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Colombian Journal of Anestesiology

Print version ISSN 0120-3347

Rev. colomb. anestesiol. vol.38 no.3 Bogotá July/Sept. 2010

 

Investigación Científica y Tecnológica

 

 

Tolerability and efficacy of morphine vs. hydromorphone in postoperative epidural analgesia: double-blind randomized control trial

 

Adriana M. Cadavid*, David M. Montes**, Maria V. Gonzalez**, Liliana M. Urrea**, Wilson J. Lescano**

*MD, anestesióloga; especialista en medicina del dolor, del Hospital San Vicente de Paul, Medellín. Profesora auxiliar de Anestesiología de la Universidad de Antioquia. Medellín, Colombia. E-mail: adcadavid@une.net.co
**MD, residentes de Anestesiología de la Universidad de Antioquia. Medellín, Colombia.

Recibido: junio 7 de 2010. Enviado para modificaciones: junio 30 de 2010. Aceptado: julio 13 de 2010.


SUMMARY

Introduction. The acceptance (tolerability) of epidural analgesia can be compromised by the side effects of opioids. This study compares the side effects and efficacy of hydromorphone or morphine combined with bupivacaine in postoperative epidural analgesia.

Methods. Double-blind prospective randomized controlled trial at Hospital Universitario San Vicente de Paul; 147 patients were randomized in two groups: 73 patients of the MB Group received 30 jug per ml of morphine with bupivacaine 0.1 % and 74 patients of the HB group received 10 ug per ml of hydromorphone with bupivacaine 0.1 %.

Results. The main outcome was the tolerability defined by the frequency of nausea and vomiting sedation urinary retention and pruritus bettween the groups at 24 hours. 142 patients were analyzed: 71 in group MB and 71 in group HB. The incidence of nausea was 36.6 % and 31 % (p = 0.54); vomiting 19.7 % and 25.4 % (p = 0.42); sedation 15.5 % and 14.1 % (p = 0.81); urinary retention 11.3 % and 7 % (p = 0.38); and pruritus 43.7 % and 31 % (p = 0.11) for groups MB and HB respectively. Five patients were excluded either because of catheter migration or disconnection. No statistically significant differences were found between the groups. The verbal numerical scale (VNS) of dynamic pain at 24 hours was 3.42 (+/- 2.8) y 2.82 (+/- 2.5) for groups MB and HB respectively (p = 0.16)

Conclusions. The choice between 30 ¡ug per ml of morphine or 10 mcg per ml of hydromorphone does not influence the incidence of side effects or the efficacy of this technique.

Keywords: Pain, postoperative, analgesia, epidural, analgesics, opioid, central nervous system, drug tolerance (Source: MeSH, NLM).


INTRODUCTION

Epidural analgesia is an effective method for postoperative pain control (1,2). This method reduces the associated morbidity with this type of pain specifically in high risk patients (3,4).

In clinical practice, local anesthetics and opioids are the most common medications used for epidural analgesia, either individually or in combination (5,6). Previous studies suggest that the combination of both medications is synergic, and even though local anesthetics have high effectiveness when administered epi-durally, the addition of an opioid can reduce the side effects compared to the doses required if each of these medications is used separately (7,8).

Even though they are effective in epidural analgesia, opioids have significant side effects well described in the literature, under the global term known as tolerability (9,10). The most common are pruritus, nausea, vomiting, urinary retention and sedation all of which adversely affect the patient's well being and can delay the postoperative rehabilitation (11,12). These effects have been described in clinical trials specifically with morphine and less frequently fentanyl, hydromorphone, meperidine and alfentanil (1315). These reflect the pharmacokinetic effect of opioids at spinal and supraspinal level or both. Among the opioids previously described, the most commonly used in epidural infusions are morphine and hydromorphone usually in combination with bupivacaine (1,5). When comparing the epidural analgesic efficacy between these two opioids no significant differences have been described in clinical trials (16).

When the side effects are analyzed, some studies suggest a better tolerability for hydromorphone in epidural analgesia because of lower incidence of pruritus, nausea and sedation (5). However, comparative trials between these neuraxial opioids as single medications have shown variable results (16,17). The common clinical practice is to combine opioids with local anesthetics to reduce the dose of opioids and therefore their side effects. However, there is no information derived from a clinical trial, about the tolerability of hydromorphone combined with local anesthetics, compared to morphine the most commonly used opioid in postoperative epidural analgesia.

Theoretically there is pharmacokinetic and pharmacodynamic variability of hydromorphone compared to morphine that could explain the different incidence of side effects (18,19).

This trial was designed to assess in clinical practice the tolerability and efficacy of morphine, compared to hydromorphone in equianalgesic doses as part of a combination with local anesthetic for postoperative epidural analgesia.

METHODS

After approval of the internal review board of our institution, patients 18 years or older scheduled for elective abdominal, thoracic, orthopedic, or vascular surgery under combined general and epidural anaesthesia, with ASA I or II physical status, were included in our study. Each consenting patient accepted both epidural anaesthesia and to be interviewed in the postoperative period. Both patients and researchers were blinded regarding the selected opioid for each analgesic group. Exclusion criteria were: contraindication for epidural anaesthesia, prior cognitive abnormality that could affect the evaluation of the patient, rejection of the epidural technique and / or the use of opioids within two weeks prior to surgery.

Randomization study intervention

The patients who fulfilled all the inclusion criteria were randomized by the pain service anesthesiologist using a random number table obtained from EpiDat v 3.1 software, into two groups of epidural analgesia: group MB received 30 µg per ML of morphine and bupivacaine 0.1 %; and group HB received 10 µg per ml of hydromorphone with bupivacaine 0.1 %. At the initiation of surgery, the anesthesiologist responsible for the case assigned a patient to one of the groups and inserted an epidural catheter according to the surgery. Each catheter was tested to detect intrathecal or intravenous location with 3 ml of lidocaine with 5 µg per ml of epinephrine.

After a negative test dose, additional five ml of lidocaine were administered to test the epidural location with cold sensation assessment. Afterwards, general anaesthesia was induced with intravenous propofol 2 mg per kg and rocuronium 0.6 mg per kg. For maintenance, sevoflurane 2 to 4 % in an air and oxygen mixture was given. After induction, the patients received an initial 8 ml bolus of the epidural mixture followed by an infusion of 5 to 10 ml per hr according to the anesthesiologists' criteria. The infusion rate was continued without change in the postoperative period.

The patient's assessment was performed in the first 24 hours of the infusion by a member of the acute pain service. We used a survey to assess the presence or not of nausea, sedation, pruritus (with a categorical scale of three levels: mild moderate or severe), vomiting (mild: one episode, moderate: two episodes, severe: three or more episodes), and urinary retention in patients who had no urinary drainage catheter. In case of vomiting metoclopramide 10 mg intravenously every 8 hours was prescribed as rescue therapy. No prophylactic antiemetics were used. Dynamic and resting pain was assessed using verbal numerical pain scale (VNS). In case of severe pain (VNS of 7 or higher) in post anesthesia care unit (PACU) that did not respond to a rescue bolus of 10 ml of 2 % lidocaine, intravenous analgesia with tramadol or morphine was started and the patient was excluded from the study, as it was considered that it was a failed epidural analgesia. Patient satisfaction was assessed with a Likert scale of four points.

Sample calculation

The main outcome of this trial was the incidence of side effects related to epidural opioids: nausea, vomiting, pruritus, sedation and urinary retention. The size of the sample was calculated using the frequency described by Dolin et al for epidural opioids. They reported for morphine an incidence of 16 % for the least common side effect (12). It was estimated that calculating the sample for least common side effects would include the higher frequency side effects in the sample.

Our study was calculated to detect a 15 % difference in the frequency of side effects using hydromorphone compared to the morphine group. For sample calculation the next considerations were made: proportion comparison of two independent groups, and the same number of subjects in the two treatments to compare. The calculated sample size was 70 patients in the morphine group and 70 patients in the hydromorphone group that would provide an 80 % power, 0.05 = alpha error. Proportion of side effects in the morphine group 16 % and proportion of the side effects expected in the hydromorphone group was 10 % (Dolin S. and Cashman, 2005; Ballantyne J and McKenna B., 2003). Additional 5 % patients were included to compensate for the possible withdrawal of patients. The secondary outcome, postoperative pain was considered in the analysis, as it has a much higher prevalence than 16 % (1,2).

Statistical analysis

Frequencies and percentages were calculated for categorical variables as sex, type of surgery, and side effects; and means with their respective standard deviations were calculated for continuous variables like age and cumulative dose of epidural opioids.

The two groups were compared using X2 test for categorical variables, and for independent samples a student's t or the Mann-Whitney U test, with prior assessment of normality (Kolmogorov-Smirnov statistic, n > 50) and variance homogeneity (Levene's test) was used. The p value of 0.05 or less was considered statistically significant. The analysis was calculated with SPSS v 15.0 software.

RESULTS

In total, 154 patients were considered eligible from which seven had some exclusion criteria. The 147 remaining patients were randomized between February and November 2008, 73 to the MB group and the 74 to the HB group. Five patients (two from group MB and three from group HB) were excluded from analysis, two with accidental catheter disconnection and the three with failed epidural analgesia that required intravenous rescue analgesia. The number of patients included in each study arm was 71. (Figure 1).

Table 1 describes the demographic characteristics of both groups. No statistically significant differences were found between the groups regarding age, sex type of surgery or cumulative dose of morphine equivalent.

Table 2 shows the frequency of nausea, vomiting, pruritus, sedation and urinary retention in each group. No statistically significant difference was found between the groups regarding assessed side effects. The intensity of side effects (Figure 2) moderate to severe were: for nausea 9.8 % and 15.4 %, vomiting 13 % and 8.4 %, sedation 2.8 % and 4.2 %, pruritus 16.8 % and 11.2 %, and urinary retention 7.1 % and 11.3 % for groups MB and HB respectively. No statistically significant difference was found when comparing the intensity of these side effects (p > 0.05).

In table 3 the results of dynamic pain and degree of satisfaction of each group are shown. The median for the verbal numerical pain scale was 3.42 (+/- 2,8) and 2,82 (+/- 2,5) for groups MB and HB respectively (p = 0.16); the frequency of patients who presented moderate to severe dynamic pain was 12.7 % and 9.9% for groups MB and HB respectively (p = 0.66), and the satisfaction assessed with the Likert scale did not show any statistically significant difference.

DISCUSSION

The present study shows a tolerability and efficacy comparable for hydromorphone and morphine at equivalent doses (10 mcg/ml and 30 mcg/ml, respectively) in a combined scheme with bupivacaine 0.1 % for postoperative epidural analgesia.

No statistically significant differences were found in the incidence of nausea, vomiting, sedation, pruritus, or urinary retention considered as the determinants of tolerability (10). These results are similar to those described by Halpern (16), when comparing a 3 mg bolus of morphine to 0.6 mg of hydromorphone for caesarean section analgesia. However, the purpose of using opioids in continuous epidural analgesia is to avoid the side effects of a bolus dose and to benefit from the synergism of the combination with a local anesthetic.

In the design of our study, we were interested in assigning equivalent doses of both opioids and also to administer the minimally effective opioid dose combined with bupivacaine in the groups, so that any difference in side effects could be attributed to the pharmacodynamic effects of the opioid in the neuraxial space and not because of a dose difference.

The doses of morphine use in our study are those described by Niiyama et al (30 mcg/ml), with efficacy demonstrated for these doses with or without local anesthetic and with a synergic effect of the combination (7). The hydromorphone dose was calculated as the equivalent to 30 ug per ml of morphine as described in the literature (17). Although the equivalence morphine: hydromorphone varies 3:1 to 7:1 in the different studies (11,20) we maintained a 3:1 ratio to obtain the best therapeutic level equivalent to hydromorphone, and also because this ratio has been described previously in the comparisons between these two opioids in continuous epidural infusions.

In our trial we used continuous epidural infusions without patient demand doses, as the evidence has not shown that using additional boluses to the epidural infusion could to improve its effectiveness (1) and on the other hand the continuous infusion minimizes opioid consumption for the comparison. As such, the morphine equivalent consumption was comparable for both groups (p > 0.5) which confirmed that none of the groups received a higher dose of opioid.

The selected does for morphine was 30 µg per ml and not higher because this dose has shown to be effective, and in the study design it was intended to administer the minimally effective dose to minimize the side effects. Even lower doses (20µg per ml) for painful surgeries like thoracotomy have shown effectiveness (15).

In the present analysis if dose related factors are dismissed, the fact that there was the same incidence of side effects for morphine and hydromorphone as coadjuvants for local anaesthetic could be explained by several reasons.

First, even though hydromorphone has an intermediate hydrophility and therefore more spinal and systemic effect, it can achieve enough bioavailability in the cerebrospinal fluid to produce nausea, vomiting, etc at the same rate, as morphine. This concept is supported by the study by Herz and Teschemacher's (21), who compared morphine, hydromorphone and fentanyl tagged with radioisotopes injected in a CSF rat model to assess their penetration into the opioid receptors in the gray substance.

Two hours after their injection into the CSF a complete clearance of fentanyl was observed, whereas morphine and hydromorphone achieved a deeper penetration of the gray substance. They found a higher affinity of fentanyl to the white substance whereas morphine and hydromorphone had a similar gray substance penetration. This experiment could explain the comparable behavior of both opioids when they are administered epidurally.

From a pharmacodynamic viewpoint, morphine and hydromorphone act preferentially over the µ receptor. A recent study found that when assessing the effect over k receptors, even though the morphine has a higher affinity for k receptor than hydromorphone, the intrinsic activity for both opioids is comparable and lesser than that of fentanyl (22).

Recent reviewed trials that describe the prevalence of side effects of epidural opioids, mainly pruritus, nausea and vomiting, have found that the differences between morphine and hydromorphone occurred with higher doses of both opioids without the benefit of the synergism of the local anesthetic which decreases the necessary doses. For example Dougherty et al (23) found an incidence of up to 73 % of pruritus when using a 1.5 mg of hydromorphone for caesarean section analgesia. Other comparative study of morphine, hydromorphone and fentanyl in children subject to orthopedic surgery, also found a higher incidence of pruritus related to the use of morphine (14). Again, this could be attributed to the lower doses of opioids used in our trial that however, still are within the therapeutic range using the synergism with local anesthetics.

Previous studies also showed higher incidences of pruritus with morphine use (17). However, in Chaplan's study they used opioid at doses higher than those used in clinical practice today, 150 µg per ml of morphine compared to 30 µg per ml in our study using the synergism of local anesthetics (7,8). We suggest that lower opioid requirement because of the synergistic combination with local anesthetic could reduce not only the incidence of side effects, but also affects the differences in hydrophility and opioid receptor affinity so their lesser differences do not alter tolerability.

In our study, the incidence of severe to moderate nausea, one of the more common and annoying side effects was present in 15.4 % in MB group and 9.8 % in group HB. These incidences are lower than those reported in the literature which range from 19 % to 32 % (10,14, and 16).

We found no difference in vomiting between the two groups in our trial (19.7 % for MB and 25.54 % for HB p = 0.42), and these incidences are within the range described by other authors for epidural analgesia (24,25). The incidence of grade one to two in the Ready sedation scale was 15.5 % for MB and 14.1 % for HB comparable to that described by Dolin et al (10). It is interesting that in our trial there were no cases of grade 3 or respiratory depression that would require reversal with naloxone.

This contrasts with a 1.2 % incidence of respiratory depression reported in Dolin's systematic review. This difference could be explained by the inclusion of studies with higher doses of epidural opioids.

As a final aspect of our discussion we found a similar analgesic efficacy for both opioids studied both in bolus and continuous infusion. Even though this was a secondary end point in our trial it confirms what has been described previously in studies comparing morphine and hydromorphone (14,16). This similar efficacy could be explained because both opioids are potent p agonists and reach enough bioavailability in the CSF to exert their effects spinally.

Even though the use of epidural analgesia exclusively with local anesthetics has demonstrated to be effective (1), higher concentrations are usually required which increases the motor blockade in patients. This justifies the use of a synergic combination with opioids in most cases.

This is the first randomized double-blind study that assesses the tolerability between morphine and hydromorphone at synergistic doses (lower) with local anesthetics (26). Both opioids seem to be appropriate as additive to local anesthetics which contradict prior findings that favored hydromorphone over morphine.

Some limitations of the study are to be considered, like the impossibility to control all the nausea and vomiting risk factors different from sex, type of surgery and opioid consumption.

In conclusion, this study demonstrated a similar proile of side effects between morphine 30 µg per ml and hydromorphone 10µg per ml as adjuvants to bupivacaine in epidural analgesia with both opioids providing satisfactory analgesia.

ACKNOWLEDGMENTS

The authors are indebted to the anesthesiologists of the Hospital Universitario San Vicente de Paul, who cooperated in the recruitment of patients for this trial.

REFERENCES

1.Wu CL, Cohen SR, Richman JM, Rowlingson AJ, Courpas GE, Cheung K, et al. Efficacy of postoperative patient-controlled and continuous infusion epidural analgesia versus intravenous patient controlled analgesia with opioids: a meta-analysis. Anesthesiology. 2005;103(5):1079-88.

2.Block BM, Liu SS, Rowlingson AJ, Cowan AR, Cowan JA Jr, Wu CL. Efficacy of postoperative epidural analgesia. JAMA. 2003;290(18):2455-63.

3.Girish PJ, Ogunnaike BO. Consequences of inadequate postoperative pain relief and chronic persistent postoperative pain. Anesthesiol Clin N Am. 2005;23(1):21-36.

4.Beattie S, Badner NH, Choi P. Epidural analgesia reduces postoperative myocardial infarction: a meta-analysis. Anesth Analg. 2001;93(4):853-8.

5.Ballantyne JC, McKenna JM, Ryder E. Epidural analgesia—experience of 5628 patients in a large teaching hospital derived through audit. Acute pain. 2003;4(3):89-97.

6.Cook TM, Riley RH. Analgesia following thoracotomy: A survey of Australian practice. Anaesth Intensive Care. 1995;25(5):520-4.

7.Niiyama Y, Kawamata T, Shimizu H, Omote K, Namiki A. The addition of epidural morphine to ropivacaine improves epidural analgesia after lower abdominal surgery. Can J Anaesth. 2005;52(2):181-5.

8.St-Onge S, Fugere F, Girard M. Bupivacaine decreases epidural meperidine requirements after abdominal surgery. Can J Anesth. 1997;44(4):360-6.

9.Dolin SJ, Cashman JN. Respiratory and haemodynamic effects of acute postoperative pain management: evidence from published data. Br J Anaesth. 2004;93(2):212-23.

10.Dolin SJ, Cashman JN: Tolerability of acute postoperative pain management: nausea, vomiting, sedation, pruritus, and urinary retention. Evidence from published data. Br J Anaesth. 2005;95(5):584-91.

11.Kehlet H, Holte K. Effect of postoperative analgesia on surgical outcome. Br J Anaesth. 2001;87(1):62-72.

12.Wu CL, Rowlingson A, Partin A, Kalish MA, Courpas GE, Walsh PC, et al. Correlation of postoperative pain to quality of recovery in the immediate postoperative period. Reg Anesth Pain Med. 2005;30(6):516-22.

13.Bromage PR, Camporesi E, Chestnut D. Epidural narcotics for postoperative analgesia. Anesth Analg. 1980;59(7):473-80.

14.Goodarzi M. Comparison of epidural morphine, hydromorphone and fentanyl for postoperative pain control in children undergoing orthopaedic surgery. Paediatr Anaesth. 1999;9(5):419-22.

15.Royse CE, Royse AG, Deelen DA. An audit of morphine versus fentanyl as an adjunct to ropivacaine 0.2% for high thoracic epidural analgesia. Anaesth Intensive Care. 2005;33(5):639-44.

16.Halpern S, Arellano R, Preston R, Carstoniu J, O'Leary G, Roger S, et al. Epidural morphine vs hydromorphone in post-caesarean section patients. Can J Anaesth. 1996;43(6):595-8.

17.Chaplan S, Duncan S, Brodsky J, Brose W. Morphine and hydromorphone epidural analgesia. A prospective, randomized comparison. Anesthesiology. 1992;77(6):1090-4.

18.Bernards CM. Understanding the physiology and pharmacology of epidural and intrathecal opioids. Best Pract Res Clin Anaesthesiol. 2002;16(4):489-505.

19.De Leon-Casasola OA, Lema MJ. Postoperative epidural analgesia: what are the choices? Anesth Analg. 1996;83(4):867-75.

20.Quigley C. Hydromorphone for acute and chronic pain. Cochrane Database Syst Rev. 2002; (1):CD003447.

21.Herz A, Teschemacher H. Activities and sites of antinociceptive action of morphine-like analgesics and kinetics of distribution following intravenous, intracerebral and intraventricular application. In: Simmonds A, editor. Advances in drug research. London: Academic; 1971. p. 79-117.

22.Gharagozlou P, Hashemi E, DeLorey T, Clark JD, Lameh J. Pharmacological proiles of opioid ligands at kappa opioid receptors. BMC Pharmacol. 2006;6:3.

23.Dougherty T, Baysinger C, Henenberger J, Gooding D. Epidural hydromorphone with and without epinephrine for postoperative analgesia after cesarean delivery. Anesth Analg. 1989;68(3):318-22.

24.Ready KA, Loper M, Nessly L, Wild L. Postoperative epidural morphine is safe on surgical wards. Anesthesiology. 1991;75(3):452-6.

25.Schug S, Saunders D, Kurowski I, Paech M. Neuraxial drug administration: a review of treatment options for anaesthesia and analgesia. CNS Drugs. 2006;20(11): 917-33.

26.Cadavid AM, Montes DM, Gonzalez MV, Urrea LM. Tolerability of two different regimens of opioids in combination with bupivacaine for postoperative epidural analgesia (Abstract). The 12th World Congress on Pain. Glasgow: International Association for the Study of Pain. IASP. August 17-22; 2008.

Conflicto de intereses: Ninguno declarado. Financiado por el Centro de Investigaciones Médicas de la Universidad de Antioquia.

 

1.Wu CL, Cohen SR, Richman JM, Rowlingson AJ, Courpas GE, Cheung K, et al. Efficacy of postoperative patient-controlled and continuous infusion epidural analgesia versus intravenous patient controlled analgesia with opioids: a meta-analysis. Anesthesiology. 2005;103(5):1079-88.        [ Links ]

2.Block BM, Liu SS, Rowlingson AJ, Cowan AR, Cowan JA Jr, Wu CL. Efficacy of postoperative epidural analgesia. JAMA. 2003;290(18):2455-63.        [ Links ]

3.Girish PJ, Ogunnaike BO. Consequences of inadequate postoperative pain relief and chronic persistent postoperative pain. Anesthesiol Clin N Am. 2005;23(1):21-36.        [ Links ]

4.Beattie S, Badner NH, Choi P. Epidural analgesia reduces postoperative myocardial infarction: a meta-analysis. Anesth Analg. 2001;93(4):853-8.        [ Links ]

5.Ballantyne JC, McKenna JM, Ryder E. Epidural analgesia—experience of 5628 patients in a large teaching hospital derived through audit. Acute pain. 2003;4(3):89-97.        [ Links ]

6.Cook TM, Riley RH. Analgesia following thoracotomy: A survey of Australian practice. Anaesth Intensive Care. 1995;25(5):520-4.        [ Links ]

7.Niiyama Y, Kawamata T, Shimizu H, Omote K, Namiki A. The addition of epidural morphine to ropivacaine improves epidural analgesia after lower abdominal surgery. Can J Anaesth. 2005;52(2):181-5.        [ Links ]

8.St-Onge S, Fugere F, Girard M. Bupivacaine decreases epidural meperidine requirements after abdominal surgery. Can J Anesth. 1997;44(4):360-6.        [ Links ]

9.Dolin SJ, Cashman JN. Respiratory and haemodynamic effects of acute postoperative pain management: evidence from published data. Br J Anaesth. 2004;93(2):212-23.        [ Links ]

10.Dolin SJ, Cashman JN: Tolerability of acute postoperative pain management: nausea, vomiting, sedation, pruritus, and urinary retention. Evidence from published data. Br J Anaesth. 2005;95(5):584-91.        [ Links ]

11.Kehlet H, Holte K. Effect of postoperative analgesia on surgical outcome. Br J Anaesth. 2001;87(1):62-72.        [ Links ]

12.Wu CL, Rowlingson A, Partin A, Kalish MA, Courpas GE, Walsh PC, et al. Correlation of postoperative pain to quality of recovery in the immediate postoperative period. Reg Anesth Pain Med. 2005;30(6):516-22.        [ Links ]

13.Bromage PR, Camporesi E, Chestnut D. Epidural narcotics for postoperative analgesia. Anesth Analg. 1980;59(7):473-80.        [ Links ]

14.Goodarzi M. Comparison of epidural morphine, hydromorphone and fentanyl for postoperative pain control in children undergoing orthopaedic surgery. Paediatr Anaesth. 1999;9(5):419-22.        [ Links ]

15.Royse CE, Royse AG, Deelen DA. An audit of morphine versus fentanyl as an adjunct to ropivacaine 0.2% for high thoracic epidural analgesia. Anaesth Intensive Care. 2005;33(5):639-44.        [ Links ]

16.Halpern S, Arellano R, Preston R, Carstoniu J, O'Leary G, Roger S, et al. Epidural morphine vs hydromorphone in post-caesarean section patients. Can J Anaesth. 1996;43(6):595-8.        [ Links ]

17.Chaplan S, Duncan S, Brodsky J, Brose W. Morphine and hydromorphone epidural analgesia. A prospective, randomized comparison. Anesthesiology. 1992;77(6):1090-4.        [ Links ]

18.Bernards CM. Understanding the physiology and pharmacology of epidural and intrathecal opioids. Best Pract Res Clin Anaesthesiol. 2002;16(4):489-505.        [ Links ]

19.De Leon-Casasola OA, Lema MJ. Postoperative epidural analgesia: what are the choices? Anesth Analg. 1996;83(4):867-75.        [ Links ]

20.Quigley C. Hydromorphone for acute and chronic pain. Cochrane Database Syst Rev. 2002; (1):CD003447.        [ Links ]

21.Herz A, Teschemacher H. Activities and sites of antinociceptive action of morphine-like analgesics and kinetics of distribution following intravenous, intracerebral and intraventricular application. In: Simmonds A, editor. Advances in drug research. London: Academic; 1971. p. 79-117.        [ Links ]

22.Gharagozlou P, Hashemi E, DeLorey T, Clark JD, Lameh J. Pharmacological proiles of opioid ligands at kappa opioid receptors. BMC Pharmacol. 2006;6:3.        [ Links ]

23.Dougherty T, Baysinger C, Henenberger J, Gooding D. Epidural hydromorphone with and without epinephrine for postoperative analgesia after cesarean delivery. Anesth Analg. 1989;68(3):318-22.        [ Links ]

24.Ready KA, Loper M, Nessly L, Wild L. Postoperative epidural morphine is safe on surgical wards. Anesthesiology. 1991;75(3):452-6.        [ Links ]

25.Schug S, Saunders D, Kurowski I, Paech M. Neuraxial drug administration: a review of treatment options for anaesthesia and analgesia. CNS Drugs. 2006;20(11): 917-33.        [ Links ]

26.Cadavid AM, Montes DM, Gonzalez MV, Urrea LM. Tolerability of two different regimens of opioids in combination with bupivacaine for postoperative epidural analgesia (Abstract). The 12th World Congress on Pain. Glasgow: International Association for the Study of Pain. IASP. August 17-22; 2008.        [ Links ]