What is the recommended dosage of diphenoxylate?

Diphenoxylate Dosing

For adults with diarrhea, diphenoxylate/atropine (Lomotil) is dosed at 1-2 tablets (2.5-5 mg diphenoxylate) every 6 hours as needed, with a maximum of 8 tablets (20 mg diphenoxylate) per day, though loperamide should be considered as first-line therapy due to superior efficacy and fewer central nervous system side effects. 1

Standard Adult Dosing

• Initial dose: 1-2 tablets (2.5-5 mg diphenoxylate with 0.025-0.05 mg atropine) orally every 6 hours as needed 1
• Maximum daily dose: 8 tablets (20 mg diphenoxylate) per day 1
• This dosing is recommended by NCCN guidelines for palliative care as an alternative antidiarrheal agent for patients not already on opioids 1

Clinical Context and Comparative Efficacy

Diphenoxylate is significantly less effective than loperamide or codeine for chronic diarrhea management. 2 In a double-blind crossover trial:

• Patients required an average of 2.5 capsules (12.5 mg) of diphenoxylate daily for symptom control 2
• While diphenoxylate reduced stool frequency similarly to loperamide (4.6 mg) and codeine (103.5 mg), it was significantly less effective at producing solid stools 2
• Diphenoxylate was less effective at relieving urgency and fecal incontinence compared to loperamide and codeine 2
• Central nervous system side effects were greatest with diphenoxylate and least with loperamide 2

Important Safety Considerations

The recommended dosage should never be exceeded due to addiction potential at high doses. 3

• Diphenoxylate is a Schedule V controlled substance chemically related to meperidine 3
• At therapeutic doses (up to 20 mg/day), diphenoxylate has not produced addiction 3
• However, doses of 100-300 mg/day (equivalent to 40-120 tablets) administered for 40-70 days produced opiate withdrawal symptoms 3
• At high doses, diphenoxylate exhibits codeine-like subjective effects 3

Alternative Therapy Recommendations

Loperamide should be used as first-line therapy instead of diphenoxylate for most patients with diarrhea. 4, 1

• Loperamide dosing: 2 mg orally every 2 hours and 4 mg every 4 hours at night 4
• Loperamide has superior efficacy with fewer problematic central nervous system effects compared to diphenoxylate 1
• For loperamide-refractory diarrhea, octreotide 500 μg three times daily subcutaneously may be considered 4

Pediatric Considerations

No specific pediatric dosing for diphenoxylate is provided in the evidence reviewed. The American Academy of Pediatrics drug formulary does not include diphenoxylate dosing recommendations for children 4, suggesting limited evidence for pediatric use.

Clinical Pitfalls to Avoid

• Do not use diphenoxylate as first-line therapy when loperamide is available and appropriate 1
• Do not exceed the maximum daily dose of 8 tablets (20 mg) due to addiction risk 3
• Avoid in neutropenic patients without careful risk-benefit assessment, as antimotility agents may increase risk of bacteremia and iatrogenic ileus 4
• Ensure infectious causes of diarrhea are excluded before initiating antimotility therapy 4
• Monitor for central nervous system effects (confusion, sedation), which are more common with diphenoxylate than alternatives 2