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

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.

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

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.

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

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