Management of constipation: A narrative review of evolving strategies and methodological challenges

Table 5 Pharmacological management of constipation

Drug class/agent	Mechanism of action	Key clinical trials	Guideline-directed management (AGA/ACG, NICE[65,66])
Bulk-forming laxatives. Psyllium (ispaghula husk)	Soluble fiber-absorbs water-stimulates peristalsis	Multiple RCTs show psyllium superior to placebo for stool frequency and consistency. Studies show that psyllium is superior to docusate for stool frequency and consistency[75]. Double-blind RCT concluded that psyllium improved stool output significantly in chronic idiopathic constipation[76]	First-line therapy for mild constipation. Mainly used for patients with low fiber intake
Osmotic laxatives	Polyethylene glycol (PEG 3350). It is a non-absorbable polymer that retains water and increases bulk of stools and accelerates transit	Various RCTs showed that PEGs have significantly improved frequency and form of stools when compared to placebo[75]. Cochrane meta-analysis comparing PEG vs Lactulose indicated PEG to be more effective and better tolerated[77]	First line of therapy after fiber for CIC. It is the preferred osmotic laxative. Safe long-term use profile. Useful in patients needing a predictable effect
	lactulose. It is a non-absorbable disaccharide which is hydrolyzed by the colonic bacteria into short-chain fatty acids, which stimulate peristalsis by exerting an osmotic effect and stool acidification	Study showed that patients with FC taking lactulose in combination with PEG exhibited better symptom relief[78]	Use only if PEG is not tolerated by the patient or is unavailable
	Magnesium salts (hydroxide, citrate). They act by stimulating CCK release and exert an osmotic effect, which increases motility	Limited modern-day high-quality trials, but older RCTs demonstrate efficacy	Mainly useful in acute conditions for rapid relief especially in young adults
Stimulant laxatives	Senna (sennosides). Anthraquinone derivatives are converted into active metabolites that stimulate the myenteric plexus and increase peristalsis and secretion	RCT in chronic constipation showed improved stool frequency when compared to placebo[79]	The second line of therapy if osmotic laxatives are inadequate. Good choice for rescue therapy
	Bisacodyl. It is a diphenylmethane derivative that stimulates colonic propulsion and secretion via activation of enteric neural pathways	Studies showed its effectiveness in spontaneous bowel movements and improved stool consistency[80]. FDA-approved trials showed superiority to placebo in both acute and chronic constipation	Effective for short-term use or as a rescue agent. Usually reserved for refractory constipation
Stool softeners	Docusate sodium. It acts as a surfactant and reduces surface tension and allowing water penetration into the stool	Evidence showed limited efficacy. RCTs have indicated that docusate is not superior to psyllium or PEG	Reserved for postoperative use or when straining must be avoided (e.g., anorectal disease), but not recommended for CIC
Serotonergic agonists	Prucalopride. Highly selective 5-HT4 agonist. Stimulates enteric neurons, enhancing acetylcholine release and coordinated colonic peristalsis, thereby accelerating colonic transit and increasing spontaneous bowel movements	Prucalopride 2 mg and 4 mg administered daily significantly increased the proportion of patients achieving ≥ 3 spontaneous complete bowel movements per week compared to placebo[81]. RCTs in the Asia-Pacific region demonstrated Prucalopride 2 mg once daily significantly improved bowel movements and symptoms vs placebo over 12 weeks[82]	Second-line drug with proven efficacy. Especially useful in slow transit constipation and colonic inertia
Secretagogues	Lubiprostone. Chloride channel activator and guanylate cyclase-c agonist. Activates ClC-2 chloride channels on intestinal epithelium and increases chloride-rich fluid secretion; it softens stool and increases transit	RCT reported significant increase in spontaneous bowel movements (SBMs) in week 1 in patients with CIC[83]. Chronic constipation Phase 3 trials showed improved stool consistency and decreased straining	Mainly used as a second agent after failure of fiber/PEG. Indicated for CIC and IBS-C (women)
	Linaclotide. Acts as an agonist of GC-C, increasing cGMP, which activates CFTR, causing increased chloride and bicarbonate secretion leading to increased intestinal fluid and decreased visceral pain	RCTs for CIC showed improved CSBM frequency and stool consistency[84]. Long-term open-label trial showed sustained efficacy	Preferred secretagogue for CIC and IBS-C when OTC measures are not effective. Has strong evidence for pain reduction too
	Plecanatide. It acts as a uroguanylin analog, causing pH-sensitive GC-C activation and increased chloride secretion and motility	RCTs demonstrated increased CBSMs vs placebo, with excellent tolerability in patients with CIC[79]	Second-line therapy for CIC and IBS-C after unsuccessful OTC therapy. Excellent safety profile in older adults
IBAT inhibitor	Elobixibat. Inhibits bile acid absorption in ileum, increasing their delivery to the colon. Enhances colonic fluid secretion and motor activity to accelerate transit and improve spontaneous bowel movements	RCTs demonstrated significant increase in spontaneous bowel movements and improved stool consistency[68,69]	Good modality to treat chronic constipation. Excellent safety profile in elderly, and those with comorbidities

ACG: American College of Gastroenterology; AGA: American Gastroenterological Association; CCK: Cholecystokinin; CFTR: Cystic fibrosis transmembrane conductance regulator; cGMP: Cyclic guanosine monophosphate; CIC: Chronic idiopathic constipation; CSBM: Complete spontaneous bowel movement; FDA: United States Food and Drug Administration; GC-C: Guanylate cyclase-C; IBAT: Ileal bile acid transporter; IBS-C: Irritable bowel syndrome with constipation; NICE: National Institute for Health and Care Excellence; OTC: Over-the-counter; PEG: Polyethylene glycol; RCT: Randomized controlled trial.