What is the role of racecadotril in treating diarrhea?

Racecadotril in Diarrhea Management

Racecadotril reduces stool volume and duration of diarrhea but is not routinely recommended due to limited availability in North America and lack of evaluation in key clinical contexts, particularly travelers' diarrhea, where loperamide remains the preferred antimotility agent. 1

Mechanism and Efficacy

Racecadotril is an oral enkephalinase inhibitor that prevents degradation of endogenous opioids (enkephalins), thereby reducing hypersecretion of water and electrolytes into the intestinal lumen without affecting intestinal motility. 2

In pediatric acute gastroenteritis:

• Reduces 48-hour stool output by approximately 46% compared to placebo (92 g/kg vs 170 g/kg, p<0.001) when added to oral rehydration therapy 3
• Decreases median duration of diarrhea from 72 hours to 28 hours 3
• Meta-analysis of 1,384 children showed hazard ratio for recovery of 2.04 (95% CI 1.85-2.32, p<0.001) 4
• However, a 2019 Cochrane review concluded that racecadotril has little benefit in improving acute diarrhea in children under five and does not support routine use outside placebo-controlled trials 5

Geographic Availability and Guideline Support

Critical limitation: Racecadotril is not available in North America, which significantly limits its clinical utility in these regions. 1

Guideline positioning:

• The Infectious Diseases Society of America (2017) acknowledges racecadotril reduces stool volume but notes its unavailability in North America 1
• The Journal of Travel Medicine guidelines (2017) recognize racecadotril "may have a role" but explicitly state it has not been evaluated in travelers' diarrhea, the most common indication for antimotility agents 1
• ESMO guidelines (2018) recommend racecadotril for Grade 1 immunotherapy-induced diarrhea as an alternative to loperamide 1

Clinical Context Where Racecadotril May Be Considered

Cancer treatment-induced diarrhea:

• Grade 1 immunotherapy-induced diarrhea: racecadotril or loperamide with oral rehydration (Level III, Grade A recommendation) 1
• Prophylactic racecadotril (100 mg three times daily for 15 days) concurrent with CPT-11 chemotherapy failed to demonstrate benefit compared to placebo 1

Pediatric acute gastroenteritis (in regions where available):

• May reduce emergency department revisits and stool frequency in the first 48 hours 6
• Effective regardless of rotavirus status, dehydration level, or inpatient/outpatient setting 4
• Better tolerated than loperamide with significantly less post-diarrheal constipation 2

Comparison with Loperamide

Loperamide is preferred over racecadotril because:

• Stronger evidence base with evaluation in travelers' diarrhea (the most common indication) 1
• FDA approval and widespread availability 7
• Strong guideline support from multiple societies for both mild and moderate-to-severe diarrhea 7
• Head-to-head trials show similar efficacy to racecadotril but with more robust clinical trial data 2

Racecadotril advantages:

• Does not affect intestinal motility, theoretically safer in inflammatory conditions 2
• Less rebound constipation after diarrhea resolution 2
• Similar tolerability profile to placebo 2

Dosing (When Available)

• Adults: 100 mg three times daily 1
• Children: 1.5 mg/kg orally every 8 hours 3

Key Contraindications and Cautions

Avoid racecadotril in:

• Bloody diarrhea or high fever (use same precautions as loperamide) 7
• Children under 18 years in North America (where loperamide is also contraindicated) 1, 7
• Before adequate hydration is established 7

Clinical Algorithm for Antimotility Agent Selection

1. First, ensure adequate hydration - this is non-negotiable before any antimotility agent 1, 7

2. Screen for contraindications:

   • Fever >38.5°C, bloody stools, severe abdominal pain → no antimotility agents 7
   • Age <18 years → no antimotility agents in acute infectious diarrhea 1, 7

3. If in North America or treating travelers' diarrhea:

   • Use loperamide (4 mg initial dose, then 2 mg after each loose stool, maximum 16 mg/day) 1, 7

4. If in regions where racecadotril is available:

   • For cancer treatment-induced diarrhea (Grade 1): racecadotril is an acceptable alternative to loperamide 1
   • For pediatric gastroenteritis: racecadotril may reduce stool output but Cochrane review does not support routine use 5
   • For adult acute watery diarrhea: loperamide remains preferred due to stronger evidence base 1, 7

Common Pitfalls

• Do not use racecadotril as first-line in travelers' diarrhea - it lacks evaluation in this context and loperamide has strong evidence 1
• Do not assume racecadotril is safer than loperamide in inflammatory diarrhea - both should be avoided when fever or bloody stools are present 7
• Do not use racecadotril prophylactically for chemotherapy-induced diarrhea - this approach failed in clinical trials 1