Efficacy of palonosetron for the prevention of postoperative nausea and vomiting: a randomized, double-blinded, placebo-controlled trial

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1 British Journal of Anaesthesia 112 (3): (2014) Advance Access publication 22 October doi: /bja/aet340 CLINICAL PRACTICE Efficacy of palonosetron for the prevention of postoperative nausea and vomiting: a randomized, double-blinded, placebo-controlled trial H. R. Chun 1, I. S. Jeon 2,S.Y.Park 1,S.J.Lee 1, S. H. Kang 1 and S. I. Kim 1 * 1 Department of Anesthesiology and Pain Medicine, Soonchunhyang University Hospital Seoul, 657, Hannam-dong, Yongsan-gu, Seoul, Republic of Korea 2 Department of Anesthesiology and Pain Medicine, Soonchunhyang University Hospital Gumi, 250, Gongdan-dong, Gumi, Gyeongsangbuk-do, Republic of Korea * Corresponding author. soonnim@schmc.ac.kr Editor s key points Effective long-acting anti-emetic treatment should help improve postoperative recovery and early discharge. Palonosetron, a new 5-HT 3 receptor antagonist, may offer advantages with a prolonged duration of action. This study found that palonosetron showed benefit over placebo mainly in the first 24 h. Further work is needed to establish the place of palonosetron in the management of postoperative nausea and vomiting. Background. The aim of this study was to evaluate the efficacy of palonosetron, the latest 5-HT 3 receptor antagonist, for the prevention of postoperative nausea and vomiting (PONV) during the first 72 h after operation. Methods. In this randomized, double-blinded, placebo-controlled study, 204 healthy inpatients who were undergoing elective surgery with general anaesthesia were enrolled. Patients were divided into two groups: the palonosetron group (palonosetron mg i.v.; n¼102) and the placebo group (normal saline i.v.; n¼102). The treatments were given after the induction of anaesthesia. The incidence of nausea, vomiting, severity of nausea, and the use of rescue anti-emetics during the first 72 h after surgery were evaluated. Results. The incidence of PONV was lower in the palonosetron group compared with the placebo group during the 0 24 h (33% vs 47%) and 0 72 h period (33% vs 52%) (P,0.05), but not during the h postoperative period (6% vs 11%). The incidence of nausea was also significantly lower in the palonosetron group than in the placebo group during the 0 24 and 0 72 h period (P,0.05), but not during the h postoperative period. However, there were no significant differences in the incidence of vomiting, and the use of rescue anti-emetics between the groups. Conclusions. Palonosetron mg i.v. effectively reduced the incidence of PONV during the first 72 h after operation, with most of the reduction occurring in the first 24 h. Keywords: anti-emetics; palonosetron; postoperative nausea and vomiting Accepted for publication: 6 July 2013 Postoperative nausea and vomiting (PONV) is one of the most common and distressing complications after anaesthesia and surgery. PONV may result in wound dehiscence, bleeding, dehydration, electrolyte imbalance, pulmonary aspiration of gastric contents, and delayed hospital discharge. 1 Despite advances in the prevention of PONV and development of new drugs, the overall incidence of PONV has been reported to be between 20% and 30%, and can increase up to 80% in high-risk patients. 2 For the prevention of PONV, several anti-emetics of different pharmacological classes are available. Currently, selective 5-hydroxytryptamine type 3 (5-HT 3 ) receptorantagonistsare frequently used for the prevention of PONV because of their efficacy and fewer side-effects compared with other anti-emetics. 34 Palonosetron, the latest 5-HT 3 receptor antagonist, exhibits significantly different characteristics from older 5-HT 3 receptor antagonists because of its unique chemical structure. Palonosetron has a greater receptor binding affinity and a much longer half-life, conferring a prolonged duration of action, exceeding 40 h, compared with other 5-HT 3 receptor antagonists. 5 6 In addition, palonosetron exhibits allosteric interactions and triggers receptor internalization resulting in a long-lived inhibition of receptor function. 7 Given these pharmacological differences, palonosetron provides better protection against chemotherapy-induced nausea and vomiting (CINV) compared with older 5-HT 3 & The Author [2013]. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please journals.permissions@oup.com

2 BJA Chun et al. receptor antagonists (ondansetron, dolasetron, granisetron) throughout the 5 day post-chemotherapy period For the prevention of PONV, two identically designed multicentre, double-blind, placebo-controlled phase III efficacy trials were published One studyshowed that palonosetron effectively prevented PONV during the 0 72 h postoperative period. 11 However, another study showed that palonosetron effectively prevented PONV during the 0 24 h period after operation, but not during the h postoperative period. 12 As a result, more clinical evidence is neededbefore palonosetron can be routinely used in the prevention of PONV. This randomized, double-blind, placebo-controlled study was designed to further evaluate the efficacy of palonosetron for preventing PONV during the first 72 h after operation. Methods The study was approved by the IRB of Soonchunhyang University Hospital (Ref: ) before study commencement and registered with CRiS (Ref: KCT ). After receiving written informed consent, 204 healthy inpatients with an ASA physical status of I II, aged yr, who were undergoing elective surgery, were enrolled in this randomized, double-blinded, placebo-controlled study. The patient underwent laparoscopic cholecystectomy or herniorrhaphy, minor orthopaedic surgery, plastic surgery, mastoidectomy and/or tympanoplasty, thyroidectomy, or tonsillectomy. Exclusion criteria included pregnancy, body weight more than 30% above the ideal body weight, vomiting or retching within 24 h before the operation, administration of anti-emetics or steroids or psychoactive medications within 24 h before the operation, or patients who electively requested an i.v. patient-controlled analgesia (i.v. PCA) using fentanyl for postoperative pain control or received an i.v. PCA using fentanyl after operation. Patients were randomly allocated to one of the two groups: palonosetron group (palonosetron mg i.v.) or placebo group (normal saline i.v.). Randomization was performed before surgery using a computer-generated randomized number table. The envelopes were opened before induction of anaesthesia by a trained nurse not involved in the study. The nurse then prepared the appropriate study medication as an injectable solution (1.5 ml) placed in identical syringes, for i.v. administration after the induction of anaesthesia. All patients and investigators collecting the postoperative data were blinded to the randomization. A standardized anaesthesia regimen was followed. All patients received midazolam 3 5 mg i.m. for premedication 30 min before surgery. General anaesthesia was induced with propofol 2 mg kg 21 and fentanyl 2 mgkg 21. Rocuronium 0.6 mg kg 21 was administered to facilitate tracheal intubation. Anaesthesia was maintained with sevoflurane or desflurane combined with nitrous oxide (50%). At the end of surgery, residual neuromuscular block was reversed with pyridostigmine and glycopyrrolate in all patients. Ketorolac ( mg kg 21 ) was administered for postoperative pain control. After surgery, patients were observed in the post-anaesthetic care unit for 1 h before ward transfer. The incidence of nausea and vomiting, severity of nausea, and use of rescue anti-emetics were evaluated at 1, 6, 24, 48, and 72 h after operation. An episode of vomiting was defined as either vomiting (expulsion of stomach contents) or retching (an involuntary attempt to vomit but not productive of stomach contents). The severity of nausea was assessed using a four-point verbal rating scale (none, mild, moderate, severe). Metoclopramide 10 mg was administered i.v. as rescue medication for PONV upon patient s request or complaint of nausea ( moderate nausea) or vomiting. For postoperative pain control, non-steroidal anti-inflammatory drugs (ketorolac, etc.) were given. Adverse events were evaluated and recorded by the investigator during the entire observation period. Patients were asked to rate their overall satisfaction with the anaesthetic experience on a three-point scale (satisfied, neutral, and dissatisfied) at 72 h after operation. The primary outcome measured in this study was the incidence of PONV 0 24 h after operation, and the secondary outcome measured included the incidence of PONV h after operation, the severity of nausea, use of rescue medication, and patient satisfaction. The sample size was predetermined using power analysis based on the following assumptions: (i) the incidence of PONV would be 60% in the placebo group 13 ; and (ii) a 34% reduction in the incidence of PONV 11 (from 60% to 40%) by palonosetron would be of clinical relevance using a¼0.05 and b¼0.2. The sample size was estimated at 97 patients per group. A larger number of patients, 102 patients per group, were enrolled to allow for possible incomplete data collection or patient dropout. Statistical analysis was performed using SPSS for Windows (version 14, SPSS Inc., Chicago, IL, USA). Student s t-test was used to compare the continuous variables between the groups. Categorical variables were analysed using the x 2 test or Fisher s exact test, as appropriate. A P-value of,0.05 was considered statistically significant. Data are presented as mean [standard deviation (SD)], numbers, or percentages. Results Among the 204 patients enrolled in this study, 15 patients were withdrawn from the study due to receiving i.v. PCA using fentanyl for pain control after being transferred to the ward. Therefore, only data obtained from the remaining 189 patients were analysed, 94 patients in the palonosetron group and 95 in the placebo group (Fig. 1). There were no significant differences between the groups with respect to patient characteristics, Apfel s risk score, duration of surgery, duration of anaesthesia, and type of surgery (Table 1). The incidence of PONV was significantly lower in the palonosetron group than in the placebo group during the 0 24 h (33% vs 47%) and the 0 72 h postoperative period (33% vs 52%) (P,0.05), but not during the h postoperative period (6% vs 11%) (Table 2). The incidence of nausea was significantly lower in the palonosetron group than in the placebo group during the 0 24 h 486

3 Palonosetron for the prevention of PONV BJA Enrolment Assessed for eligibility (n=350) Excluded (n=146) Not meeting inclusion criteria (n=118) Declined to participate (n=28) Randomized (n=204) Allocated to palonosetron group (n=102) Received allocated intervention (n=102) Did not receive allocated intervention (give reasons) (n=0) Allocation Allocated to placebo group (n=102) Received allocated intervention (n=102) Did not receive allocated intervention (give reasons) (n=0) Lost to follow-up (n=0) Discontinued intervention (n=0) Follow-up Lost to follow-up (n=0) Discontinued intervention (n=0) Analysed (n=94) Excluded from analysis because of protocol violation (n=8) Analysis Analysed (n=95) Excluded from analysis because of protocol violation (n=7) Fig 1 Consort diagram of the study. (32% vs 47%) and 0 72 h postoperative period (32% vs 52%) (P,0.05), but not during the h postoperative period (6% vs 11%) (Table 2). The incidence of vomiting was not significantly different between the groups throughout the entire observation periods (Table 2). The severity of nausea during the 0 24 h postoperative period was less in the palonosetron group compared with the placebo group, but the difference was not statistically significant (P¼0.08) (Fig. 2). There was no significant difference in rescue anti-emetics used between the groups (Table 2). There was no significant difference with regard to patient satisfaction between the groups (Table 3). The more frequently reported adverse events were dizziness and headache, which were similar between the groups (Table 3). Discussion This study demonstrated that palonosetron mg i.v. effectively reduced PONV during the 0 24 and 0 72 h period after surgery under general anaesthesia, although there was no significant difference in PONV incidence during the h postoperative period between the groups. In addition, palonosetron significantly reduced the incidence of nausea, but not of vomiting. Although the precise aetiology of PONV is unknown, various risk factors have been identified for PONV which include female gender, non-smoker status, history of PONVor motion sickness, use of perioperative opioids, use of volatile anaesthetics, duration of surgery, duration of anaesthesia, and type of surgery. 214 In this study, these risk factors were similar in the two groups. Therefore, the difference in PONV incidence between the groups can be attributed to the study drug. Palonosetron mg dose was chosen in this study based on the results of previous studies showing that palonosetron mg was effective in reducing PONV compared with placebo In addition, palonosetron mg has been approved by the US Food and Drug Administration (FDA) for the prevention of PONV up to 24 h after surgery in In a study by Kovac and colleagues 11 involving elective inpatient gynaecological surgery and breast surgery, a single mg i.v. bolus dose of palonosetron significantly increased the complete response rate (no emetic episodes and no rescue medication) compared with placebo during the 0 24 and h postoperative interval. During the 0 24 h postoperative interval, significantly fewer patients treated with palonosetron mg experienced nausea (50%) and vomiting (40%) compared with patients who received placebo [nausea 487

4 BJA Chun et al. Table 1 Patients characteristics. Dataare mean (SD), mean (range), or number of patients Placebo group (n595) Palonosetron group (n594) Age (yr) 43 (20 70) 43 (20 70) Body weight (kg) 66 (15) 66 (13) Female gender (n) Apfel risk score Duration of surgery (min) 71 (53) 74 (61) Duration of anaesthesia 103 (58) 110 (67) (min) Type of surgery Laparoscopic 11 9 cholecystectomy Laparoscopic herniorrhaphy Minor orthopaedic surgery Plastic surgery Mastoidectomy with/or 10 9 tympanoplasty Thyroidectomy 7 8 Tonsillectomy 5 6 Table 2 Incidence of nausea and vomiting, and the use of rescue anti-emetics during the first 72 h postoperative period. Data are number of patients (%). PONV, postoperative nausea and vomiting Placebo group (n595) Palonosetron group (n594) P-values 0 24 h Nausea 45 (47) 30 (32) Vomiting 13 (14) 10 (11) PONV 45 (47) 31 (33) Rescue 10 (11) 10 (11) anti-emetics h Nausea 10 (11) 6 (6) Vomiting 2 (2) 1 (1) PONV 10 (11) 6 (6) Rescue 1 (1) 1 (1) anti-emetics 0 72 h Nausea 49 (52) 30 (32) Vomiting 14 (15) 11 (12) PONV 49 (52) 31 (33) Rescue anti-emetics 10 (11) 10 (11) % 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Placebo Palonosetron Placebo Palonosetron Placebo Palonosetron 0 24 h h h None Mild Moderate Severe Fig 2 The distribution (%) of nausea severity by a four-point verbal rating scale (none, mild, moderate, severe). The severity of nausea in the palonosetron group was less than the placebo group during 0 24 h, but was not statistically significant (P¼0.08). There were also no significant differences between the groups during h (P¼0.29) and h (P¼0.12). Table 3 Incidence of adverse events and patient satisfaction. Data are number of patients (%). There were no significant differences between the groups Placebo group (n595) Palonosetron group (n594) Adverse event Dizziness 10 (11) 9 (10) Headache 17 (18) 19 (20) Satisfaction Satisfied 87 (92) 88 (94) Neutral 8 (8) 5 (5) Dissatisfied 0 (0) 1 (1) (71%), vomiting (60%)]. This corresponds to a relative risk reduction of 31% for nausea, and a relative risk reduction of vomiting by 34% for patients treated with palonosetron mg. In a study by Candiotti and colleagues 12 involving elective outpatient laparoscopic abdominal and gynaecological surgery, a single mg i.v. dose of palonosetron significantly increased the complete response rate (no emetic episodes and no rescue medication) compared with placebo during the 0 24 h postoperative period, but not during the h postoperative interval. During the 0 24 h postoperative interval, palonosetron mg significantly reduced the incidence and severity of nausea, but did not significantly reduce vomiting incidence compared with placebo (33% vs 44%). The study demonstrated that palonosetron has more prominent antinausea effect than anti-vomiting effect. In the current study, palonosetron mg significantly reduced the incidence of PONV during the 0 24 h 488

5 Palonosetron for the prevention of PONV BJA postoperative period, but not during the h postoperative period, even though palonosetron significantly reduced the overall incidence of PONV during the 0 72 h postoperative period. Although postoperative discharge nausea and vomiting (PDNV) was somewhat different from PONV, the overall incidence of PDNV was reported at 37%, even though the majority of the patients received ondansetron or dexamethasone. 15 Kovac and colleagues 11 also reported that 48% of inpatients who did not receive anti-emetics experienced emesis or used rescue anti-emetics during the h postoperative period. We believe that many of these patients may have experienced PONV beyond the 24 h postoperative period. In this study, the incidence was highest during the first 6 h postoperative period, and then decreased with time. Only 11% of patients in the placebo group experienced PONV during the h postoperative interval. One possible reason for the low incidence of late PONV in this study may be due to non-use of postoperative opioids since PONV is strongly influenced by postoperative opioids use in a dose-related manner. 16 Owing to the low incidence (11%) of PONV in the placebo group, it was difficult to demonstrate palonosetron s effect on PONV during the h period in this study. During the 0 24 h interval, our study showed that significantly fewer patients treated with palonosetron mg experienced nausea compared with patients who received placebo (32% vs 47%). This corresponds to a relative risk reduction for nausea of 33% for patients treated with palonosetron. This is consistent with the 31% relative risk reduction of nausea as reported by Kovac and colleagues 11 in a previous study. During the 0 24 h interval, palonosetron mg significantly reduced the incidence of vomiting from 60% in the placebo group to 40% in the study of Kovac and colleagues. 11 This was, however, not reproduced in another report (from 44% to 33%). 12 In contrast to these previous reports, the incidence of vomiting in the placebo group was only 14% during the 0 24 h postoperative interval in this study. The low incidence of postoperative vomiting was also due to the non-use of postoperative opioids, because postoperative opioid use was a strong risk factor for postoperative vomiting Accordingly, this study could not demonstrate the anti-vomiting effect of palonosetron due to the overall low rate of vomiting in the placebo group (14%) even during the 0 24 h postoperative interval. The frequently reported adverse events for 5-HT 3 receptor antagonist are headache and dizziness. 18 In this study, the incidence of headache and dizziness were similar between the two groups. A possible limitation of this study was the low incidence of late PONV during the h postoperative interval even in the placebo group. Perhaps too few patients were enrolled in this study to accurately evaluate palonosetron s effects on late PONV. A larger number of patients, 1000 patients, would be required to demonstrate palonosetron s effect on late PONV during the h postoperative interval. Further studies are needed to investigate palonosetron s effects on late PONV in patients who are at high risk for PONV. In conclusion, palonosetron mg i.v. effectively reduced the incidence of PONV during the first 72 h after operation, mainly during the 0 24 h postoperative interval, in patients undergoing elective surgery with general anaesthesia. Additionally, during the 0 24 h postoperative interval, palonosetron effectively reduced the incidence of nausea with a 33% relative risk reduction. Declaration of interest None declared. References 1 Watcha MF, White PF. 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