Why does Zofran (ondansetron) cause constipation?

From the Guidelines

Zofran (ondansetron) causes constipation primarily because it blocks serotonin receptors in the gut, specifically 5-HT3 receptors, which slows down intestinal motility and leads to decreased peristalsis. This action, while effective in reducing nausea and vomiting, simultaneously affects the digestive tract by preventing serotonin from binding to these receptors, thereby reducing the natural wave-like contractions of the intestines that move stool through the intestines 1. As a result, more time is allowed for water to be absorbed from the stool, making it harder and drier, which leads to constipation.

The mechanism of ondansetron-induced constipation is further supported by studies on other 5-HT3 receptor antagonists, such as alosetron and ramosetron, which are also known to cause constipation as a side effect 1. In contrast, prokinetic drugs that enhance intestinal motility, such as prucalopride, a 5-HT4 receptor agonist, have been shown to improve constipation without the cardiac risks associated with other prokinetic agents 1.

To manage constipation caused by Zofran, patients should stay well-hydrated, maintain physical activity if possible, and consider increasing dietary fiber to help counteract this side effect. If constipation becomes problematic, mild laxatives or stool softeners may be needed while continuing the medication. It is essential to weigh the benefits of Zofran in managing nausea and vomiting against the potential risk of constipation and to consider alternative treatments or management strategies as needed.

Key points to consider:

• Zofran (ondansetron) blocks serotonin receptors in the gut, leading to decreased intestinal motility and constipation.
• Patients taking Zofran should stay hydrated, maintain physical activity, and consider increasing dietary fiber to manage constipation.
• Mild laxatives or stool softeners may be needed if constipation becomes problematic.
• Alternative treatments or management strategies should be considered if constipation persists or is severe.

From the FDA Drug Label

The most common adverse reactions reported in greater than or equal to 4% of 300 adults receiving a single 24-mg dose of ondansetron tablet orally in 2 trials for the prevention of nausea and vomiting associated with highly emetogenic chemotherapy (cisplatin greater than or equal to 50 mg/m2) were: headache (11%) and diarrhea (4%) The most common adverse reactions reported in 4 trials in adults for the prevention of nausea and vomiting associated with moderately emetogenic chemotherapy (primarily cyclophosphamide-based regimens) are shown in Table 3 Table 3: Most Common Adverse Reactions in Adultsa for the Prevention of Nausea and Vomiting Associated With Moderately Emetogenic Chemotherapy [Primarily Cyclophosphamide-based Regimens] Adverse Reaction Ondansetron 8 mg Twice Daily (n = 242) Placebo (n = 262) Headache 58 (24%) 34 (13%) Malaise/Fatigue 32 (13%) 6 (2%) Constipation 22 (9%) 1 (< 1%) Diarrhea 15 (6%) 10 (4%) Prevention of Radiation-Induced Nausea and Vomiting The most common adverse reactions (greater than or equal to 2%) reported in patients receiving ondansetron tablets and concurrent radiotherapy were similar to those reported in patients receiving ondansetron tablets and concurrent chemotherapy and were headache, constipation, and diarrhea

Constipation is a reported adverse reaction of ondansetron, occurring in 9% of patients in clinical trials for the prevention of nausea and vomiting associated with moderately emetogenic chemotherapy, and also reported in patients receiving ondansetron tablets and concurrent radiotherapy 2. In the setting of ondansetron overdose, severe constipation occurred in one patient 2.

• Key points:
  • Ondansetron can cause constipation
  • Constipation is a common adverse reaction, reported in 9% of patients in some clinical trials
  • Severe constipation can occur in the setting of ondansetron overdose

From the Research

Mechanism of Constipation

• Zofran (ondansetron) is a serotonin receptor (5-HT3) antagonist that can cause constipation as a side effect 3, 4.
• The exact mechanism of constipation is not fully understood, but it is thought to be related to the drug's effect on the gastrointestinal tract.
• Ondansetron has been shown to slow colonic transit in healthy volunteers, which can lead to constipation 5.

Effects on Gut Motility

• Studies have shown that ondansetron can reduce the frequency of colonic migrating motor complexes (CMMCs), which can contribute to constipation 6.
• The drug's effect on CMMCs is not mediated by endogenous serotonin in the gut wall, suggesting that other mechanisms may be involved 6.
• Ondansetron has also been shown to improve stool consistency and reduce symptoms of irritable bowel syndrome with diarrhea (IBS-D) 7.

Clinical Evidence

• Clinical trials have reported constipation as a common side effect of ondansetron, with some studies suggesting that it occurs in up to 10% of patients 3, 4.
• The incidence of constipation may be dose-dependent, with higher doses of ondansetron associated with a greater risk of constipation 7.
• Overall, the available evidence suggests that ondansetron can cause constipation in some patients, although the exact mechanisms and incidence of this side effect are not fully understood 3, 5, 7, 6, 4.