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Effect of oral ketamine on secondary hyperalgesia, thermal and mechanical pain thresholds, and sedation in humans
Original Articles
Effect of Oral Ketamine on Secondary Hyperalgesia, Thermal and Mechanical Pain Thresholds, and Sedation in Humans Søren Mikkelsen, M.D., Henrik Jørgensen, M.D., Pia S. Larsen, Jannick Brennum, M.D., Ph.D., and Jørgen B. Dahl, M.D., D.MSc. Background and Objectives: Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist, and has been proven effective in alleviating secondary hyperalgesia in human subjects when injected intravenously. After oral ingestion, ketamine is metabolized into norketamine, which in vitro possesses NMDA receptor antagonistic effect. The aim of this study was to investigate the effects of oral administration of ketamine on secondary hyperalgesia evoked by standardized tissue injury. Methods: Twenty-four male volunteers were included in the study. Each volunteer received the following treatment regimen, in randomized, double-blind, 3-way cross-over fashion: (A) placebo; (B) ketamine, 0.5 mg/ kg; and (C) ketamine, 1.0 mg/kg. Standardized tissue injury was induced after study medication by heating the right calf with a rectangular thermode. The temperature was 47°C, and heating time was 7 minutes. The following parameters were investigated: Pain during induction of the burn injury; heat-pain detection thresholds in the injured area and a corresponding noninjured area; secondary hyperalgesia surrounding the injured area on the calf; secondary hyperalgesia induced by heating an area on the thigh with 45°C in 3 minutes; pressure-pain detection thresholds measured on the middle phalanx of the 4th left finger; pain during a 60-second thermal stimulation of 46°C on undamaged skin on the left thigh; and side effects. Results: Some degree of sedation was observed after oral administration of ketamine. No effects on any of the other investigated parameters were observed. Conclusion: Oral ketamine 0.5 or 1.0 mg/kg has no effect on secondary hyperalgesia or thermal or mechanical pain thresholds in human volunteers. Reg Anesth Pain Med 2000;25:452-458. Key Words: Oral ketamine, Hyperalgesia.
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eripheral tissue injury may lead to hyperexcitability of wide dynamic range (WDR) neurons
See Editorial page 441
From the Laboratory of Pain Physiology, Department of Anesthesiology, Copenhagen University Hospital (S.M., H.J. P.S.L., J.B.D.), Herlev, Copenhagen; and the Department of Neurosurgery, Copenhagen University Hospital (J.B.), Rigshospitalet, Copenhagen. Accepted for publication March 29, 2000. Supported by grants from the following foundations: Danish Medical Research Council, Copenhagen, Denmark (Reg. no. 28809); Novo Nordisk Foundation, Bagsvaerd, Denmark; Danish Foundation for the Advancement of Medical Science, Copenhagen, Denmark; and Agnes and Poul Friis’ Foundation, Copenhagen, Denmark. No conflicts of interest exist between any of the authors and the foundations supporting this study. Reprint requests: Søren Mikkelsen, M.D., Department of Anesthesiology 4132, Copenhagen University Hospital, Rigshospitalet, DK2100 Copenhagen, Denmark. E-mail: [email protected] r 2000 by the American Society of Regional Anesthesia and Pain Medicine. 1098-7339/00/2505-0004$5.00/0 doi:10.1053/rapm.2000.8456
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in the dorsal horn of the spinal cord. Prolonged C-afferent activity evokes wind-up, a state that results in increased receptive fields and exaggerated responses of the WDR neurons to afferent input.1 Wind-up can augment responses of dorsal horn neurons up to 20-fold in magnitude and duration, and this state of hyperexcitability may even continue after cessation of the peripheral input.2 Central sensitization induces altered processing of afferent activity evoked by both innocuous and noxious stimuli. Clinically this is manifested as allodynia and hyperalgesia.3 Injury-induced sensitization of dorsal horn neurons has been implicated in both acute and chronic pain states.4 In humans, cutaneous heat injury evokes allodynia and hyperalgesia for mechanical and thermal stimuli within the injured area (primary hyperalgesia) and allodynia for mechanical, but not thermal, stimuli in an area surrounding the injury (secondary hyperalgesia).5 There is convincing evidence that primary hyperalgesia is caused by a combination of sensitization of
Regional Anesthesia and Pain Medicine, Vol 25, No 5 (September–October), 2000: pp 452–458
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peripheral receptors and central neurons, whereas secondary hyperalgesia is a result of altered central processing of afferent activity caused by sensitization of dorsal horn neurons.6-11 Experimental studies indicate that the N-methylD-aspartate (NMDA) receptor plays a significant role in wind-up and spinal hypersensitivity.12,13 Ketamine is an NMDA receptor antagonist14 which, in experimental and clinical settings, has proven effective in alleviating secondary hyperalgesia in humans.7,15,16 After intravenous (IV) administration of ketamine, a significant degree of side effects, predominantly expressed as sedation and psychomimetic effects, is reported.7,16 The frequency of psychomimetic effects of ketamine seems to be dose related,17 and Grant et al.18 have suggested that administration of ketamine in subanesthetic doses might eliminate these side effects. Ketamine reduces wind-up–like pain in amputees with established stump and phantom limb pain.19,20 Furthermore, ketamine has been applied successfully in the treatment of otherwise difficult pain states.21,22 Although undergoing extensive first-pass metabolism, with bioavailability of only 17%,18 oral ketamine has been shown to alleviate experimentally induced ischemic pain18 and, in case reports, has been reported to be useful in several chronic pain states.21,23,24 The possible explanation for the apparent analgesic effect of oral ketamine despite the extensive first-pass metabolism may be that the metabolite of ketamine, norketamine, acts as an antagonist at the NMDA receptor complex.25 The aim of the present study was to investigate the effects of oral administration of ketamine on secondary hyperalgesia after a first-degree burn injury, on thermal and mechanical pain thresholds, and on side effects in human volunteers.
Materials and Methods Twenty-five healthy male volunteers were included in the study. None received any medication for at least 48 hours before the study periods. All subjects were to refrain from eating, drinking, or smoking from the night before the study. Each participant in the study had been familiarized with the experiment protocol and the extent of the burn injury on a separate day. The 3 study days were each separated by at least 1 week. Informed consent was obtained, as was approval by the local Ethics Committee and the Danish National Board of Health. One subject was excluded during the study because of erroneous administration of study drug on one of the study days.
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Experimental Procedures The study design was 3-way cross-over, doubleblind, 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 3 treatment regimens were as follows: (A) oral administration of 50 mL of apple juice (placebo); (B) oral administration of ketamine, 0.5 mg/kg mixed with 50 mL of apple juice; (C) oral administration of ketamine, 1.0 mg/kg mixed with 50 mL of apple juice. No spontaneous reports on whether the taste of the solutions differed on any of the 3 study days appeared. Induction of Hyperalgesia. A model, which has previously proven reliable, was applied 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 mm ⫻ 50 mm (Thermotest; Somedic A/B, Stockholm, 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°C, and heating time was 7 minutes.26-29 An electronic visual analogue scale (VAS) was used by the subject in rating pain during induction of hyperalgesia. Ratings were performed continuously by moving a lever that controlled a vertical bar on a computer screen (sample rate, 2 Hz). The VAS was anchored with the descriptors ‘‘no pain’’ (numerical value: 0) and ‘‘worst possible pain’’ (numerical value: 100). The interpretation of ‘‘pain’’ was left to the subject, who was instructed to apply the same interpretation throughout the study. Measurement of Mechanical Hyperalgesia on the Right Calf. The temperature of the injured site on the right calf was stabilized at 35°C with the thermode, from 1 minute before and throughout assessment of secondary hyperalgesia. The border area of hyperalgesia was determined by striking with a brush or by pinpricking the calf along 4 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. Testing for stroke hyperalgesia was performed by gently striking 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 second, until the subject reported a definite change in sensation (‘‘burning,’’ ‘‘tender-
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ness,’’ ‘‘more intense pricking’’). These 4 points were traced onto a clear acetate sheet for calculation of the area, using a vector algorithm. Measurement of Mechanical Hyperalgesia on the Thigh. On the thigh, similar measurements were obtained during induction of brief reversible secondary hyperalgesia. The hyperalgesia was induced by heating the area at 45°C with the thermode, from 3 minutes before, and throughout assessment of secondary hyperalgesia. Because this parameter was obtained before administration of study drug on all 3 study days, results have been normalized relative to the initial value obtained at each study session before entering statistical analyses. This was done to achieve the same point of reference in the subjects on all 3 study days. Measurement of Thermal Thresholds (HPDT). Thermal thresholds were determined at the site of injury on the right calf, and at the corresponding site of the contralateral, uninjured calf. Heat-pain detection thresholds (HPDT) were 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. HPDT were determined by increasing the temperature of the thermode from 35°C with a rate of change of 1°C per second, having instructed the subjects to press a button on a device connected to the thermode, indicating when the pertinent temperature had been reached. The temperature was electronically registered, and the thermode was automatically returned to baseline. A cut-off limit of 52°C was defined, above which the thermode was to return to baseline and a threshold of 52°C would be registered. In no instance was this cut-off limit reached. Each threshold was calculated as the average of 3 measurements, with randomized intervals (6 to 10 seconds) between each stimulation. Measurement of Pressure-Pain Detection Thresholds (PPDT). PPDT were measured on the middle phalanx of the 4th left finger. PPDT were determined with a handheld electronic algometer (Somedic A/B) and defined as the minimal pressure (force) that induced pain. The stimulation probe has a circular tip of 11 mm (0.95 cm2), and is connected to a pressure transducer built into a gun-shaped handle. The signal from the pressure transducer is amplified in a main unit, and the applied pressure is shown in kilopascals (kPa) on a digital display. A display consisting of horizontal light bars indicates whether the applied pressure is higher or lower than a preset rate (20 kPa/s). When the PPDT is reached, the subject activates a push button, which freezes the digital display.30
Measurement of Pain During 60-Second Thermal Stimulation. Pain ratings were performed continuously with an electronic VAS during a 60-second thermal stimulation of 46°C on undamaged skin on the left thigh. Assessment of Side Effects. Sedation was assessed on an 11-point numerical scale (0 ⫽ completely awake; 10 ⫽ almost asleep). Discomfort was assessed on an 11-point numerical scale (0 ⫽ no discomfort; 10 ⫽ maximal discomfort). Nausea was registered as a 4-grade verbal rating scale (none, light, moderate, or severe). Finally, subjects were asked if they experienced hallucinations or any other sensations. Schedule. Measurements were obtained and study drug was administered according to the following schedule: ⫺20 minutes: measurement of hyperalgesia on thigh, HPDT, PPDT, pain during 60second thermal stimulation, side effects; 0 minutes: administration of study drug; 20 minutes: induction of hyperalgesia on the right calf; 40, 100, 160, 220, 280 minutes: measurement of hyperalgesia on calf and thigh, HPDT, PPDT, pain during 60-second thermal stimulation, side effects. Statistical Analyses Data are presented as median (quartiles). Friedman’s 1-way nonparametric analysis of variance has been applied. Any significant P values have been corrected using Bonferroni’s correction for repeated measurements. P ⬍ .05 was considered statistically significant. Because the baseline data regarding PPDT, pain during 60-second thermal stimulation, and areas of secondary hyperalgesia on the thigh all were obtained before administration of study drugs, all data pertaining to these tests were normalized in relation to the values obtained before administration of study drugs to achieve the same point of reference in the subjects in all 3 study days.
Results Pain Scores During Induction of Hyperalgesia on the Calf No difference was observed during induction of hyperalgesia, regardless of treatment regimen (P ⫽ .81) (Table 1). Primary Hyperalgesia In all 3 experimental settings, HPDT inside the burned area on the right calf decreased significantly 60 minutes after inducing a first-degree burn injury,
Oral Ketamine and Hyperalgesia Table 1. VAS Ratings During Induction of Hyperalgesia (7 minutes, 47°C)
Induction of hyperalgesia
Placebo
Ketamine 0.5 mg/kg
Ketamine 1.0 mg/kg
24 (16-36)
25 (21-34)
26 (15-34)
NOTE. Median (quartiles) shown. No significant difference between the groups.
and remained decreased throughout the study (P ⬍ .05). HPDT did not differ in the subjects during administration of placebo, small dose of ketamine, or large dose of ketamine (P ⫽ .34, Friedman’s test). Thermal thresholds in the contralateral unburned calf did not change from a baseline value, and did not differ during administration of placebo or ketamine (P ⫽ .21, Friedman’s test) (Table 2). Secondary Hyperalgesia
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subjects. No significant difference was observed between the different treatments (P ⫽ .99, Friedman’s test). Twenty of the 24 subjects described brush hyperalgesia on the thigh. No difference was observed between treatments (P ⫽ .81) (Figs 1 and 2). Pain During 60-Second Thermal Stimulation, and Pressure-Pain Thresholds Pain was registrered as mean values of samplings obtained during the whole period (30 sampling points). No differences were observed regardless of treatment (P ⫽ .26 and P ⫽ .97, respectively) (Tables 3 and 4). Side Effects Administration of ketamine caused significantly higher sedation scores than administration of placebo (P ⫽ .02). No difference was observed between the 2 treatment regimens that included ketamine.
After induction of the burn injury, no spontaneous pain or other sensations were experienced from the site of injury. Areas of pinprick hyperalgesia surrounding the injured area on the right calf were detected easily in all subjects from 60 minutes after induction of the burn injury. No difference was observed in areas of pinprick hyperalgesia on the right calf when comparing the effects of placebo, oral ketamine 0.5 mg/kg, or oral ketamine 1.0 mg/kg (P ⫽ .45, Friedman’s test). Brush hyperalgesia surrounding the burn injury was detected in 19 subjects. No difference was observed here, regardless of treatment (P ⫽ .71, Friedman’s test). Brief reversible pinprick hyperalgesia surrounding the thermode on the thigh was detected in all Table 2. HPDT (°C), Right Calf, Injured and Uninjured Skin
Unburned calf Baseline 40 min 100 min 160 min 220 min 280 min Burned calf Baseline 40 min 100 min 160 min 220 min 280 min
Placebo
Ketamine 0.5 mg/kg
Ketamine 1.0 mg/kg
47.8 (45.9-48.7) 47.6 (46.5-48.6) 47.0 (46.5-47.8) 47.8 (46.3-48.5) 47.4 (46.7-48.5) 47.0 (45.8-47.8)
48.3 (46.2-49.0) 47.1 (45.5-47.9) 47.1 (45.7-48.3) 47.1 (45.3-48.3) 47.1 (45.6-48.3) 47.1 (45.5-48.3)
47.3 (45.9-48.6) 47.4 (46.2-48.9) 47.1 (46.1-48.5) 47.4 (46.8-48.4) 46.9 (46.1-48.8) 47.4 (46.6-48.6)
47.3 (46.0-48.4) 46.1 (44.2-47.6) 46.5 (44.0-47.3) 46.3 (44.9-47.4) 46.9 (45.5-47.8) 47.1 (46.2-47.7)
47.2 (46.4-48.3) 44.9 (41.8-46.9) 45.5 (41.6-47.2) 44.5 (42.0-46.6) 45.9 (43.3-47.9) 45.8 (43.1-47.4)
47.4 (45.6-48.7) 46.5 (44.2-48.0) 46.8 (43.6-47.8) 46.2 (44.9-48.2) 46.8 (44.4-47.7) 47.1 (45.6-47.7)
NOTE. Median (quartiles) shown. No significant difference between the groups.
Fig 1. Area of secondary hyperalgesia on the calf. Values obtained after induction of a first-degree burn injury by heating the calf for 7 minutes at 47°C. X-axis: time after induction of hyperalgesia. Y-axis: area of the zone of secondary hyperalgesia. Pinprick stimuli. n ⫽ 24. Median (quartiles) shown. (䊐), Placebo; (N), ketamine 0.5 mg/kg orally; (䊏), ketamine 1.0 mg/kg orally. There was no significant difference between the groups.
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Regional Anesthesia and Pain Medicine Vol. 25 No. 5 September–October 2000 Table 4. PPDT on the Middle Phalanx of the 4th Left Finger (percentage of initial value)
Baseline 40 min 100 min 160 min 220 min 280 min
Placebo
Ketamine 0.5 mg/kg
Ketamine 1.0 mg/kg
100 90 (82-101) 94 (83-105) 94 (85-105) 95 (73-107) 92 (77-107)
100 90 (79-100) 91 (78-105) 87 (67-104) 86 (61-110) 88 (76-106)
100 90 (76-114) 91 (72-112) 91 (74-108) 80 (70-106) 89 (69-101)
NOTE. Median (quartiles) shown. No significant difference between the groups.
scores were 0, regardless of treatment. No discomfort or nausea was noted. No hallucinations were reported.
Discussion
Fig 2. Area of secondary hyperalgesia on the thigh. Hyperalgesia was induced by heating the area at 45°C with the thermode, from 3 minutes before and throughout assessment of secondary hyperalgesia. X-axis: time after induction of hyperalgesia. Y-axis: area of the zone of secondary hyperalgesia related to baseline. Pinprick stimuli. n ⫽ 24. Values normalized in relation to first measurement on each study day. Median (quartiles) shown. (䊐), Placebo; (N), ketamine 0.5 mg/kg orally; (䊏), ketamine 1.0 mg/kg orally. There was no significant difference between the groups.
Median sedation scores of 2 were achieved 40 minutes after administration of both 0.5 mg/kg of ketamine and 1.0 mg/kg of ketamine. After 100 minutes, sedation scores were reduced to 1 and 0.5, respectively. This difference was not statistically significant. At 160 minutes and onward, all sedation Table 3. VAS Ratings During 60-Second Thermal Stimulation on the Thigh (46°C)
Baseline 40 min 100 min 160 min 220 min 280 min
Placebo
Ketamine 0.5 mg/kg
Ketamine 1.0 mg/kg
17.5 (7.5-29) 17.5 (8.5-25) 12.0 (10-29.5) 15.0 (11.5-24) 17.5 (11-26) 17.0 (12.5-28)
15.0 (6-20) 17.5 (12-30) 16.0 (7.5-24.5) 16.5 (8.5-24) 15.0 (9-23.5) 13.0 (7.5-21)
19.5 (7.5-31) 11.5 (9-20) 14.5 (7.5-22) 13.0 (9-22.5) 12.0 (7-17.5) 8.5 (3-21)
NOTE. Median (quartiles) shown. No significant difference between the groups.
After oral administration, ketamine undergoes extensive first-pass metabolism, being converted into norketamine. The affinity of the metabolites of racemic ketamine, S-norketamine and R-norketamine, to the NMDA receptor is less than that of racemic ketamine itself.25 Norketamine was shown to reach higher concentrations after oral ingestion of ketamine than after intramuscular administration of ketamine, with a peak norketamine concentration occurring at 60 minutes.18 Because both ketamine and dextromethorphan, another NMDA receptor antagonist, previously have been shown to reduce secondary hyperalgesia after a first-degree burn injury, it is highly probable that the effects shown are related to the blocking of the NMDA receptor complex.7,16,31 It was speculated, that the lower affinity of norketamine to the NMDA receptor complex than that of ketamine, and the slower increase in plasma concentration of active drug after oral ingestion, could lead to a reduction in the degree of sedating properties, yet retain the analgesic effect. Doses of 0.5 mg/kg and 1.0 mg/kg were chosen on the basis of several case reports describing the effect of oral ketamine on pain states of longer duration. We wanted to investigate a dose of ketamine that would be unlikely to induce psychomimetic side effects, yet be effective in reducing secondary hyperalgesia. In case reports, ketamine in doses ranging from 50 mg ⫻ 3 to 200 mg ⫻ 5 has been reported effective in treating longer-lasting pain states.21,22,24,32-34 In a controlled study, Lauretti et al.35 evaluated the effect of oral ketamine as adjunct to oral morphine in cancer pain, and found that the addition of ketamine, 0.5 mg/kg twice daily, reduced the daily consumption of morphine. On the other hand, the effects of oral ketamine are not
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unequivocal, because Enarson et al.36 reported that 1 year after initiation of oral ketamine, only 3 of 21 patients reported improvements in pain control, decreased use of analgesics, and continued to use oral ketamine. It is speculated that the affinity of S-norketamine to the NMDA receptor complex, approximately one fifth the affinity of S-ketamine to the NMDA receptor complex, can explain the analgesic effects reported after oral administation of ketamine.25 In the present study, no antihyperalgesic or analgesic effect of a single dose of 0.5 and 1.0 mg/kg oral ketamine could be shown. Also, primary hyperalgesia (HPDT) was unaffected by oral ketamine. Antihyperalgetic and analgetic effects of ketamine after IV administration are well documented. Ilkjaer et al.7 reported that IV infusion of ketamine 0.3 mg/kg reduced pain during induction of hyperalgesia as well as primary hyperalgesia, and Arendt-Nielsen et al.37 reported increased HPDT after injection of ketamine. IV injection of ketamine has been shown to reduce the area of secondary hyperalgesia.7,16,20 In the present study, oral ketamine did not affect secondary hyperalgesia. Pain during a 60-second, 46°C thermal stimulation was unaffected by administration of oral ketamine. However, pain intensity during stimulation was low both during administration of placebo and active drug, and as such, any difference would be difficult to demonstrate. No exact corresponding test is described in the literature. Arendt-Nielsen et al.38 described the lack of effect of ketamine on high-intensity laser pulses as well as brief electrical pulses. Investigating the effects of ketamine on heat stimulation of short duration (2 seconds), ArendtNielsen et al.37 found reduction of pain intensity after infusion of ketamine compared with placebo. No difference in pain during standardized pressure was found. Arendt-Nielsen et al.,37 however, report reduction in pressure pain after ketamine infusion. On the basis of the metabolic pathway of orally ingested ketamine, it remains difficult to explain why no antihyperalgesic or analgesic efficacy has been demonstrated. It is possible that effects of oral ketamine might have been overlooked because of a type II error. The size of the study population leads to a power of this study of 80%, given that the smallest reduction of the area of secondary hyperalgesia measurable would amount to 35 cm2 (45%). Another possible explanation for the lack of analgesic or antihyperalgesic properties of oral ketamine, 0.5 mg/kg and 1.0 mg/kg, could be that the dose chosen was too small. However, the dose chosen is well within the range reported effective.21,22,24,32,35 In these reports, however, ketamine
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has been administered over longer periods, and some degree of accumulation may have taken place. Furthermore, the clinical pain states, mostly neuropathic pain, may be more responsive to ketamine than the present model. The only effect of 0.5 and 1.0 mg/kg oral ketamine shown in this study was sedation. On an 11-point scale, the subjects scored a median of 2 40 minutes after ingestion. In another study addressing the effects of IV ketamine on secondary hyperalgesia, using the same 11-point scale and performed in a similar setting as the present study, a sedation score of 4 was achieved, this being twice as much as in the present study.7 Thus, based on the degree of sedation observed, it is hard to imagine that a larger dose of ketamine would have accomplished the desired goal, namely analgesia without side effects. Although other researchers have reported analgesic effects of similar doses of oral ketamine in case reports and clinical studies, in this study, no analgesic or antihyperalgesic effect could be shown after administration of 0.5 and 1.0 mg/kg oral ketamine.
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competitive NMDA receptor antagonist in the rat cortex and spinal cord. Eur J Pharmacol 1997;333:99104. Brennum J, Dahl JB, Arendt-Nielsen L, Møiniche S. Quantitative sensory examination of epidural anaesthesia and analgesia in man. Effects of pre- and posttraumatic morphine on hyperalgesia. Pain 1994; 59:261-271. 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. Møiniche S, Dahl JB, Kehlet H. Time course of primary and secondary hyperalgesia after heat injury to the skin. Br J Anaesth 1993;71:201-205. Pedersen JL, Kehlet H. Hyperalgesia in a human model of acute inflammatory pain: A methodological study. Pain 1998;74:139-151. Dahl JB, Rosenberg J, Jensen FM, Kehlet H. Pressure pain thresholds in volunteers and herniorrhaphy patients. Acta Anaesthesiol Scand 1990;34:673-676. Ilkjaer S, Dirks J, Brennum J, Wernberg M, Dahl JB. Effect of systemic N-methyl-D-aspartate receptor antagonist (dextromethorphan) on primary and secondary hyperalgesia in humans. Br J Anaesth 1997;79:600605. Eide PK, Stubhaug A. Relief of glossopharyngeal neuralgia by ketamine-induced N-methyl-aspartate receptor blockade. Neurosurgery 1997;41:505-508. Klepstad P, Borchgrevink PC. Four years’ treatment with ketamine and a trial of dextrometorphan in a patient with severe post-herpetic neuralgia. Acta Anaesthesiol Scand 1997;41:422-426. Hoffmann V, Coppejans H, Vercauteren M, Adriaensen H. Successful treatment of postherpetic neuralgia with oral ketamine. Clin J Pain 1994;10:240-242. Lauretti GR, Lima IC, Reis MP, Prado WA, Pereira NL. Oral ketamine and transdermal nitroglycerine as analgesic adjuvants to oral morphine therapy for cancer pain management. Anesthesiology 1999;90: 1528-1533. Enarson MC, Hays H, Woodroffe MA. Clinical experience with oral ketamine. J Pain Symptom Manage 1999;17:384-386. Arendt-Nielsen L, Nielsen J, Petersen-Felix S, Schnider TW, Zbinden AM. Effect of racemic mixture and the (S⫹)-isomer of ketamine on temporal and spatial summation of pain. Br J Anaesth 1996;77:625631. Arendt-Nielsen L, Petersen-Felix S, Fischer M, Bak P, Bjerring P, Zbinden AM. The effect of N-methyl-Daspartate antagonist (ketamine) on single and repeated nociceptive stimuli: A placebo-controlled experimental human study. Anesth Analg 1995;81: 63-68.
Effect of Oral Ketamine on Secondary Hyperalgesia, Thermal and Mechanical Pain Thresholds, and Sedation in Humans Søren Mikkelsen, M.D., Henrik Jørgensen, M.D., Pia S. Larsen, Jannick Brennum, M.D., Ph.D., and Jørgen B. Dahl, M.D., D.MSc. Background and Objectives: Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist, and has been proven effective in alleviating secondary hyperalgesia in human subjects when injected intravenously. After oral ingestion, ketamine is metabolized into norketamine, which in vitro possesses NMDA receptor antagonistic effect. The aim of this study was to investigate the effects of oral administration of ketamine on secondary hyperalgesia evoked by standardized tissue injury. Methods: Twenty-four male volunteers were included in the study. Each volunteer received the following treatment regimen, in randomized, double-blind, 3-way cross-over fashion: (A) placebo; (B) ketamine, 0.5 mg/ kg; and (C) ketamine, 1.0 mg/kg. Standardized tissue injury was induced after study medication by heating the right calf with a rectangular thermode. The temperature was 47°C, and heating time was 7 minutes. The following parameters were investigated: Pain during induction of the burn injury; heat-pain detection thresholds in the injured area and a corresponding noninjured area; secondary hyperalgesia surrounding the injured area on the calf; secondary hyperalgesia induced by heating an area on the thigh with 45°C in 3 minutes; pressure-pain detection thresholds measured on the middle phalanx of the 4th left finger; pain during a 60-second thermal stimulation of 46°C on undamaged skin on the left thigh; and side effects. Results: Some degree of sedation was observed after oral administration of ketamine. No effects on any of the other investigated parameters were observed. Conclusion: Oral ketamine 0.5 or 1.0 mg/kg has no effect on secondary hyperalgesia or thermal or mechanical pain thresholds in human volunteers. Reg Anesth Pain Med 2000;25:452-458. Key Words: Oral ketamine, Hyperalgesia.
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eripheral tissue injury may lead to hyperexcitability of wide dynamic range (WDR) neurons
See Editorial page 441
From the Laboratory of Pain Physiology, Department of Anesthesiology, Copenhagen University Hospital (S.M., H.J. P.S.L., J.B.D.), Herlev, Copenhagen; and the Department of Neurosurgery, Copenhagen University Hospital (J.B.), Rigshospitalet, Copenhagen. Accepted for publication March 29, 2000. Supported by grants from the following foundations: Danish Medical Research Council, Copenhagen, Denmark (Reg. no. 28809); Novo Nordisk Foundation, Bagsvaerd, Denmark; Danish Foundation for the Advancement of Medical Science, Copenhagen, Denmark; and Agnes and Poul Friis’ Foundation, Copenhagen, Denmark. No conflicts of interest exist between any of the authors and the foundations supporting this study. Reprint requests: Søren Mikkelsen, M.D., Department of Anesthesiology 4132, Copenhagen University Hospital, Rigshospitalet, DK2100 Copenhagen, Denmark. E-mail: [email protected] r 2000 by the American Society of Regional Anesthesia and Pain Medicine. 1098-7339/00/2505-0004$5.00/0 doi:10.1053/rapm.2000.8456
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in the dorsal horn of the spinal cord. Prolonged C-afferent activity evokes wind-up, a state that results in increased receptive fields and exaggerated responses of the WDR neurons to afferent input.1 Wind-up can augment responses of dorsal horn neurons up to 20-fold in magnitude and duration, and this state of hyperexcitability may even continue after cessation of the peripheral input.2 Central sensitization induces altered processing of afferent activity evoked by both innocuous and noxious stimuli. Clinically this is manifested as allodynia and hyperalgesia.3 Injury-induced sensitization of dorsal horn neurons has been implicated in both acute and chronic pain states.4 In humans, cutaneous heat injury evokes allodynia and hyperalgesia for mechanical and thermal stimuli within the injured area (primary hyperalgesia) and allodynia for mechanical, but not thermal, stimuli in an area surrounding the injury (secondary hyperalgesia).5 There is convincing evidence that primary hyperalgesia is caused by a combination of sensitization of
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peripheral receptors and central neurons, whereas secondary hyperalgesia is a result of altered central processing of afferent activity caused by sensitization of dorsal horn neurons.6-11 Experimental studies indicate that the N-methylD-aspartate (NMDA) receptor plays a significant role in wind-up and spinal hypersensitivity.12,13 Ketamine is an NMDA receptor antagonist14 which, in experimental and clinical settings, has proven effective in alleviating secondary hyperalgesia in humans.7,15,16 After intravenous (IV) administration of ketamine, a significant degree of side effects, predominantly expressed as sedation and psychomimetic effects, is reported.7,16 The frequency of psychomimetic effects of ketamine seems to be dose related,17 and Grant et al.18 have suggested that administration of ketamine in subanesthetic doses might eliminate these side effects. Ketamine reduces wind-up–like pain in amputees with established stump and phantom limb pain.19,20 Furthermore, ketamine has been applied successfully in the treatment of otherwise difficult pain states.21,22 Although undergoing extensive first-pass metabolism, with bioavailability of only 17%,18 oral ketamine has been shown to alleviate experimentally induced ischemic pain18 and, in case reports, has been reported to be useful in several chronic pain states.21,23,24 The possible explanation for the apparent analgesic effect of oral ketamine despite the extensive first-pass metabolism may be that the metabolite of ketamine, norketamine, acts as an antagonist at the NMDA receptor complex.25 The aim of the present study was to investigate the effects of oral administration of ketamine on secondary hyperalgesia after a first-degree burn injury, on thermal and mechanical pain thresholds, and on side effects in human volunteers.
Materials and Methods Twenty-five healthy male volunteers were included in the study. None received any medication for at least 48 hours before the study periods. All subjects were to refrain from eating, drinking, or smoking from the night before the study. Each participant in the study had been familiarized with the experiment protocol and the extent of the burn injury on a separate day. The 3 study days were each separated by at least 1 week. Informed consent was obtained, as was approval by the local Ethics Committee and the Danish National Board of Health. One subject was excluded during the study because of erroneous administration of study drug on one of the study days.
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Experimental Procedures The study design was 3-way cross-over, doubleblind, 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 3 treatment regimens were as follows: (A) oral administration of 50 mL of apple juice (placebo); (B) oral administration of ketamine, 0.5 mg/kg mixed with 50 mL of apple juice; (C) oral administration of ketamine, 1.0 mg/kg mixed with 50 mL of apple juice. No spontaneous reports on whether the taste of the solutions differed on any of the 3 study days appeared. Induction of Hyperalgesia. A model, which has previously proven reliable, was applied 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 mm ⫻ 50 mm (Thermotest; Somedic A/B, Stockholm, 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°C, and heating time was 7 minutes.26-29 An electronic visual analogue scale (VAS) was used by the subject in rating pain during induction of hyperalgesia. Ratings were performed continuously by moving a lever that controlled a vertical bar on a computer screen (sample rate, 2 Hz). The VAS was anchored with the descriptors ‘‘no pain’’ (numerical value: 0) and ‘‘worst possible pain’’ (numerical value: 100). The interpretation of ‘‘pain’’ was left to the subject, who was instructed to apply the same interpretation throughout the study. Measurement of Mechanical Hyperalgesia on the Right Calf. The temperature of the injured site on the right calf was stabilized at 35°C with the thermode, from 1 minute before and throughout assessment of secondary hyperalgesia. The border area of hyperalgesia was determined by striking with a brush or by pinpricking the calf along 4 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. Testing for stroke hyperalgesia was performed by gently striking 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 second, until the subject reported a definite change in sensation (‘‘burning,’’ ‘‘tender-
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ness,’’ ‘‘more intense pricking’’). These 4 points were traced onto a clear acetate sheet for calculation of the area, using a vector algorithm. Measurement of Mechanical Hyperalgesia on the Thigh. On the thigh, similar measurements were obtained during induction of brief reversible secondary hyperalgesia. The hyperalgesia was induced by heating the area at 45°C with the thermode, from 3 minutes before, and throughout assessment of secondary hyperalgesia. Because this parameter was obtained before administration of study drug on all 3 study days, results have been normalized relative to the initial value obtained at each study session before entering statistical analyses. This was done to achieve the same point of reference in the subjects on all 3 study days. Measurement of Thermal Thresholds (HPDT). Thermal thresholds were determined at the site of injury on the right calf, and at the corresponding site of the contralateral, uninjured calf. Heat-pain detection thresholds (HPDT) were 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. HPDT were determined by increasing the temperature of the thermode from 35°C with a rate of change of 1°C per second, having instructed the subjects to press a button on a device connected to the thermode, indicating when the pertinent temperature had been reached. The temperature was electronically registered, and the thermode was automatically returned to baseline. A cut-off limit of 52°C was defined, above which the thermode was to return to baseline and a threshold of 52°C would be registered. In no instance was this cut-off limit reached. Each threshold was calculated as the average of 3 measurements, with randomized intervals (6 to 10 seconds) between each stimulation. Measurement of Pressure-Pain Detection Thresholds (PPDT). PPDT were measured on the middle phalanx of the 4th left finger. PPDT were determined with a handheld electronic algometer (Somedic A/B) and defined as the minimal pressure (force) that induced pain. The stimulation probe has a circular tip of 11 mm (0.95 cm2), and is connected to a pressure transducer built into a gun-shaped handle. The signal from the pressure transducer is amplified in a main unit, and the applied pressure is shown in kilopascals (kPa) on a digital display. A display consisting of horizontal light bars indicates whether the applied pressure is higher or lower than a preset rate (20 kPa/s). When the PPDT is reached, the subject activates a push button, which freezes the digital display.30
Measurement of Pain During 60-Second Thermal Stimulation. Pain ratings were performed continuously with an electronic VAS during a 60-second thermal stimulation of 46°C on undamaged skin on the left thigh. Assessment of Side Effects. Sedation was assessed on an 11-point numerical scale (0 ⫽ completely awake; 10 ⫽ almost asleep). Discomfort was assessed on an 11-point numerical scale (0 ⫽ no discomfort; 10 ⫽ maximal discomfort). Nausea was registered as a 4-grade verbal rating scale (none, light, moderate, or severe). Finally, subjects were asked if they experienced hallucinations or any other sensations. Schedule. Measurements were obtained and study drug was administered according to the following schedule: ⫺20 minutes: measurement of hyperalgesia on thigh, HPDT, PPDT, pain during 60second thermal stimulation, side effects; 0 minutes: administration of study drug; 20 minutes: induction of hyperalgesia on the right calf; 40, 100, 160, 220, 280 minutes: measurement of hyperalgesia on calf and thigh, HPDT, PPDT, pain during 60-second thermal stimulation, side effects. Statistical Analyses Data are presented as median (quartiles). Friedman’s 1-way nonparametric analysis of variance has been applied. Any significant P values have been corrected using Bonferroni’s correction for repeated measurements. P ⬍ .05 was considered statistically significant. Because the baseline data regarding PPDT, pain during 60-second thermal stimulation, and areas of secondary hyperalgesia on the thigh all were obtained before administration of study drugs, all data pertaining to these tests were normalized in relation to the values obtained before administration of study drugs to achieve the same point of reference in the subjects in all 3 study days.
Results Pain Scores During Induction of Hyperalgesia on the Calf No difference was observed during induction of hyperalgesia, regardless of treatment regimen (P ⫽ .81) (Table 1). Primary Hyperalgesia In all 3 experimental settings, HPDT inside the burned area on the right calf decreased significantly 60 minutes after inducing a first-degree burn injury,
Oral Ketamine and Hyperalgesia Table 1. VAS Ratings During Induction of Hyperalgesia (7 minutes, 47°C)
Induction of hyperalgesia
Placebo
Ketamine 0.5 mg/kg
Ketamine 1.0 mg/kg
24 (16-36)
25 (21-34)
26 (15-34)
NOTE. Median (quartiles) shown. No significant difference between the groups.
and remained decreased throughout the study (P ⬍ .05). HPDT did not differ in the subjects during administration of placebo, small dose of ketamine, or large dose of ketamine (P ⫽ .34, Friedman’s test). Thermal thresholds in the contralateral unburned calf did not change from a baseline value, and did not differ during administration of placebo or ketamine (P ⫽ .21, Friedman’s test) (Table 2). Secondary Hyperalgesia
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subjects. No significant difference was observed between the different treatments (P ⫽ .99, Friedman’s test). Twenty of the 24 subjects described brush hyperalgesia on the thigh. No difference was observed between treatments (P ⫽ .81) (Figs 1 and 2). Pain During 60-Second Thermal Stimulation, and Pressure-Pain Thresholds Pain was registrered as mean values of samplings obtained during the whole period (30 sampling points). No differences were observed regardless of treatment (P ⫽ .26 and P ⫽ .97, respectively) (Tables 3 and 4). Side Effects Administration of ketamine caused significantly higher sedation scores than administration of placebo (P ⫽ .02). No difference was observed between the 2 treatment regimens that included ketamine.
After induction of the burn injury, no spontaneous pain or other sensations were experienced from the site of injury. Areas of pinprick hyperalgesia surrounding the injured area on the right calf were detected easily in all subjects from 60 minutes after induction of the burn injury. No difference was observed in areas of pinprick hyperalgesia on the right calf when comparing the effects of placebo, oral ketamine 0.5 mg/kg, or oral ketamine 1.0 mg/kg (P ⫽ .45, Friedman’s test). Brush hyperalgesia surrounding the burn injury was detected in 19 subjects. No difference was observed here, regardless of treatment (P ⫽ .71, Friedman’s test). Brief reversible pinprick hyperalgesia surrounding the thermode on the thigh was detected in all Table 2. HPDT (°C), Right Calf, Injured and Uninjured Skin
Unburned calf Baseline 40 min 100 min 160 min 220 min 280 min Burned calf Baseline 40 min 100 min 160 min 220 min 280 min
Placebo
Ketamine 0.5 mg/kg
Ketamine 1.0 mg/kg
47.8 (45.9-48.7) 47.6 (46.5-48.6) 47.0 (46.5-47.8) 47.8 (46.3-48.5) 47.4 (46.7-48.5) 47.0 (45.8-47.8)
48.3 (46.2-49.0) 47.1 (45.5-47.9) 47.1 (45.7-48.3) 47.1 (45.3-48.3) 47.1 (45.6-48.3) 47.1 (45.5-48.3)
47.3 (45.9-48.6) 47.4 (46.2-48.9) 47.1 (46.1-48.5) 47.4 (46.8-48.4) 46.9 (46.1-48.8) 47.4 (46.6-48.6)
47.3 (46.0-48.4) 46.1 (44.2-47.6) 46.5 (44.0-47.3) 46.3 (44.9-47.4) 46.9 (45.5-47.8) 47.1 (46.2-47.7)
47.2 (46.4-48.3) 44.9 (41.8-46.9) 45.5 (41.6-47.2) 44.5 (42.0-46.6) 45.9 (43.3-47.9) 45.8 (43.1-47.4)
47.4 (45.6-48.7) 46.5 (44.2-48.0) 46.8 (43.6-47.8) 46.2 (44.9-48.2) 46.8 (44.4-47.7) 47.1 (45.6-47.7)
NOTE. Median (quartiles) shown. No significant difference between the groups.
Fig 1. Area of secondary hyperalgesia on the calf. Values obtained after induction of a first-degree burn injury by heating the calf for 7 minutes at 47°C. X-axis: time after induction of hyperalgesia. Y-axis: area of the zone of secondary hyperalgesia. Pinprick stimuli. n ⫽ 24. Median (quartiles) shown. (䊐), Placebo; (N), ketamine 0.5 mg/kg orally; (䊏), ketamine 1.0 mg/kg orally. There was no significant difference between the groups.
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Regional Anesthesia and Pain Medicine Vol. 25 No. 5 September–October 2000 Table 4. PPDT on the Middle Phalanx of the 4th Left Finger (percentage of initial value)
Baseline 40 min 100 min 160 min 220 min 280 min
Placebo
Ketamine 0.5 mg/kg
Ketamine 1.0 mg/kg
100 90 (82-101) 94 (83-105) 94 (85-105) 95 (73-107) 92 (77-107)
100 90 (79-100) 91 (78-105) 87 (67-104) 86 (61-110) 88 (76-106)
100 90 (76-114) 91 (72-112) 91 (74-108) 80 (70-106) 89 (69-101)
NOTE. Median (quartiles) shown. No significant difference between the groups.
scores were 0, regardless of treatment. No discomfort or nausea was noted. No hallucinations were reported.
Discussion
Fig 2. Area of secondary hyperalgesia on the thigh. Hyperalgesia was induced by heating the area at 45°C with the thermode, from 3 minutes before and throughout assessment of secondary hyperalgesia. X-axis: time after induction of hyperalgesia. Y-axis: area of the zone of secondary hyperalgesia related to baseline. Pinprick stimuli. n ⫽ 24. Values normalized in relation to first measurement on each study day. Median (quartiles) shown. (䊐), Placebo; (N), ketamine 0.5 mg/kg orally; (䊏), ketamine 1.0 mg/kg orally. There was no significant difference between the groups.
Median sedation scores of 2 were achieved 40 minutes after administration of both 0.5 mg/kg of ketamine and 1.0 mg/kg of ketamine. After 100 minutes, sedation scores were reduced to 1 and 0.5, respectively. This difference was not statistically significant. At 160 minutes and onward, all sedation Table 3. VAS Ratings During 60-Second Thermal Stimulation on the Thigh (46°C)
Baseline 40 min 100 min 160 min 220 min 280 min
Placebo
Ketamine 0.5 mg/kg
Ketamine 1.0 mg/kg
17.5 (7.5-29) 17.5 (8.5-25) 12.0 (10-29.5) 15.0 (11.5-24) 17.5 (11-26) 17.0 (12.5-28)
15.0 (6-20) 17.5 (12-30) 16.0 (7.5-24.5) 16.5 (8.5-24) 15.0 (9-23.5) 13.0 (7.5-21)
19.5 (7.5-31) 11.5 (9-20) 14.5 (7.5-22) 13.0 (9-22.5) 12.0 (7-17.5) 8.5 (3-21)
NOTE. Median (quartiles) shown. No significant difference between the groups.
After oral administration, ketamine undergoes extensive first-pass metabolism, being converted into norketamine. The affinity of the metabolites of racemic ketamine, S-norketamine and R-norketamine, to the NMDA receptor is less than that of racemic ketamine itself.25 Norketamine was shown to reach higher concentrations after oral ingestion of ketamine than after intramuscular administration of ketamine, with a peak norketamine concentration occurring at 60 minutes.18 Because both ketamine and dextromethorphan, another NMDA receptor antagonist, previously have been shown to reduce secondary hyperalgesia after a first-degree burn injury, it is highly probable that the effects shown are related to the blocking of the NMDA receptor complex.7,16,31 It was speculated, that the lower affinity of norketamine to the NMDA receptor complex than that of ketamine, and the slower increase in plasma concentration of active drug after oral ingestion, could lead to a reduction in the degree of sedating properties, yet retain the analgesic effect. Doses of 0.5 mg/kg and 1.0 mg/kg were chosen on the basis of several case reports describing the effect of oral ketamine on pain states of longer duration. We wanted to investigate a dose of ketamine that would be unlikely to induce psychomimetic side effects, yet be effective in reducing secondary hyperalgesia. In case reports, ketamine in doses ranging from 50 mg ⫻ 3 to 200 mg ⫻ 5 has been reported effective in treating longer-lasting pain states.21,22,24,32-34 In a controlled study, Lauretti et al.35 evaluated the effect of oral ketamine as adjunct to oral morphine in cancer pain, and found that the addition of ketamine, 0.5 mg/kg twice daily, reduced the daily consumption of morphine. On the other hand, the effects of oral ketamine are not
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unequivocal, because Enarson et al.36 reported that 1 year after initiation of oral ketamine, only 3 of 21 patients reported improvements in pain control, decreased use of analgesics, and continued to use oral ketamine. It is speculated that the affinity of S-norketamine to the NMDA receptor complex, approximately one fifth the affinity of S-ketamine to the NMDA receptor complex, can explain the analgesic effects reported after oral administation of ketamine.25 In the present study, no antihyperalgesic or analgesic effect of a single dose of 0.5 and 1.0 mg/kg oral ketamine could be shown. Also, primary hyperalgesia (HPDT) was unaffected by oral ketamine. Antihyperalgetic and analgetic effects of ketamine after IV administration are well documented. Ilkjaer et al.7 reported that IV infusion of ketamine 0.3 mg/kg reduced pain during induction of hyperalgesia as well as primary hyperalgesia, and Arendt-Nielsen et al.37 reported increased HPDT after injection of ketamine. IV injection of ketamine has been shown to reduce the area of secondary hyperalgesia.7,16,20 In the present study, oral ketamine did not affect secondary hyperalgesia. Pain during a 60-second, 46°C thermal stimulation was unaffected by administration of oral ketamine. However, pain intensity during stimulation was low both during administration of placebo and active drug, and as such, any difference would be difficult to demonstrate. No exact corresponding test is described in the literature. Arendt-Nielsen et al.38 described the lack of effect of ketamine on high-intensity laser pulses as well as brief electrical pulses. Investigating the effects of ketamine on heat stimulation of short duration (2 seconds), ArendtNielsen et al.37 found reduction of pain intensity after infusion of ketamine compared with placebo. No difference in pain during standardized pressure was found. Arendt-Nielsen et al.,37 however, report reduction in pressure pain after ketamine infusion. On the basis of the metabolic pathway of orally ingested ketamine, it remains difficult to explain why no antihyperalgesic or analgesic efficacy has been demonstrated. It is possible that effects of oral ketamine might have been overlooked because of a type II error. The size of the study population leads to a power of this study of 80%, given that the smallest reduction of the area of secondary hyperalgesia measurable would amount to 35 cm2 (45%). Another possible explanation for the lack of analgesic or antihyperalgesic properties of oral ketamine, 0.5 mg/kg and 1.0 mg/kg, could be that the dose chosen was too small. However, the dose chosen is well within the range reported effective.21,22,24,32,35 In these reports, however, ketamine
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has been administered over longer periods, and some degree of accumulation may have taken place. Furthermore, the clinical pain states, mostly neuropathic pain, may be more responsive to ketamine than the present model. The only effect of 0.5 and 1.0 mg/kg oral ketamine shown in this study was sedation. On an 11-point scale, the subjects scored a median of 2 40 minutes after ingestion. In another study addressing the effects of IV ketamine on secondary hyperalgesia, using the same 11-point scale and performed in a similar setting as the present study, a sedation score of 4 was achieved, this being twice as much as in the present study.7 Thus, based on the degree of sedation observed, it is hard to imagine that a larger dose of ketamine would have accomplished the desired goal, namely analgesia without side effects. Although other researchers have reported analgesic effects of similar doses of oral ketamine in case reports and clinical studies, in this study, no analgesic or antihyperalgesic effect could be shown after administration of 0.5 and 1.0 mg/kg oral ketamine.
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