Veterinary Surgery 33:361–367, 2004
Pre-Emptive Epidural Ketamine or S(þ)-Ketamine in Post-incisional Pain in Dogs: A Comparative Study JUAN CARLOS DUQUE M. MSc, CARLOS A.A. VALADA˜O, DSc, ANDERSON FARIAS, MSc, RICARDO M. DE ALMEIDA, MSc, and NILSON OLESKOVICZ, MSc
Objective—To compare the pre-emptive analgesic effects of epidural ketamine or S(þ)-ketamine on post-incisional hyperalgesia. Study Design—Prospective randomized study. Animals—Twenty-four mongrel dogs (1–5 years, weighing 11.9 1.8 kg). Methods—Dogs were anesthetized with propofol (5 mg/kg intravenously) and a lumbosacral epidural catheter was placed. Dogs were randomly allocated to 3 groups, each with 8 dogs. The control group (CG) was administered saline solution (0.3 mL/kg); the ketamine group (KG) ketamine (0.6 mg/kg); and the S(þ)-ketamine group (SG) S(þ)-ketamine (0.6 mg/kg). The final volume was adjusted to 0.3 mL/kg in all groups. Five minutes after the epidural injection a surgical incision was made in the common pad of the right hind limb and was immediately closed with simple interrupted nylon suture. Respiratory (RR) and heart (HR) rates, rectal temperature (T), sedation (S), lameness score, and mechanical nociceptive threshold by von Frey filaments were evaluated before the propofol anesthesia and at 15, 30, 45, 60, 75, and 90 minutes and then at 2, 4, 6, 8, 12, and 24 hours after epidural injection. Results—There were no differences in RR, HR, T, or S between groups. Motor blockade of the hind limbs was observed during 20 3.6 minutes in KG and during 30.6 7.5 minutes in SG (mean SD). Mechanical force applied to obtain an aversive response was higher from 45 minutes to 12 hours in KG and from 60 to 90 minutes in SG, when compared with CG. Conclusions—Pre-emptive epidural ketamine induced no alterations in RR and HR, and reduced post-incisional hyperalgesia for a longer time than did S(þ) ketamine. Clinical Relevance—Although anesthetic and analgesic potency of S(þ) ketamine is twice that of ketamine, the racemic form is seemingly better for post-incisional hyperalgesia. r Copyright 2004 by The American College of Veterinary Surgeons Key words: dogs, epidural, hyperalgesia, ketamine, S(þ)-ketamine.
the injury and is characterized by reduction of both mechanical and thermal nociceptive threshold. Secondary hyperalgesia (SH) appears in non-damaged tissue surrounding the injured area and is characterized by diminution of mechanical nociceptive threshold (MNT) only.2,3 PH probably depends on sensitization of peripheral nociceptive fibers, while SH is a consequence of the sensitization of nociceptive and wide dynamic range neurons in
INTRODUCTION
T
HE NEUROENDOCRINE response to traumatic or post-operative pain induces several physiologic alterations. Pain and discomfort can reduce food consumption, increasing convalescence and healing periods.1 After tissue trauma 2 types of hyperalgesia can develop. Primary hyperalgesia (PH) is restricted to the site of
From the Department of Veterinary Clinic and Surgery of the FCAV/Unesp–Jaboticabal, SP, Brazil. Address correspondence to Carlos Augusto Arau´jo Valada˜o, DSc, Departamento de Clı´ nica e Cirurgia Veterina´ria, FCAV/UNESPJaboticabal, Via de Acesso Rod. Prof. Paulo Donato Castellane s/n, Jaboticabal, SP, Brazil. E-mail:
[email protected] or Dr.Duque:
[email protected]. Submitted March 2003; Accepted April 2004 r Copyright 2004 by The American College of Veterinary Surgeons 0161-3499/04 doi:10.1111/j.1532-950X.2004.04052.x
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the dorsal horn of the spinal cord. This increased sensitivity, which involves N-methyl-D-aspartate (NMDA) receptor activation and is characterized by facilitation of nociceptive transmission, has been named central sensitization.4,5 Ketamine directly depresses cortical areas of somatosensorial association that form the limbic system, and suppresses the nociceptive transmission in the mesencephalic reticular formation and in the thalamic medial nucleus6 so that the central nervous system (CNS) is unable to receive or process sensorial information and, consequently, its emotional meaning cannot be evaluated. Administration of anesthetic doses of ketamine results in anesthesia, analgesia, amnesia, and fear and anxiety suppression.7 Ketamine acts on a variety of sites, including nonNMDA glutamate receptors, opioid (m4k4d) receptors, g-amino butyric receptors type A, nicotinic and muscarinergic receptors, and on sodium, potassium, and calcium channels.8 However, most of the pharmacologic effects of ketamine are mediated by non-competitive inhibition of the NMDA receptors.7 The doses of ketamine necessary to blockade the NMDA receptors are significantly lower than the ones required to induce surgical anesthesia. This fact explains why this anesthetic keeps anti-hyperalgesic properties even in sub-anesthetic doses.9 Ketamine is a chiral drug commercialized in its racemic form, which is constituted by 2 isomers: S(þ) and R(). The S(þ) isomer has a therapeutic index 2.5 times greater than the R() form and shows stereoselectivity by the non-competitive blockade of the NMDA receptor, presenting anesthetic and analgesic potency 2–4 times greater then the racemic form, and even in hypnotic doses causes less undesirable effects than the R() isomer.10 Ketamine injected epidurally can reduce nociceptive transmission producing slight to moderate analgesia, an outcome that can be used as a therapeutic option to improve the efficiency of analgesic techniques.11–19 Little information concerning the effects of S(þ)-ketamine in dogs or its efficacy for post-operative pain is available, but considering its pharmacologic properties, it is possible to suppose that its epidural administration might offer advantages compared with the racemic form. The aim of this study was to compare the effects of the pre-emptive epidural administration of the racemic ketamine or its S(þ) isomer on the post-incisional hyperalgesia in a experimental model of incisional pain in dogs. MATERIALS AND METHODS Animals Twenty-four healthy, mongrel dogs (1–5 years; weighing 11.9 1.8 kg) were divided randomly into 3 equal groups of 8
dogs: control group (CG) administered epidural saline solution; ketamine group (KG) administered epidural ketamine; and S(þ)-ketamine group (SG) administered epidural S(þ)ketamine. After clipping and preparation of the lumbosacral region, dogs were anesthetized with propofol (5 mg/kg intravenous [IV]) and maintained with additional doses if necessary. Dogs were positioned in sternal recumbency with the hind limbs directed cranially. A 16 G epidural catheter (Portex epidural catheters, Sims Portex Ltd, UK) was passed into the epidural space through a 16 G Tuohy needle (Becton, Dickinson, IN, Ciru´rgicas Ltda., Juiz de Fora MG, Brasil) inserted in the lumbosacral space. After the catheter was positioned, either saline solution (0.3 mL/kg), ketamine (5%; 0.6 mg/kg; Ketamin, Crista´lia Produtos Quı´ micos e Farmaceˆuticos Ltda., Itapira SP, Brasil), or S(þ)-ketamine (5%; 0.6 mg/kg; ketamin S(þ), Crista´lia Produtos Quı´ micos e Farmaceˆuticos Ltda., Itapira SP, Brasil) were administered to CG, KG, and SG, respectively. The final volume of the epidural injection was adjusted to 0.3 mL/kg and was followed by a 0.3 mL flush of saline solution. The solutions were prepared by another veterinarian who was not part of the research team so that evaluators were unaware of the treatment. Five minutes after the epidural injection, a 2 cm surgical incision was made in the common pad of the right hind limb and was immediately closed with nylon suture in a simple interrupted pattern. Dogs were maintained in sternal recumbency during the surgical procedure and until they were able to stand up and walk, when the catheter was removed.
Measurements Heart rate (HR), respiratory rate (RR), rectal temperature (T), degree of sedation (S; Table 1), and lameness score (LS; Table 2), and MNT measured by von Frey filaments, were evaluated before propofol anesthesia and at 15, 30, 45, 60, 75, and 90 minutes and then at 2, 4, 6, 8, 12, and 24 hours after epidural injection. MNT was assessed using von Frey filaments (Touch-Test Sensory Evaluator, North Coast Medical Inc, San Jose, CA) in ascending order. Each filament was applied, with 3 second intervals, at 3 different points on the dorsal, lateral, medial, and ventral aspects at 3 mm spacing of the incision line (Fig 1). Measurements started with the thinnest filament placed on the peri-incisional area and pressed until the nylon bowed, for 1
Table 1. Scale Used to Score Sedation of Dogs after Epidural Administration of Ketamine, S(þ)-Ketamine, or Saline Solution Sedation Score Behavior Alert and walking normally Somnolence, remains standing with head down and eyes semiclosed Somnolence, remains in lateral or sternal recumbency, responds to calling Somnolence, remains in lateral or sternal recumbency, does not respond to calling
Score 0 1 2 3
363
DUQUE ET AL Table 2. Scale Used To Score Lameness in Dogs after Epidural Administration of Ketamine, S(þ)-Ketamine, or Saline Solution Lameness Score Position Complete weight bearing Partial weight bearing (standing and walking) Partial bearing (standing only) No weight bearing
Score 0 1 2 3
second. If a response (e.g., head movement or withdrawal or movement of the limb) was obtained at least in 2 of the points evaluated, the test was interrupted and peri-incisional MNT was established by the diameter of the previous thickest filament that did not elicit a response. If no response occurred, the next filament was applied. If a response was not obtained after the last filament the evaluation ceased. This procedure was repeated on the contralateral paw at the same time intervals to verify potential mechanical threshold effects. Data collected from von Frey filaments were recorded in grams and converted to logarithm using the scale provided by the manufacturer.
Statistical Analysis The normality of the distribution of data was evaluated by the Kolmogorov–Smirnov test (SigmaStat for Windows version 2.0, Jandel Corporation, San Rafael, CA). For the within-group comparisons of the parametric data (HR, RR, and T) a 1-way ANOVA with repeated measures followed by a Student–Newman–Keuls test was used. For between-group
comparisons 1-way ANOVA followed by the Student–Newman–Keuls test was used. Non-parametric data (LS, S, and MNT) were assessed by the Kruskal–Wallis test. Differences were considered significant when P .05. Data are reported as mean SD.
RESULTS There were no between-group differences for the mean dose of propofol administered, anesthetic recovery time, or degree of sedation. Locomotor blockade of the hind limbs was not observed after epidural saline solution administration. Motor blockade occurred during 20 3.6 minutes in KG dogs and 30.6 7.5 minutes in SG dogs. When they were able to get up and walk, ataxia was observed for 23 5.1 minutes in KG dogs and for 41.5 13.1 minutes in SG dogs (Table 3). Epidural ketamine or S(þ)-ketamine did not produce stimulation or excitation signs in any of the dogs. HR was higher at 15 minutes in KG and between 15 and 30 minutes in SG and CG when compared with baseline values, but no significant differences were observed between groups. RR was decreased at 75, 120, and 480 minutes in KG dogs but these differences were not significant between groups. Temperature was decreased from 15 to 120 minutes in SG dogs when compared with baseline values (Table 4). The number of dogs with some degree of lameness during the evaluation period was lower in KG (4 dogs) when compared with SG (6 dogs) and CG (8 dogs). No temporal differences in LS were observed in KG, whereas LSs were higher from 30 minutes until final evaluation in both SG and CG dogs when compared with baseline values for the respective groups. No significant temporal differences were observed in the force applied (filament thickness) to obtain an aversive response in KG and SG dogs. The force used after 15 minutes was lower at all intervals in CG when compared with baseline values for this group. The force needed to elicit a response was higher between 60 and 720 minutes in KG and between 60 and 90 minutes in SG, when compared with the same intervals for CG. DISCUSSION
Fig 1. Evaluation of the mechanical (MNT) using von Frey filaments. Each with 3 second intervals, at 3 different lateral, medial, and ventral aspects at incision line (white line).
nociceptive threshold filament was applied, points on the dorsal, 3 mm spacing of the
Ketamine is a highly lipid soluble drug with relatively fast absorption and distribution in the systemic circulation after epidural injection.20 We used doses of ketamine and S(þ)-ketamine that caused local effects without inducing systemic effects like sedation or excitement. Other studies have reported sedative effects after epidural ketamine administration.13,21 These differences in observations may be related to the higher doses used in those studies and possibly by interaction with other anesthetic
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KETAMINE OR S(þ)-KETAMINE IN POST-INCISIONAL PAIN IN DOGS
Table 3. Mean ( SD) Weight, Propofol Dose, Time to Wake Up after Initial Dose of Propofol, Time for Locomotor Blockade and Ataxia of the Hind Limbs after Epidural Administration of Ketamine, S( þ )-Ketamine or Saline Solution Group S( þ ) K C
Weight (kg)
Propofol (mg/kg)
11 1.8 12.05 1.9 12.72 2.3
Time to wake up (minutes)
Locomotor Blockade (minutes)
Ataxia (minutes)
19.1 7.7 14 5.4 19.4 11.8
30.6 7.5 20 3.6
41.5 13.1 23.25 5.1 –
8.8 4.3 6.5 1.9 7.9 2.4
–
S(þ), S(þ)-ketamine; K, ketamine; C, saline solution control group.
Significant difference between S( þ ) and K (t-test, P .05).
agents used. We found no significant difference for the mean dose of propofol administered, the time of anesthetic recovery, or the sedation scores between groups. This suggests that in our study, the ketamine or S(þ)ketamine doses were insufficient to potentiate the anesthetic or sedative effects of propofol. Whereas the doses we used did not produce systemic effects, they were sufficient to cause motor blockade. This observation can be explained by the local anesthetic properties of ketamine and its interaction with voltagedependent sodium channels.22,23 This is a dose-dependent effect, because Rao et al15 described a direct relationship between epidural ketamine dose and suppression of hind
limb reflexes. Valada˜o et al19 also verified no motor blockade after epidural administration of 0.2 mg/kg ketamine. Although the local anesthetic properties of ketamine have been demonstrated, it is necessary to use very high concentrations of ketamine to elicit this effect.8 However, we observed that the use of a smaller dose than the anesthetic induction dose resulted in a higher incidence of prolonged ataxia in dogs treated with S(þ)ketamine. This observation was similar to that of Oleskovicz et al17 in mares. Bra¨u et al24 reported that the R() isomer of ketamine seemed more important to block sodium and potassium channels, but that difference did not allow confirmation
Table 4. Mean ( SD) Group Values for Heart Rate (HR), Respiratory Rate (RR), Temperature (T ), and Mechanical Nociceptive Threshold (MNT) after Epidural Administration of Ketamine, S(þ)-Ketamine, or Saline Solution HR Time 0 15 30 45 60 75 90 2 4 6 8 12 24
RR
MNT
T
C
K
S(þ)
C
K
S(þ)
C
K
S(þ)
C
K
S(þ)
101 [22.5] 124w [27.5] 114w [29.3] 100 [24.2] 98 [21.1] 96 [19.8] 97 [15.6] 95 [16.9] 97 [15.7] 98 [16.5] 95 [12.5] 95 [15] 98 [12.3]
94 [17.9] 126w [47.2] 104 [33.9] 103 [22.5] 96 [20.7] 94 [20.7] 91 [20.8] 88 [21.8] 93 [18.3] 93 [14.1] 84 [12.8] 93 [18] 93 [17.2]
92 [8.2] 126w [33.3] 121w [24.2] 107 [16.6] 102 [18.5] 97 [19] 94 [17.3] 93 [15.1] 96 [10] 93 [14] 96 [14.2] 92 [17.1] 94 [14.8]
21 [3.8] 19 [3] 19 [4.6] 19 [4] 18 [3] 22 [14] 26 [19] 27 [23.1] 23 [8.6] 20 [4.8] 22 [7.5] 19 [3.5] 21 [4.3]
25 [2.8] 24 [4] 21 [4.1] 22 [5.1] 20 [3] 20w [4.1] 21 [3.3] 19w [2.8] 22 [2.6] 22 [2.9] 17w [6.5] 20 [2.7] 20 [2.3]
21 [2.8] 22 [4.2] 20 [3.7] 20 [3.1] 19 [3.5] 19 [3.7] 20 [5.5] 20 [4] 21 [4] 21 [2] 23 [4.1] 20 [4.6] 20 [3.3]
39.1 [0.7] 38.4 [0.7] 38.5 [0.7] 38.5 [0.6] 38.8 [0.7] 38.9 [0.7] 38.9 [0.6] 38.7 [0.6] 38.5 [0.7] 38.6 [0.7] 38.6 [0.6] 38.8 [0.6] 39 [0.6]
38.9 [0.4] 38.4 [0.6] 38.4 [0.3] 38.5 [0.5] 38.6 [0.4] 38.6 [0.4] 38.7 [0.5] 38.6 [0.4] 38.7 [0.5] 38.8 [0.4] 38.6 [0.4] 38.8 [0.3] 38.7 [0.4]
39 [0.4] 37.9w [0.5] 37.9w [0.5] 37.9w [0.5] 38.1w [0.4] 38.2w [0.5] 38.4w [0.4] 38.4w [0.4] 38.5 [0.5] 38.8 [0.5] 38.7 [0.8] 38.7 [0.8] 38.6 [0.5]
6.65 [0] 6.44w [1.8] 6.19w [2.2] 6.09w [2.3] 5.91w [2] 5.98w [2.2] 5.78w [0.4] 5.90w [1.9] 5.88w [2] 5.59w [0.5] 5.56w [0.4] 5.53w [0.5] 5.69w [0.4]
6.65 [0] 6.65 [0] 6.65 [0] 6.65 [0] 6.65 [0] 6.65 [0] 6.46 [1.9] 6.55 [1.6] 6.65 [0] 6.45 [1.7] 6.47 [1.7] 6.35 [2.1] 6.26 [2]
6.65 [0] 6.65 [0] 6.65 [0] 6.65 [0] 6.65 [0] 6.65 [0] 6.65 [0] 6.52 [1.7] 6.10 [2.2] 5.90 [2.2] 5.78 [1.6] 5.65 [1.6] 5.86 [2]
S(þ). S(þ)-ketamine; K. ketamine; C. saline solution control group.
Significant difference when compared with CG (P .05).
wSignificant difference when compared with T0 (P .05).
DUQUE ET AL
that stereoselectivity existed for the local anesthetic effect of ketamine. It has been suggested that the anesthetic and analgesic potency of the S(þ) isomer is 2–3 times higher than that of the R() isomer; thus, the prolonged locomotor blockade could be attributed to the relatively higher dose of S(þ)-ketamine used. Kienbaum et al8 reported that when the S(þ) isomer is used, the dose should be reduced between 50% and 70%. No data comparing the motor blockade induced by epidural injection of equipotent doses of ketamine and S(þ)-ketamine in dogs are available, but is possible that a reduction in the S(þ)ketamine dose could induce motor blockade of equal or lesser intensity and duration than ketamine. Although motor blockade occurred, we did not assess whether there was also surgical analgesia. The HR increase we observed could be attributed to the decrease in blood pressure that can be up to 30%, after anesthetic induction with propofol.25 However, HR values were within the normal range at all times. The decrease in RR observed in KG dogs could not be associated directly with ketamine. Other authors administered doses 6 times greater than the dose we used and they were not enough to cause respiratory depression.12,21,26 Perhaps the observed differences were a result of higher baseline values or improved analgesia in this group. The reduction in temperature observed in all dogs in the early evaluations was because of a diminution in basal metabolism after propofol anesthesia.27 Persistence of this effect for a longer time in SG dogs may be associated with prolonged motor blockade and an absence of muscular tonus. Propofol has an inhibitory effect on the production of the tumor necrosis factor a, interleukin 6, and interleukin 8, and also interferes with chemotaxis of polymorphonuclear cells, and with the oxidative system, in vitro and in vivo. These interactions can alter the systemic inflammatory response and the capacity to control infections.28– 31 Even though there have not been studies in dogs, these effects of propofol may have interfered with the inflammatory reaction in our experimental model, and as a consequence with the development of post-incisional hyperalgesia. However, propofol was used in all 3 groups and only the group administered epidural saline solution had a significant reduction in MNT from T15 until the end of the study. Thus it seems unlikely that an antiinflammatory effect of propofol interfered with the development of hyperalgesia or the effect of ketamine or S(þ)-ketamine. We used pre-emptive administration because it has been proposed that central sensitization can be prevented by administration of analgesic drugs before tissue trauma occurs. Nevertheless, the inflammatory response to tissue injury could have a more important role in central sensitization than did surgical stimuli of short duration.32
365
Some studies have failed to demonstrate a pre-emptive effect for several analgesic drugs,33; however, Fu et al,34 Roytblat et al,35 Stubhaug et al,4 and Tverskoy et al36 demonstrated an inhibitory effect of ketamine on central sensitization produced by nociceptive stimulation during and after the surgery, independent of the administration regime. From a clinical viewpoint, the small number of dogs with some lameness and the lower LSs observed in KG dogs suggest that ketamine was more effective in reducing post-incisional pain than S(þ)-ketamine. In fact, a higher MNT was observed for 12 hours after ketamine and for 90 minutes after S(þ)-ketamine, when compared with CG dogs. Certainly, that effect is not related to the anesthetic properties of ketamine because it exceeded its duration of action, but might be explained by different effects of ketamine on acute nociception and on hyperalgesia. Sonoda and Omote37 reported that systemic administration of ketamine could activate the monoaminergic descending system, resulting in an important analgesic activity by a supraspinal effect. On the other hand, the ketamine effect on central sensitization and, subsequently, on hyperalgesia could be related to the non-competitive inhibition of the NMDA receptors.2,3,32 Our data showed that ketamine or S(þ)-ketamine reduced post-incisional wound hyperalgesia. Kawamata et al38 demonstrated that the anti-hyperalgesic effect of ketamine in the presence of peripheral inflammation was related to inhibition of spinal and supraspinal NMDA receptors. This mechanism could be responsible for the post-incisional pain diminution, represented by increased MNT, observed in our dogs. Klimscha et al39 observed that the S(þ) isomer of ketamine reduced hyperalgesia; however, the racemic form was more effective. We observed similar effects. Although early in our study the applied force needed to induce a response was similar for KG and SG dogs, after 2 hours there was a reduction in the MNT for SG dogs even before the peak of the inflammatory response. Because the anti-hyperalgesic effect of ketamine is related to the inhibition of the NMDA receptors, and because there may exist a higher stereoselectivity for S(þ)-ketamine for this effect, one plausible explanation for the observed differences in these 2 studies may be related to pharmacokinetics differences for these isomers. When racemic ketamine is administered, the plasma clearance of S(þ)-ketamine is faster than that for the R() enantiomer. However, the metabolism of the R()enantiomer can inhibit S(þ)-enantiomer metabolism, which may explain the prolonged recovery period after racemic ketamine.40 This might explain a more prolonged reduction of the wound hyperalgesia by racemic ketamine. After epidural administration, ketamine penetrates into the cerebrospinal fluid (CSF) and is absorbed by the
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KETAMINE OR S(þ)-KETAMINE IN POST-INCISIONAL PAIN IN DOGS
epidural fat and goes into the systemic circulation. The non-ionized form of ketamine quickly reaches the CSF, and although the maximum concentrations of ketamine in the CSF and in the plasma are reached at almost the same time (18.6 and 26.4 minutes, respectively), levels of ketamine in CSF are twice those in plasma. The high lipid solubility of ketamine permits a slow release from the lipid epidural components both into the CFS and into the systemic circulation. Perhaps for that reason, the half-life of ketamine after epidural injection is greater than that observed after IV administration, and the slow release from the epidural space could be important to maintain the concentration levels either in CFS and plasma.20 Systemic redistribution could have an important role in the analgesic effects after epidural ketamine.20 If we assume that both the spinal action and the supraspinal action are responsible for the anti-hyperalgesic effects and that serum and CSF levels can be affected by the concentration gradient in the plasma, the selective metabolism of S(þ)-ketamine might explain the short diminution of the MNT caused by that drug. Although we used doses that caused local effects without inducing systemic effects like sedation or excitement, it would be necessary to measure the plasma and CFS concentrations of ketamine and S(þ)-ketamine, to confirm this hypothesis. Hartrick et al41 reported that pre-emptive epidural ketamine, independent of duration of effect, reduced but did not exclude secondary mechanical hyperalgesia. Our results go in the same direction. Despite diminishing the manifestations of central sensitization (secondary mechanical hyperalgesia) for 24 hours after administration, epidural ketamine did not abolish it completely and should not be used as a unique technique to treat postoperative pain. We concluded that although anesthetic and analgesic potency of S(þ)-ketamine is twice that of ketamine, when administrated by epidural route ketamine is superior to S(þ)-ketamine for treatment of post-incisional hyperalgesia. REFERENCES 1. Fantoni D, Krumenerl JL, Galego M: Utilizac¸a˜o de analge´sicos em pequenos animais. Clin Vet 28:23–33, 2000 2. Warncke T, Stubhaug A, Jorum E: Ketamine, an NMDA receptor antagonist, suppresses spatial and temporal properties of burn-induced secondary hyperalgesia in man; a double-blind, cross-over comparison with morphine and placebo. Pain 72:99–106, 1997 3. Warncke T, Stubhaug A, Jorum E: Preinjury treatment with morphine or ketamine inhibits the development of experimentally induced secondary hyperalgesia in man. Pain 86:293–303, 2000 4. Stubhaug A, Breivik H, Eide PK, et al: Mapping of punctuate hyperalgesia surronding a surgical incision demonstrates
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