The Journal of International Medical Research 2011; 39:

The Journal of International Medical Research 2011; 39: 399 407 A Randomized, Double-blind Trial of Palonosetron Compared with Ondansetron in Preventing Postoperative Nausea and Vomiting after Gynaecological Laparoscopic Surgery SK PARK AND EJ CHO Department of Anaesthesiology and Pain Medicine, Incheon St Mary s Hospital, College of Medicine, The Catholic University of Korea, Incheon, Republic of Korea This randomized, double-blind study evaluated the relative efficacy of palonosetron (a new, selective 5- hydroxytryptamine type 3 [5-HT 3 ] receptor antagonist) and ondansetron in preventing postoperative nausea and vomiting (PONV) in patients undergoing gynaecological laparoscopic surgery. Patients received either palonosetron 0.075 mg (n = 45) or ondansetron 8 mg (n = 45), intravenously, immediately before induction of general anaesthesia. The occurrence of nausea and vomiting and the severity of nausea according to a visual analogue scale were monitored immediately after the end of surgery and during the following 24 h. The incidence of PONV was significantly lower in the palonosetron group compared with the ondansetron group (42.2% vs 66.7%, respectively). There were no significant statistical differences in the visual analogue scale for nausea. In conclusion, palonosetron 0.075 mg was more effective than ondansetron 8 mg in preventing PONV. KEY WORDS: PALONOSETRON; ONDANSETRON; 5-HT 3 RECEPTOR ANTAGONIST; POSTOPERATIVE NAUSEA AND VOMITING (PONV); GYNAECOLOGICAL LAPAROSCOPIC SURGERY Introduction Postoperative nausea and vomiting (PONV) is the most common complication of surgery and anaesthesia, 1 leading to adverse consequences including patient dissatisfaction, unexpected hospital admission, and delayed recovery and return to work. 2 PONV is less commonly associated with more serious postsurgical complications such as wound dehiscence and surgical site bleeding. 3 The incidence of PONV can reach 80% in high-risk patients, underlining the importance of prevention and control by anaesthetists. 4 The 5-hydroxytryptamine-3 (5-HT 3 ) receptor antagonists are popular drugs for PONV prophylaxis because of their similar efficacy to droperidol or dexamethasone and their favourable side-effect profile. 2 Palonosetron is a new, potent, selective 5-HT 3 399

receptor antagonist with a strong receptorbinding affinity and a long elimination halflife and, therefore, a long duration of efficacy. 5,6 A study evaluating the efficacy and safety of palonosetron in preventing PONV found that a single 0.075 mg intravenous (i.v.) dose significantly decreased emetic episodes, nausea severity and rescuemedication use during the first 24 h after anaesthesia, in patients undergoing abdominal or gynaecological laparoscopic surgery. 7 It was also reported that palonosetron is as effective as ondansetron in preventing chemotherapy-induced nausea and vomiting following highly emetogenic chemotherapy, 8 although no study has evaluated the relative efficacy of palonosetron and ondansetron in preventing PONV. The present randomized, double-blind study was designed to evaluate the efficacy of palonosetron compared with ondansetron for preventing PONV in patients undergoing laparoscopic gynaecological surgery. Patients and methods PATIENTS Patients who were 21 years old, with American Society of Anesthesiologists physical status 1 or 2, 9 who were scheduled to undergo elective laparoscopic gynaecological surgery of > 1 h duration at Incheon St Mary s Hospital, Incheon, Republic of Korea, between June and September 2010, were randomly enrolled into the study. All the patients enrolled were female and used opioids to control post-operative pain, hence they had at least two risk factors for PONV. Patients were excluded from the study if they had received antiemetics, steroids or psychoactive medications within 24 h of study initiation. Patients with vomiting or retching in the 24 h preceding surgery, those who had received cancer chemotherapy within 4 weeks or emetogenic radiotherapy within 8 weeks before study entry, and patients with ongoing vomiting from gastrointestinal disease were excluded. Study approval was obtained from the Institutional Review Board of Incheon St Mary s Hospital, and all patients provided written informed consent before enrolment. STUDY DESIGN AND TREATMENT Patients were randomized to receive either palonosetron 0.075 mg or ondansetron 8 mg, administered by i.v. injection. Trained nurses who did not participate in the study prepared the drugs according to manufacturers instructions and placed them in numbered, sealed envelopes assigned by computergenerated random numbers. No patient received preanaesthetic medication. Palonosetron 0.075 mg was administered in a single i.v. dose, with saline solution added to bring the total volume to 4 ml, immediately before induction of anaesthesia to subjects in the palonosetron group. Subjects in the ondansetron group received ondansetron 8 mg in a single i.v. dose as a 4 ml bolus, immediately before induction of anaesthesia. Standard anaesthetic regimens were used for all patients. Anaesthesia was induced with propofol 2 mg/kg and tracheal intubation was facilitated with rocuronium 0.6 mg/kg. Anaesthesia was maintained with 50% nitrous oxide in oxygen and 1 4% sevoflurane. At the completion of surgery, patients received pyridostigmine 0.2 mg/kg and glycopyrrolate 0.008 mg/kg, for reversal of neuromuscular blockade. For postoperative pain control, a patientcontrolled anaesthesia device was used to deliver a fentanyl 4 µg bolus with 16 µg/h as background infusion; there was a 15-min lockout time. PATIENT MONITORING The occurrence of nausea and vomiting, the 400

severity of nausea according to a visual analogue scale (VAS; 0, no nausea; 10, worst nausea) and rescue antiemetic drug use were monitored immediately after the end of surgery and at 0 2 h, 2 6 h and 6 24 h postsurgery. Nausea was defined as a subjectively unpleasant sensation associated with awareness of the urge to vomit, whereas an episode of vomiting was defined as vomiting (forceful expulsion of gastric contents from the mouth) or retching (laboured, spasmodic, rhythmic contractions of the respiratory muscles without expulsion of gastric contents). 1 Metoclopramide (10 mg i.v.) was permitted as a rescue antiemetic when two episodes of PONV occurred or at VAS > 5 and the patient requested treatment. If metoclopramide treatment was ineffective, ondansetron 4 mg i.v. was permitted. A complete response was defined as the absence of PONV and no use of rescue antiemetics. Details of any adverse effects (including headaches, dizziness, constipation and myalgia) were recorded. Patients were also asked to rate their overall satisfaction on a three-point scale (satisfied, neutral, dissatisfied) 24 h after surgery completion. The primary outcome measure of this study was the incidence of nausea and vomiting during the first 24 h after anaesthesia. Secondary outcome measures were the severity of nausea, need for rescue medication, patient satisfaction and incidence of adverse effects. STATISTICAL ANALYSES Sample size was calculated by a power analysis while designing the study: allowing an α-error of 5% and a β-error of 20%, it was estimated that a minimum of 42 patients per group would be required to show a 30% difference in the incidence of PONV. 7,10 All statistical analyses were performed using SPSS statistical package, version 17.0 (SPSS Inc., Chicago, IL, USA) for Windows. The Student s t-test was used to compare intergroup differences and the χ 2 or Fisher s exact tests were used for categorical variables. The P-values were corrected by the Bonferroni method and a P-value < 0.05 was regarded as statistically significant. Results In total, 90 patients were recruited, all of whom completed the study. There were no statistically significant differences between palonosetron- and ondansetron-treated groups in terms of patient characteristics, PONV risk factors or operative data (Table 1). The incidence of PONV and nausea (not vomiting) was significantly lower in the palonosetron group than in the ondansetron group during the overall 0 24 h time interval (P < 0.05, Table 2). More patients in the palonosetron group had a complete response (no PONV and no rescue antiemetic) compared with the ondansetron group (Fig. 1); this difference was statistically significant for the 0 24 h time interval (P < 0.05). The severity of nausea (VAS), need for rescue antiemetics, incidence of adverse effects and patient satisfaction ratings were not significantly different between the two groups (Table 3). Discussion A significant proportion of patients experience PONV despite the widespread use of prophylactic antiemetics, including 5-HT 3 receptor antagonists. 11 Ondansetron was the first 5-HT 3 receptor antagonist to be marketed and has frequently been used to control PONV. 12 Palonosetron a secondgeneration 5-HT 3 antagonist has unique structural, pharmacological and clinical properties that distinguish it from other 5- HT 3 antagonists. 2 This is the first study to 401

TABLE 1: Baseline demographic data and clinical characteristics for patients undergoing laparoscopic gynaecological surgery who received ondansetron 8 mg or palonosetron 0.075 mg, intravenously, before anaesthesia Ondansetron group Palonosetron group (n = 45) (n = 45) Age (years) 42.8 ± 7.3 42.4 ± 10.0 Weight (kg) 55.3 ± 7.3 56.9 ± 7.8 Height (cm) 157.6 ± 5.5 158.3 ± 6.2 ASA PS 1 37 (82.2) 40 (88.9) 2 8 (17.8) 5 (11.1) Risk factors PONV history and/or motion sickness 19 (42.2) 20 (44.4) Non-smoker 43 (95.6) 39 (86.7) Type of surgery Laparoscopic ovarian cystectomy 18 (40.0) 17 (37.8) Laparoscopic hysterectomy 27 (60.0) 28 (62.2) Duration of surgery (min) 108.6 ± 45.2 103.3 ± 35.3 Duration of anaesthesia (min) 137.1 ± 48.2 130.4 ± 35.2 Data presented as mean ± SD or n (%) of patients. No statistically significant between-group differences (P > 0.05); Student s t-test and Fisher s exact test. ASA PS, American Society of Anesthesiologists physical status; PONV, postoperative nausea and vomiting. compare palonosetron with ondansetron for PONV. Kovac et al. 7 found that 0.075 mg palonosetron significantly reduced PONV in the first 24 h after anaesthesia, compared with placebo. In addition, Paventi et al. 13 compared the efficacy of 4 mg versus 8 mg ondansetron for the prevention of PONV after laparoscopic cholecystectomy and concluded that 8 mg was more effective than 4 mg. The doses of drugs used in the present study were based on the optimal dose for prophylaxis of PONV in these previous studies; thus, 0.075 mg palonosetron and 8 mg ondansetron were chosen. Some investigators have shown that a single i.v. dose of palonosetron 0.25 mg is as safe and effective as ondansetron 32 mg in preventing chemotherapy-induced nausea and vomiting (CINV). 14 The aetiology of CINV, however, primarily involves a large release of serotonin from the enterochromaffin cells in the small intestine in response to chemotherapeutic drugs, 2 whereas the pathophysiology of PONV is more complex and has been suggested to be of multifactorial origin. 15 The incidence of PONV may be associated with many factors including: age and gender (female gender and younger age in adulthood increase the risk of PONV); prior history of motion sickness or PONV; smoking status (smoking decreases the risk of PONV); postoperative opioid use; type and duration of surgery; anaesthesia and ambulation. 1,16,17 These factors were wellbalanced between both treatment groups in the present study. In the present study, palonosteron 0.075 mg was more effective at reducing PONV than ondansetron 8 mg. This could reflect the high receptor affinity of palonosetron for 5-HT 3, with a low affinity demonstrated for other receptors including 5-HT 1A, 5-HT 1D, 5-HT 2A 402

TABLE 2: Incidence of post-operative nausea and vomiting (PONV), need for rescue antiemetics, and severity of PONV in patients undergoing laparoscopic gynaecological surgery who received ondansetron 8 mg or palonosetron 0.075 mg, intravenously, before anaesthesia Ondansetron group Palonosetron group (n = 45) (n = 45) 0 2 h Nausea 12 (26.7) 4 (8.9) Vomiting 0 (0) 3 (6.7) Overall PONV 12 (26.7) 7 (15.6) VAS 1.5 ± 2.7 1.0 ± 2.8 2 6 h Nausea 10 (22.2) 5 (11.1) Vomiting 3 (6.7) 2 (4.4) Overall PONV 13 (28.9) 7 (15.6) VAS 2.2 ± 4.3 2.1 ± 3.1 6 24 h Nausea 15 (33.3) 9 (20.0) Vomiting 6 (13.3) 4 (8.9) Overall PONV 21 (46.7) 13 (28.9) VAS 3.4 ± 4.9 3.4 ± 4.5 0 24 h Nausea 27 (60.0) 15 (33.3)* Vomiting 7 (15.6) 8 (17.8) Overall PONV 30 (66.7) 19 (42.2)* VAS 4.5 ± 4.9 4.1 ± 4.9 Rescue antiemetics 7 (15.6) 8 (17.8) Data presented as mean ± SD or n (%) of patients. *P < 0.05 for the palonosetron group compared with ondansetron group; Student s t-test and Fisher s exact test. VAS, visual analogue scale for severity of nausea: 0, no nausea; 10, worst nausea. and 5-HT 2C, and the longer duration of action. 5,18 Although palonosetron was superior to ondansetron in reducing overall PONV, the incidence of vomiting was slightly higher (though not statistically significant) in the palonosetron group than in the ondansetron group, possibly due to the stronger antivomiting (rather than antinausea) effect of ondansetron. 19 Ondansetron is significantly superior to metoclopramide and droperidol for the prevention of vomiting, 20 but whether this antiemetic effect is stronger than that of palonosetron is unknown. Several receptor types including serotonin 5-HT 3, dopamine D 2, histamine H 2, α 2 -adrenergic, muscarinic cholinergic, neurokinin 1 and GABA are involved in the initiation and co-ordination of the vomiting reflex in patients with PONV. 15,20 It is possible that palonosetron is less effective than ondansetron at reducing the incidence of vomiting due to the weak binding affinity of ondansetron to 5-HT 1B, 5- HT 1C, α-adrenergic and µ-opioid receptors, 21 although further studies are needed to clarify this issue. The severity of nausea and need for additional rescue antiemetics were not different between the two groups in the present study. The present study showed that patients at moderate or high risk of PONV i.e. who had at least two risk factors for PONV were still 403

100 Ondansetron Palonosetron Patients with complete response (%) 80 60 40 20 * 0 0 2 2 6 6 24 0 24 Time intervals (h) FIGURE 1: Complete responses (no postoperative nausea and vomiting, no requirement for rescue antiemetic) in patients who underwent laparoscopic gynaecological surgery and received ondansetron 8 mg or palonosetron 0.075 mg intravenously, before anaesthesia (*P < 0.05 compared with ondansetron group) TABLE 3: Incidence of adverse events and patient satisfaction in patients undergoing laparoscopic gynaecological surgery who received ondansetron 8 mg or palonosetron 0.075 mg, intravenously, before anaesthesia Ondansetron group Palonosetron group (n = 45) (n = 45) Adverse event Headache 4 (8.9) 3 (6.7) Dizziness 5 (11.1) 5 (11.1) Constipation 2 (4.4) 3 (6.7) Myalgia 0 (0) 1 (2.2) Patient satisfaction Satisfied 21 (46.7) 30 (66.7) Neutral 17 (37.8) 9 (20.0) Dissatisfied 7 (15.6) 6 (13.3) Data presented as n (%) of patients. No statistically significant between-group differences (P > 0.05); χ 2 -test. at high risk for PONV after prophylactic treatment with ondansetron or palonosetron. Thus, patients at moderate or high risk of PONV 4,22 should receive multimodal prophylaxis. 23,24 The potential advantages of combination therapy using drugs that act on 404

different pathways in the emetic response include improved efficacy, extended duration of the antiemetic effect, ability to combine drugs with greater antinausea versus greater antiemetic effects and the possibility of using smaller doses of individual drugs compared with monotherapies. 25 In a previous study, a combination of granisetron 3 mg and droperidol 1.25 mg was more effective in the prevention of PONV than either antiemetic alone. 26 Another study found that ondansetron 4 mg plus dexamethasone 8 mg was more effective than ondansetron monotherapy for preventing PONV in patients undergoing laparoscopic cholecystectomy. 27 These results suggest that palonosetron combined with either droperidol or dexamethasone could be an effective combination for the prevention of PONV. Palonosetron 0.075 mg, i.v. improves the control of nausea and vomiting through the second and third postoperative days. 28 Palonosetron undergoes a slow elimination phase which results in a long half-life of approximately 40 h, in contrast with the 3 5-h half-life of ondansetron, 29 potentially mitigating the higher cost of this newly developed drug, compared with ondansetron. Further trials are necessary to compare the ability of palonosetron and ondansetron to reduce PONV 24 72 h postoperatively. The 5-HT 3 antagonists have an enviable safety profile, with most side-effects (e.g. headache, constipation, dizziness) being mild and transient. 30,31 Palonosetron has a similar safety profile to other 5-HT 3 antagonists 32 and no difference was found in the incidence of adverse effects between both groups in the present study. There were several limitations to the present study: the efficacies of palonosetron and ondansetron were compared based on the known optimal doses, without knowledge of equipotent doses; the power analysis was performed with the expected incidence of PONV estimated using patients who did not undergo identical types of surgery; and finally, the baseline incidence of PONV was not evaluated by the inclusion of a placebo group because it would be unethical to withhold prophylactic antiemetic drugs in patients at high risk for PONV. In conclusion, palonosetron 0.075 mg i.v. produced a lower incidence of PONV compared with ondansetron 8 mg i.v. in patients undergoing laparoscopic gynaecological surgery. Conflicts of interest The authors had no conflicts of interest to declare in relation to this article. Received for publication 22 October 2010 Accepted subject to revision 8 November 2010 Revised accepted 25 January 2011 Copyright 2011 Field House Publishing LLP References 1 Watcha MF, White PF: Postoperative nausea and vomiting. Its etiology, treatment, and prevention. Anesthesiology 1992; 77: 162 184. 2 Muchatuta NA, Paech MJ: Management of postoperative nausea and vomiting: focus on palonosetron. Ther Clin Risk Manag 2009; 5: 21 34. 3 Gan TJ: Risk factors for postoperative nausea and vomiting. Anesth Analg 2006; 102: 1884 1898. 4 Apfel CC, Läärä E, Koivuranta M, et al: A simplified risk score for predicting postoperative nausea and vomiting: conclusions from crossvalidations between two centers. Anesthesiology 1999; 91: 693 700. 5 Wong EH, Clark R, Leung E, et al: The interaction of RS 25259-197, a potent and selective antagonist, with 5-HT3 receptors, in vitro. Br J Pharmacol 1995; 114: 851 859. 405

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of intravenous [ 14 C]-palonosetron in healthy human volunteers. Biopharm Drug Dispos 2004; 25: 329 337. 30 Leslie JB, Gan TJ: Meta-analysis of the safety of 5-HT 3 antagonists with dexamethasone or droperidol for prevention of PONV. Ann Pharmacother 2006; 40: 856 872. 31 Ho KY, Gan TJ: Pharmacology, pharmacogenetics, and clinical efficacy of 5- hydroxytryptamine type 3 receptor antagonists for postoperative nausea and vomiting. Curr Opin Anaesthesiol 2006; 19: 606 611. 32 Navari RM: Palonosetron: a second generation 5-hydroxytryptamine 3 receptor antagonist. Expert Opin Drug Metab Toxicol 2009; 12: 1577 1586. Author s address for correspondence Associate Professor Eun Jung Cho Department of Anaesthesiology and Pain Medicine, Incheon St Mary s Hospital, College of Medicine, The Catholic University of Korea, 665-8 Bupyeong 6 dong, Bupyeonggu, Incheon 403-720, Republic of Korea. E-mail: gkjw2000@catholic.ac.kr 407