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REGIONAL ANESTHESIA

Prophylactic Intravenous Ondansetron and Dolasetron in Intrathecal Morphine-Induced Pruritus: A Randomized, Double-Blinded, Placebo-Controlled Study

Departments of Anesthesia and Surgery, Democritus University of Thrace, Alexandroupolis, Greece, and the Department of Anesthesia, "G. Gennimatas" Hospital, Athens, Greece

Address correspondence and reprint requests to Christos Dragoumanis MD, University Hospital of Alexandroupolis, Level 2, Room: 54.10, Dragana, Alexandroupolis 68100, Greece. Address e-mail to christosdr{at}panafonet.gr.

	Abstract

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Pruritus is the most common side effect of intrathecal morphine for postoperative pain relief. Activation of central 5-hydroxytryptamine subtype 3 (5-HT3) receptors is one of its possible mechanisms. The role of 5-HT3 antagonists in the prevention of pruritus has not been clearly established. In a prospective, randomized, double-blind, placebo-controlled study, we evaluated the efficacy of prophylactic administration of ondansetron and dolasetron for the prevention of intrathecal morphine-induced pruritus. The patients were randomized into 3 groups to receive either 4 mg ondansetron IV (group O, n = 35), 12.5 mg dolasetron IV (group D, n = 35) or 5 mL placebo (group P, n = 35) 30 min before administration of spinal anesthesia with 10 to 17.5 mg of 0.5% hyperbaric bupivacaine and 0.25 mg of morphine for urologic, orthopedic, or vascular surgery. Patients were evaluated for incidence and severity of pruritus at arrival to the postanesthesia care unit and at 2, 4, 8, and 24 h postoperatively. The incidence and severity of pruritus was significantly less frequent in the ondansetron and dolasetron groups compared with placebo (34%, 20%, and 66% respectively, P < 0.01). Patients who received 5-HT3 antagonist reported significantly less total severity of pruritus compared with placebo during the first 8 h and the severe pruritus was observed only in patients within P group (P group: 4 of 35; 11%, O or D group: 0 of 35; 0%, P < 0.05). We conclude that the prophylactic use of ondansetron and dolasetron helps to reduce the incidence and severity of intrathecal morphine-induced pruritus.

	Introduction

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Intrathecal morphine improves postoperative analgesia, but it is accompanied by a frequent incidence of postoperative nausea and vomiting (PONV) and pruritus (1). Pruritus is the most common side effect of intrathecal morphine, with a reported incidence of 62% to 94% (2–4). It is unpleasant for patients and difficult to treat, and its prevention remains a challenge for anesthesiologists (5,6). Although the exact mechanism is unclear, it seems that intrathecal morphine's interaction with central 5-hydroxytryptamine subtype 3 (5-HT3) receptors (6) plays some role in the genesis of pruritus. As a result, 5-HT3 receptor antagonists could be effective in its control. Ondansetron has been used for this purpose with conflicting results (3,4,7,8). Dolasetron, another 5-HT3 receptor antagonist, is usually used to control nausea and vomiting associated with chemotherapy and PONV (9,10). However, its antipruritic activity has not been evaluated. Therefore, we conducted a prospective, randomized, double-blind, placebo-controlled study to determine the effectiveness of dolasetron and ondansetron for the prevention of pruritus after spinal anesthesia performed with bupivacaine and morphine in patients undergoing elective vascular, orthopedic, or urologic surgery.

	Methods

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After institutional ethics committee approval and written informed consent, we studied 119 adult ASA physical status I–III patients undergoing elective urologic, vascular, or orthopedic surgery under spinal anesthesia. Exclusion criteria included patient refusal to participate in the study, contraindication for spinal anesthesia, prolonged QT interval, electrolyte disturbances, age older than 75 yr, morbid obesity, sleep apnea syndrome, coexisting skin disorder, and systemic diseases with pruritus. Patients with a history of allergy associated with any drug included in the study were also excluded. The study was designed in a prospective, randomized, double-blind, and placebo-controlled fashion. A computer randomization program was used to allocate the patients into 3 groups: 12.5 mg dolasetron IV (group D), 4 mg ondansetron IV (group O), or 5 mL of normal saline (group P) 30 min before administration of spinal anesthesia. Ondansetron and dolasetron were diluted in normal saline to a volume of 5 mL. Patients and anesthesiologists performing the spinal and collecting the postoperative data were blinded as to the study drugs.

Every patient was prehydrated with Ringer's lactate solution 5–10 mL/kg. Spinal anesthesia was performed at the L2-3 or L3-4 interspace with a 25-gauge Quincke-type needle using 10 to 17.5 mg of 0.5% hyperbaric bupivacaine plus 0.25 mg of preservative-free morphine. No sedation was used before the procedure. Midazolam, in 0.5 mg IV increments, was used for intraoperative sedation at the discretion of the anesthesiologist.

The patients were followed for 24 h postoperatively. Sedation level was evaluated with a 3-degree scale (1 = wide awake; 2 = drowsy; 3 = responds to stimulation). Postoperative wound pain at rest was assessed with a 10-cm visual analogue scale (VAS). Rescue treatment for postoperative pain was provided with meperidine patient-controlled analgesia (PCA), 1 mg/mL, 10 mg bolus, 20-min lockout, and 4-h limit of 50 mg. Patients were instructed to use the PCA if their pain became worse than mild.

Pruritus was evaluated at arrival in the postanesthesia care unit and at 2, 4, 8, and 24 h postoperatively by 2 blinded investigators (senior residents in anesthesiology). Pruritus was defined as the sensation that provokes the desire to scratch. The patients were questioned about the presence, location, and degree of pruritus. The degree of pruritus was classified as 0 = no pruritus, 1 = mild pruritus, 2 = moderate pruritus, and 3 = severe pruritus. Severe pruritus was treated with 3 mg nalbuphine IV (11). Patients were also asked about the presence of PONV. Patients who reported vomiting or intense nausea received 10 mg IV metoclopramide.

Statistical analysis was performed using the Statistical Package for the Social Sciences (SPSS for Windows, version 11, SPSS, Inc., Chicago, IL). We considered a 50% reduction in the incidence of pruritus to be clinically important. Power analysis was performed to determine the sample size with a probability for a type II error of 0.2 and type I error of 0.05. To detect a 50% reduction in the incidence of pruritus, using the results of a pilot study, in which pruritus was present in 13 (65%) of 20 patients who received placebo, a sample size of 35 patients in each group was estimated to be required. Dropouts of the study were compensated for by admission of a new patient into the study protocol in a blind and randomized manner any time a patient was excluded. Statistical analysis was performed with ² test for nominal data, Kruskal-Wallis test followed by Mann-Whitney U-test for ordinal data, and analysis of variance for continuous data. Confidence interval (CI) at 95% was calculated for the incidences of pruritus and PONV. The level of significance was set at P 0.05. For pairwise intergroup comparisons we used the Bonferroni correction for level (e.g., P 0.017 for pairwise comparisons among three groups).

	Results

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From December 2003 to March 2004, we enrolled 119 patients in our study, 14 of whom were excluded for the following reasons: inadequate anesthesia-received general anesthesia (n = 3), reoperation (n = 2), incomplete collection of postoperative data (n = 5), and protocol violations (n = 4). Therefore, 105 patients completed the trial, 35 in each group. The demographic and surgical data of patients who completed the study are listed in Table 1.

The overall incidence of pruritus differed significantly among the groups (P < 0.01). Pairwise comparisons showed that this significant difference was attributable to a less frequent incidence of pruritus in groups D and O compared with group P. The incidence of pruritus between the O and D groups was not significantly different (P = 0.18) (Table 2). In the first 8 h postoperatively the severity of pruritus among groups was significantly different and was significantly less in the O and D groups compared with placebo in the intergroup comparisons (Table 3). The overall allocation of the pruritus in the trigeminal, cervical, thoracic, and lumbar dermatomes is shown in Figure 1. Patient gender did not have a significant influence on the incidence of pruritus (Table 2). Severe pruritus, requiring rescue treatment, was observed only within group P (P group: 4 of 35, 11%; O and D groups: 0 of 35, 0%, P < 0.05 compared with the Kruskal-Wallis test).

View larger version (15K): [in this window] [in a new window]   Figure 1. Allocation of pruritus in dermatomes.

The incidence of PONV was significantly different between the two treatment groups, but it did not reach the adjusted significance level in the pairwise comparisons (Table 2), and no significant difference among any groups occurred in the number of rescue treatments for PONV.

There were no significant differences in the sum of pain VAS scores during the observations or the mean total meperidine consumption among groups as compared with one-way analysis of variance (Table 2).

The number of patients who received midazolam and the total dose of midazolam administered to them intraoperatively did not differ significantly among groups (Table 1). Patients were mainly wide awake during the five data collection times, and the level of sedation was similar among groups.

	Discussion

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The mechanism of intrathecal morphine-induced pruritus is complex. Although itch-specific neuronal pathways are different from pain pathways, they are close in interaction. Continuing activity of the pain-processing system tonically suppresses activity in the spinal itch-processing neurons. Thus, inhibition of pain can unmask pruritus (e.g., intrathecal morphine-induced pruritus) and pruritus can be inhibited by pain (e.g., antipruritic effect of scratching) (12). The serotoninergic system seems to play the role of modulator, providing a balance between nociception and antinociception in the network of pain processing neurons (13,14). Furthermore, morphine is able to activate 5-HT3 receptors by a mechanism independent of opioid receptors (15). The dorsal horn area of the spinal cord and the spinal tract of the trigeminal nerve in the medulla are abundant in 5-HT3 receptors. Direct stimulation of 5-HT3 receptors by morphine appears to be one of the mechanisms of intrathecal morphine-induced pruritus; thus, their occupation by a 5-HT3-receptor antagonist may prevent this pruritus. The results of our study support this hypothesis, demonstrating that patients who received preemptive 5-HT3-receptor antagonists reported significantly less pruritus and less severity during the first 8 h postoperatively compared with patients who received placebo. The frequency of pruritus was reduced by 48% and 70% for ondansetron and dolasetron, respectively, compared with placebo. Both drugs thus offer effective prophylaxis against intrathecal morphine-induced pruritus, at least for the first 8 h postoperatively.

Five clinical studies have previously evaluated the efficacy of 5-HT3 receptor antagonists as prophylaxis for intrathecal morphine-induced pruritus; all involved ondansetron (3,4,7,8,16). In three of these studies ondansetron in a dose 4–8 mg IV was more effective than placebo in the prevention of pruritus associated with spinal anesthesia using bupivacaine and 0.15 – 0.3 mg morphine (3,4,7). In the two other studies, ondansetron was ineffective in preventing pruritus (8,16). Szarvas et al. (8) reported a high frequency (73%) of intrathecal morphine-induced pruritus in a population similar to ours. However, the dose of intrathecally-administered morphine (0.57 ± 0.13 mg) was about twofold larger than the dose of morphine (0.25 mg) that we administered. This suggests that the antipruritic efficacy of ondansetron depends on the dose of intrathecally administered morphine. Yazigi et al. (16) reported the failure of 8 mg ondansetron to prevent pruritus after intrathecal injection of 25 µg sufentanil and 0.1 mg morphine but speculated that this related to the lipophilic properties of sufentanil and delayed administration of ondansetron. In our study, the percentage of patients who reported pruritus in the placebo group (66%) was similar to that of previous investigations (6,7).

Although both 5-HT3 antagonists in our study reduced the incidence and severity of pruritus, this side effect still occurred in 12 (34%) and 7 (20%) of the 35 patients in each group who received ondansetron and dolasetron respectively, showing the complexity of the pathogenesis of pruritus. Pruritus in these patients may be prevented with a larger dose of these 5-HT3 antagonists, prostaglandin synthesis inhibition (17), blocking opioid receptors (4,18), or a combination of therapies.

The prophylaxis of intrathecal morphine-induced pruritus with ondansetron or dolasetron increases the cost of perioperative care by 11.26 Euros (14.6 US$)/patient or 4.04 Euros (5.2 US$)/patient respectively.

Rescue treatments were administered to only 4 patients (11%) with severe pruritus within the placebo group, arguing against the routine use of prophylaxis for pruritus because of unnecessary drug administration and increased perioperative care cost. However, decreasing the overall frequency of intrathecal morphine-induced pruritus with preemptive ondansetron or dolasetron administration may improve the quality of postoperative care and might economize medical and nurse working time spent even for patients who complained of mild or moderate pruritus without requiring antipruritic treatment. Furthermore, pruritus induced by intrathecal morphine is occasionally difficult to treat and there are no known risk factors, except pregnancy (5), to identify patients who are at high risk to develop pruritus.

In this study there was no statistically significant difference (P = 0.12) in the severity of pruritus among groups at the 24th postoperative hour. However, power analysis for this comparison showed that its power was only 43%. Consequently, a type II error cannot be excluded. We attributed the low statistical power of the comparison of severity of pruritus at the 24th postoperative hour to an overall decrease of severity of pruritus because of elimination of morphine from the central nervous system. A larger sample size (approximately 250 patients) would be required to achieve adequate statistical power. Nonetheless, this larger sample size could offer sufficient power to compare the antipruritic potency of ondansetron and dolasetron. Our study was performed in nonpregnant patients. However, pruritus is more frequent in the obstetric population because of increased cephalic spread of spinally administered drugs and an interaction of estrogens with opioid receptors (5). Thus, our findings only apply to the nonpregnant population.

PONV are common side effects of postoperative analgesia after intrathecal morphine. Our results show a reduction in the incidence of PONV in patients who received 5-HT3 antagonists as compared with placebo. However, our study was not designed to evaluate this phenomenon. A study oriented to PONV with appropriate size and exclusion criteria could potentially more clearly define the impact of ondansetron and dolasetron on PONV in the setting of intrathecally administered morphine (19).

We conclude that preemptive administration of both ondansetron and dolasetron to patients receiving intrathecal morphine for postoperative analgesia provides a significant reduction of intrathecal morphine-induced pruritus without affecting pain relief. The use of prophylaxis involves is expensive. Thus, identifying high-risk populations would maximize its benefits.

	Footnotes

 
Accepted for publication June 9, 2005.

	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