Although a wide variety of prophylactic antiemetics have been used for the prevention of postoperative nausea and vomiting (PONV), many of the traditional antiemetics produce undesirable side effects and have mixed success (1,2). Given the limited efficacy and adverse effects associated with the antiemetic drugs available at present, the search for more ideal compounds has continued (3,4).
Tandospirone, a partial agonist of the 5-hydro-xytryptamine-1A (5-HT1A) receptor, has become available in oral tablet form for clinical use in Japan. We have recently demonstrated that tandospirone can be used as an oral premedicant drug for relieving anxiety before anesthesia and surgery (5). In animal models, 5-HT1A receptor agonists prevent emesis elicited by a wide range of emetic stimuli (6,7). Tandospirone, if used as an oral preanesthetic drug, should prevent PONV. This study was performed to test the efficacy of tandospirone (versus placebo) in the prevention of PONV in patients undergoing tympanoplasty under general anesthesia.
The protocol of this study was approved by the Ethics Committee of Gifu University School of Medicine. Written, informed consent was obtained from 90 (39 male and 51 female) consecutive patients, aged 18–64 yr, ASA physical status I or II, all scheduled for tympanoplasty. Exclusion criteria included menstruation, bronchial asthma, and the use of centrally acting or antiemetic drugs within the previous week. A randomization list was generated, and identical pills containing each drug, according to the list, were prepared by personnel who were not involved in this study. Ninety patients—39 men and 51 women—were divided in a randomized, double-blinded design into 3 groups of 30 patients consisting of 13 men and 17 women. Together with oral famotidine 20 mg, subjects received tandospirone 30 mg (T30 group), tandospirone 10 mg (T10 group), or placebo (P group) 90 min before entry into the operating room.
Standard anesthetic regimens and techniques were applied for all the patients. Anesthesia was induced with fentanyl 2 μg/kg followed by thiopental 5 mg/kg. Tracheal intubation was facilitated with vecuronium 0.16 mg/kg. Anesthesia was maintained with 66% nitrous oxide in oxygen and 0.8%–1.5% (inspired concentration) isoflurane. Fifty-microgram additional doses of fentanyl were used exclusively for analgesia during the operation. End-expiratory carbon dioxide was maintained at 30–35 mm Hg. Arterial blood pressure and heart rate were kept within 20% of preanesthetic values. A nasogastric tube was inserted so that the gastric contents could be suctioned. Before tracheal extubation, the nasogastric tube was suctioned and then removed. Postoperative pain was treated with indomethacin 50-mg suppositories.
All episodes of PONV, i.e., 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 0–3 h and 3–24 h after the end of general anesthesia. Nausea was defined as the subjective sensation of discomfort associated with the 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 through the mouth; and complete response was defined as no PONV and no need for other rescue antiemetics. Evaluation of nausea was determined by the patient’s categorical response to the question “Are you nauseated, yes or no?” If there were 2 or more episodes of PONV during the 24 h after general anesthesia, the other antiemetic (e.g., metoclopramide 10 mg IV) was given. Details of any adverse effects were also recorded throughout the study.
To compare the group data among the T30, T10, and P groups, categorical data were analyzed by using the Pearson χ2 test with Yates’ correction or Fisher’s exact probability test, as appropriate. Continuous data were analyzed by means of Bonferroni’s multiple comparison tests after a one-way analysis of variance. In all tests, a value of P < 0.05 was considered statistically different. Group data are presented as the mean ± sd or number (%). Power analysis was performed to determine the number of patients in the study on the basis of the assumptions that 1) PONV in the P group would be 67%, 2) a change from 67% to 33% in either the T10 or T30 group was considered as clinically significant, and 3) α = 0.05 and 1 − β = 0.8. On the basis of these assumptions, at least 28 patients per group were required.
There were no significant differences among the T10, T30, and P groups in terms of age, sex, height, weight, motion sickness, history of PONV, duration of surgery and general anesthesia, dose of intraoperative fentanyl, or number of patients who received indomethacin after surgery (Table 1). The incidence of a complete response during the 24 h after general anesthesia was significantly more frequent in the T30 group than in the P group (P = 0.019) (Table 2). The incidence of a complete response during 3–24 h after general anesthesia was also significantly more frequent in the T30 group than in the P group (P = 0.007). The incidence of nausea during 3–24 h after general anesthesia was significantly less frequent in each of the T30 and T10 groups than in the P group (P = 0.030). With respect to adverse effects, the incidence of vertigo was significantly more frequent in the P group than in the T10 group (P = 0.010) (Table 2). No significant differences were observed among the three groups with respect to any adverse effects other than vertigo.
In patients undergoing tympanoplasty under general anesthesia, oral tandospirone 30 mg reduced the incidence of PONV for 24 hours, especially during 3–24 hours after general anesthesia, without adverse effects. This finding suggests that premedication with oral tandospirone is effective against PONV in patients undergoing tympanoplasty under general anesthesia.
The incidence of PONV after middle ear surgery without prophylactic antiemetic treatment is very frequent, varying from 62% to 80%(8–11). The etiology of PONV is multifactorial (1). Indeed, the main causes of PONV in this study likely included inhaled anesthetics (1), opioid analgesics (1), and vestibular stimulation caused by drilling and irrigating the bone adjacent to the inner ear (8–10). Therefore, antiemetic treatment against a wide range of emetic stimuli should be required to prevent PONV.
This study is the first to demonstrate the antiemetic effects of the 5-HT1A receptor agonist tandospirone in humans. The main difference between the tandospirone and placebo groups was a decrease in the incidence of nausea rather than of vomiting (Table 2). In experimental animals, 5-HT1A receptor agonists have been demonstrated to exhibit a broad spectrum of antiemetic effects (6,7). In Suncus murinus (a house musk shrew), the 5-HT1A receptor agonists 8-hydroxy-2-(di-n-propylamino)tetrarin (8-OH-DPAT), ipsapirone, and tandospirone prevent motion sickness and emesis elicited by nicotine, veratrine, cisplatin, copper sulfate, ethanol, and mechanical stimulation of the upper gastrointestinal tract (7). In the cat, 8-OH-DPAT prevents motion sickness and emesis elicited by xylazine and cisplatin (6). However, 5-HT3 receptor antagonists prevent cisplatin-induced emesis, but not xylazine-induced emesis or motion sickness, in the cat (12). Indeed, the 5-HT3 receptor antagonist ondansetron is less effective against PONV in patients with motion sickness than in those without (10). Thus, 5-HT1A receptor agonists may demonstrate a broader antiemetic spectrum than 5-HT3 receptor antagonists.
With respect to adverse effects, no significant differences were observed among the three groups. 5-HT1A receptor-related anxiolytics are reportedly devoid of respiratory, cardiovascular, or psychomotor complications (13–15). The antimuscarinic drugs scopolamine (8) and hyoscine (9) prevent PONV after tympanoplasty under general anesthesia. However, the use of these antiemetics has been limited because of their side effects, such as sedation (8,9). Furthermore, the use of 5-HT3 receptor antagonists has been criticized because of an extremely larger cost (for example, US$68 (8160 Japanese yen) for ondansetron 4 mg and US$70 (8400 Japanese yen) for granisetron 3 mg in our hospital) (16). In contrast, the cost our hospital pharmacy pays for tandospirone 30 mg is US$1.25 (150 Japanese yen).
One limitation of this study was that we did not study a large enough number of patients to examine the safety of tandospirone. Another limitation of our study was that only two doses of tandospirone were examined. Finally, no other antiemetic drugs and only surrogate end-points, rather than clinically meaningful outcomes (e.g., patient satisfaction), were studied. Further studies in a large num-ber of patients are needed to overcome these limitations.
In conclusion, an oral dose of tandospirone 30-mg reduced PONV after tympanoplasty under general anesthesia. 5-HT1A receptor agonists may be a useful new class of antiemetic drugs against PONV.
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© 2002 International Anesthesia Research Society
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