areas of the world would provide the trial with real generalizability to the rest of the world. It would also help to complete the trial regarding numbers quickly, and the evidence can be generalized to areas other than the Western world. This approach will also reduce the global health inequalities and ensure the therapy is relevant, acceptable, and accessible where most children with FC live. However, challenges such as dietary and lifestyle differences, the need for culturally adapted outcome measures, pharmacokinetic differences in different ethnic groups, and administrative difficulties also need to be considered during the planning of such a study.

What other strategies may pediatricians and researchers adopt to use novel drugs in children?

Despite the failure of novel drugs, it is imperative to continue the struggle to improve the quality of care by using these promising agents. Table 5 presents several methods to enhance trials and to utilize available data to evaluate the beneficial effects.

Table 5 Novel strategies to improve clinical trials in pediatric constipation.

Suggestion	Description
Adaptive trial design	Use adoptive Bayesian or response-adaptive randomization designs, which allow modification of the study as data accumulate. It may help to find subgroups that respond to the intervention
Biomarker or mechanism-based approach	Instead of using the symptom-based outcome measures, it is possible to use biomarkers such as improved colonic transit and alteration of anorectal physiology after therapy as endpoints
Emphasize more on patient-centered outcomes	Rather than relying on symptom-based endpoints, using other measures, including improvement of quality of life, improvement of school attendance, can be used to assess the efficacy
Network meta-analysis to assess relative efficacy	This method helps to combine direct and indirect evidence to estimate the relative efficacy for each pair of interventions

CONCLUSION

FC represents a significant global public health concern. Although often perceived as a benign condition, its impact is far-reaching-children frequently experience substantial physical discomfort, psychological distress, and social challenges. Chronic constipation can erode quality of life and negatively influence academic performance, daily activities, and peer relationships, underscoring the need for timely and effective management.

In this context, aggressive yet individualized treatment strategies are essential to restore normal bowel function and improve overall well-being. The integration of novel pharmacological agents alongside conventional therapies presents a promising approach to both alleviating symptoms and expanding our understanding of treatment safety and efficacy in children. Future drug development must prioritize well-designed, adequately powered pediatric trials, utilizing innovative endpoints that extend beyond simple stool frequency to capture broader quality-of-life and functional outcomes.

Collaboration among pediatricians, pediatric gastroenterologists, molecular biologists and researchers is crucial to accelerate the discovery and validation of novel molecules, translating advances from adult studies into effective, evidence-based pediatric interventions. With such efforts, the future for children suffering from FC can be markedly improved, transforming a commonly underestimated disorder into one that is better recognized, managed, and prevented.