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A prospective, randomized, double-blind clinical trial.To compare the effect of ramosetron with that of ondansetron on opioid-based IV patient-controlled analgesia (PCA) related postoperative nausea and vomiting (PONV) in highly susceptible patients after lumbar spine surgery.Optimal postoperative pain management is important to facilitate early mobilization after lumbar spine surgery. Opioid analgesia is associated with a high incidence of PONV. Among the currently available 5-hydroxytryptamine receptor 3 antagonists (5-HT3), ondansetron is being most widely used with unsatisfactory results regarding opioid-based IV PCA related PONV. Ramosetron is a newly developed 5-HT3 antagonist with higher receptor affinity and longer duration of action having theoretical advantage over ondansetron in this setting. However, data to support this view are lacking.All 94 female nonsmoker patients (aged 18–65 years) were randomly allocated into either ondansetron group (group O, n = 47) or ramosetron group (group R, n = 47). Fentanyl-based IV PCA was administered for 48 hours after surgery. Overall incidence and severity of nausea and incidence of vomiting were assessed for 48 hours after surgery. Secondary measures included: pain intensity and total amount of administered rescue analgesic.Patients’ characteristics were similar between the groups. Overall incidence of nausea was similar between the groups; however, moderate to severe degree of nausea was significantly more in the group O (34%) than in the group R (13%) 6 to 24 hours after surgery. Overall incidence of vomiting and use of rescue antiemetic 6 to 24 hours after surgery was significantly lower in the group R (30% vs. 11% and 28% vs. 11%, respectively). Pain scores at 24 to 48 hours after surgery were significantly lower in the group R (31 ± 25 vs. 13 ± 15).Ramosetron was superior to ondansetron in terms of preventing vomiting and reducing the severity of nausea related to fentanyl-based IV PCA, with less adverse events, in patients with high susceptibility, undergoing lumbar spine surgery.