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

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.