REGIONAL ANESTHESIA: Research Report
The addition of small-dose intrathecal fentanyl (10–25 μg) to local anesthetics during spinal anesthesia enhances and increases the duration of sensory analgesia without intensifying the motor block or prolonging recovery (1–3). The addition of 10–25 μg of intrathecal fentanyl allows the use of less local anesthetic; however, pruritus is reported in 60%–100% of patients (1,4).
Ondansetron, a selective serotonin Type 3 receptor antagonist, is often used for nausea and vomiting in patients undergoing chemotherapy or general anesthesia (5). Furthermore, there has been some clinical evidence for a significant antipruritic effect of ondansetron in patients with renal failure, cholestatic jaundice, and neuroaxial morphine (6–9). Because the side effects of intrathecal morphine are more pronounced than those of intrathecal fentanyl (4), the addition of fentanyl to local anesthetics during spinal anesthesia is preferred for most patients. It has been demonstrated that prophylactic IV ondansetron reduces the incidence of intrathecal morphine-induced pruritus in patients undergoing cesarean delivery (10), but a study evaluating the efficacy of prophylactic ondansetron treatment for intrathecal fentanyl-induced pruritus has not been reported. We therefore performed a prospective, randomized, double-blinded, placebo-controlled study to investigate the efficacy of pro-phylactic ondansetron in the prevention of pruritus after intrathecal fentanyl administration during spinal anesthesia.
The study was designed in a prospective, randomized, double-blinded, and placebo-controlled manner. After institutional ethics committee approval and informed consent from each patient were obtained, 150 ASA status I–II patients, aged 18–70 yr, receiving spinal anesthesia for elective arthroscopic knee or urologic surgery, were included in the study. Patients were randomly assigned, by use of sealed envelopes, to receive either placebo or ondansetron. Exclusion criteria were known allergy to ondansetron, history of any disease associated with pruritus, complaint of pruritus before surgery, increases in liver function tests (alanine aminotransferase or aspartate aminotransferase more than two times the reference range), and preoperative intake of histamine blockers.
All patients received an intrathecal injection of 7–10 mg of hyperbaric bupivacaine 0.5% (the decision about the dose of hyperbaric bupivacaine was left to the attending anesthesiologist responsible for the case) and 25 μg of preservative-free fentanyl, both to increase the quality of anesthesia and to provide postoperative analgesia. Intrathecal bupivacaine and fen-tanyl were administered with separate syringes. Intrathecal fentanyl was given first, followed by an appropriate dose of intrathecal bupivacaine for surgery. Patients in the ondansetron group received ondansetron 8 mg IV, and patients in the placebo group received 2 mL of normal saline IV before the commencement of spinal anesthesia. The dose of 8 mg of ondansetron was chosen because previous studies have shown that this dose is effective both in the treatment and prevention of morphine-induced pruritus (10,11). The degree of pruritus was classified as 0 = no pruritus, 1 = mild pruritus, 2 = moderate pruritus, and 3 = severe pruritus. The patients were evaluated by an anesthesia research fellow who was blinded to the treatment group. Evaluations were performed every 15 min in the first hour after the injection of study drugs. Afterward, evaluations were performed at 1, 2, 3, 4, 5, and 6 h after the administration of study drugs. Patients were asked about the presence of pruritus. The site and the degree of pruritus and whether treatment was wanted was asked of those patients who had pruritus. If treatment was wanted, 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). Patients were asked for the presence and the characteristics of headache, if present. The presence of cardiac arrhythmia was evaluated with patient complaint of palpitation. Twelve-lead electrocardiograms were performed for verification. None of the patients received intra- or postoperative sedation with propofol. Intraoperative sedation was provided with IV midazolam 0.03–0.05 mg/kg bolus doses.
A power analysis showed that 55 patients per group would provide 80% power to detect a 50% decrease in the incidence of pruritus from 60% in the placebo group to 30% in the ondansetron group. Statistical analysis was performed with χ2 tests and Student’s t-test, as appropriate. Results are expressed as mean ± sd. For all determinations, a P value of <0.05 was considered significant.
The two groups were similar with regard to age, sex, height, weight, and the type of surgery performed (Table 1). The overall incidence of pruritus was significantly more frequent in the placebo group compared with the ondansetron group (68% versus 39%) (P = 0.001). The sites of pruritus were around the nose and chest in most of the patients. The incidence of pruritus was significantly more frequent in the placebo group 45 min, 1 h, and 2 h after the administration of study drugs compared with the ondansetron group (Table 2). Pruritus score was ≤1 in most patients (Table 2). Seven patients in the placebo group and three patients in the ondansetron group required treatment for severe itching. Five patients in the placebo group and two patients in the placebo group responded to a propofol 10 mg IV injection. Time to pruritus was similar in both groups (placebo group, 55 ± 32 min versus ondansetron group, 50 ± 31 min). Duration of pruritus was also similar in both groups (placebo group, 98 ± 60 min versus ondansetron group, 103 ± 58 min).
The incidence of pruritus was similar between male and female patients. The type of surgery, whether orthopedic or urological, did not have a significant influence on the incidence of pruritus in the study groups. The dose of bupivacaine did not have a significant influence on the incidence of pruritus. Postoperative pain visual analog scale scores were not significantly different between the groups.
None of the patients had abdominal cramps, cardiac arrhythmia, or extrapyramidal symptoms. Six patients in the ondansetron group had mild headache, whereas five patients in the placebo group had headache. Only one patient in the placebo group had postdural puncture headache.
A study about the effects of intrathecal fentanyl on analgesia, pruritus, and ventilation during labor found that there was a dose-response relationship between the dose of fentanyl and the incidence of pruritus. The overall incidence of pruritus was 65.6% in patients receiving intrathecal fentanyl 5, 7.5, 10, 15, 20, and 25 μg (12). Intrathecal administration of 25 μg of fentanyl to provide labor analgesia may result in up to a 100% incidence of pruritus. When ropivacaine 2.5 mg or bupivacaine 2.5 mg was added to fentanyl, the incidence of pruritus decreased to 85% and 75%, respectively. Pruritus was noted within 30 minutes in most patients (13). It has been demonstrated that both procaine and bupivacaine (55%) have an increased incidence of pruritus compared with lidocaine (21%) when combined with intrathecal fentanyl for spinal anesthesia. The severity of pruritus was more severe in combination with procaine than with lidocaine or bupivacaine. Pruritus may start as early as 30 minutes after intrathecal fentanyl administration (14). We found that the incidence of pruritus was 68% when 25 μg of fentanyl was added to bupivacaine 7–10 mg. Although this study was not designed to determine the effect of local anesthetics on pruritus, it seems that the addition of local anesthetics to intrathecal fentanyl administration decreases the incidence of pruritus when compared with pure fentanyl administration. Yet further studies are required to determine whether this effect is simply due to the residual effect of local anesthetics or if other mechanisms are involved.
The precise mechanism of pruritus after intrathecal opioids is not completely clear. Borgeat and Stirnemann (11) reported that ondansetron was effective for the treatment of spinal or epidural morphine-induced pruritus. 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 (15,16). Fan (17) reported that morphine can activate serotonin Type 3 receptors by a mechanism independent of opioid receptors. Therefore, a direct stimulation of serotonin Type 3 receptors in the dorsal horn of the spinal cord and in the medulla by intrathecal injection of opioids may be a possible mechanism for the pruritus. These observations suggest that the serotonin Type 3 receptor is, to a certain degree, implicated in the development of the pruritus associated with the application of neuroaxial opioids.
Although ondansetron significantly decreased the incidence of fentanyl-induced pruritus, this complication still occurred in 39% of the patients. Yeh et al. (10) demonstrated that ondansetron treatment decreased the incidence of pruritus from 85% in patients undergoing cesarean delivery receiving placebo to 25% in patients receiving 0.15 mg of intrathecal morphine. Kyriakides et al. (18) showed that 4 mg of ondansetron decreased the incidence of nasal scratching from 70% in the placebo group to 43% in the ondansetron group after alfentanil 10 mg/kg IV. Further studies are necessary to determine whether ondansetron is more effective for pruritus after morphine application than fentanyl or alfentanil.
Because pruritus was mild and of relatively short duration in most patients, the routine prophylactic use of this drug may be associated with unnecessary drug administration in a large majority of the patients who might not develop pruritus or who would not have requested treatment. Although routine use of ondansetron would be associated with a somewhat higher cost of care, it should be questioned whether this might be balanced by increased patient satisfaction as a result of the decreased incidence of pruritus.
Although IV ondansetron significantly decreased the incidence of fentanyl-induced pruritus, this complication still occurred in 39% of patients. It is possible that other mechanisms, independent of serotonin receptors, might be involved in the pathogenesis of fentanyl-induced pruritus.
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