Acta Anaesthesiol Scand 2006; 50: 239—244 Printed in UK. All rights reserved
Copyright # Acta Anaesthesiol Scand 2006 ACTA ANAESTHESIOLOGICA SCANDINAVICA
doi: 10.1111/j.1399-6576.2006.00934.x
Ondansetron and tropisetron do not prevent intraspinal morphine- and fentanyl-induced pruritus in elective cesarean delivery P. J. SARVELA, P. M. HALONEN, A. I. SOIKKELI, J. P. KAINU and K. T. KORTTILA Department of Anaesthesia and Intensive Care, Helsinki University Central Hospital, Helsinki, Finland
Background: Although intraspinal morphine has been shown to be effective in providing analgesia after cesarean delivery, pruritus as a side-effect remains a common cause of dissatisfaction. The role of ondansetron has been studied in preventing pruritus but the results have been contradictory. Methods: We randomized 98 parturients undergoing elective cesarean section using combined spinal-epidural anesthesia into a double-blinded trial to receive tropisetron 5 mg (T group) or ondansetron 8 mg (O group) or placebo (NaCl group) after delivery, when intrathecal morphine 160 mg and fentanyl 15 mg were used for post-operative pain control. The patients additionally received ketoprofen 300 mg per day. Postoperative itching, nausea and vomiting, sedation and need for rescue analgesics were registered every 3 h up to 24 h, and all patients were interviewed on the first post-operative day. Results: Seventy-six percent of the parturients in the placebo group, 87% in the ondansetron, and 79% in the tropisetron group had itching. The incidence of post-operative nausea and
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morphine is commonly used for pain relief after cesarean delivery. In patients undergoing a cesarean section, morphine has been proven to be effective for post-operative pain control with minimal exposure to opioids in lactating parturients (1). Both epidural and intrathecal routes are associated with a high incidence of side-effects, most commonly post-operative itching and nausea, which are the most common causes for dissatisfaction with post-operative analgesia (1, 2). Ondansetron, a specific 5-hydroxytryptamine antagonist (5-HT3), has been used with success to prevent neuraxial morphine-induced pruritus according to some studies (3—6), but not all such studies support this effect (7, 8). Because itching after a single dose of morphine seems to last for as long as 24 h, the longer lasting effect of tropisetron, than that of ondansetron, could be more suitable for this purpose. To our knowledge, no such studies PINAL
vomiting was 21%, 20% and 11% of the patients in the placebo, ondansetron and tropisetron groups, respectively. Medication for pruritus was needed by 31%, 23% and 39% of the patients in the placebo, ondansetron and tropisetron groups, respectively. In the post-operative questionnaire, the patients reported less post-operative nausea in the tropisetron group than in the placebo group (P < 0.01). Conclusion: Neither ondansetron nor tropisetron prevent itching caused by intrathecal morphine with fentanyl. However, tropisetron reduced post-operative nausea.
Accepted for publication 1 October 2005
Key words: obstetrics; anesthesia; spinal; intrathecal; epidural; post-operative nausea and vomiting. #
Acta Anaesthesiologica Scandinavica 50 (2006)
have been carried out. We wanted to answer the question: ‘Does prophylactic administration of single doses of ondansetron 8 mg or tropisetron 5 mg prevent itching after intrathecal morphine 160 mg with fentanyl combined with ketoprofen in a prospective, double-blinded and controlled study’. The secondary purpose of the study was to evaluate the effect of the study drugs on other side-effects.
Methods After obtaining the approval of the institutional ethics committee, 98 elective parturients scheduled for elective cesarean delivery were enrolled in the study between January and November 2003 (Fig. 1). Written informed consent was obtained from all patients. Patients with a major systemic disease, hepatogestosis or parturients who had fetuses with known anomalies or were allergic to any of the
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Assessed for eligibility, n = 148 Not meeting inclusion criteria (n = 25) Refused to participate (n = 25)
Allocation
Follow-up
Analysis
Group saline Allocated to intervention, n = 33 Received allocated intervention, n = 29 Did not receive allocated intervention, n = 4 - study medicine was not ready, n=1 - more than 5 ml epidural top-up needed, n = 3
Lost to follow-up, n = 0
Group ondansetron Allocated to intervention n = 31 Received allocated intervention, n = 30 Did not receive allocated intervention, n = 1 - more than 5 ml epidural top-up needed, n = 1
Lost to follow-up, n = 0
Analyzed, n = 29
Analyzed, n = 30
Group tropisetron Allocated to intervention n = 34 Received allocated intervention n = 28 Did not receive allocated intervention, n = 6 - more than 5 ml epidural top-up needed, n=5 - intrathecal space not found, n = 1
Lost to follow-up, n = 2 - post-operative questionnaire lost, n = 2
Analyzed, n = 28 Post-operative questionnaire analyzed, n = 26
Fig. 1. The consort flow chart.
drugs used were excluded. Also patients needing epidural top-ups of more than 5 ml were excluded. Randomization was stratified with an equal number of multiparous and primiparous parturients in each group, using computer-generated random numbers. After pre-hydration with 1 l of acetated Ringer’s solution, the parturients received 8—9 mg of plain bupivacaine 0.5% (1.6—1.8 ml), 15 mg of fentanyl (0.3 ml) and 160 mg of preservative-free morphine (0.4 ml) for spinal anesthesia. We used a combined spinal-epidural needle-through-needle technique with a G16 Tuohy epidural needle and a Whitacre G26 spinal needle. The injection site was the L3—4 interspace. After spinal anesthesia, an epidural catheter was inserted. Initially the patient lay on her right side with a pillow under her head and was then turned to a supine position. The operating table was immediately tilted at least 20 to the left and a urinary catheter was inserted. If the anesthesia level did not reach T5 at 15 min, the epidural catheter was tested with lidocaine 2% with epinephrine, and epidural top-ups were administered as needed. Oxygen 4 l/ min was administered through a facial mask until delivery. Intravenous (i.v.) boluses of 5—10 mg ephedrine and additional i.v. fluids were administered to treat hypotension, which was defined as systolic blood pressure below 95 mmHg or a decrease in systolic pressure of > 20% from the baseline value. The surgical technique was uniform for all patients and
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included exteriorization of the uterus. After delivery, 5 IU of oxytocin were administered i.v. Five minutes after delivery, the patient was given either ondansetron 8 mg (ZofranÒ, Group O), tropisetron 5 mg (NavobanÒ, Group T) or saline (Group NaCl). The study drugs were diluted with saline as needed, to obtain a 5 ml volume of study medication; they were prepared by an anesthesiologist who was not participating in the care and evaluation of the patients. Maternal ECG and oxygen saturation were monitored, and non-invasive blood pressure was measured from the right arm every 1 or 2 min until the birth of the child, and thereafter every 5 min until the patient was moved to the post-anesthesia care unit (PACU). Peri-operative itching, nausea or vomiting after delivery and pain were estimated using a numerical rating score (NRS) from 0 (no pain, itching, nausea or vomiting) to 10 (worst possible pain, itching, nausea or vomiting, respectively). At the end of surgery, 100 mg of ketoprofen was administered rectally and thereafter every 8 h per-orally or rectally. Intravenous fentanyl 50 mg was used during surgery and in the PACU, and oxycodone 5 mg po on the ward as rescue analgesics if requested and/or if the VAS score for pain was > 3. Nurses assessed the patients up to 24 h after inducing spinal anesthesia at 2 and 3 h during their stay in PACU and thereafter every 3 h on the ward, and registered itching, nausea or vomiting
Setrones in C-section
and pain. Respiratory rate, the adequacy of respiration and sedation (0 ¼ none, 1 ¼ mild sedation, 2 ¼ considerable sedation, arousable) were assessed hourly for 18 h. Possible side-effects and pain were recorded as follows: itching, nausea and vomiting and pain were estimated using the numeral rating scale (NRS) from 0 to 10 as described previously. The investigators were blinded to the study group. In the ward, the nurse categorized nausea and vomiting into three groups from zero to two (0 ¼ none, 1 ¼ nausea, 2 ¼ disturbing nausea or vomiting) unless the patient was asleep. The nature of the side-effects was explained to the patients and they were told about the treatment. Side-effects were treated only on request. Nausea and vomiting were treated with i.v. droperidol 0.5 mg or i.v. metoclorapide 10 mg, and itching with anti-histamine hydroxyzine hydrochloride 25 mg po or naloxone 0.04 mg repeatedly i.v. or 0.4 mg intramuscularly (i.m.) as necessary. Twenty-four hours after the surgery, the patients received a questionnaire. The side-effects in their entirety, itching, need to scratch, post-operative nausea and sedation were categorized into five groups (1 ¼ no side-effects, 2 ¼ mild side-effects, 3 ¼ moderate, 4 ¼ considerable, 5 ¼ intolerable). The success of pain control was rated into five groups (1 ¼ poor, 2 ¼ rather poor, 3 ¼ rather good, 4 ¼ good, 5 ¼ excellent). Possible dysphoric feelings were also inquired. For statistical analysis, the Kruskall—Wallis test and w-square test (cross-tabs) for quantitative and categorical data, respectively, were used, applying SPSS (Version 12.0 for Windows) (SPSS Inc., Chicago, IL). When the results were statistically significant, an intergroup analysis using the Mann—Whitney U-test and w-square tests was applied. A P-value < 0.05 was considered significant. The data are expressed
as means SD or medians and 5% and 95% percentiles or range as appropriate. In this study, group size was determined to be 28 patients in order to detect a decrease of itching from 75% to 40% at the 0.05 significance level with 80% power.
Results The characteristics (mean and SD) of the groups were as follows: age 33 (5) years, weight 77 (11) kg, height 165 (6) cm and pregnancy weeks 39 (1). There were no statistical differences between the groups. Eleven patients (six in group T, one in group O and four in group NaCl) were excluded from the study because more than 5 ml of epidural supplementation was needed to achieve adequate anesthesia (nine patients), intrathecal anesthesia did not succeed (one patient) and the study medicine was not available when needed (one patient; Fig. 1). No patient required general anesthesia due to a failed block. There was no difference between the groups in the requirements for ephedrine, length of surgery, bleeding or number of patients perceiving pain during surgery. Neither did the groups differ in the incidence of nausea or vomiting experienced after delivery, nor itching during surgery (Table 1). Postoperative complications requiring re-operation did not occur in any of the patients. During the stay in PACU, 76%, 77% and 79% of the patients perceived itching 2 h after spinal anesthesia in group NaCl, group O and group T, respectively. At 3 h, the respective percentages were 69%, 87%, 79% (NS). Only one patient in the placebo group felt nausea and vomiting in the PACU at 2 h, two patients in the ondansetron group, and none in the tropisetron group. The severity of side-effects measured using a NRS did not differ between the groups (Table 2).
Table 1 Data during surgery.
Number of patients requiring epidural local anesthetic top-ups Number of patients experiencing pain during surgery Number of patients experiencing nausea or vomiting during surgery after delivery Number of parturients experiencing itching during surgery Ephedrine required (mg), mean (SD) Length of surgery (min), mean (SD) Bleeding during surgery (ml), mean (SD)
Placebo n ¼ 29
Ondansetron n ¼ 30
Tropisetron n ¼ 28
6 2 4 7 16 (14) 39 (9) 600 (500)
6 3 5 4 13 (15) 36 (9) 500 (300)
3 1 3 5 19 (19) 41 (12) 700 (500)
No significant differences between the groups.
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P. J. Sarvela et al. Table 2 Data collected in the recovery area up to 3 h after the start of anesthesia.
Pruritus at 2 h NRS of those having pruritus Pruritus at 3 h NRS of those having pruritus Medication required for pruritus during the first 3 h Hydroxyzine hydrochloride Naloxone PONV at 2 h PONV at 3 h Medication required for PONV during the first 3 h Medication required for pain
Placebo n ¼ 29
Ondansetron n ¼ 30
Tropisetron n ¼ 28
22 2.5 (1—6) 20 2.5 (1—6) 3 3 — 1 0 1 3
23 3 (1—6) 26 3.0 (1—5) 4 4 — 2 2 0 4
22 3 (1—8) 22 3.0 (1—9) 8 8 3 0 0 0 6
Data expressed as number of patients, NRS (numeric rating score, 0—10, 0 ¼ no pruritus, 10 ¼ worst imaginable pruritus) as median and range. PONV, post-operative nausea and vomiting; no significant differences between the groups.
During the post-operative follow-up in the ward up to 24 h after surgery, the occurrence of itching and nausea and vomiting were divided into two periods from 4 to 12 h and from 12 to 24 h. There was no difference between the groups in itching, post-operative nausea and vomiting (PONV) or the severity of these side-effects during either of the periods. There was no difference in the need for medication for itching or PONV. No patient had respiratory depression (respiratory rate < 10) or a sedation score of more than 1. The need for rescue analgesics is shown in Fig. 2 and Table 3. When the side-effects were inquired 24 h after surgery, they were reported to be non-existent or mild by 80 Saline Ondansetron Incidence (%)
60
Tropisetron
83%, 77% and 84% of the patients in the NaCl, O and T groups, respectively. Moderate or severe pruritus was reported by 40%, 27% and 46% and a moderate or strong need to scratch by 28%, 10% and 35% in the NaCl, O and T groups, respectively (NS). There was a statistical significant (P < 0.01) difference in the occurrence of post-operative nausea between the groups. In the subgroup, more patients in the NaCl group (11 patients) compared with the T group (two patients, P < 0.01) reported nausea but the difference with the O group (8 patients) was not statistically significant. Satisfaction with pain control was rated good or excellent by 93%, 90% and 89% in the NaCl, O and T groups, respectively. None of the patients reported poor or rather poor pain relief. Most of the patients felt mild to moderate sedation (86%, 87% and 81% in the NaCl, O and T groups, respectively). The occurrence of sedation did not correlate with the use of hydroxyzine hydrochloride or with the use of ondansetron or tropisetron.
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Discussion
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Fig. 2. Prevalence of recorded post-operative side-effects and the requested treatment up to 24 h after the operation in the saline, ondansetron and tropisetron groups. PONV, post-operative nausea and vomiting.
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The reported incidence of itching in this study lay between 76% (placebo group) and 87% (ondansetron group) and is similar or higher than reported in other obstetric studies using a comparable intrathecal dose of morphine (1, 4, 6, 7). In the post-operative interview, 36% of all parturients considered the pruritus as moderate or severe and no one unbearable. Twenty-four percent of the parturients felt a moderate or strong need to scratch. However, the medication requirements for pruritus ranged from group to group from 23% (Group O) to
Setrones in C-section Table 3 Data collected in the ward up to 24 h after the start of anesthesia.
Sedation score 0 1 2 NRS for pain > 3 Oxycodone dose required (mg) Pruritus experienced during 4—12 h post-operatively Maximal NRS for pruritus Pruritus experienced during 12—24 h post-operatively Maximal NRS for pruritus Medication required for pruritus Hydroxyzine hydrochloride Naloxone PONV experienced during 4—12 h post-operatively Mild PONV (grade 1) Considerable PONV (grade 2) PONV experienced during 12—24 h post-operatively Medication required for PONV Dehydrobenzperidol Metoclopramide
Placebo n ¼ 29
Ondansetron n ¼ 30
Tropisetron n ¼ 28
26 3 0 13 5 (5—10) 22 3.0 (1—7) 14 2.0 (1—7) 9 9 1 6 2 4 0 3 2 2
25 5 0 13 5 (5—20) 20 2.5 (1—8) 10 2.0 (1—5) 7 7 1 6 1 5 1 4 3 2
21 7 0 11 0 (0—10) 20 2.5 (1—8) 10 3.5 (1—6) 11 11 3 3 2 1 0 1 0 1
Data expressed as number of patients, NRS (numeric rating score, 0—10, 0 ¼ no pruritus/pain, 10 ¼ worst imaginable pruritus/pain) as median and range. PONV, post-operative nausea and vomiting; no significant differences between the groups.
39% (Group T). The high overall incidence of itching reflects the fact that the nature of the side-effects was explained before surgery to the patients and that it was specifically asked and the rather low incidence of medication, on the other hand, reflects the fact that it was most often considered as mild. Furthermore, women with newborn babies are probably less reluctant to ask for medication because of the side-effects, compared with other patient groups. Also the use of fentanyl in conjunction with morphine probably increased the occurrence of itching which reached its peak at 2 and 3 h hours after spinal anesthesia. Combined spinal-epidural anesthesia was used because of its reliability and flexibility (9) enabling the use of small amounts of local anesthetics for spinal anesthesia and potential supplementation of spinal anesthesia with epidural top-ups. Nine patients were excluded from the study when more than 5 ml of extradural supplementation was required to achieve an adequate level of anesthesia (Th 5 dermatome) (10). This was done because there was a possibility that with larger extradural anesthetic requirements all of the anesthetic solution with opioids had not reached the intrathecal space. This study did not find any antipruritic effect using either ondansetron or the longer acting tropisetron.
Neither did the incidence of itching nor the rating scores of itching differ between the groups. It is difficult to explain the contradictory results of similar studies because the exact mechanism of opioidinduced pruritus is unclear. According to present knowledge, it is centrally induced and not associated with the release of histamine. A possible proposed explanation has been that the addition of lipophilic short-acting opioids to morphine would act faster than the 5-HT3-antagonists could block the serotonin receptors in the spinal cord and thus prevent its action (7, 11—13). This could be the reason why no effect of 5-HT3-antagonist was found in our study where fentanyl was used in conjunction with morphine. However, in a study by Gu¨rkan et al., shortacting opioids displayed anti-pruritogenic action (14). Moreover, in studies where ondansetron has been shown to counteract itching, relatively large intrathecal doses of morphine, i.e. 0.2 mg or more, have been used (3, 6). The incidence of PONV was 21% in the placebo group during follow-up in the PACU and in the ward; this was a rather low percentage compared with other studies (8, 7). In the ondansetron and tropisetron groups, the incidences were 20% and 11%, respectively. However, when interviewed 24 h after anesthesia, the incidences of nausea were 38%, 27%
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and 8%, respectively, which was a statistically significant difference. In subgroup comparisons, only the use of tropisetron reduced the incidence of nausea. In the other studies (5, 7, 8), ondansetron reduced the incidence of PONV when used for cesarean delivery with intrathecal morphine. The longer half-life of tropisetron would also theoretically make it more suitable than ondansetron to prevent this side-effect which was most common during the time period 4—12 h after anesthesia. The higher incidence of nausea on the day after the operation may indicate that the patients were focused on reporting itching and did not spontaneously report mild feelings of nausea unless directly asked. Also in the post-operative questionnaire, only feelings of nausea (and not vomiting) were asked while the fact that during follow-up emesis was considered as moderate PONV (grade 2) and was not studied separately. Moreover, the incidence of PONV of the different groups did not reach statistical significance probably due to the too low power of this study to investigate this secondary endpoint. The parturients were able to report other possible side-effects too. No one complained of headache or restlessness, whereas sedation was common. In the ward, sedation (score 1) was registered in 10% (group NaCl) to 25% (group T), and no scores 2 were observed. However, when asked on the following day moderate or heavy sedation ranged from 27% (group T) to 67% (group O) reflecting the difficulty of estimating this parameter, as it was not directly asked. The high incidence of sedation is probably related to the sedative effect of intrathecal morphine and the overall disappearance of stress symptoms after delivery. In conclusion, neither ondansetron 8 mg nor tropisetron 5 mg reduced the incidence or severity of itching induced by intrathecal morphine (160 mg) when used with fentanyl (15 mg) and bupivacaine in cesarean delivery. However, tropisetron may diminish post-operative nausea.
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2. Ayoub CM, Sinatra RS. Postoperative analgesia: epidural and spinal techniques. In: Chestnut DH, ed. Obstetric Anesthesia. Principles and Practice, 3rd edn. Philadelphia: Mosby. 2004: 472—97. 3. Borgeat A, Stirnemann HR. Ondansetron is effective to treat spinal or epidural morphine-induced pruritus. Anesthesiology 1999; 90: 432—6. 4. Yeh HM, Chen LK, Lin CJ, Chan WH, Chen Y, Lin CS et al. Prophylactic intravenous ondansetron reduces the incidence of intrathecal morphine-induced pruritus in patients undergoing cesarean delivery. Anesth Analg 2000; 91: 172—5. 5. Tzeng JI, Chu KS, Ho ST, Tang CS, Liu YC, Lee SC. Prophylactic iv ondansetron reduces nausea, vomiting and pruritus following epidural morphine for postoperative pain control. Can J Anaesth 2003; 50: 1023—6. 6. Charuluxananan S, Kyokong O, Somboonviboon W, Narasethakamol A, Promlok P. Nalbuphine versus ondansetron for prevention of intrathecal morphine-induced pruritus after cesarean delivery. Anesth Analg 2003; 96: 1789—93. 7. Yazigi A, Chalhoub V, Madi-Jebara S, Haddad F, Hayek G. Prophylactic ondansetron is effective in the treatment of nausea and vomiting but not on pruritus after cesarean delivery with intrathecal sufentanil-morphine. J Clin Anesth 2002; 14: 183—6. 8. Szarvas S, Chellapuri RS, Harmon DC, Owens J, Murphy D, Shorten GD. A comparison of dexamethasone, ondansetron, and dexamethasone plus ondansetron as prophylactic antiemetic and antipruritic therapy in patients receiving intrathecal morphine for major orthopedic surgery. Anesth Analg 2003; 97: 259—63. 9. Choi DH, Kim JA, Chung IS. Comparison of combined spinal epidural anesthesia and epidural for cesarean section. Acta Anaesthesiol Scand 2000; 44: 214—9. 10. Sarvela PJ, Halonen PM, Korttila KT. Comparison of 9 mg of intrathecal plain and hyperbaric bupivacaine both with fentanyl for cesarean delivery. Anesth Analg 1999; 89: 1257—62. 11. Szarvas S, Harmon D, Murphy D. Neuraxial opioid-induced pruritus: a review. J Clin Anesth 2003; 15: 234—9. 12. Wells J, Paech MJ, Evans SF. Intrathecal fentanyl-induced pruritus during labour: the effect of prophylactic ondansetron. Int J Obstet Anesth 2004; 13: 35—9. 13. Korhonen AM, Valanne JV, Jokela RM, Ravaska P, Korttila K. Ondansetron does not prevent pruritus induced by lowdose intrathecal fentanyl. Acta Anaesthesiol Scand 2003; 47: 1292—7. 14. Gu¨rkan Y, Toker K. Prophylactic ondansetron reduces the incidence of intrathecal fentanyl-induced pruritus. Anesth Analg 2002; 95: 1763—6. Address: Johanna Sarvela Department of Anesthesia and Intensive Care Helsinki University Central Hospital PO Box 140 Haartmaninkatu 2 FI-00029 HYKS Finland e-mail:
[email protected]
