Assessment of Ketamine Effect as Adjuvant to Morphine in Post- Operative Pain Reduction in Donor Kidney Transplanted

This Article

Citations


Creative Commons License
Except where otherwise noted, this work is licensed under Creative Commons Attribution-NonCommercial 4.0 International License.

Article Information:


Group: 2010
Subgroup: Volume 12, Issue 1
Date: January 2010
Type: Original Article
Start Page: 38
End Page: 44

Authors:

  • M Lak
  • Associate Professor of Department of Anesthesiology and Critical Care, Faculty of Medical Sciences, Baqiyatallah (a.s.) University of Medical Sciences, Tehran, Tehran, Iran
  • MJ Foroozanmehr
  • Department of Anesthesiology, Baqiyatallah (a.s.) University of Medical sciences, Tehran, Tehran, Iran
  • MA Ramazani
  • Department of Community and Preventive Medicine, Baqiyatallah (a.s.) University of Medical sciences, Tehran, Tehran, Iran
  • H Araghizadeh
  • Department of Anesthesiology, Baqiyatallah (a.s.) University of Medical sciences, Tehran, Tehran, Iran
  • L Zahedi-Shoolami
  • Medical Research and Consult Center, Tehran, Tehran, Iran
    • Correspondence:

      Affiliation: Associate Professor of Department of Anesthesiology and Critical Care, Faculty of Medical Sciences, Baqiyatallah (a.s.) University of Medical Sciences
      City, Province: Tehran, Tehran
      Country: Iran
      Tel: +98-912-5262585
      Fax: +98-912-5262585
      E-mail: Marziehlak@gmail.com

Abstract:


Background: Morphine is a strong analgesic agent being used in acute pain but adverse effects may lead to its discontinuation before sufficient pain relief is obtained. Ketamine is an anti-nociceptive drug which blocks N-Methyl-D-Aspartate receptors and can modulate acute pain. In this study, ketamine effect as an adjuvant with morphine for post-operative pain management is evaluated.

 

Method: In a double blind randomized clinical trial, 50 kidney donors undergoing nephrectomy and receiving morphine as analgesics were enrolled. Patients were divided into two groups receiving ketamine (ketamine group) and saline serum (placebo group). Post-operative pain was assessed by measuring cumulative morphine consumption and visual analog scale pain scores were assessed in 48 hours duration after surgery.

 

Results: Pain intensity and cumulative morphine consumption were lower and sedation score was higher in the ketamine group. Both groups were similar regarding the side effects.

 

Conclusion: Regarding post-operative analgesia management, ketamine administration improved pain intensity and when its administration was continued for 48 hours post-operatively, there was a significant decrease in morphine consumption.

 

Keywords: Ketamine; Morphine; Pain; Analgesia; Post-operation

Manuscript Body:


Introduction

 

Pain control after surgery is an important issue in pain management. Morphine is a strong analgesic agent used routinely in acute pains. Repeated morphine administration or continual infusion usually provides rapid and effective analgesia after surgery. However, adverse effects sometimes occur and may require discontinuation of morphine before sufficient pain relief is obtained.1 The combination of non-opioid analgesics with morphine provides a morphine-sparing effect and decreases toxicity. This concept is the basis of multimodal analgesia.2

Ketamine is an anti-nociceptive drug which blocks N-Methyl-D-Aspartate (NMDA) receptors. The role of the NMDA receptor in modulating acute pain and the subsequent central sensitization has been demonstrated.3-5 In addition to that of morphine, the effect of NMDA antagonist like ketamine on pain control, solely or in combination with other drugs has been shown in animal models.6-11 Although clinical studies have provided evidence for the potentiating effect of ketamine on morphine analgesic effects,12-24 some studies could not find an association between morphine and ketamine in pain relief.25-29

Post-nephrectomy pain is very severe because of large subcostal incision and interaction with breathing.30 On the other hand, post-operation pain in living donor kidney transplantation is a disincentive factor. Pain control in these patients is critical and requires significant and effective intervention. Thus larger doses of opioids are needed for analgesia in the first few days after surgery.31

The aim of the current clinical trial was to determine the effects of ketamine on post-operation opioid consumption, pain intensity and the side-effects when used simultaneously with morphine during the first 48 hrs after nephrectomy in donor kidney transplantation.

 

 

Materials and Methods

 

The research proposal was approved in two research and medical ethics committees in Baqiyatallah University of Medical Sciences. The study was a double blind randomized clinical trial. Sixty subjects who were candidate for nephrectomy as donors were selected in Baqiyatallah Hospital. The hospital is one of the greatest general hospitals in Tehran affiliated to Baqiyatallah University of Medical Sciences. All subjects were donors of renal transplantation admitted to the hospital from May 2007 to December 2008. During the day before surgery, an anesthesiologist visited the patients and included the ones with the American Society of Anesthesiologists (ASA) class I criteria. Informed consent was obtained from each patient, and the patients were instructed before surgery on the use of the Visual Analogue Scale (VAS), and Pain Faces Scale (PFS). They were randomly divided into two parallel groups. Randomization was assigned to patients of the two groups according to random numbers table.

All patients had the same anesthesia protocol. They received 0.1 mg/kg of morphine as premedication. Anesthesia was induced by thiopental (5-7 mg/kg) and atracurium (0.5 mg/kg) afterwards. Maintenance of anesthesia was done with isoflurane (proportionate to the patients’ hemodynamic status), N2O (50%) and O2 (50%).

All operations were done in lateral decobitus position and flank incision was performed for all the patients. At the end of the surgery, the patients’ neuromuscular relaxation was reversed pharmacologically and they were extubated in the operating room. The patients were taken to the recovery room for immediate postoperative follow-up.

When patients entered the recovery room and achieved an acceptable level of consciousness, VAS was measured. In the ketamine group, ketamine was administered separately with an initial bolus of 0.5 mg/kg followed by infusion of 2 μg/kg/min during the first 24 hours and 1 μg/kg/min in the following 24 hours. In the placebo group, ketamine was replaced by saline serum as placebo and administered under the same conditions. In both groups, if the patients requested analgesia, 2 mg of morphine was administered by nurses without any limitations as the loading dose followed by 1 mg every 5 minutes until the VAS became less than 4.

All the patients were monitored in the wards in an intensive care unit setting. In both groups; morphine consumption, pain intensity, the sedative effect and the side effects were evaluated 0, 1, 2, 3, 4, 8, 12, 24, 48 hours after operation. The side effects included nausea, vomiting, itching, headache, hallucinations, and nightmares. Pain intensity was assessed in rest and during cough, using two ways; the first was the use of a 100-mm VAS an anchored by “no pain” at one end and by “worst possible pain” at the opposite end. The second one was the Pain Faces Scale (PFS) consisting of six schematic face pictures among which the patients selected the most similar pictures to themselves. For evaluation of the sedative effect, we used Ramsey Sedative Score (RSS). It is an objective evaluation ranging 0-6, which was done by the anesthesiologist. 

The analyses were performed, using the SPSS software for Windows, Version 15 (SPSS Inc., Chicago, IL, USA). The data are presented as proportion and mean±SD. The dependent and independent variables were the treatment group and pain intensity (VAS, PFS), amount of morphine consumption, and RSS, respectively. T-test was used for comparison between the two groups. The repeated measurement of ANOVA model was utilized to determine the changes of pain intensity and morphine consumption during the study. For ordinal variables like RSS, we used Mann-Whitney test for the independent comparison and Freidman test was conducted for the measurement during 48 h. Differences with p<0.05 were considered statistically significant.

 

 

Results

 

Sixty patients fulfilled the study criteria for randomization, but five in the ketamine group and five in the Placebo group dropped out of the study. Table 1 shows the demographic and surgical characteristics of the patients. The data were similar between the two study groups. Itching, headache, hallucination, and nightmares were not detected in either group, but there were 3 (12%) cases in each group with nausea and vomiting. There was only one case of short-term hallucination (less than 3 hours) in ketamine group which appeared as a feeling of a unilateral face inflammation. Both groups were comparable with respect to pain intensity after surgery before any analgesic administration (86±12.6 in the ketamine group vs. 83.6±14.4 in the placebo group; t=0.628, p=0.533).

 

 

Table 1: Patients demographic and surgical characteristics in two study groups

Variable

Ketamine group

Placbo group

P value

Sex (M/F)

24/1

20/5

0.189*

Age (mean±SD)

27.3±5.5

27.9±3.9

0.656**

Weight (mean±SD)

68.8±8.1

70.3±10

0.57**

History of previous surgery

10/15

12/13

0.776**

Operation duration

106±7

106.8±10

0.745**

* Fisher’s exact test; **Two sample t test

 

 

The cumulative morphine consumption reduced significantly in the ketamine group (3.0±2.0 mg in ketamine, in contrast to 17.8±9.2 mg morphine in the placebo group; t=7.817, p<0.001). There was a ~83% reduction in the total amount of morphine administration in the ketamine group during the 48 hrs of study.

Ketamine administration reduced the morphine dose and declined pain intensity significantly (Table 2).

 

 

Table 2: The comparison of pain intensity (VAS) mean between ketamine and placebo groups 

 

Group

No.

Mean

SD

t

P value

VAS before analgesia

placebo

25

83.6

14.4

0.628

0.533

ketamine

25

86

12.6

vas1

placebo

25

81.6

16.5

4.984

P<0.001

ketamine

25

53.2

23.2

vas2

placebo

25

80

14.7

7.01

P<0.001

ketamine

25

49.2

16.3

vas3

placebo

25

80.4

12.4

8.948

P<0.001

ketamine

25

44.4

15.8

vas4

placebo

25

80

12.6

8.256

P<0.001

ketamine

25

45.6

16.6

vas8

placebo

25

78.8

13.9

8.1

P<0.001

ketamine

25

45.6

15

vas12

placebo

25

73.2

16

5.936

P<0.001

ketamine

25

43.6

19.1

vas24

placebo

25

65.6

13.6

8.413

P<0.001

ketamine

25

32.8

14

vas48

placebo

25

46

  9.6

7.477

P<0.001

ketamine

25

24.8

10.4

 

 

Moreover, the repeated measured ANOVA showed that pain intensity in rest and with cough (VAS) during the 48 hours follow-up period was consistently and significantly (p<0.001) lower for the ketamine group compared with that in their placebo counterparts (Figure1).

 

 

 

 

Fig. 1: Pain intensity during 48 hours follow-up in two study groups

 

This was the case despite the larger amounts of morphine administered to the placebo group. Figure 1 shows the significant pain intensity reduction between the two study groups. In contrast to pain reduction, sedation score was higher in the ketamine group. The patients with ketamine administration had a higher rank in RSS significantly, while this increased rank continued until 12 hours after surgery. The two groups were, of course, comparable in 24 and 48 hours follow up in this regard (Figure 2).

 

 

 

 

Fig. 2: The Ramsey sedative score during 48 hours follow up in two study groups



Discussion

 

The main finding of this double blind randomized trial was that the adjunction of small doses of ketamine with morphine resulted in a significant reduction in pain intensity associated with a reduction in cumulative morphine consumption in post nephrectomy. Many studies showed that ketamine interacts with opiate receptors, and it has been suggested that ketamine-induced analgesia is mediated through opiate receptors.32-34 Release of peptide from the spinal cord during surgery evokes NMDA receptors’ activity and neuronal excitation. This activation leads to hyperalgesia and wind-up.35 Therefore, it seems logical to encourage the ketamine use (NMDA Antagonist) as an adjuvant therapy with morphine for post-operative analgesia.

Our findings were similar to those of some studies with the same design. Nesher et al. (2008) and Michelet et al. (2007) examined the aforementioned hypothesis in thoracotomy. They declared 50% reduction in pain and 25% reduction in morphine consumption in the ketamine group.36,37 The same results have been published by Kollender et al. in bone and soft tissues surgery,38 Snijdelaar et al. in prostatectomy,24 and Taura et al. in liver resection.21 Weinbroum used a single dose 250 μg/kg ketamine adjunct with morphine for post-operation pain release. After 120 min, the pain intensity was 2.5 folds, approximately lesser in ketamine injection.22 Adriaenssens et al. found that VAS score decreased significantly during 48 hrs. However, this was similar in both groups. Cumulative morphine consumption at 48 hrs was lower in the ketamine group than that in the placebo one (28 vs. 54 mg).18 Guillou et al. (2003) got the same results like Adriaenssons’.23 Ketamine used through epidura with a combination of morphine had the same effect as that used intravenously (IV).15-17,39,40 Many studies used ketamine preemptively to manage post-operation pain. They found that it was effective but it should be administered over 75 μg/kg.41,42 However, other studies which have used preemptive ketamine are not conclusive.27,43-46

Bilgin et al. conducted a triple group randomized trial. The patients in group 1 received ketamine (0.5 mg/kg IV) bolus before the induction of anesthesia; The patients in group 2 received 0.5 mg/kg of ketamine (IV bolus) before the induction of anesthesia, followed by ketamine infusion (600 μg/kg/h), which was stopped at wound closure; the patients in group 3 received normal saline (IV bolus) before the induction of anesthesia followed by saline infusion and then 0.5 mg/kg ketamine (IV bolus) immediately after wound closure. The results of this study showed that there was a significant difference between groups 1 and 2 and groups 1 and 3 regarding pain intensity (VAS).47 Perhaps, these differences were due to pain intensity experienced before the operation.18

Nevertheless, some studies could not support the post-operative analgesic effect of ketamine with a combination of morphine. Edwards et al. did not find any difference either in pain intensity or in lung function and morphine consumption. They conducted their study on the elderly (>65 yrs) patients.25 In two separate studies on females who underwent abdominal hysterectomy, neither pain intensity nor morphine consumption was different in the ketamine and control groups.28,29 Becke et al. explained that intra-operative low-dose ketamine had no effect on morphine consumption during the first 72 hrs after urologic surgery. They believed that the difference in pain intensity reflected additional sedation and anti-nociceptive effects of ketamine rather than a true 'prevention' of pain,43 but we believe that they used ketamine during operation but not after it. In addition, neither post-tonsillectomy nor appendectomy pain was reduced in children by adding ketamine to morphine.48-51

Overall, it seems that ketamine is an appropriate adjuvant therapy with morphine in post-operative period. Ketamine decreases the tolerance to morphine and declines morphine consumption. Conflicting results existing among studies refer to the following factors: 1) time of injection (pre, intra or post- operative), 2) kind of injection (IV, subcutaneous, epidural …), 3) duration of administration (0 to 72 h), 4) Ketamine dose, 5) age of patients and 6) kind of operation.

There were some limitations in our study. The sedation was only assessed but mental and physical status should also be evaluated. We did not have any intravenous patient control analgesia (IV-PCA) devices and could not prepare them. At the end, a systematic review and meta-analysis is necessary to evaluate the ketamine effect as adjuvant with morphine for analgesia.

 

 

Acknowledgment

 

All the authors wish to thank Dr Ali Kabir for his consult in the study design and preparing the research proposal.

 

Conflict of interest: None declared.

References: (51)

  1. Paqueron X, Lumbroso A, Mergoni P, Aubrun F, Langeron O, Coriat P, Riou B. Is morphine-induced sedation synonymous with analgesia during intravenous morphine titration? Br J Anaesth 2002;89:697-701. [12393765] [doi:10.1093/bja/aef262]
  2. Kehlet H, Dahl JB. The value of "multimodal" or "balanced analgesia" in postoperative pain treatment. Anesth Analg 1993;77:1048-56. [8105724] [doi:10.1213/00000539-199311000-00030]
  3. Woolf CJ. Recent advances in the pathophysiology of acute pain. Br J Anaesth 1989;63:139-46. [2669905] [doi:10.1093/bja/63.2.139]
  4. Woolf CJ, Chong MS. Preemptive analgesia--treating postoperative pain by preventing the establishment of central sensitization. Anesth Analg 1993;77:362-79. [8346839] [doi:10.1213/00000539-199377020-00026]
  5. Woolf CJ. Windup and central sensitization are not equivalent. Pain 1996;66:105-8. [8880830]
  6. Pelissier T, Laurido C, Kramer V, Hernandez A, Paeile C. Antinociceptive interactions of ketamine with morphine or methadone in mononeuropathic rats. Eur J Pharmacol 2003;477:23-8. [14512094] [doi:10.1016/S0014-2999(03)02192-7]
  7. Alvarez P, Saavedra G, Hernandez A, Paeile C, Pelissier T. Synergistic antinociceptive effects of ketamine and morphine in the orofacial capsaicin test in the rat. Anesthesiology 2003;99:969-75. [14508333] [doi:10.1097/00000542-200310000-00033]
  8. Okulicz-Kozaryn I, Kaminska E, Luczak J, Szczawinska K, Kotlinska-Lemieszek A, Baczyk E, Mikolajczak P. The effects of midazolam and morphine on analgesic and sedative activity of ketamine in rats. J Basic Clin Physiol Pharmacol 2000;11:109-25. [11037766]
  9. Suzuki T, Kato H, Aoki T, Tsuda M, Narita M, Misawa M. Effects of the non-competitive NMDA receptor antagonist ketamine on morphine-induced place preference in mice. Life Sci 2000;67:383-9. [11003048] [doi:10.1016/S0024-3205(00)00639-1]
  10. Suman P, Talwar A, Tandon OP. Effect of glutamic acid and ketamine on morphine-induced analgesic response in rats. Indian J Physiol Pharmacol 2000;44:33-42. [10919093]
  11. Shimoyama N, Shimoyama M, Inturrisi CE, Elliott KJ. Ketamine attenuates and reverses morphine tolerance in rodents. Anesthesiology 1996;85:1357-66. [8968183] [doi:10. 1097/00000542-199612000-00017]
  12. Cherry DA, Plummer JL, Gourlay GK, Coates KR, Odgers CL. Ketamine as an adjunct to morphine in the treatment of pain. Pain 1995;62:119-21. [7478701] [doi:10.1016/0304-3959(95)00010-P]
  13. Javery KB, Ussery TW, Steger HG, Colclough GW. Comparison of morphine and morphine with ketamine for postoperative analgesia. Can J Anaesth 1996;43:212-5. [8829857] [doi:10.1007/BF03011736]
  14. Yang CY, Wong CS, Chang JY, Ho ST. Intrathecal ketamine reduces morphine requirements in patients with terminal cancer pain. Can J Anaesth 1996;43:379-83. [8697554] [doi:10.1007/BF03011718]
  15. Yaksh TL. Epidural ketamine: a useful, mechanistically novel adjuvant for epidural morphine? Reg Anesth 1996;21:508-13. [8956385]
  16. Wong CS, Liaw WJ, Tung CS, Su YF, Ho ST. Ketamine potentiates analgesic effect of morphine in postoperative epidural pain control. Reg Anesth 1996;21:534-41. [8956390]
  17. Choe H, Choi YS, Kim YH, Ko SH, Choi HG, Han YJ, Song HS. Epidural morphine plus ketamine for upper abdominal surgery: improved analgesia from preincisional versus postincisional administration. Anesth Analg 1997;84:560-3. [9052301] [doi:10.1097/00000539-199703000-00017]
  18. Adriaenssens G, Vermeyen KM, Hoffmann VL, Mertens E, Adriaensen HF. Postoperative analgesia with i.v. patient-controlled morphine: effect of adding ketamine. Br J Anaesth 1999;83:393-6. [10655908]
  19. Aida S, Yamakura T, Baba H, Taga K, Fukuda S, Shimoji K. Preemptive analgesia by intravenous low-dose ketamine and epidural morphine in gastrectomy: a randomized double-blind study. Anesthesiology 2000;92:1624-30. [10839912] [doi:10.1097/00000542-200006000-00020]
  20. Subramaniam K, Subramaniam B, Pawar DK, Kumar L. Evaluation of the safety and efficacy of epidural ketamine combined with morphine for postoperative analgesia after major upper abdominal surgery. J Clin Anesth 2001;13:339-44. [11498314] [doi:10.1016/S0952-8180(01)00278-1]
  21. Taurá P, Fuster J, Blasi A, Martinez-Ocon J, Anglada T, Beltran J, Balust J, Tercero J, Garcia-Valdecasas JC. Postoperative pain relief after hepatic resection in cirrhotic patients: the efficacy of a single small dose of ketamine plus morphine epidurally. Anesth Analg 2003;96:475-80. [12538199] [doi:10.1097/00000539-200302000-00033]
  22. Weinbroum AA. A single small dose of postoperative ketamine provides rapid and sustained improvement in morphine analgesia in the presence of morphine-resistant pain. Anesth Analg 2003;96:789-95. [12598264] [doi:10.1213/01.ANE.0000048088.17761.B4]
  23. Guillou N, Tanguy M, Seguin P, Branger B, Campion JP, Mallédant Y. The effects of small-dose ketamine on morphine consumption in surgical intensive care unit patients after major abdominal surgery. Anesth Analg 2003;97:843-7. [12933413] [doi:10.1213/01.ANE.0000075837.67275.36]
  24. Snijdelaar DG, Cornelisse HB, Schmid RL, Katz J. A randomised, controlled study of peri-operative low dose s(+)-ketamine in combination with postoperative patient-controlled s(+)-ketamine and morphine after radical prostatectomy. Anaesthesia 2004;59:222-8. [14984518] [doi:10.1111/j.1365-2044.2003.03620.x]
  25. Edwards ND, Fletcher A, Cole JR, Peacock JE. Combined infusions of morphine and ketamine for postoperative pain in elderly patients. Anaesthesia 1993;48:124-7. [8460758]
  26. Ilkjaer S, Nikolajsen L, Hansen TM, Wernberg M, Brennum J, Dahl JB. Effect of i.v. ketamine in combination with epidural bupivacaine or epidural morphine on postoperative pain and wound tenderness after renal surgery. Br J Anaesth 1998;81:707-12. [10193280]
  27. Reeves M, Lindholm DE, Myles PS, Fletcher H, Hunt JO. Adding ketamine to morphine for patient-controlled analgesia after major abdominal surgery: a double-blinded, randomized controlled trial. Anesth Analg 2001;93:116-20. [11429351] [doi:10.1097/00000539-200107000-00025]
  28. Burstal R, Danjoux G, Hayes C, Lantry G. PCA ketamine and morphine after abdominal hysterectomy. Anaesth Intensive Care 2001;29:246-51. [11439794]
  29. Murdoch CJ, Crooks BA, Miller CD. Effect of the addition of ketamine to morphine in patient-controlled analgesia. Anaesthesia 2002;57:484-8. [12004808] [doi:10.1046/j.0003-2409.2001.02409.x]
  30. Chung E, Grant AB, Hibberd AD, Sprott P. Why potential live renal donors prefer laparoscopic nephrectomy: a survey of live donor attitudes. BJU Int 2007;100:1344-6. [17850384] [doi:10.1111/j.1464-410X.2007.07126.x]
  31. Ashcraft EE, Baillie GM, Shafizadeh SF, McEvoy JR, Mohamed HK, Lin A, Baliga PK, Rogers J, Rajagopalan PR, Chavin KD. Further improvements in laparoscopic donor nephrectomy: decreased pain and accelerated recovery. Clin Transplant 2001;15:59-61. [11903389] [doi:10.1034/j.1399-0012.2001.00011.x]
  32. Finck AD, Samaniego E, Ngai SH. Morphine tolerance decreases the analgesic effects of ketamine in mice. Anesthesiology 1988;68:397-400. [3344994] [doi:10.1097/00000542-198803000-00013]
  33. Fidecka S. Interactions of ketamine, naloxone and morphine in the rat. Pol J Pharmacol Pharm 1987;39:33-40. [3671186]
  34. De Simoni MG, Giglio R, Dal Toso G, Conforti I, Algeri S. Cross tolerance between ketamine and morphine to some pharmacological and biochemical effects. Neuropharmacology 1985;24:541-5. [4022268] [doi:10.1016/0028-3908(85)90060-7]
  35. Dickenson AH. NMDA receptor antagonists: interaction with opioids. Acta Anaesthesiol Scand 1997;41:112-5. [9061093] [doi:10.1111/j.1399-6576.1997.tb04624.x]
  36. Nesher N, Serovian I, Marouani N, Chazan S, Weinbroum AA. Ketamine spares morphine consumption after transthoracic lung and heart surgery without adverse hemodynamic effects. Pharmacol Res 2008;58:38-44. [18602474] [doi:10.1016/j.phrs.2008.06.003]
  37. Michelet P, Guervilly C, Hélaine A, Avaro JP, Blayac D, Gaillat F, Dantin T, Thomas P, Kerbaul F. Adding ketamine to morphine for patient-controlled analgesia after thoracic surgery: influence on morphine consumption, respiratory function, and nocturnal desaturation. Br J Anaesth 2007;99:396-403. [17576969] [doi:10.1093/bja/aem168]
  38. Kollender Y, Bickels J, Stocki D, Maruoani N, Chazan S, Nirkin A, Meller I, Weinbroum AA. Subanaesthetic ketamine spares postoperative morphine and controls pain better than standard morphine does alone in orthopaedic-oncological patients. Eur J Cancer 2008;44:954-962. [18396035] [doi:10.1016/j.ejca.2008.02.021]
  39. Miyamoto H, Saito Y, Kirihara Y, Hara K, Sakura S, Kosaka Y. Spinal coadministration of ketamine reduces the development of tolerance to visceral as well as somatic antinociception during spinal morphine infusion. Anesth Analg 2000;90:136-41. [10624994] [doi:10.1097/00000539-200001000-00030]
  40. Wong CS, Shen TT, Liaw WJ, Cherng CH, Ho ST. Epidural coadministration of ketamine, morphine and bupivacaine attenuates post-herpetic neuralgia--a case report. Acta Anaesthesiol Sin 1996;34:151-5. [9084539]
  41. Aveline C, Hetet HL, Vautier P, Gautier JF, Bonnet F. Peroperative ketamine and morphine for postoperative pain control after lumbar disk surgery. Eur J Pain 2006;10:653-8. [16324861] [doi:10.1016/j.ejpain.2005.10.005]
  42. Suzuki M, Tsueda K, Lansing PS, Tolan MM, Fuhrman TM, Ignacio CI, Sheppard RA. Small-dose ketamine enhances morphine-induced analgesia after outpatient surgery. Anesth Analg 1999;89:98-103. [10389785] [doi:10.1097/00000539-199907000-00017]
  43. Becke K, Albrecht S, Schmitz B, Rech D, Koppert W, Schüttler J, Hering W. Intraoperative low-dose S-ketamine has no preventive effects on postoperative pain and morphine consumption after major urological surgery in children. Paediatr Anaesth 2005;15:484-90. [15910349] [doi:10.1111/j.1460-9592.2005.01476.x]
  44. Holthusen H, Backhaus P, Boeminghaus F, Breulmann M, Lipfert P. Preemptive analgesia: no relevant advantage of preoperative compared with postoperative intravenous administration of morphine, ketamine, and clonidine in patients undergoing transperitoneal tumor nephrectomy. Reg Anesth Pain Med 2002;27:249-53. [12016597] [doi:10.1053/rapm.2002.30669]
  45. Subramaniam B, Subramaniam K, Pawar DK, Sennaraj B. Preoperative epidural ketamine in combination with morphine does not have a clinically relevant intra- and postoperative opioid-sparing effect. Anesth Analg 2001;93:1321-6. [11682423] [doi:10.1097/00000539-200111000-00059]
  46. Kucuk N, Kizilkaya M, Tokdemir M. Preoperativr epidural ketamine does not have a postoperative opioid sparing effect. Anesth Analg 1998;87:103-6. [9661555]
  47. Bilgin H, Ozcan B, Bilgin T, Kerimoğlu B, Uçkunkaya N, Toker A, Alev T, Osma S. The influence of timing of systemic ketamine administration on postoperative morphine consumption. J Clin Anesth 2005;17:592-7. [16427528] [doi:10.1016/j.jclinane.2005.04.005]
  48. Abu-Shahwan I. Ketamine does not reduce postoperative morphine consumption after tonsillectomy in children. Clin J Pain 2008;24:395-8. [18496303] [doi:10.1097/AJP.0b013e3181668aad]
  49. Umuroğlu T, Eti Z, Ciftçi H, Yilmaz Göğüş F. Analgesia for adenotonsillectomy in children: a comparison of morphine, ketamine and tramadol. Paediatr Anaesth 2004;14:568-73. [15200654] [doi:10.1111/j.1460-9592.2004.01223.x]
  50. Marcus RJ, Victoria BA, Rushman SC, Thompson JP. Comparison of ketamine and morphine for analgesia after tonsillectomy in children. Br J Anaesth 2000;84:739-42. [10895748]
  51. Dix P, Martindale S, Stoddart PA. Double-blind randomized placebo-controlled trial of the effect of ketamine on postoperative morphine consumption in children following appendicectomy. Paediatr Anaesth 2003;13:422-6. [12791116] [doi:10.1046/j.1460-9592.2003.01090.x]