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BJA Advance Access published online on February 27, 2008
British Journal of Anaesthesia, doi:10.1093/bja/aen025
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© The Board of Management and Trustees of the British Journal of Anaesthesia 2008. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Comparison of high- and low-dose intrathecal morphine for spinal fusion in children

S. Eschertzhuber1,*, M. Hohlrieder1, C. Keller1, E. Oswald1, G. Kuehbacher2 and P. Innerhofer1

1 Department of Anaesthesiology and Critical Care Medicine, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria
2 Department of Anaesthesiology and Critical Care Medicine, Hall i.T. County Hospital, Milser Strasse 10, 6060 Hall in Tirol, Austria

* Corresponding author. E-mail: stephan.eschertzhuber{at}i-med.ac.at

Accepted for publication January 21, 2008.


   Abstract
Top
 Abstract
Introduction
 Methods
 Statistical analyses
 Results
 Discussion
 Appendix A
 References
 
Background: The purpose of this prospective study was to assess the blood-sparing effect, the quality of analgesia, and the incidence of side-effects of a low-dose regime of intrathecal opioids (ITO) when compared with those of a high-dose regime in scoliosis surgery in children.

Methods: Forty-six children were randomly included into one of the three groups to receive morphine 5 µg kg–1 plus sufentanil 1 µg kg–1 [low-dose intrathecal opioid (LITO)], morphine 15 µg kg–1 plus sufentanil 1 µg kg–1 [high-dose intrathecal opioid (HITO)] intrathecally, or no intrathecal opioid. Postoperative analgesia was provided by i.v. opioids. Intraoperative blood loss, postoperative quality of analgesia, opioid requirements, and the incidence of side-effects were recorded for 3 days.

Results: Intraoperative blood loss was significantly reduced by ITOs [LITO: 41.4 (SD 18.8) ml kg–1; HITO: 37.5 (6.9) ml kg–1; control: 76.9 (15.3) ml kg–1, P<0.001], with no difference between the two intrathecal opioid groups. Mean pain scores on the day of surgery were lower in both intrathecal opioid groups (LITO: 2.2 and HITO: 2.1) when compared with the control group (4.1, P<0.03) and opioid consumption was significantly decreased [LITO: 304.3 (65.0) µg kg–1; HITO: 224.1 (51.8) µg kg–1; control: 667.7 (89.5) µg kg–1, P<0.002]. Side-effects of intrathecally administered opioids were similarly frequent in all groups.

Conclusions: Intrathecal administration of opioids significantly reduces blood loss and postoperative opioid demand, thereby showing side-effects comparable with the control group. These effects were already seen with the low-dose regimen and high dose did not further improve efficacy.

Keywords: children; analgesics, opioid; surgery, spinal


   Introduction
Top
 Abstract
 Introduction
Methods
 Statistical analyses
 Results
 Discussion
 Appendix A
 References
 
Since the first report on the intrathecal use of opioids for acute pain treatment in 1979 by Wang and colleagues,1 anaesthetists have used this method of analgesia for numerous indications2 and in many different manners.3 Administration of intrathecal opioids (ITO) for spinal surgery in children has proved to have special advantages such as decreased intraoperative blood loss, lower incidence of pulmonary complications, protection of gastrointestinal function, and above all a high quality of analgesia.4–7 Despite these convincing benefits, the popularity of ITO was repeatedly undermined by reports of side-effects such as respiratory depression, pruritus, and postoperative nausea and vomiting. The incidence of these side-effects was postulated to be dose-dependent and thus increases with higher doses.8–10 Gall and colleagues11 compared two low-dose regimes of ITO (morphine 2 and 5 µg kg–1) for their analgesic effect after spinal fusion in children and neither reported differences in analgesia nor the incidence of side-effects. However, they found the lower ITO dose to have a diminished blood-sparing effect.

This study was conducted to evaluate the differences in analgesic and blood-sparing effect and the incidence of side-effects by comparing a low-dose ITO (LITO) (morphine 5 µg kg–1 plus sufentanil 1 µg kg–1) and a high-dose ITO (HITO) (morphine 15 µg kg–1 plus sufentanil 1 µg kg–1) regime in spinal surgery in children and adolescents.


   Methods
Top
 Abstract
 Introduction
 Methods
Statistical analyses
 Results
 Discussion
 Appendix A
 References
 
The study was designed in a prospective, randomized, single-blinded manner according to the guidelines for Good Clinical Practice. After the approval from institutional ethics committee and after written informed consent had been obtained from the children and their parents, 46 patients were included in the study. The patients (ASA physical status I–II) aged 12–17 yr, scheduled for dorsal spinal fusion because of idiopathic scoliosis were randomly allocated to one of the three groups using a computer-generated list: (a) LITO: 5 µg kg–1 intrathecal morphine plus 1 µg kg–1 intrathecal sufentanil; (b) HITO: 15 µg kg–1 intrathecal morphine plus 1 µg kg–1 intrathecal sufentanil; (c) control group with no intrathecal opioid. The maximum doses for morphine were 1000 µg and for sufentanil 50 µg. Exclusion criteria were chronic pain or pruritus, neurological or coagulation disorders, contraindications for spinal puncture, presumed inability to quantify pain on a visual analogue scale (VAS), or inability to use a patient-controlled analgesia (PCA) device. Preoperative coagulation status (prothrombin time, partial thromboplastin time, plasma fibrinogen concentration, antithrombin III concentration, platelet count) and hematocrit were assessed in all patients.

Thirty minutes before anaesthesia, patients were premedicated with oral midazolam (<55 kg body weight, 3.75 mg; ≥55 kg body weight, 7.5 mg). Anaesthesia was induced with i.v. fentanyl (3 µg kg–1) and propofol (2.5–4 mg kg–1). After oral intubation facilitated by rocuronium (0.6 mg kg–1) in addition to standard monitoring, a central venous and an arterial line was established as was a Foley catheter inserted. Patients of the ITO groups were turned to a lateral position for spinal puncture. Under aseptic conditions, a mixture of 1 µg kg–1 sufentanil and 5 µg kg–1 (LITO) or 15 µg kg–1 (HITO) morphine was diluted with normal saline to give a total volume of 3 ml and injected in the L3–4 or L4–5 intervertebral space using a 25-gauge pencil-point spinal needle (B. Braun AG, Melsungen, Germany). Anaesthesia was maintained with sevoflurane in oxygen/air mixture and continuous remifentanil infusion by an anaesthetist blinded to the study groups. The remifentanil infusion rate was set to keep the mean arterial pressure (MAP) within (15%) baseline. If the MAP increased above this limit, the infusion rate was also increased by 0.075 µg kg–1 min–1. If the increased MAP was present 5 min later, the increment of the remifentanil rate was repeated. If the MAP decreased below the limits and it did not respond to an i.v. fluid bolus, the remifentanil dose was decreased.

In all patients, a cell saver device (CATS®, Fresenius, Bad Homburg, Germany) was used to minimize allogeneic blood exposure. All patients were actively warmed using fluid warmers and a convective warming system (Bair Hugger®, Arizant Healthcare Inc., USA). All patients received 60–80 µg kg–1 tropisetron, 4 mg lornoxicam, 50 mg ranitidine, and 30 mg diphenhydramine i.v. after induction of anaesthesia. Antibiotic prophylaxis was maintained by a single shot of cefuroxime.

Perioperative monitoring consisted of ECG, pulse oximetry, invasive arterial and central venous pressure, end tidal capnography, urine output, temperature, and sequential blood gas and haematocrit analyses. In all patients, spinal function was monitored using evoked sensomotoric potentials. During operation, MAP, heart rate, end tidal sevoflurane concentrations, and remifentanil requirements were recorded every 5 min.

Intraoperative blood loss was assessed by measuring the amount of collected blood in the cell saver, suction bottles, and by weighing the sponges. Intraoperative fluid regimen consisted of crystalloid solution 10 ml kg–1 h–1 and additional colloid solution which were administered in a ratio of 1:1 to occurring blood loss until transfusion trigger was reached at a haematocrit below 25%.

After termination of surgery, all patients were monitored for 24 h in the post-anaesthesia care unit (PACU) and for another 48 h in a postoperative step-down unit. According to our clinical routine in treating children after scoliosis repair, all patients were mechanically ventilated until standardized extubation criteria were reached. All nurses and doctors involved in the postoperative care were blinded to the study randomization of the patients. In order to exactly register postoperative i.v. opioid demand (number of demands and the cumulative dose), a PCA pump (Grasbey 3300 PCA; Graseby Medical Ltd, Watford, UK) using piritramide (Dipidolor®, Janssen-Cilag Pharma GmbH, Austria) (1.5 mg piritramide i.v. equivalent to 1.0 mg morphine i.v.) was immediately connected to the patients at arrival in the PACU. Each bolus delivered an i.v. dose of 30 µg kg–1 piritramide at a lockout time of 10 min. The maximum piritramide dose was set at 600 µg kg–1 in 4 h. Until extubation, the administration of i.v. opioid was achieved according to signs of pain by the attending anaesthetist and nurse who were blinded to study groups. After extubation, the children were instructed to achieve maximal comfort by controlling the PCA pump by their demand. All patients received 4 mg lornoxicam every 12 h i.v. for the first three postoperative days.

The blinded observers evaluated intensity of pain by asking the children to use a VAS (VAS 0–10; where 0 denotes no pain and 10 denotes unbearable pain) and estimated the concentration of sedation using the modified Ramsay Sedation Score (Appendix A) and recorded the worst scores of each day.

After achieving standardized extubation criteria [arterial oxygen saturation >95% and normocapnea while breathing spontaneously (FIO2<50%), a tidal volume >6.0 ml kg–1, a ventilatory frequency adequate for the patient’s age, complete reversal of neuromuscular block, ability to follow verbal commands, haemodynamic stability, and a core body temperature >36.0°C], patients were orally extubated and then intermittently treated with continuous positive airway pressure therapy via face mask. The lowest oxygen saturation measured with pulse oximetry and verified by arterial blood gas analysis, at 0.21 inspiratory oxygen concentration, time of extubation, and the need for reintubation were recorded for the first 72 h after surgery.

Besides respiratory depression (defined as ventilatory frequency <10 min–1, SaO2<95%, or PaCO2>50 mm Hg), the occurrence of other side-effects such as sedation, pruritus, itching or postoperative nausea, and vomiting was recorded by the nurses using standardized data forms.


   Statistical analyses
Top
 Abstract
 Introduction
 Methods
 Statistical analyses
Results
 Discussion
 Appendix A
 References
 
Data were collected using standardized observation protocols. All statistical analyses were performed using the SPSS software package (SPSS Inc., Chicago, IL, USA). Results are presented as mean (SD). Nominal data were compared with Chi-squared analysis and Fisher’s exact t-test where appropriate. Numerical data were assessed using analysis of variance (ANOVA), with group-by-group comparisons accomplished using post hoc Bonferroni tests. P-values below 0.05 were considered significant.


   Results
Top
 Abstract
 Introduction
 Methods
 Statistical analyses
 Results
Discussion
 Appendix A
 References
 
Of the 46 patients enrolled in the study, four were excluded from analysis because of early surgical revision or violation of the postoperative study protocol. Finally, the remaining 42 patients from the three groups (14 in each group) were comparable for patient characteristics and preoperative laboratory values (Table 1).


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  		Table 1 Demographic data and preoperative laboratory values. Data are presented as mean (SD); HITO, high-dose intrathecal opioid (15 µg kg–1 morphine+1 µg kg–1 sufentanil); LITO, low-dose intrathecal opioid (5 µg kg–1 morphine+1 µg kg–1 sufentanil)

 
Intraoperative data
Duration of surgery, intraoperative haemodynamics, and end tidal sevoflurane concentrations were similar in all groups (Table 2). In all patients of the ITO groups, subarachnoid injection of the opioids was successfully performed without complications such as nerve injury, haematoma, liquor leakage, or infection.


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  		Table 2 Intraoperative characteristics. Data are presented as mean (SD). *P<0.001; HITO, high-dose intrathecal opioid; LITO, low-dose intrathecal opioid

 
Mean intraoperative blood loss was significantly less in the ITO groups [LITO 41.4 (18.8) ml kg–1, HITO 37.5 (6.9) ml kg–1] when compared with control [76.9 (15.3) ml kg–1] (P<0.001). Blood loss was least in the HITO group but the difference in blood loss did not reach statistical significance as compared with the LITO group (Table 2).

As expected, the total intraoperative requirement of i.v. remifentanil was significantly higher in the control group than in the ITO groups (Table 2).

Postoperative data
On the day of surgery, the worst recorded mean pain scores at rest were 2.2 in the LITO, 2.1 in the HITO when compared with 4.1 in the control group (P<0.03). Consequently, mean piritramide consumption showed significant differences between the three groups on the day of surgery (P<0.002). The lowest piritramide requirements within the first 24 h after surgery were found in the HITO group [224.1 (51.8) µg kg–1] when compared with the LITO group [304.3 (65.0) µg kg–1] and the control group [667.7 (89.5) µg kg–1].

On postoperative days 1–3, pain scores were similar in all groups (Fig. 1) as was piritramide consumption. However, the need for systemic opioids in the LITO group was slightly higher on all three postoperative days (Fig. 2).


Figure 1
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  		Fig 1 Visual analogue scale pain scores (worst daily value) on postoperative days 0–3 given as mean. *Statistical differences between control and morphine groups (P<0.03).

 


Figure 2
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  		Fig 2 Comparison of postoperative i.v. piritramide requirements. Given in mean µg kg–1. *Statistical difference between control and morphine groups (P<0.002).

 
Mean time to extubation was 1.9 (2.0), 3.9 (2.6), and 3.9 (2.0) h in the LITO, HITO, and control group, respectively (P<0.03). Comparison of lowest arterial blood oxygen saturation during the first 72 postoperative hours [87.6 (6.6), 85.5 (5.1), and 88.4 (3.8)% in the LITO, HITO, and control groups, respectively] showed no differences between the groups. None of the patients needed tracheal reintubation or administration of an opioid antagonist for the management of respiratory depression.

Mean sedation scores during the 96-h observation period ranged from 2.2 to 2.9 and showed no significant differences between the three groups.

Postoperative vomiting occurred in all groups equally frequent with an incidence of 21.4% on the day of surgery and postoperative day 1. On postoperative days 2 and 3, up to 14.3% and 21.4% of the children suffered from vomiting with the highest incidence in the control group. During the whole observation period of 96 h, nine patients (64.3%) in the LITO group, 10 patients (71.4%) in the HITO group, and 11 patients (78.6%) in the control group complained of nausea (Fig. 3).


Figure 3
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  		Fig 3 Frequency of postoperative vomiting, nausea, and pruritus registered during 72 h after scoliosis surgery in children receiving additional intraoperative intrathecal morphine or not. No statistically significant differences between the groups.

 
No significant differences in the incidence of pruritus were seen between the three study groups (Fig. 3).


   Discussion
Top
 Abstract
 Introduction
 Methods
 Statistical analyses
 Results
 Discussion
Appendix A
 References
 
This study evaluated the effects of intrathecal morphine in two different doses (5 and 15 µg kg–1) combined with a fixed dose of intrathecal sufentanil (1 µg kg–1) in children undergoing elective spinal fusion. The major findings were a significant reduction in intraoperative blood loss, lower pain scores, and decreased systemic opioid requirement during the first 24 h in both ITO groups when compared with the control group. No statistically significant differences were seen between the LITO (5 µg kg–1) and the HITO (15 µg kg–1) group regarding these values.

A blood-sparing effect of intrathecally administered morphine/sufentanil in children during spinal fusion procedures was first described by Goodarzi using 20 µg kg–1 morphine mixed with 50 µg sufentanil.6 They found that intraoperative blood loss was related to a decreased MAP in the intrathecal morphine group when compared with the control group. The authors assumed that the hypotensive effect resulted from blockage of autonomic A and C fibres together with a direct sympatholytic effect of opioids at the spinal cord level. Also Dalens and Tanguy12 showed that intrathecal morphine reduced MAP and blood loss in children undergoing scoliosis repair. Interestingly, in the present study no difference in MAP was observed although blood loss was significantly reduced in the ITO groups. This observation suggests an unknown specific effect of ITO as the underlying mechanism for reduction of blood loss. We expected that the HITO regime would provide a marked blood-sparing effect. However, children receiving 15 µg kg–1 morphine combined with 1 µg kg–1 sufentanil showed only a slightly further decrease in intraoperative blood loss when compared with the LITO. Nevertheless, it is likely that a significant difference in blood loss could be observed in a larger study population. Gall and colleagues11 compared two low-dose regimes (2 and 5 µg kg–1) of intrathecal morphine in children undergoing spinal fusion. Although comparable analgesia profiles and occurrence of side-effects were found, the investigators observed a diminished blood-sparing effect in the 2 µg kg–1 morphine group when compared with the 5 µg kg–1 morphine group (34 vs 14 ml kg–1). Taking these findings together, intrathecal morphine should be administered at least at dosages of 5 µg kg–1 mixed with sufentanil 1 µg kg–1 to result in a sufficient reduction in blood loss.

In volunteers, during hip surgery and in obstetrics, endeavours have been made to reduce the dosage of ITO because of the assumed relation of frequency of side-effects and the morphine dosage used.8–10 13 Other investigators comparing intrathecal morphine of 0.3–1.0 mg in patients undergoing knee replacement surgery with 0.015–0.25 mg in non-surgical pain patients found no dose-dependence for the incidence of side-effects, but observed a lower quality of analgesia when using the smaller dose of intrathecal morphine.14 15 The potent analgesic effect of ITO in patients undergoing various surgical procedures is well documented. In the recent past, investigators showed that even doses as small as 1 or 2 µg kg–1 ITO provide satisfactory analgesia in major orthopaedic surgery.9 11 16 However, Bowrey and colleagues14 found that 0.5 mg intrathecal morphine produces better analgesia than 0.2 mg intrathecal morphine after total knee replacement. Gall and colleagues,11 comparing 2 and 5 µg kg–1 intrathecal morphine in 30 children undergoing scoliosis surgery, reported significantly higher postoperative morphine consumption with the lower dosage regimen. In the present study, not surprisingly, intraoperative and postoperative i.v. opioid requirement was significantly less in the ITO groups than in the control group during the first 24 h as were pain scores. A trend to a lower i.v. opioid demand during the whole postoperative observation period of 4 days was observed with the high dose regime, without reaching statistical significance.

Despite prophylactic treatment with a 5-HT3 antagonist and avoidance of nitrous oxide, we registered a high incidence of postoperative nausea and vomiting (PONV) in children undergoing spinal fusion. However, no significant differences were observed between the three groups, and there was clearly no association between the use of ITO and the occurrence of PONV (Fig. 3).

The incidence of pruritus after the administration of ITO without prophylactic treatment has been reported to be as high as 60%.17 18 In our study, all patients received a 5-hydroxytryptamine subtype 3 (5-HT3) antagonist during induction of anaesthesia, and the incidence of pruritus was <30% in all three groups. Despite the findings of other investigators who showed a relationship between ITO dose and incidence of pruritus,9 16 19 the incidence of pruritus in the present study was lowest in the 15 µg kg–1 morphine group. Confirming our findings, Raffaeli and colleagues15 reported the lowest incidence of pruritus in the group with the highest ITO dose. Gall and colleagues11 also observed the smallest number of patients with pruritus in the group with the higher intrathecal morphine dose. Pruritus was easily treated in all patients with small i.v. bolus injections of propofol.

Some limitations of our study need to be discussed: as no data on the blood-sparing effect of morphine 15 µg kg–1 combined with sufentanil 1 µg kg–1 compared with morphine 5 µg kg–1 combined with sufentanil 1 µg kg–1 are available, we performed no sample size calculation before. It is conceivable that the comparison of the intraoperative blood loss in the HITO group showing values of 38 (7) ml kg–1 with that of the LITO group showing 41 (19) ml kg–1 would become significant in a larger study population.

In addition to an initial dose of fentanyl, continuous infusion of remifentanil was used to provide sufficient intraoperative analgesia. In experimental studies, remifentanil has been shown to induce opioid tolerance, while results of human studies are controversial.20 21 Thus, one might assume that the higher pain scores and consequent i.v. opioid demand seen in the control group during the first 24 h after surgery resulted from remifentanil-associated hyperalgesia. However, remifentanil was used in all groups and intraoperative doses were adjusted to the actual need of the patients. If postoperative pain scores were influenced by remifentanil-associated hyperalgesia, this influence would have been observed in all groups.

In summary, the intrathecal dose of morphine 5 µg kg–1 combined with sufentanil 1 µg kg–1 provides an excellent blood-sparing effect, sufficient postoperative analgesia, and shows side-effects comparable with that observed in patients receiving no intrathecal opioid.

Smaller doses of ITO have shown to be ineffective with regard to reduction in blood loss11 and should be avoided. The administration of morphine 15 µg kg–1 showed no statistically significant advantages when compared with the morphine 5 µg kg–1, although a trend towards lower postoperative pain scores and systemic opioid demand was registered. We found no respiratory depression with the high-dose regimen, however time until extubation was significantly longer when compared with the low-dose regimen, which should be considered in planning postoperative management.

Prophylaxis and treatment of pruritus can be achieved by the use of 5-HT3 antagonists, while the high incidence of PONV remains a clinical problem.


   Appendix A
Top
 Abstract
 Introduction
 Methods
 Statistical analyses
 Results
 Discussion
 Appendix A
References
 


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  		Modified Ramsay Sedation Score

 

   References
Top
 Abstract
 Introduction
 Methods
 Statistical analyses
 Results
 Discussion
 Appendix A
 References
 
1 Wang JK, Nauss LA, Thomas JE. Pain relief by intrathecally applied morphine in man. Anesthesiology (1979) 50:149–51.[CrossRef][Web of Science][Medline]

2 Gwirtz KH, Young JV, Byers RS, et al. The safety and efficacy of intrathecal opioid analgesia for acute postoperative pain: seven years’ experience with 5969 surgical patients at Indiana University Hospital. Anesth Analg (1999) 88:599–604.[Abstract/Free Full Text]

3 Morgan M. The rational use of intrathecal and extradural opioids. Br J Anaesth (1989) 63:165–88.[Free Full Text]

4 Vaught JL, Cowan A, Gmerek DE. A species difference in the slowing effect of intrathecal morphine on gastrointestinal transit. Eur J Pharmacol (1983) 94:181–4.[CrossRef][Medline]

5 Jones SE, Beasley JM, Macfarlane DW, Davis JM, Hall-Davies G. Intrathecal morphine for postoperative pain relief in children. Br J Anaesth (1984) 56:137–40.[Abstract/Free Full Text]

6 Goodarzi M. The advantages of intrathecal opioids for spinal fusion in children. Paediatr Anaesth (1998) 8:131–4.[CrossRef][Web of Science][Medline]

7 Tobias JD. A review of intrathecal and epidural analgesia after spinal surgery in children. Anesth Analg (2004) 98:956–65.[Abstract/Free Full Text]

8 Bailey PL, Rhondeau S, Schafer PG, et al. Dose-response pharmacology of intrathecal morphine in human volunteers. Anesthesiology (1993) 79:49–59.[Web of Science][Medline]

9 Murphy PM, Stack D, Kinirons B, Laffey JG. Optimizing the dose of intrathecal morphine in older patients undergoing hip arthroplasty. Anesth Analg (2003) 97:1709–15.[Abstract/Free Full Text]

10 Milner AR, Bogod DG, Harwood RJ. Intrathecal administration of morphine for elective Caesarean section. A comparison between 0.1 mg and 0.2 mg. Anaesthesia (1996) 51:871–3.[Web of Science][Medline]

11 Gall O, Aubineau JV, Berniere J, Desjeux L, Murat I. Analgesic effect of low-dose intrathecal morphine after spinal fusion in children. Anesthesiology (2001) 94:447–52.[CrossRef][Web of Science][Medline]

12 Dalens B, Tanguy A. Intrathecal morphine for spinal fusion in children. Spine (1988) 13:494–8.[Web of Science][Medline]

13 Kuipers PW, Kamphuis ET, van Venrooij GE, et al. Intrathecal opioids and lower urinary tract function: a urodynamic evaluation. Anesthesiology (2004) 100:1497–503.[CrossRef][Web of Science][Medline]

14 Bowrey S, Hamer J, Bowler I, Symonds C, Hall JE. A comparison of 0.2 and 0.5 mg intrathecal morphine for postoperative analgesia after total knee replacement. Anaesthesia (2005) 60:449–52.[CrossRef][Web of Science][Medline]

15 Raffaeli W, Marconi G, Fanelli G, Taddei S, Borghi GB, Casati A. Opioid-related side-effects after intrathecal morphine: a prospective, randomized, double-blind dose-response study. Eur J Anaesthesiol (2006) 23:605–10.[CrossRef][Medline]

16 Slappendel R, Weber EW, Dirksen R, Gielen MJ, van Limbeek J. Optimization of the dose of intrathecal morphine in total hip surgery: a dose-finding study. Anesth Analg (1999) 88:822–6.[Abstract/Free Full Text]

17 Iatrou CA, Dragoumanis CK, Vogiatzaki TD, Vretzakis GI, Simopoulos CE, Dimitriou VK. Prophylactic intravenous ondansetron and dolasetron in intrathecal morphine-induced pruritus: a randomized, double-blinded, placebo-controlled study. Anesth Analg (2005) 101:1516–20.[Abstract/Free Full Text]

18 Charuluxananan S, Somboonviboon W, Kyokong O, Nimcharoendee K. Ondansetron for treatment of intrathecal morphine-induced pruritus after cesarean delivery. Reg Anesth Pain Med (2000) 25:535–9.[CrossRef][Web of Science][Medline]

19 Demiraran Y, Ozdemir I, Kocaman B, Yucel O. Intrathecal sufentanil (1.5 microg) added to hyperbaric bupivacaine (0.5%) for elective cesarean section provides adequate analgesia without need for pruritus therapy. J Anesth (2006) 20:274–8.[CrossRef][Medline]

20 Cortinez LI, Brandes V, Munoz HR, Guerrero ME, Mur M. No clinical evidence of acute opioid tolerance after remifentanil-based anaesthesia. Br J Anaesth (2001) 87:866–9.[Abstract/Free Full Text]

21 Crawford MW, Hickey C, Zaarour C, Howard A, Naser B. Development of acute opioid tolerance during infusion of remifentanil for pediatric scoliosis surgery. Anesth Analg (2006) 102:1662–7.[Abstract/Free Full Text]


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