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enay F. Tuncay, MD
Ba
kent University Faculty of Medicine, Department of Anesthesiology, Ankara, Turkey and Department of Anesthesiology, Air Force Hospital, Etimesgut, Ankara, Turkey
Address correspondence and reprint requests to Arash Pirat, MD, Bakent Üniversitesi Hastanesi Anesteziyoloji Anabilim Dalí 10. Sok. No: 45 Bahçelievler 06490, Ankara, Turkey. Address electronic mail to arashp{at}baskent-ank.edu.tr.
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Abstract |
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Introduction |
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Orally disintegrating tablets (ODT) of ondansetron, which disperse rapidly when placed on the tongue, have been used to treat radiotherapy- and chemotherapy-induced nausea and vomiting (11,12). This new formulation of ondansetron is also attractive as a drug for anesthesia practice, where the need for preoperative fasting and nil per os orders precludes the use of traditional oral medications. The literature contains a few reports on use of the ODT form of ondansetron (hereafter referred to as ODT ondansetron) for PONV (13,14); however, there are no published data on the use of ODT ondansetron for preventing IT opioid-induced pruritus and PONV, and it is not clear whether the ODT formulation of this drug is as effective as the IV form.
In this study, we compared the efficacy of ODT ondansetron 8 mg, IV ondansetron 4 mg, and placebo for preventing IT morphine-induced pruritus and PONV in a group of young men who underwent minor elective surgeries.
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Methods |
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Patients in the ODT group (n = 50) received ODT ondansetron 8 mg and 5 mL of normal saline IV. Patients in the IV group (n = 50) received IV ondansetron 4 mg in 5 mL saline and an oral placebo. Those in the placebo group (n = 50) received 5 mL normal saline IV and an oral placebo. All substances (ondansetron or placebo) were administered 10 min before spinal anesthesia. Unfortunately, at the time the study was conducted, the manufacturer of ODT ondansetron stated it was unable to provide us with placebo pills. Therefore, we used a mild peppermint candy that disperses when placed on the tongue as the oral placebo. Although this was not a one-to-one placebo for ODT ondansetron, we believe it was a suitable substitute because none of the patients had used ODT ondansetron previously.
Patients, anesthesiologists who attended the intraoperative care, and nurse anesthesiologists who performed the postoperative evaluations were unaware of patient group allocations. To ensure the study was blinded, the nurse who prepared and administered the study drugs was not involved in patient care. Standard intraoperative monitoring with electrocardiogram (ECG), noninvasive arterial blood pressure, and pulse oximetry was used. Before spinal anesthesia, normal saline 15 mL/kg IV was given over 30 to 60 min. Then the patient was placed in sitting position and a 25-gauge Quincke needle was placed in the L2-3 or L3-4 interspace using a midline approach. Once successful dural puncture was confirmed by observation of a free flow of cerebrospinal fluid, an IT injection of 0.5% hyperbaric bupivacaine (12.5 mg if <75 kg body weight and 15.0 mg if 
75 kg) with 0.2 mg of preservative-free morphine was administered with the bevel of the needle oriented caudally. In all cases, two anesthesiologists who were blinded as to the study performed the spinal anesthesia and determined the level of sensory blockade by pinprick testing. For intraoperative sedation, each patient received an IV injection of midazolam 0.05 mg/kg before spinal anesthesia, and this was repeated as required during the surgery. All patients received supplemental oxygen via nasal cannulae (rate 3–5 L/min) during the procedure.
Intraoperative hemodynamic and respiratory complications were recorded. Hypotension was defined as a 15% decrease in systolic blood pressure from baseline or the appropriate age-adjusted values. Bradycardia was defined as heart rate less than 40 bpm or as an inappropriately slow heart rate despite hypovolemia. Hypoxia was defined as an oxygen saturation value <90%. Hypotension was treated with IV boluses of ephedrine 0.1 mg/kg and normal saline 5 mL/kg, and the same doses were repeated if required. Bradycardia was treated with atropine 1 mg IV.
At the end of the surgery, patients were transferred to the postanesthesia care unit (PACU), where nurse anesthesiologists who were unaware of the group allocations cared for them. A patient was transferred to the surgery ward from the PACU when the following criteria were met: hemodynamic and respiratory stability, full recovery from motor block, sensory block no higher than the T10 level, no or minimal pain, no or minimal nausea, no or minimal pruritus, and absence of vomiting or surgical bleeding. Postoperative pain was treated with an IM injection of diclofenac sodium 100 mg. This was administered if the patient asked for an analgesic medication or his pain visual analog scale (VAS) score was 5 (see VAS details below).
Each patient was assessed in the PACU and at 2, 6, 12, 18, and 24 h postoperatively for frequency and severity of PONV, pruritus, and postoperative pain. Patients who were sleeping at the assessment time were considered to be symptom-free and were asked if they had any complaints at the next assessment time. Anesthesiology nurses who were blinded as to the study performed all these evaluations. Nausea was defined as an unpleasant feeling associated with inclination to vomit, and vomiting was defined as the forceful ejection of gastric contents through the mouth. Retching (defined as involuntary gastric and esophageal movements of vomiting without expulsion of vomitus) was also recorded as vomiting. Pruritus was defined as an uncomfortable sensation of irritation of the skin or mucous membranes that provokes the desire to scratch or rub the affected sites. Patients were asked about the presence of PONV, pruritus, and pain and, if present, their location and intensity. Three distinct standard 10-cm VASs (0 representing no symptom and 10 representing the worst imaginable severity of the symptom) were used to determine the intensity of PONV, pruritus, and pain. We also recorded the frequencies of vomiting episodes, use of rescue antiemetic, and adverse reactions to ondansetron (headache, cardiac arrhythmias, extrapyramidal signs) in the first 24 h after surgery. Patients were asked about the presence and characteristics of headache. If a patient complained of palpitations, 12-lead ECG was used to verify the arrhythmia. The rescue medications for PONV and pruritus were droperidol 1.25 mg IV and diphenhydramine 10 mg IV, respectively. Droperidol was administered if a patient had 2 or more vomiting episodes, if the nausea VAS score was 5, or if the patient asked for an antiemetic. Diphenhydramine was given if the pruritus score was 5 or if the patient asked for an antipruritic.
The n values for the study groups were established using power analysis. A preliminary survey of similar patients who underwent similar operations and anesthesia revealed PONV and pruritus incidences of 55% and >75%, respectively. Assuming respective PONV and pruritus frequencies of 55% and 75%, the calculation revealed that 49 patients per group would be adequate to provide a ß value of 0.2 and an 
value of 0.05 for detection of a 50% difference in incidences of PONV and pruritus. All values are presented as mean ± sd or number (%), as appropriate. For continuous data, statistical analyses were performed with one-way analysis of variance. Repeated measures of analysis of variance were used to compare the groups’ pruritus, nausea, and pain VAS scores and also to determine the significance of group x time (G x T) interactions. Where a significant difference was detected, the Student’s t-test with Bonferroni correction was applied for multiple comparisons within the groups. The time to the start of PONV and pruritus were analyzed by means of Kaplan-Meier probability curves and the log-rank test. The 
2 test was used to analyze categorical variables, as appropriate. For all determinations, P values < 0.05 were considered significant.
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Results |
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The proportion of the placebo group that developed pruritus in the first 24 h postsurgery (86%) was significantly larger than the corresponding proportions in the ODT group (56%, P = 0.001) and the IV group (66%, P = 0.017), but the rates in the ODT and IV groups were not significantly different (Table 2). Repeated-measures analysis of variance revealed significantly different mean pruritus VAS scores within each group at the different time points studied (Table 3). The same analysis also demonstrated a significantly lower overall mean pruritus VAS score in the ODT group than the placebo group (P = 0.001) and no significant G x T interactions among the 3 groups. The ODT group had significantly lower mean pruritus VAS scores in the PACU and at 2, 6, and 12 h postsurgery than the placebo group (P< 0.03 for all comparisons) (Table 3). However, the mean pruritus VAS scores in the IV group were not significantly different from those in the other groups at any of the time points assessed. Forty percent of the patients in the placebo group required rescue antipruritic treatment in the first 24 h, and this proportion was significantly larger than that in the ODT group (18%) (P = 0.013) (Table 2). However, there were no significant differences between the ODT and IV groups (18% and 34%, respectively; P = 0.055) or the placebo and IV groups (40% and 34%, respectively; P > 0.05) with respect to requirement for this type of rescue therapy. At the end of the study period, 44% of the patients in the ODT group, 34% in the IV group, and only 14% in the placebo group were free of pruritus (log-rank test: P = 0.0008 for ODT versus placebo and P = 0.03 for IV versus placebo) (Fig. 1). There were no differences among the groups with respect to time to onset of pruritus (ODT: 122 ± 114 min, IV: 132 ± 203 min, placebo: 113 ± 145 min; P> 0.05) or sites of pruritus. Of the total 104 patients who developed pruritus in the first 24 h postsurgery, 83% (n = 85) experienced this symptom at more than one body site. The most common sites of pruritus in descending order were the chest (66%, n = 67), face (60%, n = 61), back (46%, n = 47), abdomen (38%, n = 39), and lower extremities (30%, n = 30).
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There were no significant differences among the three groups with respect to incidence of PONV, number of vomiting episodes, and use of rescue antiemetics in the first 24 h after surgery (Fig. 2, Tables 2 and 3). The mean numbers of vomiting episodes during the 24-h study period in the ODT, IV, and placebo groups were 0.6 ± 1.4, 0.8 ± 3.0, and 0.9 ± 2.5, respectively (P> 0.05). Repeated-measures analysis of variance revealed significantly different mean nausea VAS scores within each group at the different time points studied and no significant G x T interactions among the groups (Table 3).
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There were no significant differences among groups with respect to overall mean pain VAS score for the first 24 h or mean pain VAS scores at each time point studied (Table 3). There were also no significant differences among the groups with respect to frequency of need for additional analgesics (ODT: 16%; IV: 24%; placebo: 22%; P> 0.05) or amount of diclofenac sodium received (ODT: 90 ± 117 mg; IV: 98 ± 112 mg; placebo: 112 ± 137 mg; P> 0.05).
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Discussion |
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IT morphine is an attractive option for postoperative pain control because it causes intense and long-lasting analgesia, does not prolong motor recovery, and does not delay ambulation after surgery (15). However, the incidences of the IT morphine-associated side effects PONV and pruritus are reportedly as frequent as 60% to 80% (4,10). These undesirable side effects of IT morphine can be very disturbing to the patient, may be refractory to conventional antiemetic and antipruritic treatments, and may affect patient satisfaction and thus limit the use of this method of postoperative pain control.
IT morphine induces nausea and vomiting by acting on the chemoemetic trigger zone and vomiting center in the area postrema (3). Serotonin receptor antagonists act on serotonin receptors in the chemoreceptor trigger zone of the area postrema and have been shown to be effective against chemotherapy-induced nausea and vomiting and PONV (16,17). Several studies have tested the efficacy of these drugs for preventing nausea and vomiting induced by spinal opioids, and the results have been mixed (6,18–22). The diversity of these results is probably, at least in part, attributable to the fact that emetic symptoms have complex and multifactorial etiologies and are correlated with factors such as hormonal changes, sex, age, pain, surgical procedure, duration of operation, previous PONV, history of motion sickness, smoking status, and weight (6). Other reasons for discrepancies among the results of these studies could be the types and doses of IT opioids administered, different regimens of 5HT3 receptor antagonists tested, and different scales and definitions of PONV that have been used. Our findings suggest that neither IV ondansetron 4 mg nor ODT ondansetron 8 mg is more effective than placebo as prophylaxis for IT morphine-induced PONV in healthy young men who have no known risk factors for these side effects.
We believe ours is the first study to have investigated the efficacy of prophylactic ondansetron relative to IT morphine-induced-PONV in a homogeneous group of patients with no risk factors for such symptoms. We excluded all the patients with known risk factors for PONV, and all the participants were healthy young men. Based on the results, it appears that routine prophylactic administration of ondansetron for antiemetic purposes is not advisable in this patient group. All our patients were men, and this might partially explain why ondansetron did not reduce the incidence of PONV in this study. Apfel et al. (23) noted that droperidol is only effective at preventing PONV in females. The lack of effect on PONV in our study setting might also have been related to the short half-life of ondansetron (4–6 hours) and to the fact that IT morphine-induced PONV can last for a much longer period (up to 24 hours).
Pruritus is the most common side effect of IT opioids, with reported incidence rates of 57% to 95% (9,10,18,22,24,25). Several theories have been proposed to explain the mechanism of IT opioid-induced pruritus, but the exact pathogenesis remains unclear. The histamine-release theory does not explain this side effect because pruritus can also be induced by opioids that do not cause histamine release, and antihistamines are not effective treatment (18,24,25). The efficacy of ondansetron for preventing and treating of this form of pruritus indicates that serotonin type 3 receptors play a role (10,26). Serotonin receptor antagonists probably inhibit the direct excitatory effect of opioids on the non-nociceptive neurons in the posterior horn of the medulla spinalis and the nucleus of the spinal tract of the trigeminal nerve (24,26). Studies have demonstrated that ondansetron is effective at both treating (26) and preventing (9,22,27) IT morphine-induced pruritus. However, the efficacy of ondansetron for prophylaxis against pruritus when IT lipophilic opioids are administered is not clear (19,24,25). A report by Szarvas et al. (18) is the only one that has disputed this beneficial effect of ondansetron with IT morphine use. Compared with other studies mentioned above (9,22,27), Szarvas et al. administered a much larger amount of IT morphine (0.01 mg/kg, up to 0.7 mg) and they did not compare the efficacy of ondansetron with results in a placebo group. In our study, the onset and distribution of pruritus were similar to results that have been reported previously (22,26). We found that both the ODT (8 mg) and IV (4 mg) forms of ondansetron were associated with significantly less frequent pruritus than placebo (rates 56%, 66%, and 86%, respectively; P 
0.017 for all comparisons). We also found that only the prophylactic ODT ondansetron was associated with statistically less rescue antipruritic requirement than placebo treatment (18% versus 40%, respectively; P = 0.013). The same relationship held true for the mean VAS pruritus scores in the PACU and at 2, 6, and 12 hours postsurgery (P 0.023 for all comparisons). None of the corresponding comparisons involving the IV group (i.e., IV versus placebo or IV versus ODT) revealed significant differences. These results clearly indicate that, when compared with placebo treatment, prophylactic ODT ondansetron 8 mg effectively reduces the incidence and severity of IT morphine-induced pruritus and is even more effective in this respect than IV ondansetron 4 mg.
The ODT form of ondansetron seems to offer important advantages for anesthesia practice, as it avoids IV injection while maintaining the desired preoperative fasting state. Another important advantage of this formulation of the drug is that it can be used in ambulatory surgery after patient discharge. Still, the current literature contains only two reports on the use of ODT ondansetron for preventing PONV after general anesthesia (13,14). Our study is the first to have focused on prophylactic use of ODT ondansetron for IT morphine-induced pruritus and PONV. We used a 4-mg dose of IV ondansetron because previous studies have shown that this dose is adequate for preventing and treating emesis and pruritus after IT opioid administration (6,9,18,22,28). The dose of ODT ondansetron was chosen based on the pharmacokinetic properties of oral ondansetron and its 60% to 67% bioavailability (29,30). However, it is not clear whether the bioavailability of this newer formulation of the drug is identical to that of conventional tablets. It could be speculated that the higher antipruritic efficacy of ODT ondansetron compared with the IV formulation in our study might be a result of the fact that 8 mg of the ODT form results in a larger absorbed dose than 8 mg of conventional tablets or 4 mg of IV form. Timing of drug administration might also be important. In our study, both forms of ondansetron were administered at the same time (10 minutes before spinal anesthesia). It is logical to speculate that the IV ondansetron would have peaked before pruritus onset, whereas the ODT form probably peaked closer to the time of pruritus onset. It is also possible that ODT ondansetron was absorbed into the circulation more slowly than the IV form, thus providing a longer period of effective antipruritic blood levels.
One important limitation of this study is that the incidence of PONV in our placebo group was less frequent than the expected value we used to calculate required sample size (actual incidence 50% as opposed to estimated 55%). This increases the risk of type II error. Post hoc power analysis revealed that 50 patients per group gave this trial a power of 74% (for < 0.05). Another limitation is that we did not measure patients’ blood ondansetron levels. Without comparing the groups’ blood levels, it is impossible to make a clear-cut statement about why ODT ondansetron provided superior pruritus prophylaxis in this study. Third, the placebos that were used also constitute a limitation. It would have been preferable to administer placebo tablets that tasted and looked identical to the ODT form of ondansetron.
In conclusion, neither ODT ondansetron 8 mg nor IV ondansetron 4 mg is more effective than placebo as prophylaxis for IT morphine-induced PONV in young men with no known risk factors for PONV. Compared with placebo, both regimens of ondansetron were associated with less incidences of IT morphine-induced pruritus in this patient group. However, only the ODT form of ondansetron significantly reduced the severity of pruritus and the need for rescue antipruritic administration.
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Footnotes |
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This article has been cited by other articles:
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  M.-P. Bonnet, E. Marret, J. Josserand, and F. J. Mercier Effect of prophylactic 5-HT3 receptor antagonists on pruritus induced by neuraxial opioids: a quantitative systematic review Br. J. Anaesth., September 1, 2008; 101(3): 311 - 319. [Abstract] [Full Text] [PDF]
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P = 0.03, IV versus placebo (log-rank test).
