Epidural ondansetron is more effective to prevent postoperative pruritus and nausea than intravenous ondansetron in elective cesarean delivery

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1 Acta Obstetricia et Gynecologica. 007; 86: ORIGINAL ARTICLE Epidural ondansetron is more effective to prevent postoperative pruritus and nausea than intravenous ondansetron in elective cesarean delivery DONG WOO HAN 1, SOON WON HONG, JA-YOUNG KWON, JAE WOO LEE 1 & KI JUN KIM 1 1 Department of Anesthesiology and Pain Medicine, Anesthesia and Pain Research Institute, Department of Pathology, and Department of Obstetrics and Gynecology, International Health Care Center, Yonsei University College of Medicine, CPO Box 8044, Seoul 10-75, Korea Abstract Background. Postoperative pruritus, nausea, and vomiting are common side effects of intrathecal or epidural opioids. Intravenous ondansetron has been used for postoperative emesis. However, there are no reports regarding epidural ondansetron. Two studies were conducted to evaluate the prophylactic effects of epidural ondansetron for opioid-induced pruritus, nausea, and vomiting. Methods. Neurotoxic signs were checked after epidural injection of ondansetron in rats. A clinical study was conducted to compare the prophylactic effects of epidural ondansetron with intravenous ondansetron for opioid-induced pruritus, nausea, and vomiting in cesarean delivery. Results. No neurotoxic evidence was found in rats. The incidence of pruritus and nausea was significantly lower in the epidural ondansetron group than in the intravenous ondansetron group at 4 and 48 h postoperatively. Conclusions. Epidural ondansetron is more effective in preventing postoperative pruritus and nausea than intravenous ondansetron. Key words: Nausea, ondansetron, pruritus Postoperative pruritus, nausea, and vomiting are common side effects of intrathecal (IT) or epidural (EP) opioids (1). Ondansetron, a selective 5-HT receptor antagonist, has been used for nausea and vomiting in chemotherapy. However, Sarvela et al. () recently reported that intravenous (IV) ondansetron did not prevent IT opioid-induced pruritus. It has been known that 5-HT receptors are related to pruritus and emesis (). 5-HT receptors are abundant in the medulla and dorsal horn of the spinal cord (4). Therefore, EP ondansetron may be more effective in preventing neuraxial opioid-induced pruritus, nausea, and vomiting than IV ondansetron. However, reports on the effects of EP ondansetron are lacking. A clinical study was performed to compare the effects of EP ondansetron with IV ondansetron for prophylaxis of opioid-induced pruritus, nausea, and vomiting in cesarean delivery after an animal study. Material and methods The study was approved by the Yonsei University Animal Research Ethics Committee. Male Sprague Dawley rats (18000 g) were used. The rats were anesthetized using enflurane in 95% oxygen. An 8-cm polyethylene catheter (PE-10 TM, Becton Dickinson, USA) was advanced caudally through the atlanto-occipital membrane. After surgery, the rats were allowed to recover for one week and observed. Only those rats having normal motor behavior were included in this study. Correspondence: Ki Jun Kim, Department of Anesthesiology and Pain Medicine, Anesthesia and Pain Research Institute, Yonsei University College of Medicine, CPO Box 8044, Seoul 10-75, Korea. kkj606@yumc.yonsei.ac.kr (Received 11 September 006; accepted February 007) ISSN print/issn online # 007 Taylor & Francis DOI: /

2 684 D.W. Han et al. Seven days after operation, 18 rats in the study were randomly assigned to one of three groups: 1. ondansetron (Zofran TM, GlaxoSmithKline, UK) 10-mg group (n6);. ondansetron 0-mg group (n6); and. 0.9% normal saline group (n6). Ondansetron was given intrathecally in a volume of 10 ml, and the catheter was flushed with 10 ml of normal saline. In the saline group, the animals were given 0 ml of saline. The injections were done in each animal once daily between 6 and 7 a.m. for 14 days. Neurological functions such as posture, gait, eating habits, and righting reflexes were observed. Twenty-four hours after the last IT injection, the rats were anesthetized with enflurane and the L1 segment of the spinal cord was excised. The segment was cut coronally and slices were stained with hematoxylin-eosin. The ultrathin sections were stained with uranyl acetate and examined under an electron microscope. A pathologist who was blinded to the experiment analyzed the slides. The study was approved by the institutional review board and written informed consent was obtained. Sample size was predetermined using a power analysis based on the assumptions that: a. the incidence of pruritus in patients undergoing IV ondansetron would be about 50%; b. reduction of pruritus from 50% to 0% was considered as having clinical importance; and c. a0.05 with a power of 0.8. Eighty-two pregnant women (ASA I) who were scheduled for cesarean delivery were included. Combined spinal EP anesthesia was conducted. All patients received a single injection of 10 mg of hyperbaric bupivacaine (Marcaine TM, AstraZeneca) and fentanyl (15 mg). An EP catheter was inserted. The surgical technique was kept uniform for all patients. After delivery of the fetus, all patients were given 4 mg ondansetron intravenously over a minute. Then, patients were randomly allocated into two groups using a random number sequence. After the operation, ondansetron (8 mg/4 ml) (IV group) or 0.9% normal saline (4 ml) (EP group) mixed with normal saline 1,000 ml was continuously infused intravenously for 48 h (1 ml/h). Simultaneously, continuous EP infusion was initiated by attaching Two-day Infusors TM (Baxter, USA) containing either 7 mg morphine sulfate in 100 ml of 0.% ropivacaine (Naropin TM, AstraZeneca) (IV group) or 8 mg ondansetron and 7 mg morphine sulfate in 100 ml of 0.% ropivacaine (EP group). The study drugs were prepared by an anesthesiologist who was not participating in the evaluation of the patients. The incidence and degree of nausea, vomiting, pruritus, pain, and side effects such as headache, cardiac arrhythmia (with stethoscope), and extrapyramidal symptoms were assessed by an anesthesiologist who was blinded to the groups during the following 48 h. The degrees of nausea, vomiting, pruritus, and pain are shown in Table I. When of pruritus or nausea was required, diphenhydramine (5 mg) or metoclopramide (5 mg) was administered. Demographic variables between the two groups were compared using the t-test. The incidence and severity of nausea, vomiting, pruritus, and pain were analyzed by chi-square test. Data were presented as mean9sd and a p value of 0.05 or less was considered significant. Results All rats showed normal behaviors and motor functions. Macroscopic examinations of the spinal cord revealed that the catheter tip was located at the lumbar enlargement area in all rats. Hemorrhage or necosis was not found. Under light and electron microscopy, there were no specific morphological Table I. The grades for nausea, vomiting, pruritus, and pain. Condition Grading criteria Nausea 0 No nausea 1 Mild nausea, not requesting pharmacological Moderate nausea, requesting pharmacological Severe nausea resistant to pharmacological Vomiting 0 No vomiting 1 Mild vomiting, not requesting pharmacological Moderate vomiting, requesting pharmacological Severe vomiting resistant to pharmacological Pruritus 0 No pruritus 1 Mild pruritus not requesting pharmacological Moderate pruritus, requesting pharmacological Severe pruritus resistant to pharmacological Pain 0 No pain 1 Mild pain, not requesting pharmacological Moderate pain, requesting pharmacological Severe pain resistant to pharmacological

3 The effect of epidural ondansetron 685 Figure 1. Spinal cord of normal saline administered rat (A: H&E, #40; B: H&E, #00; C: EM, #4,400) and spinal cord of ondansetron 0 mg administered rat (D: H&E, #40; E: H&E, #00; F: EM, #4,400). Pictures of spinal cord of ondansetron 10 mg administered rat were not shown. In lower power view, there is no identifiable histologic difference such as hemorrhage, necrosis, or edema among the groups. In medium power view, there is also no identifiable inflammation, vasculitis, or necrosis in experimental groups. Ultrastructural manifestations have no specific differences among the groups and shapes of microstructures of experimental groups are normal. Black arrow indicates mitochondria and white arrow indicates RBC. The calibration bars represent 5 mm for all electromicroscopic photographs or histological changes in any the three groups (Figure 1). Eighty patients (40 in each group) completed the protocol. Two patients were excluded due to accidental removal of the EP catheter (IV group) and postoperative bleeding (EP group). There were no differences in the demographic characteristics between the two groups (Table II). Table II. Patients characteristics. IV group (n40) EP group (n40) Age (years) Weight (kg) Height (cm) Operation time (min) Anesthesia time (min) There is no specific difference between two groups. The overall incidence of pruritus was significantly lower in the EP group (.5% and 15%) than that in the IV group (55% and 0%) at 4 and 48 h postoperatively (p B0.05). Four patients (10%) in the IV group experienced moderate pruritus compared with none in the EP group 4 h postoperatively. The overall incidence of nausea was significantly lower in the EP group (5% and 10%) compared with the IV group (45% and 5%) at 4 and 48 h postoperatively (p B0.05). There were no differences in the incidence and severity in vomiting and pain between the two groups (Tables III and IV). No side effects such as headache, cardiac arrhythmia, and extrapyramidal symptoms were found in either group. No evidence of neurologic impairment was detected in any of the patients. Discussion Ondansetron can be administered via oral, IV, intramuscular, subcutaneous, and sublingual routes. However, no information on the EP injection of ondansetron in humans has been reported except for

4 686 D.W. Han et al. Table III. The number of patients for nausea, vomiting, pruritus, and pain at 4 h postoperatively. Grade IV group (n40) EP group (n40) Nausea 0 (55.0%) 0 (75.0%)* 1 15 (7.5%) 8 (0.0%)* (7.5%) (5.0%) Vomiting 0 4 (85.0%) 6 (90.0%) 1 6 (15.0%) 4 (10.0%) Pruritus 0 18 (45.0%) 1 (77.5%)* 1 18 (45.0%) 9 (.5%)* 4 (10.0%) Pain 0 6 (90.0%) 7 (85.0%) 1 4 (10.0%) (15.0%) 0, none; 1, mild;, moderate;, severe. Values are the number of patients and percent. *p B0.05. one case report. Ondansetron had been inadvertently administered into the EP space in a parturient patient but there were no neurologic sequelae (5). Neurotoxicity after neuraxial administration is related to many factors such as ph, osmolarity, preservatives, concentration, dose, and duration Table IV. The number of patients for nausea, vomiting, pruritus, and pain at 48 h postoperatively. Grade IV group (n40) EP group (n40) Nausea 0 6 (65.0%) 6 (90.0%)* 1 1 (0.0%) (7.5%)* (5.0%) 1 (.5%) Vomiting 0 7 (9.5%) 9 (97.5%) 1 (7.5%) 1 (.5%) Pruritus 0 4 (70.0%) 4 (85.0%)* 1 16 (0.0%) 6 (15.0%)* Pain 0 6 (90.0%) 8 (95.0%) 1 4 (10.0%) (5.0%) 0, none; 1, mild;, moderate;, severe. Values are the number of patients and percent. *p B0.05. (6,7). Ondansetron is stable and osmolarity is 70 mosm/l; pka is 7.4 and ph is 4.6, which is similar to lidocaine mixed with epinephrine (8). Ondansetron injectate contains no preservatives (9). We examined the histopathological changes of the spinal cord after IT administration of ondansetron. Although the IT and EP drug may have different mechanisms of action, histological damage is considered more severe after IT injection than EP injection. The spinal cord concentration of ondansetron after IT administration may be much higher than that after EP administration due to the barrier function of the dura (6). Therefore, spinal administration of a certain drug is considered a more appropriate route for evaluation of neurotoxicity. The large concentrations and doses were demonstrated to have neurotoxic potential (7). Much smaller IT doses are usually required for an equal effect compared to EP doses (6). An IT 0 mg of ondansetron in rat corresponds to approximately 78 mg/day in parturient women on a weight basis, which is above the recommended clinical dose. Therefore, continuous administration of EP ondansetron diluted in local anesthetics in human would be expected to produce much lower concentrations in the spinal cord than in rats. Pruritus is a common adverse effect of neuraxial opioids. It occurs more often in the obstetric population, which may result from an interaction of estrogen with opioid receptors (10). This type of pruritus is resistant to conventional and therefore requires drugs such as histamine blockers, propofol, and opioid antagonists. Histamine blockers and propofol have limitations because of sedation and reversal of analgesia (11). Pruritus associated with neuraxial opioids results from activation of m-opioid receptors or non-nociceptive neurons in the medulla and dorsal horn of the spinal cord involving the trigeminal nerve distribution (1). Direct stimulation of 5-HT receptors is another mechanism (). When administered epidurally, ondansetron could more easily reach and provide a higher concentration at the spinal dorsal horn. A small fraction of EP ondansetron might be absorbed systemically through EP venous plexus and have a supraspinal anti-pruritic effect. In patients receiving EP morphine, the incidence of nausea and vomiting is frequent (0 50%). Although prophylactic IV ondansetron has prevented opioid-induced nausea and vomiting, certain studies failed to demonstrate an anti-emetic effect (1,14).

5 The effect of epidural ondansetron 687 During general anesthesia, 5-HT is released from the enterochromaffin cells of the gastrointestinal tract (15). Released 5-HT sends impulses via vagal afferents to the chemoreceptor trigger zone (CTZ) in the area postrema and then to the vomiting center. Therefore, postoperative nausea and vomiting can be prevented or treated by blocking either peripheral or central 5-HT receptors. The role of ondansetron in blocking central 5-HT receptors would be more effective than peripheral 5-HT receptors for reducing neuraxial opioid-induced nausea and vomiting due to the central migration of opioids. Ondansetron might be involved in the pain pathway through various serotonergic systems (16). Ondansetron has a potent local anesthetic effect that blocks sodium channels and interrupts spinal nerve conduction (17). Therefore, it would be expected that EP ondansetron might produce an analgesic effect, although IV ondansetron has been reported to have little effect on postoperative pain (18,19). It might be difficult to determine whether EP ondansetron would have any antinociceptive effect as the opioid and local anesthetics administered with ondansetron prevented postoperative pain so efficiently. The most common adverse effect after systemic administration of ondansetron is headache, which is dose dependent (0). EP administration of a drug may reduce the development of systemic side effects of the drug due to its lower plasma concentration (1). In conclusion, EP ondansetron is more effective in preventing postoperative pruritus and nausea than IV ondansetron. References 1. Chaney MA. Side effects of intrathecal and epidural opioids. Can J Anaesth. 1995;/4:/ Sarvela PJ, Halonen PM, Soikkeli AI, Kainu JP, Korttila KT. Ondansetron and tropisetron do not prevent intraspinal morphine- and fentanyl-induced pruritus in elective cesarean delivery. Acta Anaesthesiol Scand. 006;/50:/944.. Yeh HM, Chen LK, Lin CJ, Chan WH, Chen YP, Lin CS, et al. Prophylactic intravenous ondansetron reduces the incidence of intrathecal morphine-induced pruritus in patients undergoing cesarean delivery. Anesth Analg. 000;/91:/ Laporte AM, Doyen C, Nevo IT, Chauveau J, Hauw JJ, Hamon M. Autoradiographic mapping of serotonin 5-HT1A, 5-HT1D, 5-HTA and 5-HT receptors in the aged human spinal cord. J Chem Neuroanat. 1996;/11:/ Huang JJ. Inadvertent epidural injection of ondansetron. J Clin Anesth. 006;/18:/ Kirihara Y, Saito Y, Sakura S, Hashimoto K, Kishimoto T, Yasui Y. Comparative neurotoxicity of intrathecal and epidural lidocaine in rats. Anesthesiology. 00;/99:/ Yamashita A, Matsumoto M, Matsumoto S, Itoh M, Kawai K, Sakabe T. A comparison of the neurotoxic effects on the spinal cord of tetracaine, lidocaine, bupivacaine, and ropivacaine administered intrathecally in rabbits. Anesth Analg. 00;/97:/ Simpson KH, Hicks FM. Clinical pharmacokinetics of ondansetron. A review. J Pharm Pharmacol. 1996;/48:/ Malinovsky JM, Lepage JY, Cozian A, Mussini JM, Pinaudt M, Souron R. Is ketamine or its preservative responsible for neurotoxicity in the rabbit? Anesthesiology. 199;/78:/ Chadwick HS, Ready LB. Intrathecal and epidural morphine sulfate for post-cesarean analgesia a clinical comparison. Anesthesiology. 1988;/68:/ Borgeat A, Wilder-Smith OH, Saiah M, Rifat K. Subhypnotic doses of propofol relieve pruritus induced by epidural and intrathecal morphine. Anesthesiology. 199;/76:/ Thomas DA, Williams GM, Iwata K, Kenshalo DR Jr, Dubner R. The medullary dorsal horn. A site of action of morphine in producing facial scratching in monkeys. Anesthesiology. 199;/79:/ Pitkanen MT, Numminen MK, Tuominen MK, Rosenberg PH. Comparison of metoclopramide and ondansetron for the prevention of nausea and vomiting after intrathecal morphine. Eur J Anaesthesiol. 1997;/14:/ Millo J, Siddons M, Innes R, Laurie PS. Randomized doubleblind comparison of ondansetron and droperidol to prevent postoperative nausea and vomiting associated with patientcontrolled analgesia. Anaesthesia. 001;/56:/ Roila F, Ballatori E, Tonato M, Del Favero A. 5-HT receptor antagonists: differences and similarities. Eur J Cancer. 1997;/:/ Bardin L, Lavarenne J, Eschalier A. Serotonin receptor subtypes involved in the spinal antinociceptive effect of 5-HT in rats. Pain. 000;/86:/ Ye JH, Mui WC, Ren J, Hunt TE, Wu WH, Zbuzek VK. Ondansetron exhibits the properties of a local anesthetic. Anesth Analg. 1997;/85:/ Davies PR, Warwick P, O Connor M. Antiemetic efficacy of ondansetron with patient-controlled analgesia. Anaesthesia. 1996;/51:/ Yazigi A, Chalhoub V, Madi-Jebara S, Haddad F, Hayek G. 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