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

Table 1 Classification and etiologies of constipation

Category	Subtype	Causes	Key features
Primary (functional) constipation	Normal-transit constipation	Associated with irritable bowel syndrome-constipation predominant, stress, and visceral hypersensitivity. Low fiber and fluid intake. Sedentary lifestyle	Normal colonic transit time, but patient feels constipated due to perceived difficulty. Reduced bulk of stool. Weaker colonic stimulation. Dry stools
	Slow-transit constipation	Colonic neuropathy. Colonic myopathy. Possible association with eating disorders. Altered serotonin levels	Delayed colonic transit time due to impaired colonic motility. Predominant in young women. Reduced high-amplitude propagated contractions
	Defecatory disorders (pelvic floor dysfunction/outlet obstruction)	Dyssynergic defecation (inappropriate pelvic floor contraction). Impaired rectal propulsive forces. Obstructed defecation syndrome. Structural abnormalities (rectocele, rectal prolapse, excessive perineal descent)	Failure of anorectal coordination. Difficult or blocked evacuation
Secondary (organic) constipation	Systemic/metabolic/endocrine	Diabetes mellitus. Dehydration. Amyloidosis. Uremia. Chronic kidney disease. Pregnancy. Hypercalcemia. Hypokalemia. Hypothyroidism	Systemic or metabolic slowing of the GI tract
	Neurologic	Parkinson’s disease. Multiple sclerosis. Spinal cord injury. Stroke. Hirschsprung disease. Autonomic neuropathies	Due to impaired neural control of bowel movements and defecation
	Structural/mechanical	Colonic strictures (ischemia, radiation induced, inflammatory). Colorectal cancer. Anal fissures (pain leading to stool retention). Megacolon	Mechanical obstruction or pain-related stool withholding
	Medication-induced	Opioids. Anticholinergics (TCAs, antihistamines). Calcium channel blockers. Iron supplements. Calcium or aluminum containing antacids. Antipsychotics/anticonvulsants (gabapentin, pregabalin). Diuretics (due to dehydration)	Common and most important cause. Due to motility or increased water absorption of water or reduced secretions

GI: Gastrointestinal; TCA: Tricyclic antidepressant.

Table 2 Rome IV diagnostic criteria for functional constipation (diagnosis requires the presence of at least two or more of six symptoms in criteria 1 for the last 3 months, with symptom onset at least 6 months prior to diagnosis)

No.	Criterion
1	Must include two or more of the following: (1) Straining during > 25% of defecations; (2) Lumpy or hard stools > 25% of defecations (Bristol Stool Form Scale 1 or 2); (3) Sensation of incomplete evacuation > 25% of defecations; (4) Sensation of anorectal obstruction/blockage > 25% of defecations; (5) Manual maneuvers to facilitate > 25% of defecations (digital evacuation, support of the pelvic floor); and (6) Fewer than three spontaneous bowel movements per week
2	Loose stools are rarely present without the use of laxatives
3	Insufficient criteria for irritable bowel syndrome

Table 3 Alarm symptoms in patients with constipation

Symptoms
Unintentional weight loss (more than 10% in 3 months)
Blood in stools
Family history of colorectal cancer or inflammatory bowel disease
New-onset symptoms after 50 years of age
Rectal tenesmus
Iron deficiency anemia
Jaundice
Cachexia
Positive fecal occult blood test

Table 4 History and assessment in patients with constipation

Diagnostic tool	Technique	Utility	Limitations
History and physical examination (including DRE)	Detailed bowel history, which includes frequency, stool form (Bristol chart), straining, sensation of blockage, and incomplete evacuation. Review of fluid, dietary intake, and activity. History of medication use. History of comorbidities (thyroid disease, diabetes, neurologic disorders. Digital rectal examination-Assess the anal tone, voluntary squeeze, pelvic floor relaxation during simulated defecation, and for the presence of stool, hemorrhoids, rectocele[8]	Used to identify secondary causes. DRE can strongly indicate dyssynergic defecation by detecting paradoxical anal sphincter contraction and inadequate pelvic floor contraction[34]. Identifies fecal retention or impaction, anorectal fissures, strictures, masses, or pain-avoidant behavior	It is a highly subjective tool. Dependent on the clinician’s expertise. DRE has low sensitivity for subtle pelvic floor lesions[26]. Cannot diagnose slow-transit constipation. Cannot identify structural lesions higher in the colon
Laboratory evaluation	Blood tests like CBC, TSH, serum calcium, glucose, electrolytes, serum creatinine, etc.[25,34]	Used to identify endocrine or metabolic causes of constipation[8]. It also helps to rule out systemic disease mimicking constipation	Cannot identify the type of constipation (e.g., slow transit vs pelvic floor dysfunction)[27]
Colonoscopy and sigmoidoscopy	Endoscopic evaluation of colonic mucosa with the ability to biopsy[32]	Very useful tool in the presence of alarm symptoms like bleeding per rectum, anemia, weight loss, age > 50 with new onset symptoms, and family history of colorectal cancer[31]. Used to detect neoplasia (polyps, colorectal cancer), strictures, IBD, and solitary rectal ulcer syndrome[31]	Cannot diagnose functional constipation. Normal in most cases of chronic idiopathic constipation[26]. Invasive procedure. Requires patient preparation
Radiographic imaging	Plain abdominal X-ray (KUB)-simple supine radiograph[34]	Detects colonic dilation, megacolon, fecal loading or obstruction[31]	Correlates poorly with the severity of symptoms. Adds limited diagnostic value[26]. Cannot differentiate motility disorders
	CT abdomen/CT colonography-Imaging with contrast (IV or oral) or air insufflation for colonography[8]	Used to identify mechanical obstruction, tumors, volvulus, and strictures[8]. Helpful in identifying complications of constipation, stercoral colitis, and perforation	Radiation exposure. Cannot be used to diagnose functional constipation[26]. Cannot give information about motility
Colonic transit studies	Radiopaque marker test[35]. Patient ingests capsules containing makers. Abdominal X-rays are taken on day 3 and day 5. Distribution pattern is analyzed for segmental or global delay	Gold standard for diagnosing slow transit constipation[8]. Helps to distinguish between normal transit, colonic inertia (severe delay) and segmental delay (often left colon). Helps to distinguish slow transit constipation from pelvic floor dyssynergia	Requires multiple visits over days. Radiation exposure. Does not assess pelvic floor coordination directly. Interpretation requires experience[26]
	Scintigraphic colonic transit studies[35]. Patient eats a radiolabeled meal, and serial gamma camera images track transit through the GI tract	Provides more detailed regional motility mapping. Measures gastric, small bowel, and colonic transit	Costly and limited availability. Radiation exposure
	Wireless motility capsule (smart pill). Patient swallows a capsule that records pH, temperature, and pressure of the tract as it moves. Data are transmitted to the external receiver	Measures segmental transit times-gastric emptying time, small bowel transit, colonic transit. Useful in suspected cases of generalized dysmotility. Can distinguish between global motility disorders and isolated constipation	Expensive. Should not be used if there are strictures or obstructions. Limited availability. Cannot assess pelvic floor mechanics
Anorectal function studies	Anorectal manometry[36]. A high-resolution catheter is inserted into the rectum, which measures resting and squeeze pressures, recto anal inhibitory reflex, rectal compliance, and simulated defecation dynamics	Primary diagnostic tool for dyssynergic dysfunction[38]. Helps to detect paradoxical anal sphincter contraction, inadequate propulsive forces, and sensory deficits. Helps in tailoring biofeedback therapy	Cannot identify structural abnormalities like rectocele, prolapse, etc. Not standardized[38]. Cannot measure transit. Requires experienced and trained personnel
	Balloon expulsion test. Balloon filled with water in rectum and patient attempts to expel it in less than 1-2 minutes	A simple screening test for outlet obstruction. Highly specific when abnormal	Not sensitive. Normal result doesn’t exclude dyssynergia[40]. Does not distinguish the exact type of pelvic floor disorder
	Defecography[40]. Contrast paste is inserted into the rectum, and patient tries to defecate under fluoroscopy	It can be used to visualize structural abnormalities, such as rectocele, internal intussusception, external prolapse, megarectum, and perineal descent	Radiation exposure. Does not evaluate physiology. Very uncomfortable procedure
	MRI defecography. Gel is inserted into rectum and pelvic MRI is performed during rest, squeeze, and defecation phases	It has better soft tissue resolution. Helps in detecting pelvic floor dyssynergia, multi-compartment organ prolapses, and rectocele[41]. No radiation exposure	Expensive. Limited availability. Difficult for patients to defecate in an MRI environment
Endoanal ultrasound	A high-frequency probe is inserted into anal canal[42]	Can identify sphincter defects. Helpful in identifying postpartum sphincter injury or suspected trauma	Not useful for most cases of constipation. Provides very little functional information
Rectal biopsy	Suction or full-thickness biopsy to identify ganglion cells	Definitive diagnostic tool for Hirschsprung disease[43]. Can also identify chronic intestinal pseudo-obstruction with neuropathic or myopathic features	Invasive. Not usually indicated in adults unless there is severe and unexplained megacolon
Psychosocial and behavioral assessment	Evaluate for anxiety, depression, eating disorders, trauma, and abuse history[44]	Can be useful to identify behavioral contributors to constipation[44]. Important tool of assessment in IBS-C and functional GI disorders	It is a very subjective tool. Cannot diagnose primary motility disorders. Requires patient cooperation

CBC: Complete blood count; CT: Computed tomography; DRE: Digital rectal examination; GI: Gastrointestinal; IBD: Inflammatory bowel disease; IBS-C: Irritable bowel syndrome with constipation; KUB: Kidneys, ureters, and bladder (plain abdominal radiograph); MRI: Magnetic resonance imaging; TSH: Thyroid-stimulating hormone.

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.

Table 6 Methodological challenges in constipation research and treatment

Domain	Methodological challenges
Heterogeneity of constipation phenotypes	Many studies fail to categorize participants by subtype, leading to heterogeneous study populations, weak treatment effects, and difficulty in comparing trials
Diagnostic heterogeneity	ROME IV criteria exclude patients with abdominal discomfort (not pain) from the IBS-C category, leading to internal shift of patients from the IBS-C category to FC category. Variable classification in different studies leads to conflict in inclusion criteria, variability in symptom severity, and confounded treatment outcomes
Excess reliability on subjective symptom reporting	Difficult to standardize across various populations
Lack of universal biomarkers for identifying colonic motility patterns, pelvic floor dyssynergia, gut sensory abnormalities, and neuroenteric dysfunction	Hinders objective diagnosis and classification
Variance in diagnostic tools across centers	Limits comparability across different studies and complicates meta-analysis
Variability in outcome measures across trials	Rapidly evolving endpoints make historical comparisons difficult
Placebo response is high, as constipation trials often show 25%-40% placebo response for CSBM improvements	Needs larger sample sizes to demonstrate drug efficacy and complicates understandability
Short duration of many trials	Constipation is usually a chronic condition, but most of the trials are conducted for few months only. Long-term efficacy, tolerance, and safety remain uncertain in many therapies
Underrepresentation of special populations like children, elderly, pregnant women, and patients with neurological disabilities	Limits generalizability
Difficulty differentiating cause and consequence	Domination of cross-sectional designs; only a few longitudinal studies exist
Cross-cultural differences in symptom interpretation	Affects global trial reproducibility
Regulatory differences across different regions. FDA, EMA, and Asian regulatory agencies require different endpoints, PRO instruments, and trial durations	Development of new drugs must navigate through incoherent methodological standards
Limited integration of multidimensional techniques. Optimal study design requires combining motility testing, sensory testing, neuroimaging, microbiome analysis, and psychological assessment	Limited mechanistic depth as most clinical trials tend to use only one or two modalities

CSBM: Complete spontaneous bowel movement; EMA: European Medicines Agency; FC: Functional constipation; FDA: Food and Drug Administration; IBS-C: Irritable bowel syndrome with constipation; PRO: Patient-reported outcome; ROME IV: Rome IV diagnostic criteria for functional gastrointestinal disorders.