Free
Clinical Science  |   June 1999
The Effect of Naloxone on Ketamine-induced Effects on Hyperalgesia and Ketamine-induced Side Effects in Humans
Author Notes
  • (Mikkelsen, Dahl) Assistant Professor, Laboratory of Pain Physiology, Department of Anesthesiology, Copenhagen University Hospital, Herlev, Copenhagen, Denmark.
  • (Ilkjaer) Research Fellow, Department of Anesthesiology, Skejby Sygehus, Aarhus University Hospital.
  • (Brennum) Assistant Professor, Department of Neurosurgery, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
  • (Borgbjerg) Associate Professor, The Pain Clinic, Department of Anesthesiology, Copenhagen University Hospital, Bispebjerg, Copenhagen, Denmark.
  • Associate Professor, Laboratory of Pain Physiology, Department of Anesthesiology, Copenhagen University Hospital, Herlev, Copenhagen, Denmark.
  • Received from the Department of Anesthesiology, Copenhagen University Hospital, Herlev, Copenhagen, Denmark. Submitted for publication September 8, 1998. Accepted for publication January 19, 1999. Supported by grants from the following foundations: Danish Medical Research Council (Reg. no. 28809), Copenhagen, Denmark; Novo Nordisk Foundation, Bagsvaerd, Denmark; Danis Foundation for the Advancement of Medical Science, Copenhagen, Denmark; and Agnes and Poul Friis' Foundation, Copenhagen, Denmark. Presented in poster form at the 6th European Society of Anaesthesiologists Annual Meeting, Barcelona, Spain, April 25-28, 1998.
  • Address reprint requests to Dr. Mikkelsen: Department of Anesthesiology 4132, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. Address electronic mail to: mikkelsen@dadlnet.dk
Article Information
Clinical Science
Clinical Science   |   June 1999
The Effect of Naloxone on Ketamine-induced Effects on Hyperalgesia and Ketamine-induced Side Effects in Humans
Anesthesiology 6 1999, Vol.90, 1539-1545.. doi:
Anesthesiology 6 1999, Vol.90, 1539-1545.. doi:
Key words: Blockade; NMDA; N-methyl-D-aspartate; opioid.
EXPERIMENTAL studies indicate that the N-methyl-D-aspartate (NMDA) receptor plays a significant role in wind-up and spinal hypersensitivity. [1,2] Ketamine is an NMDA-receptor antagonist, [3] and in experimental settings has proven effective in alleviating secondary hyperalgesia in humans. [4,5] Furthermore, ketamine has been applied successfully in the management of otherwise difficult pain states, [6-8] and ketamine may even eliminate wind-up-like pain. [9] It is clear that the actions of ketamine are brought about by noncompetitive antagonism at the phencyclidine site in the NMDA receptor complex. It has been suggested, however, that parts of the effect of ketamine could be ascribed to an opioid receptor agonism. Interaction of ketamine with opioid receptors in rats has been reported. [10] Also in rats, the analgesic effect of ketamine has been antagonized by injecting naloxone, thus suggesting that at least part of the action of ketamine is achieved by interaction with opioid receptors. [11] Ketamine has been suggested to act partly as a [Greek small letter kappa]-opioid agonist, and the psychotomimetic effects of ketamine in part may be ascribed to [Greek small letter kappa]-receptor binding. [12] Other researchers have found that efficient analgesic effect of ketamine may in part be mediated by the opioid [micro sign]-receptor. [13] Supporting the notion that ketamine at least partly acts by interacting with opioid receptors, Stella et al. [14] were able to counteract ketamine-induced anesthesia by injecting naloxone, 0.006 mg/kg in humans.
Thus, there seems to be evidence for an opioid-mediated effect of ketamine, apart from the well-known NMDA-receptor antagonism. On the other hand, contradictory results have been obtained, as Hao et al. [15] were unable to demonstrate any opioid receptor-mediated effect of ketamine in spinal preparations, and other researchers have also failed to show any effects of ketamine on opioid receptors. [16] 
To investigate a possible opioid receptor-mediated effect of ketamine, an experimental model that has previously shown ketamine to inhibit secondary hyperalgesia in humans was used. [4] Also, this model has been shown to be sensitive to opioid-mediated analgesia, and naloxone has been shown to inhibit this analgesic effect. [17] 
This experimental model uses the fact that cutaneous heat injury in humans evokes allodynia and hyperalgesia for mechanical and thermal stimuli within an injured area (primary hyperalgesia) and allodynia for mechanical, but not thermal, stimuli in an area surrounding the injury (secondary hyperalgesia). [18] There is convincing evidence that primary hyperalgesia is caused by sensitization of peripheral receptors and central neurons, whereas secondary hyperalgesia is a result of altered central processing of afferent activity because of sensitization of dorsal horn neurons. [4,19-23] 
The present study sought to counteract the inhibitory effect of ketamine on secondary hyperalgesia by preceding infusion of naloxone.
Material and Methods
Twenty-five healthy male volunteers were included in the study. None received any medication for at least 48 h before the study periods. Each participant in the study had been familiarized with the experiment protocol and the extent of the burn injury on a separate day. Informed consent was obtained, as was approval by the local ethics committee and the Danish National Board of Health.
Two subjects were excluded during the study, one because of a psychotomimetic reaction during infusion of study drug, and one because of recurring second-degree burn injuries to the test area.
Experimental Procedures
The study was three-way cross-over, double-blind, randomized, and placebo-controlled. According to a computer-generated randomization list, the study drugs were prepared by a certified registered nurse with no other connection to the study. The three treatment regimens were:
1. Injection of naloxone, 0.8 mg/15 min, followed by 0.4 mg/h; 30 min after injection of naloxone, injection of intravenous ketamine 0.3 mg [middle dot] kg-1[middle dot] 15 min-1followed by 0.3 mg [middle dot] kg-1[middle dot] h-1
2. Injection of normal saline solution followed by infusion of normal saline; 30 min after injection of saline, injection of intravenous ketamine 0.3 mg [middle dot] kg-1[middle dot] 15 min-1followed by 0.3 mg [middle dot] kg-1[middle dot] h-1
3. Injection of normal saline solution followed by infusion of normal saline; after 30 min, injection of normal saline followed by infusion of saline
Schedule
At 0 min, heat-pain detection threshold (HPDT) values were obtained, followed by induction of hyperalgesia.
At 60 min, measurements of HPDT values, areas of secondary hyperalgesia, and sedation were made.
At 75 min, initiation of naloxone-placebo-placebo infusion took place.
At 90 min, measurements of HPDT values, areas of secondary hyperalgesia, and sedation were made.
At 105 min, initiation of ketamine-ketamine-placebo infusion took place.
At 135 min, measurements of HPDT values, areas of secondary hyperalgesia, and sedation were made.
Heat-pain Detection Thresholds (Thermal Thresholds)
Heat-pain detection threshold was defined as the lowest temperature perceived as painful. A thermode identical to the thermode used for induction of the burn injury was applied to the skin.
Heat-pain detection thresholds were determined by increasing temperature of the thermode from 35 [degree sign]C with a rate of change of 1 [degree sign]C/s, having instructed the subjects to press a button on a device connected to the thermode indicating that the pertinent temperature had been reached. This temperature was registered, and the thermode automatically returned to baseline. A cut-off temperature limit of 52 [degree sign]C was defined, above which the thermode was to return to baseline and a threshold of 52 [degree sign]C would be registered. In no instances was this cut-off limit reached. Each threshold was calculated as the average of three measurements with randomized intervals (6-10 s) between each stimulation. Thermal thresholds were determined at the site of injury and at the corresponding site of the contralateral, unburned calf.
Induction of Hyperalgesia
A model that has previously proven reliable was used to produce hyperalgesia. A first-degree burn injury was induced in the subjects by heating the medial surface of the right calf (L3-L4 dermatome) with a rectangular thermode measuring 25 x 50 mm (Thermotest, Somedic A/B, Sollentuna, Sweden) strapped to the skin. The borders of the thermode were carefully marked on the skin for subsequent accurate placement of the thermode at the same site. The temperature was 47 [degree sign]C, and heating time was 7 min. One hour after heating the area, primary hyperalgesia in the burned area and a zone of persistent secondary hyperalgesia around the burn injury could be demonstrated, as had previously been shown [24,25] and had recently been reproduced. [26] 
Measurement of Mechanical Hyperalgesia
The temperature of the injured site on the right calf was stabilized at 35 [degree sign]C with the thermode, from 1 min before assessment, and throughout assessment of secondary hyperalgesia. The border area of hyperalgesia was determined by stroking with a brush or by pinpricking the calf along four linear paths arranged radially around the thermal injury. Pinprick was performed with the von Frey technique using a nylon filament with a diameter of 1 mm and a bending force of 1.15 N. Stroke hyperalgesia was induced by gently stroking the calf with a brush made of foam. The stimulation was initiated in an area well outside the area of hyperalgesia and gradually continued toward the area of the burn injury in steps of 5 mm at intervals of 1 s. Immediately after the determinations of hyperalgesia, the thermode was removed.
Assessment of Side Effects
Sedation was assessed on an 11-point numeric scale (0 = completely awake; 10 = almost asleep). Discomfort was assessed on an 11-point numeric scale (0 = no discomfort; 10 = maximal discomfort). Nausea was registered on a four-grade verbal rating scale (none, light, moderate, or severe). Finally, subjects were asked if they experienced hallucinations or any other sensations.
Statistical Analyses
Data are presented as medians (quartiles). Friedman's analysis of variance has been applied. All significant P values have been corrected, using Bonferroni correction for repeated measurements. Statistically significance was considered to be at P < 0.05.
Before entering statistical analyses, data regarding HPDT and areas of secondary hyperalgesia were normalized to achieve the same point of reference in subjects from all of the three study days.
Results
Primary Hyperalgesia
In all three experimental settings, HPDT inside the burned area on the right calf decreased significantly 60 min after inducing a first-degree burn injury and remained decreased throughout the study (P < 0.05).
Heat-pain detection thresholds did not differ in the subjects regardless of infusion of naloxone or placebo (P = 0.96), nor did the combined effects of placebo followed by placebo, placebo followed by ketamine, or naloxone followed by ketamine induce any changes in HPDT (P = 0.07; Table 1). Thermal thresholds in the contralateral unburned calf did not differ from a baseline value, regardless of treatment (Table 1).
Table 1. Heat Pain Detection Threshold ([degree sign]C)
Image not available
Table 1. Heat Pain Detection Threshold ([degree sign]C)
×
Secondary Hyperalgesia
After induction of burn injury, no spontaneous pain or other sensations were experienced from the site of injury. Areas of secondary hyperalgesia toward pinprick or stroking with a brush around the injured area on the right calf were detected easily in all subjects from 60 min after induction of burn injury. Administration of naloxone compared with administration of placebo induced no significant changes in areas of secondary hyperalgesia toward pinprick (P = 0.20) or toward brush (P = 0.48; Figure 1and Figure 2). The ensuing infusion of ketamine, however, was found to reduce the areas of secondary hyperalgesia for both pinprick (P < 0.05) and stroking (P < 0.05) on the calf compared with placebo, regardless of preceding naloxone or placebo infusion (Figure 1and Figure 2). No significant differences in the degree of reduction of secondary hyperalgesia were observed between the two regimens in which ketamine was infused in the area of secondary hyperalgesia using either pinprick (P = 0.53) or stroke stimuli (P = 0.67).
Figure 1. Area of secondary hyperalgesia with pinprick (n = 23). Medians (quartiles) are shown. White bars = naloxone infusion followed by ketamine infusion; hatched bars = placebo infusion followed by ketamine infusion; black bars = placebo infusion followed by placebo infusion; asterisk = significantly larger area of secondary hyperalgesia in the group not receiving ketamine (P < 0.05). There was no significant difference between the two groups receiving ketamine.
Figure 1. Area of secondary hyperalgesia with pinprick (n = 23). Medians (quartiles) are shown. White bars = naloxone infusion followed by ketamine infusion; hatched bars = placebo infusion followed by ketamine infusion; black bars = placebo infusion followed by placebo infusion; asterisk = significantly larger area of secondary hyperalgesia in the group not receiving ketamine (P < 0.05). There was no significant difference between the two groups receiving ketamine.
Figure 1. Area of secondary hyperalgesia with pinprick (n = 23). Medians (quartiles) are shown. White bars = naloxone infusion followed by ketamine infusion; hatched bars = placebo infusion followed by ketamine infusion; black bars = placebo infusion followed by placebo infusion; asterisk = significantly larger area of secondary hyperalgesia in the group not receiving ketamine (P < 0.05). There was no significant difference between the two groups receiving ketamine.
×
Figure 2. Area of secondary hyperalgesia with stroking stimuli (n = 23). Medians (quartiles) are shown. White bars = naloxone infusion followed by ketamine infusion; hatched bars = placebo infusion followed by ketamine infusion; black bars = placebo infusion followed by placebo infusion; asterisk = significantly larger area of secondary hyperalgesia in the group not receiving ketamine (P < 0.05). There was no significant difference between the two groups receiving ketamine.
Figure 2. Area of secondary hyperalgesia with stroking stimuli (n = 23). Medians (quartiles) are shown. White bars = naloxone infusion followed by ketamine infusion; hatched bars = placebo infusion followed by ketamine infusion; black bars = placebo infusion followed by placebo infusion; asterisk = significantly larger area of secondary hyperalgesia in the group not receiving ketamine (P < 0.05). There was no significant difference between the two groups receiving ketamine.
Figure 2. Area of secondary hyperalgesia with stroking stimuli (n = 23). Medians (quartiles) are shown. White bars = naloxone infusion followed by ketamine infusion; hatched bars = placebo infusion followed by ketamine infusion; black bars = placebo infusion followed by placebo infusion; asterisk = significantly larger area of secondary hyperalgesia in the group not receiving ketamine (P < 0.05). There was no significant difference between the two groups receiving ketamine.
×
Side Effects
No sedation was noted when infusing naloxone or placebo. However, when the subsequent infusion of ketamine was initiated, median sedation scores of 4 (quartiles, 2-6) for naloxone-ketamine infusion and 5 (quartiles, 3-6) for placebo-ketamine infusion were achieved. These scores did not differ (P = 0.82). The scores, however, proved significantly different from the infusion of placebo-placebo, for which the median sedation score was 0 (quartiles, 0; P < 0.05).
In six instances, reports of changed perceptions of body parts were encountered during infusion of ketamine regardless of concomitant infusion of naloxone. No nausea was reported. No other forms of discomfort were noted, and no definite hallucinations were reported.
Discussion
The objective of this study was to investigate to what extent opioid receptor blockade by naloxone could inhibit a well-known clinical response to intravenous injection of ketamine. A prerequisite for the present study was the reproduction of results obtained by Ilkjaer et al., [4] showing that infusion of ketamine, 0.3 mg [middle dot] kg-1[middle dot] h-1, can decrease the secondary hyperalgesia occurring after a first-degree burn injury in humans. These findings have been reproduced.
In the present study, no opioid-mediated effect of ketamine was demonstrated, as the clinical effect of ketamine remained unchanged regardless of concomitant infusion of naloxone. This finding is in line with those of Maurset et al. [27] - that naloxone, 1.6 mg, prevented the analgesic effect of meperidine but had no effect on ketamine analgesia. Our findings, however, contradict animal studies, indicating that there is an effect of ketamine on the opioid receptor. [10,28] 
Regarding the size of our study population, the power of the study is 80%, given that the smallest reduction of the area of secondary hyperalgesia not to be overlooked would amount to 21%.
It could be argued that the dose of naloxone chosen was too small. A larger dose might have been required to antagonize any opioid-mediated effect of ketamine. In a study by Brennum et al., [17] which investigated the effect of opioids on the secondary hyperalgesia after a first-degree burn injury, the inhibitory effect of 4 mg epidurally injected morphine on this secondary hyperalgesia was antagonized by intravenous injection of naloxone, 0.1 mg/kg. However, Smith et al. [28] have demonstrated that the in vitro affinity of ketamine to opioid receptors is considerably weaker than other drugs showing primarily opioid receptor antagonism, and as such it should be possible to antagonize effects on the opioid receptor with a relatively smaller dose than that necessary to revert opioid receptor agonism in a normal clinical setting. It should be noted that the cumulative dose of naloxone given in the present study is the same as that used to reverse heroin-induced coma in drug addicts, [29] and as such any clinically significant effect of ketamine on the opioid receptors should be antagonized using this dose. Doses similar to or even smaller than those used in the present study have been effective in managing opioid-induced side effects. A dose of 0.8 mg (0.4 mg intravenously and 0.4 mg subcutaneously) has been shown to improve respiratory parameters after high-dose alfentanil anesthesia, [30] and considerably smaller doses of naloxone have been shown to antagonize pruritus after epidural morphine. [31] 
Apart from studying the effects of naloxone on the well-known effects of ketamine on secondary hyperalgesia, we have investigated the effects of naloxone on ketamine-induced sedation. No difference in sedation scores was found after ketamine infusion, regardless of concomitant naloxone infusion. This finding does not support findings by Stella et al., [14] who reported inhibition of the loss of consciousness after injection of ketamine, 0.4 mg/kg, by injection of naloxone, 0.006 mg/kg. Our findings rather support the findings of Hao et al., [15] who found that ketamine does not possess any opioid agonistic effect but acts by antagonizing excitatory amino acids. Based on our findings in this experimental setting, the beneficial effects of a combination of opioids and ketamine in controlling acute (postoperative) pain, as observed by Bristow and Orlikowski, [32] Javery et al., [33] and Wong et al., [34] may be explained by the different receptors involved and the possibility of acquiring an additive [35] or even a synergistic effect [36] by combining opioids and NMDA-receptor antagonists. This topic, however, is not fully elucidated yet, as Edwards et al. [37] failed to demonstrate any improvement in analgesia by adding ketamine to an infusion of morphine, and Ilkjaer et al. [38] were unable to improve postoperative pain control by adding ketamine to a combination of epidural local anesthetics and patient-controlled morphine injections.
Conclusion
Infusion of ketamine can decrease secondary hyperalgesia occurring after a first-degree burn injury in humans. In the present study, this effect was not significantly abolished by the concomitant administration of naloxone, although it is possible that some effect of naloxone might have been overlooked because of a type II error.
Sedation observed after administration of ketamine is not affected by naloxone. In this experimental setting, the effect of ketamine on secondary hyperalgesia was not affected by blocking opioid receptors with naloxone.
REFERENCES
Dickenson AH, Sullivan AF: Evidence for a role of the NMDA receptor in the frequency dependent potentiation of deep rat dorsal horn nociceptive neurones following C-fibre stimulation. Neuropharmacology 1987; 26:1235-8
Davies SN, Lodge D: Evidence for involvement of N-methyl-D-aspartate receptors in wind-up of class 2 neurones in the dorsal horn of the rat. Brain Res 1987; 424:402-6
Martin D, Lodge D: Ketamine acts as a non competitive N-methyl-D-aspartate antagonist on frog spinal cord in vitro. Neuropharmacology 1985; 24(10):999-1003
Ilkjaer S, Petersen KL, Brennum J, Wernberg M, Dahl JB: Effect of systemic N-methyl-D-aspartate receptor antagonist (ketamine) on primary and secondary hyperalgesia in humans. Br J Anaesth 1996; 76:829-34
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 1997; 72:99-106
Nikolajsen L, Hansen CL, Nielsen J, Keller J, Arendt-Nielsen L, Jensen TS: The effect of ketamine on phantom pain: A central neuropathic disorder maintained by peripheral input. Pain 1996; 67:69-77
Franks JF, Olesen AS, Mikkelsen SS, Borgbjerg FM: Ketamine in the management of intractable phantom pain [in Danish]. Ugeskr Laeger 1995; 157:3481-2
Nikolajsen L, Hansen PO, Jensen TS: Oral ketamine therapy in the treatment of postamputation stump pain. Acta Anaesthesiol Scand 1997; 41:427-9
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 Anaesthesiol Scand 1997; 41:1124-32
Finck AD, Samaniego E, Ngai SH: Morphine tolerance decreases the analgesic effects of ketamine in mice. Anesthesiology 1988; 68:397-400
Smith DJ, Pekoe GM, Martin LL, Coalgate B: The interaction of ketamine with the opiate receptor. Life Sciences 1980; 26:789-95
Hustveit O, Maurset A, Oye I: Interaction of the chiral forms of ketamine with opioid, phencyclidine, sigma and muscarinic receptors. Pharmacol Toxicol 1995; 77:355-9
Freye E, Latasch L, Schmidhammer H, Portoghese P: Interaction of S-(+)-ketamine with opiate receptors [in German]. Anaesthetist 1994; 43(suppl 2):S52-8
Stella L, Crescenti A, Torri G: Effect of naloxone on the loss of consciousness induced by i.v. anaesthetic agents in man. Br J Anaesth 1984; 56:369-73
Hao J-X, Sjolund BH, Wiesenfeld-Hallin Z: Electrophysiological evidence for an antinociceptive effect of ketamine in the rat spinal cord. Acta Anaesthesiol Scand 1998; 42:435-41
Fratta W, Casu M, Balestrieri A, Loviselli A, Biggio G, Gessa GL: Failure of ketamine to interact with opiate receptors. Eur J Pharmacol 1980; 61:389-91
Brennum J, Dahl JB, Moiniche S, Arendt-Nielsen L: Quantitative sensory examination of epidural anaesthesia and analgesia in man: Effects of pre- and posttraumatic morphine on hyperalgesia. Pain 1994; 59:261-71
Treede RD, Meyer RA, Raja SN, Campbell JN: Peripheral and central mechanisms of cutaneous hyperalgesia. Prog Neurobiol 1992; 38:397-421
Baumann TK, Simone DA, Shain CN, LaMotte RH: Neurogenic hyperalgesia: The search for the primary cutaneous afferent fibers that contribute to capsaicin-induced pain and hyperalgesia. J Neurophysiol 1991; 66:212-27
LaMotte RH, Shain CN, Simone DA, Tsai EF: Neurogenic hyperalgesia: Psychophysical studies of underlying mechanisms. J Neurophysiol 1991; 66:190-211
LaMotte RH, Lundberg LE, Torebjork HE: Pain, hyperalgesia and activity in nociceptive C units in humans after intradermal injection of capsaicin. J Physiol (Lond) 1992; 448:749-64
Simone DA, Sorkin LS, Oh O, Chung JM, Owens C, LaMotte RH, Willis WD: Neurogenic hyperalgesia: Central neural correlates in responses of spinothalamic tract neurons. J Neurophysiol 1991; 66:228-46
Torebjork HE, Lundberg LE, LaMotte RH: Central changes in processing of mechanoreceptive input in capsaicin-induced secondary hyperalgesia in humans. J Physiol (Lond) 1992; 448:765-80
Dahl JB, Brennum J, Arendt-Nielsen L, Jensen TS, Kehlet H: The effect of pre- versus postinjury infiltration with lidocaine on thermal and mechanical hyperalgesia after heat injury to the skin. Pain 1993; 53:43-51
Moiniche S, Dahl JB, Kehlet H: Time course of primary and secondary hyperalgesia after heat injury to the skin. Br J Anaesth 1993; 71:201-5
Pedersen JL, Kehlet H: Hyperalgesia in a human model of acute inflammatory pain: A methodological study. Pain 1998; 74:139-51
Maurset A, Skoglund LA, Hustveit O, Oye I: Comparison of ketamine and pethidine in experimental and postoperative pain. Pain 1989; 36:37-41
Smith DJ, Bouchal RL, deSanctis CA, Monroe PJ, Amedro JB, Perrotti JM, Crisp T: Properties of the interactions between ketamine and opiate binding sites in vivo and in vitro. Neuropharmacology 1987; 26:1253-60
Pedersen CB, Stentoft A, Worm K, Sprehn M, Mogensen T, Sorensen MB: Prehospital treatment of patients with iv heroin overdose: What are we treating. Prehospital Disaster Med 1997; 12:163-6
Valgardsson A, Werner O, Svensson G: Antagonism of fentanyl and alfentanil by intravenous plus subcutaneous naloxone: Pattern of ventilatory depression after a short procedure. Anaesthesia 1985; 40:772-6
Kendrick WD, Woods AM, Daly MY, Birch RF, DiFazio C: Naloxone versus nalbuphine infusion for prophylaxis of epidural morphine-induced pruritus. Anesth Analg 1996; 82:641-7
Bristow A, Orlikowski C: Subcutaneous ketamine analgesia: Postoperative analgesia using subcutaneous infusions of ketamine and morphine. Ann R Coll Surg Engl 1989; 71:64-6
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
Wong C-S, Liaw W-J, Tung C-S, Su Y-F, Ho ST: Ketamine potentiates analgesic effect of morphine in postoperative epidural pain control. Reg Anesth 1996; 21:534-41
Sethna NF, Liu M, Gracely R, Bennett GJ, Max MB: Analgesic and cognitive effects of intravenous ketamine-alfentanil combinations versus either drug alone after intradermal capsaicin in normal subjects. Anesth Analg 1998; 86:1250-6
Plesan A, Hedman U, Xu X-J, Wiesenfeld-Hallin Z: Comparison of ketamine and dextromethorphan in potentiating the antinociceptive effect of morphine in rats. Anesth Analg 1998; 86:825-9
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
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
Figure 1. Area of secondary hyperalgesia with pinprick (n = 23). Medians (quartiles) are shown. White bars = naloxone infusion followed by ketamine infusion; hatched bars = placebo infusion followed by ketamine infusion; black bars = placebo infusion followed by placebo infusion; asterisk = significantly larger area of secondary hyperalgesia in the group not receiving ketamine (P < 0.05). There was no significant difference between the two groups receiving ketamine.
Figure 1. Area of secondary hyperalgesia with pinprick (n = 23). Medians (quartiles) are shown. White bars = naloxone infusion followed by ketamine infusion; hatched bars = placebo infusion followed by ketamine infusion; black bars = placebo infusion followed by placebo infusion; asterisk = significantly larger area of secondary hyperalgesia in the group not receiving ketamine (P < 0.05). There was no significant difference between the two groups receiving ketamine.
Figure 1. Area of secondary hyperalgesia with pinprick (n = 23). Medians (quartiles) are shown. White bars = naloxone infusion followed by ketamine infusion; hatched bars = placebo infusion followed by ketamine infusion; black bars = placebo infusion followed by placebo infusion; asterisk = significantly larger area of secondary hyperalgesia in the group not receiving ketamine (P < 0.05). There was no significant difference between the two groups receiving ketamine.
×
Figure 2. Area of secondary hyperalgesia with stroking stimuli (n = 23). Medians (quartiles) are shown. White bars = naloxone infusion followed by ketamine infusion; hatched bars = placebo infusion followed by ketamine infusion; black bars = placebo infusion followed by placebo infusion; asterisk = significantly larger area of secondary hyperalgesia in the group not receiving ketamine (P < 0.05). There was no significant difference between the two groups receiving ketamine.
Figure 2. Area of secondary hyperalgesia with stroking stimuli (n = 23). Medians (quartiles) are shown. White bars = naloxone infusion followed by ketamine infusion; hatched bars = placebo infusion followed by ketamine infusion; black bars = placebo infusion followed by placebo infusion; asterisk = significantly larger area of secondary hyperalgesia in the group not receiving ketamine (P < 0.05). There was no significant difference between the two groups receiving ketamine.
Figure 2. Area of secondary hyperalgesia with stroking stimuli (n = 23). Medians (quartiles) are shown. White bars = naloxone infusion followed by ketamine infusion; hatched bars = placebo infusion followed by ketamine infusion; black bars = placebo infusion followed by placebo infusion; asterisk = significantly larger area of secondary hyperalgesia in the group not receiving ketamine (P < 0.05). There was no significant difference between the two groups receiving ketamine.
×
Table 1. Heat Pain Detection Threshold ([degree sign]C)
Image not available
Table 1. Heat Pain Detection Threshold ([degree sign]C)
×