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OBSTETRIC ANESTHESIA

Prophylactic Intravenous Ondansetron Reduces the Incidence of Intrathecal Morphine-Induced Pruritus in Patients Undergoing Cesarean Delivery

Department of Anesthesiology, National Taiwan University Hospital, Taipei, Taiwan

Address correspondence and reprint requests to Li-Kuei Chen, MD, Department of Anesthesiology, National Taiwan University Hospital, No. 7, Chung-Shan South Rd., Taipei, Taiwan, 100.

	Abstract

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Pruritus is a common side effect of intrathecal morphine injection for postoperative pain control. Its incidence is especially high in patients undergoing cesarean delivery. We investigated the effectiveness of ondansetron in preventing intrathecal morphine-induced pruritus in such patients. We included 60 consecutive nonbreastfeeding women who were scheduled for elective cesarean delivery. After the administration of spinal anesthesia with bupivacaine and intrathecal morphine 0.15 mg injection, the patients were randomly divided into three groups. Group 1 received placebo (normal saline) IV injection, Group 2 diphenhydramine 30 mg IV injection, and Group 3 ondansetron 0.1 mg/kg IV injection. The incidence of pruritus was significantly lower in the ondansetron group (25%) when compared with that in the placebo group (85%) and in the diphenhydramine group (80%) (both P < 0.05). The postoperative pain score and time to flatus passage were not significantly different among the three groups. There were no headache or extrapyramidal signs associated with ondansetron use. In conclusion, ondansetron prophylaxis significantly reduced the incidence of intrathecal morphine-induced pruritus in patients undergoing cesarean delivery.

Implications: Ondansetron prophylaxis significantly decreases the incidence of pruritus, a common side effect of intrathecal morphine used to treat postcesarean delivery pain.

	Introduction

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Intrathecal injection of morphine is highly effective for the management of postoperative pain (1). Unfortunately, its use may be limited by side effects, such as pruritus (2,3). The pruritus often occurs 3–7 h after morphine injection. The symptoms typically spread rostrally from the site of administration to the trunk, then to the facial regions. Itching on the nose and around the eyes is typical (2). The pruritus is often difficult to treat and is refractory to conventional antipruritic treatments (3).

Ondansetron, a selective serotonin type 3 receptor antagonist (4), is commonly used for nausea and vomiting in patients undergoing cancer chemotherapy. Several studies have shown that ondansetron is effective in treating pruritus of various causes, including intrathecal morphine-induced pruritus (5–11). In a prospective, randomized, double-blinded study, Borgeat and Stirnemann (12) demonstrated that ondansetron was effective in treating spinal or epidural morphine-induced pruritus. The incidence of intrathecal morphine-induced pruritus is especially high after cesarean delivery (13,14), but a study evaluating prophylaxis in patients undergoing cesarean delivery has never been reported. We therefore undertook a prospective, randomized, double-blinded clinical study to test the hypothesis that ondansetron is more effective in decreasing the incidence of pruritus associated with intrathecal injection of morphine in patients undergoing cesarean delivery than either placebo or diphenhydramine (commonly used to treat pruritus).

	Methods

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In this randomized, double-blinded, placebo-controlled study, we included 60 consecutive nonbreastfeeding women who were scheduled for elective cesarean delivery. Only ASA physical status I and II patients were included. Approval of the institutional ethical committee was obtained, and all patients gave informed consent before the study. A power analysis showed that 17 patients per group would provide 80% power to detect a 50% decrease in the incidence of pruritus from 80% in the placebo group to 40% in the ondansetron group. To accommodate patient dropout, 20 patients in each group were studied. Patients with preeclampsia, eclampsia, placenta previa, impaired liver or renal function, major cardiac diseases, pruritus before cesarean delivery, and known allergy to ondansetron were excluded.

All patients received an intrathecal injection of 8–10 mg of bupivacaine (dosage adjusted according to body height) for spinal anesthesia and preservative-free morphine of 0.15 mg for postoperative pain control. The morphine was diluted with 0.9% saline to a concentration of 1 mg/mL. By using a 1-mL syringe, 0.15 mL of the diluted morphine was added to the bupivacaine solution, mixed well, and injected. The patients were randomly divided into three groups. Group 1 received placebo (normal saline) IV injection, Group 2 diphenhydramine 30 mg IV injection, and Group 3 ondansetron 0.1 mg/kg IV injection, immediately after the baby was delivered. All injections were IV infused for 10 min. The dose of ondansetron used was 0.1 mg/kg, and the average amount was 7.1 mg. This dose was chosen because it has previously been reported (4) and is similar to that which has been used in treating pruritus (12). The patients were evaluated by an anesthesia research fellow who was blinded to the treatment group. Evaluations were performed every 5 min in the first 2 h after the IV injection of the study medicine, every 15 min for another 2 h, then every 30 min in the following 24 h. Pruritus was evaluated for 28 h postoperatively. The following items were evaluated: symptoms and location of pruritus, postoperative pain, time to flatus passage, and previously reported adverse reactions of ondansetron including headache, cardiac arrhythmia, and extrapyramidal signs (4,15). The degree of pruritus was classified as 0 = no pruritus, 1 = mild pruritus (no treatment needed), and 2 = severe pruritus (treatment needed). Patients were asked about the presence of pruritus and whether treatment was wanted. If treatment was needed, propofol 10 mg was injected IV. Postoperative pain was evaluated by using a visual analog scale (from 0 = no pain to 100 = worst pain imaginable). Cardiac arrhythmia was evaluated with cardiac auscultation and patient report of palpitations. Twelve-lead electrocardiograms were performed for verification. The time to flatus passage was evaluated because ondansetron has been reported to be associated with constipation (4).

Data were presented as mean ± SD. The ² test was used to test associations among dichotomous parameters, and Yate’s correction was used when necessary. Analysis of variance was used to compare numeric parameters among the three study groups.

	Results

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The patients were 18–46 yr old and weighed 61–92 kg. The demographic data are listed in Table 1. Pruritus occurred in 85% of the patients who received placebo injection. The incidence of pruritus in the diphenhydramine injection group was 80%, which was not significantly different from that in the placebo group. In contrast, the incidence of pruritus was 25% in the ondansetron group (Table 1). The incidence was significantly lower than that of the placebo group or diphenhydramine group (P < 0.01). Time to pruritus did not differ among the groups. The sites of pruritus were trunk, back, neck, and around the nose and eyes in all patients except for two patients of the placebo group and one patient in the ondansetron group, who had mild pruritus in the facial area only. Nine patients requested treatment for their pruritus (four in the placebo group, four in the diphenhydramine group, and one in the ondansetron group). In patients with mild pruritus (treatment not needed as judged by the patients), the duration of pruritus did not differ among the groups. For the nine patients with severe pruritus (treatment needed as judged by the patients), propofol 10 mg was given. Among them, six patients responded to propofol injection with relief of pruritus within 1 h, whereas two in the placebo group and one in the diphenhydramine group did not respond within 1 h. A repeat injection of propofol 10 mg was given for these three patients, and the pruritus improved in two. In the remaining patient, the pruritus did not improve after the second injection of propofol, and the patient refused further treatment. This patient was in the placebo group.

	Discussion

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The incidence of pruritus after intrathecal morphine injection in patients undergoing cesarean delivery was high (85%). We demonstrated that ondansetron injection significantly decreased the incidence of pruritus whereas diphenhydramine injection did not. Furthermore, ondansetron administration was well tolerated without interfering with the analgesic effect of morphine.

The incidence of intrathecal morphine-induced pruritus in untreated patients in our study was similar to that reported in the literature (70%–85%) (13,14). This pruritus is refractory to conventional antipruritic treatment, such as topical drug application and diphenhydramine or steroid injection (3). Several reports have shown promising results with ondansetron, a serotonin type 3 receptor antagonist (9–12). Borgeat and Stirnemann (12) reported that ondansetron was effective for the treatment of spinal or epidural morphine-induced pruritus in a randomized, double-blinded study of 100 patients. The incidence of prophylactic failure in our study was comparable to the treatment failure rates of previous reports (11,12).

The mechanisms of intrathecal morphine-induced pruritus remain unclear. The effectiveness of ondansetron to prevent and treat this pruritus indicates a role for serotonin type 3 receptors in its pathogenesis. It has been reported that serotonin type 3 receptors are abundant in the dorsal horn area of the spinal cord and in the spinal tract of the trigeminal nerve in the medulla (16–19). The role of ondansetron in nociception has also been reported (20). Fan (21) reported that morphine can activate serotonin type 3 receptors by a mechanism independent of opioid receptors. Therefore, direct irritation of serotonin type 3 receptors in the dorsal horn of the spinal cord and in the medulla by intrathecal injection of morphine is a possible mechanism for the pruritus. This is also compatible with the clinical observation that pruritus occurred in an ascending pattern.

Because treatment for pruritus was considered absolutely necessary in only 20% (4 of 20) of patients in the placebo group, the routine prophylactic use of this drug may be associated with unnecessary drug administration in some patients who might not have developed pruritus or who would not have requested treatment. There are, however, no good predictors to indicate which patient will develop pruritus, and given the option, most patients would rather not experience this side effect. Although routine use of ondansetron would be associated with a somewhat higher cost of care, this might be balanced by greater patient satisfaction as a result of a decreased incidence of pruritus.

Although IV ondansetron significantly decreased the incidence of morphine-related pruritus, this complication still occurred in approximately 25% of patients. These patients might need other treatment, such as naloxone or propofol (12,22). Whether these patients might respond to more potent serotonin type 3 antagonists or a larger dose of ondansetron remains unclear. It is also possible that other mechanisms independent of serotonin receptors are involved in the pathogenesis of morphine-induced pruritus. A dose-response effect was not evaluated in our study and would be worthwhile to examine in a future study. Because ondansetron is lipophilic, it may be excreted in breast milk, although there are no reports defining the concentration of this drug in breast milk (23). Therefore, ondansetron is not currently recommended for routine use in breastfeeding mothers, and this may limit its use in patients undergoing cesarean delivery until further data are available.

	References

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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