Effect of pre-emptive ketamine on sensory changes and postoperative pain after thoracotomy: comparison of epidural and intramuscular routes

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1 British Journal of Anaesthesia 93 (3): (2004) DOI: /bja/aeh220 Advance Access publication July 9, 2004 Effect of pre-emptive ketamine on sensory changes and postoperative pain after thoracotomy: comparison of epidural and intramuscular routes N. S. Ozyalcin 1, A. Yucel 14 *, H. Camlica 3, N. Dereli 2, O. K. Andersen 4 and L. Arendt-Nielsen 4 1 Department of Algology and 2 Department of Anaesthesiology, Istanbul Medical Faculty and 3 Department of Cancer Epidemiology and Biostatistics, Institute of Oncology, Capa Klinikleri, Istanbul, Capa, Istanbul, Turkey. 4 Laboratory for Experimental Pain Research, Center for Sensory-Motor Interaction, Aalborg University, Denmark *Corresponding author. yucel@istanbul.edu.tr Background. In this study we have evaluated the efficacy of ketamine via i.m. and epidural routes for the control of post-thoracotomy pain. Methods. The study was randomized, double blinded and placebo controlled. With the approval of the Faculty Ethics Committee, 60 patients undergoing elective thoracotomy were randomized into three equal groups. Group IM had i.m. ketamine 1 mg kg 1 in 2 ml plus epidural normal saline; Group EPI had epidural ketamine 1 mg kg 1 in 10 ml plus i.m. normal saline; Group C had epidural normal saline 10 ml plus i.m. normal saline 10 ml. Anaesthesia was standardized. Postoperative analgesia was maintained with epidural patient-controlled analgesia using bupivacaine and morphine. Visual analogue scale values and analgesic consumption were evaluated at 2, 4, 6, 8, 10, 12, 24 and 48 h after surgery. The areas of allodynia, pin-prick hyperalgesia and pressure hyperalgesia were measured at 48 h, and days 15 and 30 in all groups. Results. Intraoperative fentanyl requirement was significantly lower in Group EPI than Group C. The morphine and bupivacaine requirements were significantly lower in Group EPI than the other two groups in the postoperative period. There was reduced pin-prick hyperalgesia and touch allodynia in the EPI group. There were no side-effects attributable to ketamine. Conclusion. The results of the present study demonstrate that pre-emptive epidural ketamine is effective in reducing intra- and postoperative analgesic requirements, hyperalgesia and touch allodynia. Br J Anaesth 2004; 93: Keywords: analgesics, postoperative; analgesic techniques, extradural; analgesic techniques, i.m.; measurement techniques, quantitative sensory testing; pain, acute; pain, mechanism; pain, postoperative; pain, threshold; pharmacology, ketamine; surgery, postoperative period; surgery, thoracic; theory of analgesic action Accepted for publication: March 20, 2004 Pre-emptive analgesia is based on the concept of administering analgesic drugs before the occurrence of nociceptive input. 1 3 Despite several experimental studies on the mechanism of peripheral and central sensitization, the effect of pre-emptive analgesia using different drugs is still controversial. 4 Several experimental studies have shown that administration of the N-methyl-D-aspartate (NMDA) receptor antagonists inhibits the spinal processing of nociceptive input. 5 7 Ketamine has been used for postoperative pain relief. It not only abolishes peripheral afferent noxious stimulation, but it may also prevent central sensitization of nociceptors. 7 9 There are several contradictory results in the literature regarding the analgesic properties of pre-emptively administered ketamine. Studies using i.v. ketamine have heterogenous designs such as single bolus, 10 continuous infusion or continuous infusion combined with other drugs. 711 Authors have suggested that subanesthetic doses of i.v. ketamine significantly improved postoperative analgesia in these studies. Some investigators have suggested that i.v. ketamine might have some advantages over epidural ketamine when # The Board of Management and Trustees of the British Journal of Anaesthesia 2004

2 Pre-emptive ketamine for post-thoracotomy pain relief administered with epidural morphine in blocking nociceptive sensitization. 12 Moreover, this beneficial effect may only be obtained after systemic administration. 8 Chronic post-thoracotomy pain syndrome occurs in 50% of patients after thoracotomy and is generally considered to be neuropathic in origin It is thought that providing preemptive analgesia to minimize postoperative neuropathic pain may be important in these patients. The prevention of chronic pain after thoracotomy is an area in need of further research. The aim of this randomized, double-blind, placebocontrolled study was to evaluate the efficacy of pre-emptive ketamine via i.m. and epidural routes for the control of postoperative and chronic post-thoracotomy pain. Methods Patient selection and study design Sixty patients (ASA physical status I III) aged yr and scheduled for elective thoracotomy procedures were enrolled in this randomized, prospective, double-blind study. The study was performed in accordance with the Helsinki Declaration, and the local ethical committee approved the study protocol. The indications for elective thoracotomies were both malignant and benign disease. Surgical interventions were performed through standard posterolateral thoracotomy incisions in all patients by the same surgical team. Patients with a history of drug or alcohol abuse, severe ischaemic heart disease, psychiatric disease or chronic low back pain were excluded from the study. Any contraindication for epidural catheter placement, use of daily analgesics and patient rejection were also considered as exclusion criteria. After obtaining written informed consent, patients were randomly allocated into three groups using a table of random numbers. All syringes were prepared and marked by oneoftheauthorswhowasnotpresentduringthestudyperiod. During the preoperative anaesthetic evaluation, patients were instructed in the use of quantitative sensory tests, visual analogue scale (VAS) and the patient-controlled analgesia (PCA) pump. Patients were not premedicated. In all patients, using the loss-of-resistance technique and under fluoroscopic control, an 18G epidural catheter (Perifix Ò, Braun Melsungen, Germany) was placed before the operation at T6 7, T7 8 or T8 9 interspace as appropriate to the surgical incision. The catheters were advanced approximately 5 cm into the epidural space. In the i.m. injection group (Group IM), ketamine (Ketalar Ò, Parke-Davis) 1 mg kg 1 in 2 ml normal saline was injected i.m. and normal saline 10 ml was injected epidurally. In the epidural injection group (Group EPI), normal saline 2 ml was injected i.m. and preservative-free ketamine (Ketalar Ò, Parke-Davis) 1 mg kg 1 in 10 ml of normal saline was injected epidurally. The control group (Group C) received normal saline 2 ml i.m. and 10 ml epidurally. All injections were performed 15 min before the induction of general anesthesia. General anesthesia and surgical techniques In all three groups, anesthesia was induced with propofol 2 3 mg kg 1, fentanyl 2 mg kg 1 and vecuronium 0.1 mg kg 1. Following oral intubation using a doublelumen technique, anaesthesia was maintained with isoflorane 1 1.5% in oxygen/air mixture (FI O2 50%), fentanyl 0.5 g kg 1 and vecuronium 0.03 mg kg 1. Intraoperative analgesia was controlled with i.v. fentanyl boluses 0.5 mg kg 1 titrated to clinical variables such as heart rate and arterial pressure. The isoflurane concentration and fentanyl doses were adjusted with the intention of keeping heart rate and arterial pressure within 20% of pre-incisional baseline values. Continuous monitoring of ECG, arterial pressure, central venous pressure, Sp O2 and E 0 CO 2 were performed. The final fentanyl dose was given approximately 20 min before the end of surgery. The total intraoperative fentanyl requirement was recorded. All incisions were conventional 6th rib posterolateral thoracotomies, and conventional 28 French apical and basal drains were placed before closure in all patients. Postoperative analgesia All patients received a standardized epidural PCA (PCEA) regimen (APM Ò, Abbott Laboratories); the solution contained bupivacaine 1.25 mg ml 1 and morphine mg ml 1, and the PCEA device was programmed to administer a 5 ml loading dose with a bolus dose of 5 ml, and with a 4 h limit of 20 ml. The lockout interval was 30 min. The total bupivacaine and morphine consumption was noted at 48 h. Measurements The intensity of pain was rated using a 10 cm VAS (0=no pain; 10=most intense pain imaginable) at 0, 2, 4, 6, 12, 24 and 48 h after the operation. The PCEA regimen was adjusted according to the pain intensity and VAS <3 at rest was considered as satisfactory pain relief. Areas of pin-prick hyperalgesia, allodynia and pressure hyperalgesia were measured. Pin-prick hyperalgesia was tested using a von Frey hair (745 mn) on the skin starting from outside the hyperalgesic area where no pain sensation was experienced and advancing toward the centre of the incision until the patient reported a distinct change in perception. The measurement was repeated in eight vectors separated by 45, the distance to the centre was noted, and the surface area calculated using a vector algorithm Allodynia was tested by a brush, which was applied in the same manner as the von Frey hair. Pressure hyperalgesia was tested by a manual algometer (Pain Diagnostic & Thermography Ò, Italy). The threshold was measured before and after surgery in each patient; pressure hyperalgesia was tested in eight vectors 357

3 Ozyalcin et al. separated by 45, starting from outside the hyperalgesic area and advancing toward the centre of the incision. At the point where the threshold was different from the preoperative measure, its distance to the centre was noted, and surface area calculated using a vector algorithm. Sensory measurements were performed at 48 h, day 15 and one month after the operation. An anaesthetist blinded to the drug given recorded all parameters. Side-effects such as sedation, nausea, vomiting, pruritus, urinary retention, hypotension and respiratory depression were noted. The areas of pin-prick hyperalgesia in Group EPI were significantly smaller than in Group IM, 2 and 15 days after surgery (P=0.04, P<0.001 respectively). Also, the areas of pin-prick hyperalgesia in Group EPI were significantly smaller than in Group C, 2 and 15 days and 1 month after surgery (P=0.07, P<0.0001, P=0.002, respectively). There were no significant differences between Group IM and Group C 2 and 15 days after surgery (Table 2). However, the areas of Group IM were significantly smaller than of Group C 1 month after surgery (P=0.008). The results concerning areas of brush allodynia are displayed in Table 3. The areas in the Group EPI were Statistical analysis Age, weight, duration of surgery, total requirement of intraoperative fentanyl, and postoperative bupivacaine and morphine requirements were analysed using Student s t-test. Areas of allodynia, pin-prick hyperalgesia and pressure hyperalgesia were compared using the Mann Whitney U-test. P<0.05 was considered to be statistically significant. Data were analysed using the Statistical Package for Social Scientist (SPSS, Version 7.5) for Windows TM. Results There were no significant differences between the study groups with respect to age, gender, weight or duration of surgery (Table 1). Median use of chest drain was 3 (range 2 5) days. There were no significant differences in drain removal times. VAS scores decreased significantly in all groups at 2, 4, 6, 12, 24 and 48 h after surgery (P<0.01). Intraoperative fentanyl requirements were significantly lower in Group EPI than Group C (P<0.01). Total fentanyl requirements in Group IM were no different from that of Group EPI or Group C (Fig. 1). The morphine dose was adjusted to 0.1 mg in two patients in Group C according to the pain intensity. Morphine and bupivacaine requirements were significantly lower in Group EPI than the other two groups during the postoperative period (Fig. 2). Postoperative morphine requirements in Group IM were significantly lower than in Group C (P<0.001). There was no significant difference between Group IM and Group C regarding postoperative bupivacaine requirements (Fig. 2). Fig 1 Intraoperative fentanyl consumption. *Fentanyl consumption was significantly lower in the epidural ketamine group than in the control group (P<0.01). Table 1 Patientcharacteristics and surgical data. Data aremean (range) forage, or mean (SD). EPI, epidural ketamine group; IM, i.m. ketamine group; C, control group; n=20 in all groups. *L, lobectomy; P, pneumonectomy; O, other (bullectomy, segmentectomy, metastasectomy). There were no significant differences between the groups EPI IM C Mean age (yr) (range) 47.8 (24 65) 42.1 (20 64) 46.1 (25 62) Weight (kg) 64.2 (13.3) 64.6 (11.1) 66 (12.2) Gender (M/F) 9/11 12/8 14/6 Type of operation (L/P/O)* 14/3/3 9/4/7 12/3/5 Side of incision (left/right) 7/13 11/9 5/15 Duration of surgery (min) (44.6) (43) 135 (42.7) Fig 2 Postoperative morpine (A) and marcaine (B) consumptions. (A) *Total morphine requirement was significantly lower in the i.m. ketamine group than in the control group. **Total morphine requirement was significantly lower in the epidural ketamine group than in the i.m. ketamine and control groups. (B) **Total bupivacaine requirement was significantly lower in the epidural ketamine group than in the i.m. ketamine and control groups. 358

4 Pre-emptive ketamine for post-thoracotomy pain relief Table 2 Areas of pin-prick hyperalgesia (in cm 2 ) after surgery. Data are mean (SD); median (min max), n=20 in all groups. EPI, epidural ketamine group; IM, i.m. ketamine group; C, control group; *Mann Whitney U-test Group 48 h Day 15 Day 30 EPI 7.36 (17.22); 0 ( ) 5.45 (15.62); 0 (0 60) 3.53 (9.47); 0 ( ) IM 8.85 (4.43); 8.52 ( ) 7.53 (6.55); 7.19 ( ) 4 (8.00); 0 ( ) C (14.94); 3.56 (0 48) (7.13); (0 28) (12.17); 4.02 (0 42) P-values* EPI vs IM EPI vs C IM vs C Table 4 Areas of pressure hyperalgesia (in cm 2 ). Data are mean (SD); median (min max), n=20 in all groups. EPI, epidural ketamine group; IM, i.m. ketamine group; C, control group; *Mann Whitney U-test Group 48 h Day 15 Day 30 EPI (16.25); ( ) (27.01); 8.84 ( ) (29.92); ( ) IM (39.71); ( ) (41.92); ( ) (37.02) 8.67 (0 9.00) C (19.22); (17.94); ( ) (18.05); ( ) ( ) P-values* EPI vs IM EPI vs C IM vs C Table 3 Areas of brush allodynia (in cm 2 ) after surgery. Data are mean (SD); median (min max), n=20 in all groups. EPI, epidural ketamine group; IM, i.m. ketamine group; C, control group; *Mann Whitney U-test Group 48 h Day 15 Day 30 EPI 3.18 (8.02); 0 ( ) 1.74 (2.93); 0 (0 8.38) 1.19 (2.63); 0 (0 8.38) IM 4.22 (3.99); 3.5 (0 12) 3.81 (3.64); 2.5 (0 9) 2.30 (2.66); 2.5 (0 9) C 8.04 (6.00); 6.17 (0 19) 7.49 (5.38); 5 (0 16) 5.35 (5.09); 3.5 (0 15) P-values* EPI vs IM EPI vs C < IM vs C significantly smaller than in Group IM and Group C; areas of brush allodynia in Group IM were significantly smaller than in Group C. The results concerning areas of pressure hyperalgesia are displayed in Table 4. The areas of pressure hyperalgesia in the Groups EPI and IM were significantly smaller than in Group C 2 days after surgery. The areas in Group EPI were significantly smaller than in Group C 15 days after surgery. There were no significant differences between Group EPI and Group IM. There was no significant difference between the groups 1 month after surgery. Side-effects such as nausea, vomiting, urinary retention and pruritus were similar in the three groups and did not require any treatment or result in discontinuation of treatment. There was no psychotropic side-effects attributable to the use of ketamine. Discussion The results of the present study demonstrate that pre-emptive epidural ketamine is effective in reducing intra- and postoperative analgesic requirements. We have also shown reduced pin-prick hyperalgesia and touch allodynia in the group receiving epidural ketamine. These findings are in keeping with reduced central sensitization. The analgesic properties of ketamine have been known for a long time; the mechanism or mechanisms are still unclear. Ketamine can act on several receptor systems such as opioid, 17 cholinergic and monoaminergic systems. 19 It also shows local anaesthetic effects by the blockade of sodium channels. 20 Most clinicians have observed that a low dose of epidural ketamine (4 10 mg) does not produce significant postoperative analgesic effects in adults. 421 The different results of various studies using epidurally administered ketamine may be due to malposition of the epidural catheter either placement outside the epidural space or inappropriate dermatomal placement. In our study, the epidural catheters were inserted under radiographic guidance; thus, the catheter location was confirmed. Another debatable point is the effect of multireceptor applications in postoperative pain. Pre-emptive multireceptor analgesia with ketamine, morphine and local anaesthetics improves postoperative analgesia Wu and colleagues 22 have shown that multimodal pre-incisional analgesia with morphine, bupivacaine and ketamine is better than postincisional administration. There are several contradictory results in the literature regarding the analgesic properties of pre-emptive ketamine. 4 Burton and colleagues 24 have reported that mechanical allodynia is reduced after administration of intrathecal ketamine in a rat model, probably by preventing sensitization in the spinal cord. They further suggested that this effect was sustained for at least 2 weeks, but diminished after 1 month. Lee and colleagues 25 have reported that only i.v. ketamine produced pre-emptive analgesia in a rat model. However, the observation period was shorter than that in the Burton study. It seems that blocking the NMDA receptors to inhibit central sensitization may be necessary for only a relatively short time. Contrary to these results, in the present study, the areas of pin-prick hyperalgesia and touch allodynia were significantly smaller in the group receiving epidural ketamine and i.m. ketamine than in controls, even 1 month after surgery. It could be argued that the results of the experimental 359

5 Ozyalcin et al. studies have limited clinical relevance. However, many clinicians believe that in surgical procedures such as thoracotomy and mastectomy, pre-emptive approaches may help to prevent post-surgical neuropathic pain In most of the clinical studies using ketamine, authors have not assessed wound hyperalgesia Tverskoy and colleagues 27 have shown that ketamine is effective for wound hyperalgesia but not for postoperative pain. They believe the pre-emptive inhibitory effect on wound hyperalgesia by fentanyl and ketamine is due to prevention of central sensitization. Ilkjaer and colleagues 26 have studied pre-emptive i.v. ketamine infusion and found no effect on the pressure pain threshold or pin-prick sensation using a von Frey hair on the second postoperative day. In the present study, the areas of pin-prick hyperalgesia and touch allodynia were significantly smaller in Group EPI than in Groups IM and C 15 days and 1 month after surgery. The areas of pressure hyperalgesia were significantly smaller in Groups EPI and IM than in Group C, and the areas of Group EPI were significantly smaller than in Group C patients 1 and 15 days after surgery. The differences between our findings and Ilkjaeker s results could be explained by differences in methodology, as their evaluation of mechanical hyperalgesia was 10 cm from the surgical incision, not in the area of hyperalgesia around the wound. In addition, their observation period was only 2 days, which was shorter than our study. Stubhaug and colleagues 7 reported a reduction of the area of mechanical hyperalgesia around the surgical wound on postoperative days 1, 3 and 7. However, they did not find reduced pain intensity or morphine consumption. The results of De Kock and colleagues study 8 support our results, which suppose that a subanesthetic dose of ketamine reduces wound hyperalgesia. However, they only evaluated mechanical hyperalgesia using a von Frey hair and only found an effect after systemic administration. The results of the present study support their results as we have also found significant differences between Groups IM and C 1 month after surgery. However, there is an important difference between the two studies; the results of the group receiving epidural ketamine are better than that of the group receiving i.m. ketamine in our study with respect to pin-prick hyperalgesia and allodynia. This difference could be explained by different protocols. De Kock and colleagues used local anaesthetics, opioids and a 2 agonists before and during surgery. 8 It may be that these agents blocked the effect of ketamine on spinal NMDA receptors. Another important difference is that they only evaluated mechanical hyperalgesia for 72 h. Despite the differences between our results and De Kock s study, both evaluated the long-term effects of ketamine and found reduced wound hyperalgesia and residual pain, which supports the proposal that central sensitization can be blocked by pre-emptive ketamine. Different stimulation modalities are widely used to study the mechanisms of pain in humans Despite experience with experimental pain models using sensory testing such as thermal, mechanical and electrical stimuli, the appropriate measurements in clinical trials of acute and chronic pain are still unclear. We still do not know if unrelieved acute postoperative pain is a risk factor for developing chronic postoperative pain, and whether we can inhibit such a mechanism. The use of different types of stimuli and stimulus response functions such as the degree of hyperalgesia may give more information about the mechanisms of chronic neuropathic pain after surgery, as well as the effect of different drugs and modalities to control it. In conclusion, pre-emptive epidural ketamine is effective in reducing pin-prick hyperalgesia, and touch allodynia. Unfortunately, there are several issues for future investigation such as the most effective dose, timing of administration and necessity for continuous infusion. References 1 Wall PD. The prevention of postoperative pain. Pain 1988; 33: McQuay HJ. Pre-emptive analgesia. Br J Anaesth 1992; 69: Woolf CJ, Chong MS. Preemptive analgesia: treating postoperative pain by preventing the establishment of central sensitization. Anesth Analg 1993; 77: Möiniche S, Kehlet H, Dahl JB. A qualitative and quantitative systematic review of preemptive analgesia for postoperative pain relief. Anesthesiology 2000; 96: Murray CW, Cowan A, Larson AA. Neurokinin and NMDA antagonists (but not a kainic acid antagonist) are antinociceptive in the mouse formalin model. Pain 1991; 44: Wong CS, Shen TT, Liaw WJ, Cherng CH, Ho ST. Epidural co-administration of ketamine, morphine and bupivacaine attenuates post-herpetic neuralgia: a case report. Acta Anaesthesiol Scand 1996; 34: Stubhaug A, Breivik H, Eide PK, Kreunen M, Foss A. Mapping of punctuate hyperalgesia around a surgical incision demonstrates that ketamine is a powerful suppressor of central sensitization to pain following surgery. Acta Anaesthiol Scand 1997; 41: De Kock M, Lavand homme P, Waterloos H. Balanced analgesia in the perioperative period: is there a place for ketamine? Pain 2001; 92: Kalso E, Mennander S, Tasmuth T, Nilsson E. Chronic poststernotomy pain. Acta Anaesthesiol Scand 2001; 45: Ngan Kee WD, Khaw KS, Ma ML, Mainland PA, Gin T. Postoperative analgesic requirement after Caesarean section: a comparison of anesthetic induction with ketamine or thiopental. Anesth Analg 1997; 85: Wilder-Smith OH, Arendt-Nielsen L, Gäumann D, Tassonyi E, Rifat KR. Sensory changes and pain after abdominal hysterectomy: a comparison of anesthetic supplementation with fentanyl versus magnesium or ketamine. Anesth Analg 1998; 86: 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: Senturk M, Ozcan PE, Talu GK, et al. The effects of three different analgesia techniques on long-term postthoracotomy pain. Anesth Analg 2002; 94: Devers A, Galer BS. Topical lidocaine patch relieves a variety of neuropathic pain conditions: an open-label study. Clin J Pain 2000; 16:

6 Pre-emptive ketamine for post-thoracotomy pain relief 15 Andersen OK, Felsby S, Nicolaisen L, Bjerring P, Jensen TS, Arendt-Nielsen L. The effect of ketamine on stimulation of primary and secondary hyperalgesic areas induced by capsaicin: a doubleblind, placebo-controlled, human experimental study. Pain 1996; 66: Yucel A, Nielsen J, Andersen OK, Arendt-Nielsen L. Heat hyperalgesia in humans: Assessed by different stimulus temperature profiles. Eur J Pain 2002; 6: Hustveit O, Maurset A, Oye I. Interaction of the chiral forms of ketamine with opioid, phencyclidine, sigma and muscarinic receptors. Pharmacol Toxicol 1995; 77: Scheller M, Bufler J, Hertle I, Schneck HJ, Franke C, Kochs E. Ketamine block currents through mammalian nicotinic acetylcholine receptor channels by interaction with both the open and the closed state. Anesth Analg 1996; 83: Pekoe GM, Smith DJ. The involvement of opiate and monoaminergic neuronal systems in the analgesic effects of ketamine. Pain 1982; 12: Tung AS, Yaksh TL. Analgesic effect of intrathecal ketamine in the rat. Reg Anesth 1981; 6: Ravat F, Dorne R, Baechle JP, et al. Epidural ketamine or morphine for postoperative analgesia. Anesthesiology 1987; 66: Wu CT, Yeh CC, Yu JC, Lee MM, Tao PL, Ho ST, Wong CS. Preincisional epidural ketamine, morphine and bupivacaine combined with epidural and general anaesthesia provides pre-emptive analgesia for upper abdominal surgery. Acta Anaesthesiol Scand 2000; 44: 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: Burton AW, Lee DH, Saab C, Chung JM. Preemptive intrathecal ketamine injection produces a long-lasting decrease in neuropathic pain behaviours in a rat model. Reg Anesth Pain Med 1999; 24: Lee IO, Lee IH. Systemic, but not intrathecal, ketamine produces preemptive analgesia in the rat formalin model. Acta Anaesthesiol Scan 2001; 39: 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: Tverskoy M, Oz Y, Isakson A, Finger A, Bradley EL Jr, Kissin I. Preemptive effect of fentanyl and ketamine on postoperative pain and wound hyperalgesia. Anesth Analg 1994; 78: Nielsen J, Arendt-Nielsen L. The importance of stimulus configuration for temporal summation of first and second pain to repeated heat stimuli. Eur J Pain 1998; 2: