Is Benadryl Less Constipating Than Zofran?
No, Benadryl (diphenhydramine) is significantly less constipating than Zofran (ondansetron), making it the preferred choice when constipation is a concern. Ondansetron's constipating effect is well-established and clinically significant, while diphenhydramine's anticholinergic properties cause different side effects but not typically constipation.
Ondansetron's Constipation Profile
Constipation is one of the most common and clinically significant side effects of ondansetron, documented across multiple clinical contexts:
- The British Society of Gastroenterology explicitly states that 5-HT3 antagonists like ondansetron "can result in constipation" when used for vomiting management 1
- The American Gastroenterological Association confirms that "constipation is a common side effect" when ondansetron is used for irritable bowel syndrome with diarrhea 2
- In chemotherapy patients, constipation was reported as one of the two most frequent adverse events (along with headache) in multiple large trials 3, 4
- Oral ondansetron administered three times daily resulted in constipation in 7% of patients in controlled trials 5
The mechanism is pharmacologically predictable: Ondansetron blocks 5-HT3 receptors in the gut, which slows gastrointestinal transit and reduces intestinal fluid secretion. This is the same mechanism that makes it useful for diarrhea-predominant conditions but problematic when constipation is already a concern 1.
Diphenhydramine's Side Effect Profile
Diphenhydramine does not cause constipation as a primary side effect, though its anticholinergic properties produce a different adverse event profile:
- The American Gastroenterological Association lists diphenhydramine's adverse effects as "hypotension, dizziness, blurred vision, dry mouth, epigastric discomfort, urinary retention, and wheezing" - notably absent is constipation 1
- Diphenhydramine has anticholinergic effects that theoretically could slow gut motility, but this is not clinically significant enough to be listed among its common adverse effects 1
- When used as an adjunct for sedation during colonoscopy, diphenhydramine improved patient comfort without reports of constipation 1
Clinical Decision-Making Algorithm
When choosing between these agents for nausea/vomiting:
If the patient has existing constipation or is at high risk (opioid use, immobility, dehydration): Choose diphenhydramine 25-50 mg IV/PO over ondansetron 1
If the patient has diarrhea or needs potent antiemetic effect: Ondansetron is more effective for chemotherapy-induced and postoperative nausea/vomiting, but accept the constipation risk 6, 7
If sedation is acceptable or desirable: Diphenhydramine's sedative properties may be beneficial, whereas ondansetron does not cause sedation 1, 7
If the patient needs to remain alert: Ondansetron is preferred despite constipation risk, as diphenhydramine causes significant sedation 7
Important Caveats
Diphenhydramine is not as potent an antiemetic as ondansetron - it functions primarily as an adjunct rather than first-line therapy for severe nausea 1. In emergency department settings, ondansetron is recommended as first-line due to superior efficacy and lack of sedation or akathisia, despite the constipation risk 7.
Both drugs have anticholinergic effects, but they manifest differently: diphenhydramine causes dry mouth, urinary retention, and blurred vision, while ondansetron's primary GI effect is constipation through 5-HT3 receptor blockade 1.
Never combine ondansetron with other QT-prolonging agents like domperidone, as this creates additive cardiac toxicity risk 8. This is unrelated to constipation but critical for safety.