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Anesth Analg 1999;89:476
© 1999 International Anesthesia Research Society

GENERAL ARTICLES

Comparison of Ramosetron and Granisetron for Preventing Postoperative Nausea and Vomiting After Gynecologic Surgery

Yoshitaka Fujii, MD*, Yuhji Saitoh, MD{dagger}, Hiroyoshi Tanaka, MD{dagger}, and Hidenori Toyooka, MD*

Departments of Anesthesiology, *University of Tsukuba Institute of Clinical Medicine, Tsukuba City; and {dagger}Toride Kyodo General Hospital, Toride City, Ibaraki, Japan

Address correspondence and reprint requests to Y. Fujii, Department of Anesthesiology, University of Tsukuba Institute of Clinical Medicine, 2–1-1, Amakubo, Tsukuba City, Ibaraki 305, Japan.


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
In a prospective, randomized, double-blinded study, we evaluated the efficacy of granisetron and ramosetron for preventing postoperative nausea and vomiting (PONV) in major gynecologic surgery. One hundred twenty patients, ASA physical status I or II, aged 23–65 yr, received IV granisetron 2.5 mg or ramosetron 0.3 mg (n = 60 each) at the end of surgery. A standard general anesthetic technique and postoperative analgesia were used. The incidence of a complete response, defined as no PONV and no need for another rescue medication, 0–3 h after anesthesia was 87% with granisetron and 90% with ramosetron; the corresponding incidence 3–24 h after anesthesia was 85% and 90%; the corresponding incidence 24–48 h after anesthesia was 70% and 92% (P < 0.05). No clinically serious adverse events due to the drugs were observed in any of the groups. In conclusion, prophylactic therapy with ramosetron is more effective than granisetron for the long-term prevention of PONV after major gynecologic surgery.

Implications: We compared the efficacy of granisetron and ramosetron for preventing postoperative nausea and vomiting in major gynecologic surgery. Prophylactic therapy with ramosetron was more effective than granisetron for preventing postoperative nausea and vomiting 24–48 h after anesthesia.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Postoperative nausea and vomiting (PONV) are distressing symptoms that often occur in women after major gynecologic surgery performed under general anesthesia (1). A number of pharmacological approaches (antihistamines, butyrophenones, dopamine receptor antagonists) have been investigated for the prevention and treatment of PONV, but undesirable adverse effects, such as excessive sedation, hypotension, dry mouth, dysphoria, hallucinations, and extra-pyramidal symptoms, have been noted (2). We previously demonstrated that granisetron, a selective 5-hydroxytryptamine type 3 (5-HT3) receptor antagonist, reduces the incidence of PONV after major gynecologic surgery (3). We also demonstrated that granisetron is more effective than other commonly used and well established antiemetics, such as droperidol and metoclopramide, for preventing PONV in major gynecologic surgery (3,4). Ramosetron, (R)-5-[(1-methyl-3-indolyl)cardonyl]-4,5,6,7-tetrahydro-1H-benzimidazole hydrochloride (Nasea®; Yamanouchi, Tokyo, Japan), another new 5-HT3 receptor antagonist, is more potent and has longer acting properties than granisetron against cisplatin-induced emesis (5). We hypothesized that ramosetron is more effective than granisetron for the long-term prevention of PONV. To test this hypothesis, we designed this prospective, randomized, double-blinded trial to assess the efficacy and safety of granisetron and ramosetron for preventing PONV in major gynecologic surgery.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
After obtaining institutional review board approval and informed consent from all patients, we studied 120 women, ASA physical status I or II, aged 23–65 yr, scheduled for major gynecologic surgery. Patients who had gastrointestinal disease, those who had a history of motion sickness and/or previous PONV, those who were pregnant or menstruating, or those who had taken an antiemetic medication within 24 h before surgery were excluded.

Patients were randomly allocated to receive one of two treatment regimens (n = 60 each): granisetron 2.5 mg or ramosetron 0.3 mg. These drugs were administered IV immediately after surgery. A randomization list was generated, and identical syringes containing each drug were prepared by personnel not involved in this study, according to the list.

No patients received preanesthetic medication. Standard monitoring was used. A 17-gauge Tuohy needle was inserted at either the L2-3 or L3-4 interspace with a loss of resistance technique, and an 18-gauge epidural catheter was placed cephalad (approximately 5 cm) through the needle. Correct placement of the catheter was confirmed by administering 2 mL of lidocaine 1.5% plus epinephrine (i.e., test dose). Anesthesia was induced with thiopental 5 mg/kg IV and fentanyl 2 µg/kg IV, and vecuronium 0.2 mg/kg IV was used to facilitate tracheal intubation. After tracheal intubation, anesthesia was maintained with 66% nitrous oxide (N2O) and 0.5%–2.0% isoflurane (inspired concentration) in oxygen. Ventilation was controlled mechanically and was adjusted to maintain PETCO2 between 35 and 40 mm Hg throughout surgery, as measured by an anesthetic/respiratory gas analyzer. When hemodynamic variables were stable, 10–15 mL of lidocaine 1.5% was injected through the epidural catheter during surgery. Muscle relaxation was maintained with vecuronium as required. A nasogastric tube was inserted, and suction was applied to empty the stomach of air and other contents. Before tracheal extubation, the nasogastric tube was again suctioned, then removed. At the completion of surgical procedure, N2O and isoflurane were stopped. Residual neuromuscular blockade was antagonized with atropine 0.02 mg/kg IV and neostigmine 0.04 mg/kg IV, and the trachea was extubated when the patient was awake. Rectal temperature was monitored and maintained at 37 ± 1°C using a warming pad. Postoperative analgesia was provided with a mixture of 100 mL of 0.25% bupivacaine, and morphine 0.2 mg/kg was started after surgery at a rate of 2 mL/h with an infusion balloon catheter. All patients were also allowed to receive indomethacin 50 mg rectally if they complained of pain.

All episodes of PONV (nausea, retching, and vomiting) were recorded by direct questioning by trained nurses blinded to the study group or by spontaneous complaint by the patients during three periods within the first 48 h after anesthesia: 0–3 h in the postanesthetic care unit, 3–24 h in the postoperative ward, and 24–48 h in the general ward. Nausea was defined as the subjectively 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 content; and vomiting was defined as the forceful expulsion of gastric contents from the mouth (2). Complete response (i.e., emesis-free) was also defined as no PONV and no need for another rescue medication. If there were two or more episodes of PONV during the first 48 h after anesthesia, another rescue antiemetic (e.g., domperidone rectally) was given. At the end of each observation period, the patients evaluated the severity of nausea and satisfaction with the study drug. The evaluations were performed on a linear numerical scale ranging from 0 (no nausea; complete dissatisfaction) to 10 (severe nausea; complete satisfaction). The details of any other adverse effects were recorded by the nurses who interviewed the patients and recorded their spontaneous complaints.

Statistical analyses of data between the groups were performed by using analysis of variance with Bonferroni correction for multiple comparison, {chi}2 test, two-tailed Fisher’s exact probability test, or the Mann-Whitney U-test, as appropriate. A P value of <0.05 was considered significant. Values are expressed as mean ± SD, number (%), or median (range). Before post hoc analysis, power analysis was used to determine the number of patients in the study based on the assumptions that (a) a complete response (no PONV, no rescue) in a patient receiving granisetron would be 70%, (b) an improvement from 70% to 90% was considered of clinical importance, and (c) {alpha} = 0.05 and a power (1 - ß) of 0.8. Based on these assumption, 60 patients per group were required.


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
There were no differences in patient demographics between the treatment groups (Table 1).


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  		Table 1. Patient demographics
 
The incidence of a complete response (no PONV, no rescue) 0–3 h after anesthesia was 87% with granisetron and 90% with ramosetron; the corresponding incidence 3–24 h after anesthesia was 85% and 90%; the corresponding incidence 24–48 h after anesthesia was 70% and 92%. Thus, a complete response 24–48 h after anesthesia was more frequent in patients who had received ramosetron than in those who had received granisetron (P < 0.05). At 24–48 h after anesthesia, nausea was less severe in patients who received ramosetron than in those who received granisetron (P < 0.05). Patients who received ramosetron were also more satisfied than those who received granisetron (P < 0.05) (Table 2).


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  		Table 2. Patients Having a Complete Response (No PONV, No Rescue), Side Effects, Severity of Nausea, and Patient Satisfaction
 
The most frequently reported adverse events were headache, dizziness, and drowsiness, but these were not clinically serious. There were no differences in the incidence of adverse effects between the groups (Table 3).


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  		Table 3. Adverse Events
 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The etiology of PONV after major gynecologic surgery performed under general anesthesia is complex and is dependent on a variety of factors, including age, obesity, a history of motion sickness and/or previous PONV, menstruation, surgical procedure, anesthetic technique, and postoperative pain (2). In this study, however, the treatment groups were comparable with respect to patient demographics, types of surgery, anesthetics administered, and analgesics used postoperatively. Patients with a history of motion sickness and/or previous PONV and those who were menstruating were excluded because they had a relatively high risk of PONV. Therefore, the difference in a complete response (no PONV, no rescue) between the groups can be attributed to the study drug.

Granisetron is effective treatment for emesis induced by cancer chemotherapy (6). We have demonstrated that it is effective for preventing PONV in major gynecologic surgery (3,4). The precise mechanism of granisetron for the prevention of PONV remains unclear, but it has been suggested that granisetron may act on sites containing 5-HT3 receptors with demonstrated antiemetic effects (7). Ramosetron is a highly potent 5-HT3 receptor antagonist with relatively high pharmacological bioavailability (8), and it is also effective for the treatment of cisplatin-induced emesis (9). Our results demonstrate that ramosetron, as well as granisetron, reduced the incidence of PONV after major gynecologic surgery. The exact mechanism of ramosetron in the prevention of PONV is unknown, but ramosetron may act at the area postrema and the nucleus tractus solitarius, which contain a number of 5-HT3 receptors (8). Therefore, the possible mechanism of this antiemetic for preventing PONV is similar to that of granisetron.

The effective dose of granisetron is 40–80 µg/kg for the treatment of cancer chemotherapy-induced nausea and vomiting (10). We demonstrated that the efficacy of granisetron 40 µg/kg is similar to that of granisetron 60 µg/kg for preventing PONV after major gynecologic surgery (11). The dose of granisetron 2.5 mg (approximately 45 µg/kg) we chose was within its effective dose range (40–60 µg/kg). However, the dose of ramosetron to be used for the prevention of PONV is not established but was extrapolated from the dose used in the clinical trials (9,12). These investigations demonstrated that ramosetron 0.3 mg is effective for the prevention or treatment of cisplatin-induced emesis. Although the same dose (0.3 mg) of ramosetron used in the present clinical trial has been shown to be effective for preventing PONV, it is not necessarily the optimal dose. Further studies ranging the dose-response curve available for the antiemetic effect of ramosetron are required to determine the optimal dose.

We could not find any report to compare the efficacy of granisetron and ramosetron for preventing PONV in major gynecologic surgery. Our results demonstrate that the antiemetic efficacy of ramosetron is similar to that of granisetron for preventing PONV during the first 24 hours (0–24 hours) after anesthesia and that ramosetron is more effective than granisetron for increasing a complete response (no PONV, no rescue) within the next 24 hours (24–48 hours). This suggests that ramosetron has a more potent antiemetic effect that lasts up to 48 hours longer than granisetron. The exact reason for the difference in effectiveness between granisetron and ramosetron is not known but may be related to the elimination half-life (granisetron 3.1 ± 1.2 hours versus ramosetron 5.8 ± 1.2 hours) (12,13) and/or the affinities of 5-HT3 receptor antagonists (granisetron 1 versus ramosetron 41) (14).

The major deficiency in this study design is the failure to include a control group receiving placebo. We have previously demonstrated that granisetron is a better antiemetic than placebo for preventing PONV in major gynecologic surgery (3,4). Aspinall and Goodman (15) have also suggested that placebo-controlled trials may be unethical if active drugs are available because PONV are common and distressing symptoms against which there is effective treatment. Therefore, a control group was not included in this study.

Adverse effects with a single therapeutic dose of granisetron or ramosetron against emesis induced by anticancer drugs are extremely rare and generally minor (9,16). As previously demonstrated (3,4), the prophylactic use of granisetron for preventing PONV reveals no sedative, dysphoric, and extrapyramidal signs. The adverse events we observed were not clinically serious, and there were no differences in the incidence of headache, dizziness, and drowsiness between the treatment groups. Thus, ramosetron, like granisetron, is devoid of clinically important side effects.

Several investigators have criticized new antiemetics, 5-HT3 receptor antagonists (e.g., ondansetron) because of their high cost (17,18). In Japan, ondansetron ($103.00 for 3 mg), granisetron ($102.00 for 3 mg), and ramosetron ($100.00 for 0.3 mg) are much more expensive than other commonly used antiemetics, such as droperidol ($1.80 for 1.25 mg) and metoclopramide ($0.60 for 10 mg). However, the use of droperidol and metoclopramide as antiemetics has been limited because these drugs sometimes cause excessive sedation or extrapyramidal symptoms (2). Based on our results, however, ramosetron is more effective than granisetron in increasing a complete response (no PONV, no rescue) and patient satisfaction 24–48 hours after anesthesia. Therefore, the choice of antiemetics should be based not only on the calculation of costs, but also on the preference of patients.

In conclusion, prophylactic therapy with ramosetron is more effective than prophylactic therapy with granisetron for the long-term prevention of PONV in major gynecologic surgery.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

  1. Madej T, Simpson K. Comparison of the use of domperidone, droperidol and metoclopramide in the prevention of nausea and vomiting following gynecological surgery. Anaesth 1986;58:879–83.
  2. Watcha MF, White PF. Postoperative nausea and vomiting: its etiology, treatment, and prevention. Anesthesiology 1992;77:162–84.[ISI][Medline]
  3. Fujii Y, Tanaka H, Toyooka H. Reduction of postoperative nausea and vomiting with granisetron. Can J Anaesth 1994;41:291–4.[Abstract/Free Full Text]
  4. Fujii Y, Tanaka H, Toyooka H. Prevention of postoperative nausea and vomiting with granisetron: a randomized, double-blind comparison with droperidol. Can J Anaesth 1995;42:852–6.[Abstract/Free Full Text]
  5. Fujihara A, Akuzawa S, Miyata K, Miyake A. Ramosetron hydrochloride: affinity for cloned human 5-HT3 receptor and 5-HT3 receptor antagonistic and antiemetic effect in the ferret. Lab Clin 1996;30:1965–72.
  6. Bermudez J, Boyle EA, Minter WD, Sanger GJ. The antiemetic potential of the 5-hydroxytryptamine3 receptor antagonist BRL 43694. Br J Cancer 1988;58:644–50.[ISI][Medline]
  7. Carmichael J, Cantwell BMJ, Edwards CM, et al. A pharmacokinetic study of granisetron (BRL 43694A), a selective 5-HT3 receptor antagonist: correlation of anti-emetic response. Cancer Chemother Pharmacol 1989;24:45–9.[ISI][Medline]
  8. Kamato T, Ito H, Nagakura Y, et al. Mechanism of cisplatin- and m-chlorophenylbiguanide-induced emesis in ferret. Eur J Pharmacol 1993;238:369–76.[ISI][Medline]
  9. Noda K, Ikeda M, Yoshida O, et al. Clinical evaluation of ramosetron against the nausea and vomiting induced by anticancer drugs. Jpn J Clin Exp Med 1994;71:2765–76.
  10. Furue H, Oota K, Taguchi T, Niitani H. Clinical evaluation of granisetron against nausea and vomiting induced anticancer drugs: optimal dose-finding study. J Clin Ther Med 1990;6:49–61.
  11. Fujii Y, Tanaka H, Toyooka H. Optimal anti-emetic dose of granisetron for preventing postoperative nausea and vomiting. Can J Anaesth 1994;41:794–7.[Abstract/Free Full Text]
  12. Kawabata Y, Sakiyama H, Muto S, et al. Clinical evaluation and pharmacokinetics of ramosetron against the nausea and vomiting induced by anticancer drugs. Nishinihon J Urol 1994;56:1445–56.
  13. Kumakura H, Koyanagi J, Nishioka Y, et al. Phase I study of granisetron: pharmacokinetics of granisetron following single and repeat intravenous drips infusion in Japanese healthy volunteers. J Clin Ther Med 1990;5:25–34.
  14. Fujihara A, Akuzawa S, Miyata K, Miyake T. Ramosetron hydrochloride: affinity for cloned human 5-HT3 receptor and 5-HT3 receptor antagonistic and antiemetic effect in the ferret. Lab Clin 1996;30:1955–64.
  15. Aspinall RL, Goodman NW. Denial of effective treatment and poor quality of clinical information in placebo controlled trials of ondansetron for postoperative nausea and vomiting: a review of published trials. BMJ 1995;311:844–6.[Abstract/Free Full Text]
  16. Yarker YE, McTavish D. Granisetron: an update of its therapeutic use in nausea and vomiting induced by antineoplasmic therapy. Drugs 1994;48:761–93.[ISI][Medline]
  17. White PF, Watcha MF. Are new drugs cost-effective for patients undergoing ambulatory surgery? Anesthesiology 1993;78:2–5.[ISI][Medline]
  18. Lerman J. Are antiemetics cost-effective for children? Can J Anaesth 1995;42:263–6.[Free Full Text]
Accepted for publication April 28, 1999.




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This Article
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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press