Postoperative Nausea and Vomiting Prophylaxis: A Comparative Study of Ramosetron and Palonosetron in Patients Undergoing Laparoscopic Cholecystectomy - A Prospective Randomized Trial.

BACKGROUND: In spite of the availability of several antiemetic drugs, postoperative nausea and vomiting (PONV) is very common following laparoscopic surgery. Selective 5-hydroxytryptamine type 3 receptor antagonists are considered first-line agents for prophylaxis for PONV. AIMS: In this study, we investigated and compared the efficacy of ramosetron and palonosetron in preventing PONV following laparoscopic cholecystectomy. STATISTICAL ANALYSIS: The data were analyzed with Student's t-test and Chi-square test. SETTINGS AND
DESIGN: This was a randomized, prospective, double-blinded, observational clinical study.
METHODS: A total number of 80 patients, undergoing elective laparoscopic cholecystectomy surgeries under general anesthesia, were randomly assigned to one of the two equal groups to receive either of the following: Group R - received injection ramosetron 0.3 mg and Group P - received injection palonosetron 0.075 mg intravenous bolus immediately before the induction of anesthesia. The incidence of PONV, adverse effects of the study drugs, and need for rescue antiemetics were recorded over the next 48 h. Primary outcome was the incidence of PONV. Secondary outcomes were adverse effects of the study drugs and need for rescue. STATISTICAL ANALYSIS: The data were analyzed with Student's t-test and Chi-square test.
RESULTS: The incidence of a complete response (no PONV and no rescue medication) during 0-3 h in the postoperative period was 82.5% with ramosetron and 90% with palonosetron; the incidence during 3-24 h postoperatively was 80% with ramosetron and 87.5% with palonosetron. During 24-48 h, the incidence was 65% and 90%, respectively (P < 0.05). The incidences of adverse effects were statistically insignificant between the groups.
CONCLUSION: Prophylactic therapy with palonosetron is more effective than ramosetron for long-term prevention of PONV following laparoscopic cholecystectomy.

INTRODUCTION

Postoperative nausea and vomiting (PONV) are one of the most distressing symptoms that commonly seen after surgeries under general anesthesia, the incidence being around 25% in adults.[1] Adverse consequences of PONV may range from delayed recovery to unexpected prolonged hospital stay. Prevention and treatment of PONV helps in accelerating postoperative recovery and early discharge and thereby increases patient satisfaction.[2]

For prevention and treatment of PONV, a number of pharmacological agents including dopamine receptor antagonists, histamine antagonists, anticholinergic, serotonin antagonists, dexamethasone, and neurokinin antagonists have been tried with some undesirable adverse effects such as excessive sedation, hypertension, dry mouth, dysphoria, hallucinations, and extrapyramidal symptoms.[34]

Recently selective serotonin receptor (5-hydroxytryptamine type 3 [5-HT3]) antagonists are considered first line in the management of PONV, due to their proven efficacy and favorable side effect profile. 5-HT3 antagonists act by preventing serotonin binding to 5-HT3 receptors, which present on the vagus afferent nerve endings, which send signals directly to the vomiting center in the medulla oblongata and in the chemoreceptor trigger zone (CTZ) of the brain. By preventing activation of these receptors, 5-HT3 antagonists interrupt one of the pathways leading to vomiting.[5]

Ramosetron is a newer long-acting selective 5-HT3 receptor antagonist. It exhibits a higher affinity toward the serotonin receptors with a slower dissociation, resulting in a longer duration of action.[6] Palonosetron is a unique 5-HT3 receptor antagonist having a greater binding affinity and longer half-life than other 5-HT3 antagonists.[7]

We conducted this prospective, randomized, double-blinded study to evaluate the antiemetic efficacy of ramosetron compared with palonosetron in patients undergoing elective laparoscopic cholecystectomy. Primary outcome was the incidence of PONV. Secondary outcomes were adverse effects of the study drugs and need for rescue.

METHODS

After Institutional Ethics Committee approval, written informed consent was taken from all patients who were included in the study. Totally 80 patients, with the American Society of Anesthesiologists (ASA) physical status Classes I and II of either sex, aged between 20 and 60 years, undergoing elective laparoscopic cholecystectomy under general anesthesia were randomized into two groups [Figure 1]. Patients, who had gastrointestinal disease, were smokers, had history of motion sickness and/or PONV, and were pregnant or menstruating and those who had taken antiemetic medication within the last 24 h were excluded from the study. All patients were examined preoperatively, and all routine investigations were done. Patients were explained about the concerned procedure and were instructed to keep fasting for 6 h.

Figure 1

Consort diagram showing the number of patients included and analyzed

Patients were randomized using a computer-generated random number list. Patients were assigned randomly to one of the two groups. Eighty patients were randomly assigned to one of the two equal groups to receive either of the following: Group R – received injection ramosetron 0.3 mg diluted in 10 ml of normal saline 0.9% and Group P – received injection palonosetron 0.075 mg diluted in 10 ml of normal saline 0.9%. All patients received test drug intravenous (i.v.) over a period of 5 min, immediately before induction of anesthesia. The study drugs were loaded in identical syringes with 10ml volume each, labelled ‘antiemetic’ by a resident doctor who was not a part of the study. A consultant anesthesiologist who performed general anesthesia and used the study drug was unaware of the type of study drug used and did not participate in the study.

On arrival to operating room, an 18-gauge i.v. catheter was inserted and 6 ml/kg/h crystalloid was infused. Noninvasive monitors, such as electrocardiography, noninvasive blood pressure, and oxygen saturation (SpO2), were attached, and baseline parameters such as heart rate, systemic arterial pressure, and peripheral SpO2 and level of sedation were noted down.

After preoxygenation for 3 min, anesthesia was induced with a standard anesthetic protocol using midazolam (0.05 mg/kg), fentanyl (2 mg/kg), and propofol (2 mg/kg) followed by succinylcholine (2 mg/kg) to facilitate tracheal intubation; trachea was intubated with an appropriate-sized cuffed, endotracheal tube. Orogastric tube was introduced after endotracheal intubation, and suction through tube was done. Lungs were mechanically ventilated with O2-N2O (33%–66%), sevoflurane 0.8% minimum alveolar concentration, and vecuronium bromide 0.1 mg/kg bolus followed by 1 mg intermittently for neuromuscular blockade. Tidal volume and ventilator frequency were adjusted to maintain normocapnia (EtCO2 40 ± 4 mmHg). Pneumoperitoneum was created by insufflation of CO2, and intra-abdominal pressure was not allowed to exceed 15 mmHg. Injection tramadol 100 mg i.v. and diclofenac 75 mg intramuscular was given to all patients, 30 min before the end of surgery and diclofenac repeated 8 hourly.

At the end of the operation, neuromuscular blockade was antagonized with injection of neostigmine (0.05 mg/kg) and glycopyrrolate (0.008 mg/kg) i.v. and the patient was extubated when respiration was deemed sufficient and they were able to obey commands. Before tracheal extubation, the nasogastric tube was suctioned and removed. For postoperative analgesia, diclofenac transdermal patch was applied on body surface.

Patients were transferred to postanesthesia care unit (PACU), and blood pressure, heart rate, and SpO2 were monitored. In PACU, all patients were monitored by resident doctors who were unaware of the study drug. All episodes of PONV (nausea, retching, and vomiting) were recorded for 0–3 h in PACU and from 3 to 48 h in postoperative ward.

Nausea was defined as unpleasant sensation associated with awareness of the urge to vomit. Retching was defined as the labored, spastic, rhythmic contraction of the respiratory muscles without the expulsion of gastric contents. Vomiting was defined as the forceful expulsion of gastric contents from mouth. Complete response (free from emesis) was defined as no PONV and no need for any rescue medication. If there were two or more episodes of PONV during the first 48 h, rescue antiemetic (injection metoclopramide 10 mg i.v.) was given.

Sample size was predetermined using a power analysis to achieve an 80% chance (β =0.2) of detecting a 40% reduction in PONV from a basal incidence of 70% (from 70% to 42%) with an assumed significance level of a = 0.05.[8] A calculated minimum sample size was 36 patients in each group. We included forty patients in each group for better validation of results. Data were checked, entered, and analyzed using SPSS version 19 for Windows (IBM Corp., Armonk, NY, USA). Quantitative data were represented as mean ± standard deviation, and for qualitative data, number and percentages were used. Student's t-test was used as test of significance to find an association for quantitative data. Chi-square test was used as test of significance to find the association for qualitative data. P < 0.05 was considered statistically significant.

RESULTS

There was no statistical significant difference with respect to age, sex, weight, and ASA physical status of the patients; duration of surgery; and anesthesia time [Table 1]. The incidence of a complete response (no PONV and no rescue medication during 0–3 h in the postoperative period was 82.5% with ramosetron and 90% with palonosetron; the incidence during 3–24 h postoperatively was 80% with ramosetron and 87.5% with palonosetron. During 24–48 h, the incidence was 65% and 90%, respectively [Table 2]. Thus, a complete response during 24–48 h in the postoperative period was significantly more patients who had received palonosetron than in those who had received ramosetron (P < 0.05) [Table 2].

Table 1

Demographic data

Variables	Group R (n=40)	Group P (n=40)	P
Age (years)	52.4±8.6	51.7±7.1	0.42
Weight (kg)	73.9±8.3	74.1±7.7	0.55
Height (cm)	164.3±6.2	164.8±6.8	0.65
BMI (kg/m2)	20.8±1.8	21.3±1.4	0.32
Gender (male/female)	22:18	21:19	0.34
ASA (I/II)	31/9	32/8	0.67
Mean duration of surgery (min)	100.2±34.1	99.4±25.3	0.46
Duration of anesthesia (min)	140.0±54.6	135.9±52.0	0.81

Data are represented as mean±SD. BMI=Body mass index, ASA=American Society of Anesthesiologists, SD=Standard deviation

Table 2

Incidence of postoperative nausea and vomiting

Postoperative Period (h)	Group R (n=40), n (%)	Group P (n=40), n (%)	P
0-3
Complete response	33 (82.5)	36 (90)	0.65
Nausea	5 (12.5)	3 (7.5)	0.67
Retching	1 (2.5)	1 (2.5)	1
Vomiting	2 (5)	1 (2.5)	0.42
Rescue antiemetic	0	0	1
3-24
Complete response	32 (80)	35 (87.5)	0.58
Nausea	5 (12.5)	2 (5)	0.72
Retching	1 (2.5)	1 (2.5)	1
Vomiting	3 (7.5)	2 (5)	0.68
Rescue antiemetic	0	0	1
24-483
Complete response	26 (65)	36 (90)	0.003
Nausea	8 (20)	4 (10)	0.09
Retching	3 (7.5)	1 (2.5)	0.49
Vomiting	6 (15)	2 (5)	0.07
Rescue antiemetic	0	0	1

Data represented as the number of patients (%). P<0.05 was taken as statistically significant

The commonly observed adverse effects were headache, dizziness, and drowsiness, but those were not clinically serious or significant. The incidences of adverse effects were statistically not significant between the groups [Table 3].

Table 3

Incidence of adverse effects

Postoperative Period (h)	Group R (n=40), n (%)	Group P (n=40), n (%)	P
0-3
Headache	3 (7.5)	5 (10)	0.79
Dizziness	5 (12.5)	2 (5)	0.62
Drowsiness	1 (2.5)	1 (2.5)	1
3-24
Headache	3 (7.5)	3 (7.5)	1
Dizziness	4 (10)	2 (5)	0.52
Drowsiness	1 (2.5)	1 (2.5)	1
24-48
Headache	0	2 (5)	0.38
Dizziness	0	0	1
Drowsiness	0	0	1

Data represented as the number of patients (%)

DISCUSSION

Results of this prospective, randomized, double-blinded study demonstrated that the incidence of PONV was less with palonosetron compared to ramosetron after the first 48 h following laparoscopic cholecystectomy. Furthermore, the overall number of patients with no PONV was higher in the palonosetron group than in the ramosetron group (P < 0.05). The incidences of adverse effects were statistically not significant between the groups.

The incidence of PONV is variable and depends on the duration of surgery, the type of anesthetic agents used (dose, inhalational drugs, and opioids), smoking habit, etc.[9] The primary event in the initiation of vomiting reflex is the stimulation of 5-HT3 receptors. These 5-HT3 receptors are situated on the nerve endings of the vagus nerve in the periphery and centrally on the CTZ of the area postrema. Anesthetic agents induce vomiting reflex by stimulating the central 5-HT3 receptors which are present in CTZ and also by releasing serotonin from the enterochromaffin cells of the small intestine and subsequent stimulation of 5-HT3 receptors on vagus nerve afferent fibers.

Laparoscopic surgeries are associated with high incidence of PONV (40%–75%). The etiology of PONV after laparoscopic surgery is complex and is dependent on number of factors including age, obesity, history of previous PONV, surgical procedure, anesthetic technique, and postoperative pain.[10] In this study, however, both the study groups were comparable with respect to patient demographics, types and duration of surgery, and anesthesia and analgesics used postoperatively. Therefore, the difference in a complete response (no PONV and no rescue medication) between the groups can be attributed to the study drug.

One previous study by Fujii et al. reported that ramosetron is an effective antiemetic in preventing PONV after gynecological surgery.[11] They also concluded that ramosetron 0.3 mg is an effective dose for preventing PONV. In addition, the manufacturer's recommended dose is 0.3 mg i.v. once a day. Therefore, we have chosen ramosetron at the 0.3 mg dose in our study. Candiotti et al., in their study, found that the minimum effective dose of palonosetron in the prophylaxis of PONV was 0.075 mg, and this has been approved by the Food and Drug Administration. Kovac et al. also concluded that palonosetron 75 μg is the more effective dose for the prevention of PONV after major gynecological and laparoscopic surgery than 25 μg and 50 μg.[12] In our study, we have decided to use palonosetron 0.075 mg.

Our study demonstrates that the antiemetic efficacy of palonosetron is higher to that of ramosetron in preventing PONV during the first 24 h (0–24 h) after laparoscopic cholecystectomy and that palonosetron is more effective than ramosetron for getting a complete response (no PONV and no rescue medication) for 24–48 h. This suggests that palonosetron has an antiemetic effect which lasts longer than ramosetron.

The exact reason for the difference in effectiveness between ramosetron and palonosetron is not clearly known, but can be explained by 30 times higher binding affinity to the 5-HT3 receptors than ramosetron and to by the extended half-life of palonosetron (approximately 40 h).[13] The possible mechanisms of palonosetron and ramosetron for preventing PONV are similar, but palonosetron is further differentiated from other 5-HT3 receptor antagonists including ramosetron, by interacting with the receptors in an allosteric and positively cooperative manner, and may promote internalization of the 5-HT3 receptor and decrease the function of the receptor. This may be explained by unique structural characteristics; while older drugs are based on a 3-substituted indole structure resembling serotonin, palonosetron is based on a fused tricyclic ring system attached to a quinuclidine moiety.

Our results are very similar to various studies that the palonosetron was observed as better long-duration effect than ramosetron. In a randomized comparative study by Fujii et al., there was complete response in 90% of the patients in ramosetron group while 86% in patients who were given granisetron. During 24–48 h postoperative period, a complete response was noted in ramosetron and granisetron group as 90% and 66%, respectively. Various researchers also observed similar effectiveness of ramosetron in their studies during the first 24 h postoperatively, although they compared the drug with ondansetron.[1415]

Very similar observations were also seen in a study by Suman and Sebanti, in which they found that the severity of nausea was statistically significant with ramosetron group within 3–48 h postoperatively. In high-risk patients, after thyroidectomy, palonosetron proved to be more effective than ondansetron, especially 3–24 h after surgery.[16]

In our study, we did not include a control group, receiving placebo. Aspinall and Goodman concluded that if active drugs are available, placebo-controlled trials may be unethical because PONV is very much distressing after laparoscopic surgery.[17]

The adverse effects after single therapeutic dose of ramosetron or palonosetron were not clinically big issue.[18] In our study, there were no significant differences in the incidence of adverse events, namely headache, dizziness, and drowsiness between both the groups. Thus, both palonosetron and ramosetron are devoid of clinically important and serious side effects.

One limitation of our study was ramosetron has a short half-life than palonosetron, and in such scenario, the dosing schedule for ramosetron should be multiregimen, but including more dosing schedules of ramosetron would lead to bias in the study. Another limitation was, we have given injection fentanyl during induction of anesthesia, being an opioid it can exaggerate PONV. However, in recent study, it is observed that pain treated with opioids actually prevents PONV.

CONCLUSION

Prophylactic therapy with palonosetron is more effective than prophylactic therapy with ramosetron for the long-term prevention of PONV after laparoscopic surgery. The present study clearly states that palonosetron is a better and effective alternative for PONV in elective laparoscopic cholecystectomy under general anesthesia during the first and second postoperative day.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.