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Original Article

Preoperatively administered ramosetron oral disintegrating tablets for preventing nausea and vomiting associated with patient-controlled analgesia in breast cancer patients

Lee, H.-J.*; Kwon, J.-Y.*; Shin, S.-W.*; Kim, C.-H.; Baek, S.-H.*; Baik, S.-W.*; Kim, H.-K.*; Kim, K.-H.*

Author Information
European Journal of Anaesthesiology: September 2008 - Volume 25 - Issue 9 - p 756-762
doi: 10.1017/S0265021508004262

Abstract

Introduction

Postoperative nausea and vomiting (PONV) are distressing adverse events that frequently follow breast cancer surgery with an incidence of up to 80% [1-3]. Patient-controlled analgesia (PCA) using intravenously (i.v.) administered opioids is commonly used and provides highly satisfactory postoperative analgesia in breast surgical patients, but are associated with a frequent incidence of PONV [4].

Several new drugs and anaesthetic techniques have been introduced during the last few decades reported to minimize PONV. With respect to PONV associated with PCA there have been several reports concerning a reduction of the incidence of PONV using metoclopramide, droperidol and ondansetron [5-7]. Although the greatest success has been achieved by a combination therapy involving more than two drugs, recently [8,9], single use of 5-hydroxytryptamine type 3 receptor (5-HT3) antagonists remains the most common method for prevention of PONV.

Some investigators have suggested oral administration of 5-HT3 antagonists instead of i.v. injection for antiemetic therapy during the perioperative period [10-13]. A single dose of potent and long-acting antiemetics, in an orally disintegrating tablets formulation with minimal swallowing difficulties, could be a simple and effective way of reducing the incidence of PONV.

Ramosetron (Nasea® OD; Astellas Pharma Inc., Tokyo, Japan) is a new potent and long-acting, selective 5-HT3 receptor antagonist, the effects of which may last up to 48 h [14,15]. No investigators have examined whether preoperative administration of the long-acting 5-HT3 antagonist, ramosetron, in an oral formulation prevents PONV effectively.

In this study, we evaluated the acceptability and therapeutic efficacy of premedication with oral ramosetron for preventing PONV in patients undergoing breast cancer surgery.

Methods

This study was approved by the Institutional Review Board of the Pusan National University Hospital. After signed informed consent from patients, 240 adult women aged between 24 and 60 yr with an ASA physical status of I or II who were scheduled to undergo elective breast cancer surgery were enrolled. Patients with a history of smoking, PONV, motion sickness, gastrointestinal disease or who had taken an antiemetic medication within 48 h before surgery were excluded. Pregnant patients were also excluded from the study. All patients accepted the use of PCA for perioperative pain control. The patients were assigned to three groups using computer-generated random numbers inserted into sealed envelopes:

  1. Group A (control) received no prophylactic antiemetics before the surgery and received 0.9% normal saline i.v. (2 mL of volume) at the end of surgery.
  2. Group B (ramosetron i.v.) received 0.1 mg of ramosetron i.v. (Nasea® injectable; Astellas Pharma Inc.) (mixed with 0.9% normal saline to a total 2 mL of volume) at the completion of surgery but before recovery.
  3. Group C (ramosetron oral dispersible tablet) received 0.1 mg of oral ramosetron (Nasea® OD, Astellas Pharma Inc.) 30 min before the induction and received 0.9% normal saline i.v. (2 mL of volume) at the end of surgery.

Patients were not allowed to have solid food or clear liquids after midnight on the day before surgery. All patients received 3 mg of midazolam and 0.2 mg of glycopyrrolate, intramuscularly, 30 min before surgery. Anaesthesia was induced with 4 mg kg−1 of thiopental sodium i.v. and 0.9 mg kg−1 of rocuronium i.v. was used to facilitate tracheal intubation. After tracheal intubation, anaesthesia was maintained by a 1 : 1 mixture of oxygen and nitrous oxide and sevoflurane 1.0-3.0% (inspired concentration). Ventilation was mechanically controlled and adjusted to maintain an end-tidal concentration of carbon dioxide of 35-40 mmHg throughout surgery using an anaesthetic/respiratory gas analyzer. Neuromuscular blockade was achieved with 0.2 mg kg−1 of rocuronium, intermittently, and reversed by combined glycopyrrolate i.v. (0.008 mg kg−1) and pyridostigmine (0.2 mg kg−1) at the completion of surgery. The trachea was extubated after the patient awakened. Postoperatively, no oral intake was allowed for 8 h after recovery from anaesthesia. The same surgical and anaesthesia teams performed all the procedures. At the start of surgery, patients were connected to a PCA device (Pain Management ProviderTM; Abbott Laboratories, Chicago, IL, USA) programmed to deliver demand doses of 15 μg of fentanyl and 1.5 mg of ketorolac having a 20 min lockout interval and continuous infusion of the same dose per hour. No other analgesics were administered during the use of PCA.

All episodes of nausea and vomiting were recorded by nurses who were blinded to the treatment assignment. Nausea was defined as a subjective feeling of being sick, and vomiting was defined as an expulsion of gastric contents or retching. PONV included both nausea and vomiting. During two periods within the first 24 h after anaesthesia, nurses asked the patients by direct yes/no questioning about the occurrence of PONV. The two time-periods were as follows: 0-12 h and 12-24 h in the general ward. Subjects who experienced vomiting or required antiemetic therapy within the 24 h postanaesthetic period were given ondansetron 50 μ kg−1 i.v. The severity of pain was evaluated with a visual analogue scale (VAS) graded from 0 (no pain) to 10 (the worst pain imaginable) recorded 12 h and 24 h after the recovery. The consumption of fentanyl was recorded at 24 h. Adverse events caused from antiemetic medications (headache, dizziness, sedation or constipation/diarrhoea) were recorded.

We used a five-point sedation scale (0 = awake; 1 = drowsy; 2 = asleep but easily aroused; 3 = asleep but difficult to arouse; 4 = coma) to assess the level of sedation and a score of more than 2 was defined as ‘sedated'. The number of patients who were recorded as sedated during the 24 h postanaesthetic period was counted. The nurses who checked the presence of PONV recorded other adverse effects. At the termination of every observation period (24 h later), the nurses asked the patients their satisfaction with control of nausea and vomiting and analgesia, using five-point scales (1 = very good; 2 = good; 3 = fair; 4 = poor; 5 = very poor).

Statistical analysis

All statistical analyses were performed using Statview 5.0 (SAS Institute, Cary, NC, USA). P < 0.05 was deemed statistically significant. Data are presented as mean ± SD for continuous data and absolute frequencies (n) and percentages for frequency data. Analysis of variance was used to compare continuous parameters such as age, weight, height and consumption of fentanyl at 24 h. Repeated measures of analysis of variance was used to compare the postoperative pain with Scheffe posthoc comparison. χ2 analysis was performed, except when 50% of cells in the contingency table had expected counts of less than 5, in which case Fisher's exact test was used to compare proportions of patients, incidence of PONV and adverse events, and satisfaction score. Bonferroni correction for multiple comparisons or χ2-test was performed to adjust the α-error [16]. Sample size per group (N ≥ 52) was predetermined with reference to Cohen's study, assuming a medium effect size with α = 0.05 and a power (1−β) of 0.8 compared with the three groups [17]. To compensate for possible exclusions, we decided to randomize 80 patients in each group.

Results

Two hundred and forty patients were enrolled. Four patients were excluded from the study because of the onset of intolerable dizziness (n = 3) and headache (n = 1). In the final analysis we had 236 patients: 77 in Group A, 79 in Group B and 80 in Group C. No significant differences existed among the groups in factors that could modify the incidence of PONV, patient characteristics, factors related to the operation and anaesthesia (Table 1).

Table 1
Table 1:
Patient characteristics and surgical and anaesthetic factors.

The incidence of PONV and the use of rescue antiemetic medication during the 24 h postoperative period are summarized in Table 2. The incidence of nausea was significantly reduced in Groups B and C, whereas the incidence of vomiting was similar among the groups. All the incidence of PONV during the 24 h postoperative period was significantly reduced in Groups B and C compared with Group A: 27.8% and 25%, and 75.3%, respectively. The number of patients who received rescue antiemetics in Group C (5.0%) during the 24 h postoperative period was significantly less than Groups A (53.2%) and B (15.2%).

Table 2
Table 2:
Number and percentage of patients with PONV episodes in each group and period.

No significant differences existed in the degree of pain and the consumption of fentanyl by PCA at 24 h after the operation (Table 3). The incidence of adverse events is summarized in Table 4. The most frequently reported adverse events were dizziness, headache and sedation; however, clinically serious adverse events did not occur. No significant difference existed among the groups in adverse events. Although the incidence of sedation (sedation score ≥ 2) was increased in Group B compared with Groups A and C, no statistically significant difference existed. Furthermore, no patients recorded a level of sedation more than 3.

Table 3
Table 3:
Postoperative visual analogue scores (VAS) and cumulative fentanyl consumption during the first 24 h after surgery.
Table 4
Table 4:
Incidences of adverse events.

With respect to satisfaction, patients in Group A were significantly less satisfied with their control of nausea and vomiting and analgesia compared with Groups B and C during the first 24 h (Table 5). In Group A, many patients (41.6%) were significantly ranked as ‘poor' on satisfaction (satisfaction scale 4 and 5) compared with Groups B and C (15.2% and 16.3%). The rate of ‘very good' satisfaction in Group C was the highest among the groups: 0%, 1.3% and 10% in Group A, B and C, respectively.

Table 5
Table 5:
Satisfaction Scale.

Discussion

This study demonstrated that a preoperative single administration of long-acting 5-HT3 receptor antagonist as an oral formulation, ramosetron, was an acceptable and effective way to reduce the incidence of PONV during the first 24 h after the recovery in breast cancer patients using PCA. Premedication with oral ramosetron reduced the use of rescue antiemetics and increased satisfaction significantly compared with the other groups.

Breast cancer surgery is associated with a high incidence of PONV in the absence of prophylactic treatment [18]. Apfel and colleagues [19] reported that the four most important predictors were female gender, prior history of motion sickness or PONV, non-smoking and the use of postoperative opioids. Most of the breast cancer surgical patients require pain control and the opioids are commonly used for PCA. Based on Apfel's simplified score [19], the assumption of the incidence of PONV in breast cancer patients could be more than 60%. As our result shows, the incidence of PONV with no prophylactic antiemetics was 75.3%. Hence, the routine prophylaxis of PONV in patients undergoing breast cancer surgery may be necessary.

Recently, Tramer [20] suggested combination therapy in preventing PONV using butyrophenones (e.g. droperidol), 5-HT3 receptor antagonists and steroids (e.g. dexamethasone), which are the most rational choices for antiemetic prophylaxis, but complexity and economic constraints of such therapy still remain a problem.

Ramosetron hydrochloride reaches a peak plasma level (Cmax) at 15 min after oral administration with high bioavailability and then decreases with a terminal half-life (t1/2) of 2.1 h [21]. Drugs in an oral disintegrating tablet formulation dissolve in the mouth without water and have minimal effect on the fasting state [22]. Therefore, we hypothesized that premedication with oral ramosetron could be an adequate single therapy technique in preventing PONV in breast cancer patients.

The incidence of PONV during the 24 h postoperative period was significantly reduced in the group with ramosetron prophylaxis. Although preoperatively administered oral ramosetron at 0.1 mg showed a similar effect to the same dose given intravenously, the proportion of the use of rescue antiemetics during the 24 h postoperative period was significantly reduced compared with other groups. We assumed that time of administration would make differences in antiemetic action among the groups. The timing of prophylactic antiemetics is important in the use of some antiemetics. Dexamethasone is more effective when administered before surgery [23] but ondansetron is equally effective irrespective of whether given after induction or at the end of anaesthesia [24]. Sun and colleagues [25] demonstrated that ondansetron administered at the end of the operation significantly reduced the need for rescue antiemetics compared with other treatment groups (ondansetron administered before the induction). However, there has been no study looking at the ideal timing for ramosetron when given as antiemetic prophylaxis. Although the same dose of ramosetron was used in both active groups in the current study, we could not determine whether different routes of administration of ramosetron (i.v. or oral) have equipotent antiemetic effect because of the lack of a plasma concentration study.

In our study, a small dosage of ramosetron at a dose of 0.1 mg was used as a prophylactic antiemetic compared with previous other studies [26-29]. There is some debate concerning the actual dose of ramosetron for prophylaxis of PONV. Fujii and colleagues reported that ramosetron at a dose of 6 μg kg−1 is the smallest effective dose for preventing PONV in adult patients [26]. Other investigators reported that oral ramosetron at a dosage of 0.2 mg was as effective as 0.3 mg ramoseton i.v. [30]. Thus, the minimal dosage of ramosetron in an oral formulation in the prevention of PONV in breast cancer surgical patients has not been confirmed yet. Based on Kazemi-Kjellberg and colleagues [31], they could not find the evidence for a clinically relevant dose-response in antiemetic prophylaxis, so minimally effective doses may be used. In our study, we demonstrated that 0.1 mg of ramosetron prevent PONV effectively compared with the control.

The side-effects of antiemetics may limit their use. The incidence of adverse events was similar in all groups. Clinically serious adverse events did not occur during the study period. Recently, several investigators have reported the effect of ramosetron on irritable bowel syndrome with diarrhoea, whereas this effect does not occur in normal subjects [32,33]. Only one patient complained of constipation but it was controlled without medication.

With respect to satisfaction, antiemetic prophylaxis with ramosetron improved the score and decreased the rate of ‘poor' satisfaction compared with the control group. Also the use of oral ramosetron significantly increased the ‘very good' satisfaction rate compared with the i.v. group.

There are several limitations to this study. The first limitation is the presence of patient bias because of not using a placebo oral drug with the same taste and flavour. The second limitation is the lack of quantification of PONV. Tramer [20] described that the sensitivity and specificity of nausea remain particularly unsatisfactory. Furthermore, subjective PONV scoring sometimes depends not on the severity of symptoms but on the comprehension of the patients. We injected rescue antiemetics whenever there was patient requirement, so the use of rescue antiemetics may reflect the onset of intolerable PONV. The third limitation is the contribution of midazolam administered preoperatively. Several studies have reported an antiemetic effect of midazolam [34,35]; however, the incidence of PONV in the control group with midazolam premedication in this study is similar to previous other studies without premedication. We could not, however, exclude the additive effect of midazolam on ramosetron because a low dose of ramosetron suppressed PONV more than other studies reported [36].

We did not investigate the antiemetic effect of oral ramosetron after 24 h because the incidence of PONV after 24 h was too low for analysis. Further studies are needed to confirm the prolonged effect of ramosetron premedication.

In conclusion, preoperative single administration of ramosetron at a dose of 0.1 mg oral disintegrating tablet in combination with midazolam premedication was an acceptable and effective way of reducing the incidence of PONV during the first 24 h after recovery in breast cancer patients using PCA. This technique not only is simple and effective but also improved patient satisfaction.

Acknowledgements

This study was supported by a grant from Medical Research Institute, Pusan National University, Busan, Korea. The authors have no conflicts of interest that are directly relevant to the content of this study.

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Keywords:

BREAST SURGERY; ORAL ADMINISTRATION; POSTOPERATIVE NAUSEA AND VOMITING; PREMEDICATION; RAMOSETRON

© 2008 European Society of Anaesthesiology