What is the preferred treatment option between Prucalopride (prucalopride) and Itopride (itopride) for an adult patient with chronic constipation and potential gastrointestinal (GI) comorbidities such as Gastroesophageal Reflux Disease (GERD) or functional dyspepsia?

Prucalopride vs Itopride for Chronic Constipation and GI Comorbidities

Prucalopride is the strongly preferred treatment option for chronic idiopathic constipation in adults, with robust guideline support and FDA approval, while itopride lacks evidence-based recommendations and regulatory approval for this indication. 1, 2

Evidence-Based Recommendation

Prucalopride: Strong Guideline Support

The 2023 AGA-ACG clinical practice guideline makes a strong recommendation (with moderate certainty evidence) for prucalopride use in adults with chronic idiopathic constipation who do not respond to over-the-counter agents. 1

• Prucalopride is FDA-approved specifically for chronic idiopathic constipation at 2 mg once daily in adults with normal renal function 2
• The 2025 British Society of Gastroenterology guidance acknowledges prucalopride as a recommended option for constipation, though notes its mechanism is upstream from opioid receptors 1
• Can be used as replacement or adjunct to OTC laxatives 1

Itopride: Insufficient Evidence

Itopride has no guideline support for chronic constipation and appears only in low-quality evidence for functional dyspepsia, not constipation. 3

• The single study identified evaluated itopride combined with rabeprazole for functional dyspepsia/NERD, not constipation 3
• No major gastroenterology society guidelines (AGA, ACG, BSG) recommend itopride for constipation management 1
• Itopride is a dopamine D2 antagonist prokinetic, similar to metoclopramide, which the European Medicines Agency recommends against for long-term use due to extrapyramidal side effects and tardive dyskinesia risk 1, 4

Clinical Efficacy Data

Prucalopride Performance

In six randomized controlled trials with 2,484 patients, prucalopride demonstrated significant efficacy with 19-38% responder rates (≥3 complete spontaneous bowel movements per week) versus 10-20% with placebo. 2

• Mean increase of 0.96 complete spontaneous bowel movements per week (95% CI 0.64-1.29) 5
• Responder rates significantly higher (RR 2.37,95% CI 1.97-2.85) 5
• Median time to first bowel movement: 0.1-0.4 days versus 1.0-1.6 days with placebo 2
• Sustained efficacy maintained through 12-24 weeks of treatment 2

Mechanism and Safety Advantages

Prucalopride is a highly selective 5-HT4 receptor agonist that does not interact with cardiac hERG potassium channels, avoiding the QT prolongation and cardiac arrhythmia risks seen with older agents like cisapride and tegaserod. 1, 5

• No significant action on 5-HT1B/D receptors or cardiac potassium channels 5
• No extrapyramidal side effects unlike dopamine antagonists (metoclopramide, domperidone, itopride) 5
• Cardiovascular adverse events not more common than placebo in clinical trials 5

Addressing GI Comorbidities

GERD Considerations

For patients with concurrent GERD, prucalopride may provide additional benefit beyond constipation relief. 6

• Case series data shows prucalopride reduced reflux episodes and improved symptoms in GERD patients with constipation 6
• 5-HT4 receptors in the stomach regulate gastric motility and emptying 7
• The 2002 Gut guidelines recommend full-dose PPI therapy as first-line for epigastric pain/ulcer-like dyspepsia, with prokinetics as an option for dysmotility-like symptoms 1

Functional Dyspepsia/Gastroparesis

Prucalopride demonstrates efficacy for gastroparesis symptoms, providing broader benefit than constipation alone. 8, 9, 10

• Randomized placebo-controlled crossover study showed prucalopride significantly improved Gastroparesis Cardinal Symptom Index (1.65 vs 2.28, P<0.0001) 8
• Gastric half-emptying time significantly enhanced (98 vs 143 minutes with placebo, P=0.005) 8
• Improved quality of life scores and symptoms of fullness/satiety, nausea/vomiting, and bloating 8

Dosing and Safety Profile

Recommended Dosing

Standard adult dose: 2 mg orally once daily; reduce to 1 mg once daily in severe renal impairment (CrCl <30 mL/min). 5, 2

• Can be taken with or without food 2
• No dose adjustment needed based on age 5
• Efficacy in elderly patients (≥65 years) comparable to overall adult population 5

Common Adverse Events

Most common side effects occur during the first week and typically resolve within days: headache (24%), nausea (12%), diarrhea (12%), and abdominal pain (15%). 5, 2

• Diarrhea leading to discontinuation may be higher than placebo (RR 3.00,95% CI 1.89-4.78) 5
• Serious adverse events rare; monitor for unusual mood changes or suicidal ideation 2
• Generally well-tolerated with discontinuation rates approximately 8% versus 4% with placebo 1

Contraindications

Prucalopride is contraindicated in intestinal perforation/obstruction, severe inflammatory bowel disease (Crohn's, ulcerative colitis), and toxic megacolon. 5, 2

Clinical Algorithm

1. Initial assessment: Confirm chronic idiopathic constipation diagnosis (exclude secondary causes, medication-induced constipation) 1, 2

2. First-line therapy: Trial of OTC agents (osmotic laxatives, fiber supplements) 1

3. Inadequate OTC response: Initiate prucalopride 2 mg once daily (1 mg if CrCl <30 mL/min) 1, 5, 2

4. Concurrent GERD: Add full-dose PPI therapy (omeprazole 20 mg daily) for epigastric pain/heartburn 1

5. Concurrent functional dyspepsia: Prucalopride addresses both constipation and dysmotility symptoms 8, 10

6. Evaluate response: Assess at 4 weeks; sustained efficacy demonstrated through 12-24 weeks 5, 2

Critical Pitfalls to Avoid

Do not use itopride for chronic constipation—it lacks evidence, guideline support, and FDA approval for this indication. 3

• Avoid long-term dopamine antagonist prokinetics (metoclopramide, domperidone, itopride) due to extrapyramidal side effects and tardive dyskinesia risk 1, 4
• Do not confuse functional dyspepsia treatment (where prokinetics may have limited role) with chronic constipation management (where prucalopride has strong evidence) 1
• Warn patients about initial side effects (headache, nausea) that typically resolve within days to improve adherence 5
• Screen for contraindications (inflammatory bowel disease, intestinal obstruction) before initiating prucalopride 2