The height and intensity of spinal block are influenced by several factors, such as the injected drug, technical aspects, level of injection, needle type, patient position, and patient characteristics, such as age, height, weight, pregnancy, and spinal anatomy.1 Systemic administration of drugs may enhance the subarachnoid block produced by lidocaine as has been shown with opioids,2–4 nitrous oxide,5 nimodipine,6 and clonidine.7
On the other hand, systemic administration of ondansetron, a selective 5-hydroxytryptamine (5-HT)3 antagonist, results in a faster regression of the sensory block produced by subarachnoid lidocaine.8 Similarly, the selective 5-HT3 receptor antagonist granisetron antagonizes sensory block after subarachnoid injection of bupivacaine.9
We hypothesized that ondansetron may antagonize the subarachnoid block produced by plain ropivacaine. The aim of this study was to investigate the effect of ondansetron on the sensory and motor block produced by intrathecal ropivacaine.
After obtaining approval from our IRB, 50 ASA physical status II-III male patients undergoing transurethral surgery for prostatectomy or excision of bladder papillomas under subarachnoid anesthesia were recruited for the study. All patients gave written informed consent. Exclusion criteria were central or peripheral nervous system disease, bleeding disorders, intake of anticoagulants or analgesics of all types, including the peripherally acting drugs, such as nonsteroidal antiinflammatory drugs, during the last 2 wk, topical infection at the puncture site, and difficulty understanding the Greek language.
An anesthesiologist who did not participate in the study randomized patients to the treatment or placebo group using sealed opaque envelopes containing odd or even numbers to receive ondansetron or placebo, respectively. The evening before surgery, ondansetron 8 mg or placebo tablets were given to the ondansetron group or to the control group, respectively. Placebo tablets and solutions were provided by the hospital pharmacy and were given by the anesthesiologist responsible for randomization. No premedication was given. Until completion of measurements, no sedatives, analgesics, or other adjuvants were given perioperatively except for the drugs determined by the study protocol (ondansetron or placebo). Patients requiring sedatives or analgesics before or during the measurement of sensory or motor block were excluded.
On arrival at the operating room, standard monitors (electrocardiogram, noninvasive arterial blood pressure, and pulse oximetry [Datex Ohmeda S/5™ Anesthesia Monitor, Helsinki, Finland]) were applied to all patients. An 18-gauge catheter was inserted in a peripheral vein. Fifteen minutes before subarachnoid injection, 8 mg ondansetron or an equal volume of normal saline was given to the ondansetron and control group, respectively.
Subarachnoid block was performed at the L3-4 interspace using a 25-gauge Whitacre spinal needle with the patient in the sitting position by an anesthesiologist who was blinded to the randomization. When free flow of cerebrospinal fluid was observed, 2.2 mL of 0.75% ropivacaine was injected at a rate of 1 mL per 10 s without barbotage. Subsequently, the patients were placed in the lithotomy position.
Sensory and motor block were assessed every 30 min after the subarachnoid injection for 3 h or until recovery from the motor block was evident. For the assessment of sensory level, a pressure palpator (Pressure FEELER 650 g, Sedatelec, Irigny, France) was used as described previously.10 The palpator was moved along 4 lines drawn along the posterior, middle, and anterior axillary lines as well as 5 cm medial to the anterior axillary line. Sensory block was defined by moving the pressure palpator in a cephalad to caudad direction. The points at which the patient reported a change from normal to decreased sensation and from decreased to no sensation of the pressure palpator were marked along each line. The 4 points corresponding to decreased sensation to the pressure palpator were connected to a line indicating the dermatome corresponding to decreased sensation at that time point. A similar procedure was followed for the points corresponding to loss of sensation to the pressure palpator. Motor block was assessed using a modified Bromage scale (0 = no block, able to flex hips, knees, and ankles; 1 = able to move knees, unable to raise extended legs; 2 = able to flex ankles, unable to flex knees; 3 = inability to move any part of the lower extremities).
The spread of sensory block was the primary outcome of the study. Initial sample size estimation showed that, to ensure a power of 0.80, approximately 23 patients were needed in each group for detecting a difference of approximately 1 dermatome between the ondansetron and control groups at each time point. This is a clinically meaningful difference, based on the increase in dermatomal levels produced by other analgesics/anesthetics.2,3,5 Standard deviations estimated from a sample of initial pilot observations (n = 8 patients in each group) were approximately 1.2 for each group. An α error was assumed at 0.05. Sample size estimation was calculated using the Java Applets for power and sample size software (Lenth RV. 2006. Java Applets for Power and Sample Size [computer software]. Last retrieved April 9, 2007. Available at: http://www.stat.uiowa.edu/∼rlenth/Power).
Statistical analysis was performed with SPSS statistical package (version 15.0, SPSS, Chicago, IL). Demographics and duration of surgery between the 2 groups were analyzed with unpaired Student’s t-test. The type of surgical procedure between the 2 groups was analyzed with χ2 test. For comparisons between groups, the levels of sensory block expressed as dermatomes and the degree of motor block expressed as Bromage scale values at each time point were analyzed with Mann-Whitney test. The P values for the sensory and motor block intergroup multiple comparisons were corrected by multiplying each P value by the number of comparisons, thus by 6. A P value ≤0.05 was considered significant.
Two patients assigned to the control and 2 patients to the treatment group had an incomplete block and general anesthesia was administered. Therefore, 46 patients were included in the final analysis. Patient characteristics and the type of surgery (transurethral resection of bladder papillomas versus transurethral resection of the prostate) did not differ between groups (Table 1). Duration of surgery was 49 ± 11.6 min in the control and 47 ± 10.1 min in the ondansetron group and did not differ between groups (t = 0.746, df = 44, P = 0.460).
There was no significant difference in sensory block defined as a change from normal to decreased response to stimulus (Table 2) or sensory block defined as no response to the stimulus (Table 3) between groups at any time point.
Motor block in each group 30, 60, 90, 120, 150, and 180 min after subarachnoid injection is shown in Table 4. There were no significant differences in the motor block between the 2 groups at any time point.
In contrast to previous studies, the results of this study show that pretreatment with ondansetron the night before surgery and 15 min before subarachnoid injection of ropivacaine had no effect on sensory block.
Several factors influence the spread and the regression of subarachnoid block including the systemic administration of drugs.1 The IV administration of opioids such as fentanyl and diamorphine and the inhalation of nitrous oxide enhance the spread of lidocaine.2–5 Other drugs such as serotonin antagonists may antagonize the sensory block produced by subarachnoid administration of local anesthetic.8,9 In fact, IV ondansetron antagonizes the sensory but not the motor block produced after intrathecal administration of lidocaine.8 Similarly, IV administration of granisetron has no effect on motor block but shortens the duration of sensory block produced by intrathecal bupivacaine.9
In mice, intrathecal injection of 5-HT is associated with antinociception, most likely mediated by the 5-HT3 but not the 5-HT1B receptor subtypes.11 The antinociceptive effect of tramadol injected subcutaneously in mice is antagonized by the antiemetic ondansetron, which is a 5-HT3 receptor antagonist.12 In rats, the antinociceptive effect of nifedipine assessed by tail-flick latency was also antagonized by ondansetron.13
In humans, 5-HT3 antagonists appear to decrease the analgesic effect of drugs such as tramadol. Ondansetron 4 mg given IV 1 min before the induction of anesthesia in patients undergoing lumbar laminectomy was associated with higher tramadol consumption during the first 24 h.14 In 1 study, patients receiving tramadol patient-controlled analgesia postoperatively and treated simultaneously with continuous infusion of ondansetron for postoperative nausea and vomiting consumed higher doses of analgesics over the first 12 h postoperatively compared with the control group.15 However, these results are not consistent with the results of another study in which ondansetron had no effect on the analgesic effects of alfentanil in healthy volunteers in whom experimental pain was induced with heat, cold, mechanical, and electrical stimuli.16
In a previous study, we concluded that ondansetron antagonizes the sensory block produced by intrathecal lidocaine.8 In this study, we failed to demonstrate an effect of ondansetron on the sensory and motor block produced by intrathecal plain ropivacaine. There are several possible explanations for this difference in findings. Discrepancies between the type and the baricity of the local anesthetics used in the different studies and in the different time intervals between block assessments may explain why the results obtained with hyperbaric lidocaine and bupivacaine do not appear to extrapolate to subarachnoid plain ropivacaine.
On the other hand, the pharmacokinetics of the individual 5-HT3 antagonist and the pharmacokinetics of the local anesthetic administered in the subarachnoid space may account for a clinically evident interaction of the 5-HT3 receptor antagonist and sensory subarachnoid block.
The block performed in this study using spinal ropivacaine has a longer duration than the block produced by spinal lidocaine in a previous study.17,18 Therefore, a possible interaction between ropivacaine and ondansetron may have been terminated before the regression of the ropivacaine block. Regarding the effect of granisetron on bupivacaine sensory subarachnoid block, granisetron drug has a longer elimination half-life compared with the elimination half-life of ondansetron.17,19,20 Another difference between the present and a previous study investigating the effect of ondansetron on ropivacaine and lidocaine spinal block, respectively, is the direction of measurement, which was cephalad to caudal in this study and the opposite in the previous study. However, as we have shown in a previous study, the level of sensory block after spinal anesthesia is independent of the direction of testing.21
The fact that we assessed the subarachnoid block every 30 min may be a limitation of our study, because in the study investigating the regression of lidocaine block after ondansetron, measurements were repeated every 5 min. Mowafi et al.9 assessed changes in the bupivacaine block after pretreatment with granisetron or placebo every 15 min. Thus, we may have missed a possible interaction between the ropivacaine and ondansetron because of the long intervals between measurements, particularly because the effect of ondansetron is expected to wear off sooner than that of ropivacaine.
Considering the longer duration of action of ropivacaine than lidocaine, we administered a higher dose of ondansetron than the usual antiemetic dose assuming that a possible antagonism between ondansetron and subarachnoid ropivacaine might be more readily detected. These findings might not apply to a different clinical setting, such as IV administration of the labeled antiemetic dose of ondansetron (4 mg) during an already established or subsiding sensory block.
In conclusion, under the present experimental design, the subarachnoid block of ropivacaine does not appear to be affected by ondansetron. Further studies investigating the clinical interaction of these drugs should consider the kinetics of each drug.
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