Differential effects of systemically administered ketamine and lidocaine on dynamic and static hyperalgesia induced by intradermal capsaicin in humans

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1 British Journal of Anaesthesia 84 (2): (2000) Differential effects of systemically administered ketamine and lidocaine on dynamic and static hyperalgesia induced by intradermal capsaicin in humans H. Gottrup 1 *, P. O. Hansen 1, L. Arendt-Nielsen 2 and T. S. Jensen 1 1 Department of Neurology, University Hospital of Aarhus, DK-8000 Aarhus, Denmark and Danish Pain Research Centre, University of Aarhus, DK-8000 Aarhus, Denmark. 2 Centre for Sensory Motor Interaction, University of Aalborg, DK-9220 Aalborg, Denmark *Corresponding author: Danish Pain Research Centre, Bygning 1C, Aarhus Kommunehospital, DK-8000 Aarhus C, Denmark We have examined the effect of systemic administration of ketamine and lidocaine on brushevoked (dynamic) pain and punctate-evoked (static) hyperalgesia induced by capsaicin. In a randomized, double-blind, placebo-controlled, crossover study, we studied 12 volunteers in three experiments. Capsaicin 100 µg was injected intradermally on the volar forearm followed by an i.v. infusion of ketamine (bolus 0.1 mg kg 1 over 10 min followed by infusion of 7 µgkg 1 min 1 ), lidocaine 5 mg kg 1 or saline for 50 min. Infusion started 15 min after injection of capsaicin. The following were measured: spontaneous pain, pain evoked by punctate and brush stimuli (VAS), and areas of brush-evoked and punctate-evoked hyperalgesia. Ketamine reduced both the area of brush-evoked and punctate-evoked hyperalgesia significantly and it tended to reduce brush-evoked pain. Lidocaine reduced the area of punctateevoked hyperalgesia significantly. It tended to reduce VAS scores of spontaneous pain but had no effect on evoked pain. The differential effects of ketamine and lidocaine on static and dynamic hyperalgesia suggest that the two types of hyperalgesia are mediated by separate mechanisms and have a distinct pharmacology. Br J Anaesth 2000; 84: Keywords: pharmacology, capsaicin; anaesthetics local, lidocaine; anaesthetics i.v., ketamine; pain, experimental; pain, mechanism; complications, hyperalgesia Accepted for publication: August 24, 1999 Hyperalgesia to mechanical stimuli is an essential part of painful area. Several lines of evidence indicate that these many chronic pain conditions. 1 4 Experimentally, different two types of hyperalgesia depend on different mechanisms. types of mechanical hyperalgesia can be distinguished First, on the basis of compression blocks it has been LaMotte and colleagues 5 described two types of mechanical shown that the dynamic type is mediated by large hyperalgesia in a capsaicin model: a large hyperalgesic area myelinated A-beta fibres and the punctate form by to normally painful punctate stimuli and a smaller tender unmyelinated C-fibres. 268 Second, while both dynamic and area which was painful to stroking stimuli. Kilo and static hyperalgesia involve central plastic changes induced colleagues 7 provided evidence for at least four types of by peripheral nociceptor activity, the dynamic form seems mechanical hyperalgesia: one induced by gently brushing, to depend on persistent input from nociceptors, and the one by punctate stimuli, one by blunt pressure and one by static form can persist without such nociceptor activity, impact stimuli. While the two former types were suggested because anaesthetizing an area with hypersensitivity induced to depend on central sensitization resulting from central by capsaicin abolishes brush-evoked hyperalgesia but not plastic changes, it was suggested that the latter two were punctate-evoked hyperalgesia. 5 Third, in a recent clinical caused by sensitization of peripheral nociceptors. study in patients with neuropathic pain, it was shown that In neuropathic pain patients, different types of mechanical brush-evoked pain and punctate-evoked hyperalgesia were hyperalgesia can also be delineated. Ochoa and Yarnitsky 2 not related, although both types are probably maintained described a dynamic and a static type, where the former by heat sensitive nociceptors. 9 Taken together, it is likely that was induced by gently brushing the injured area, whereas different neural mechanisms are responsible for mechanical the static type was induced by punctate stimuli in the hyperalgesia. Further insight into the mechanisms of The Board of Management and Trustees of the British Journal of Anaesthesia 2000

2 Gottrup et al. and dynamic hyperalgesia hyperalgesia may be obtained by examination of the angle between each line was 60. A point was marked 3 cm pharmacology of dynamic and static mechanical hyper- proximal to the injection site. algesia. All injections were carried out on the right volar forearm. Intradermal capsaicin, the pungent ingredient of chilli In the first experiment, injection was carried out 5 cm peppers, is a well known human experimental pain model proximal from the wrist and in subsequent sessions the to induce neurogenic inflammation. Capsaicin activates injection was moved 1 cm proximal from the preceding C-fibres causing an intense burning pain sensation and injection site to avoid injection at the same site. development of primary and secondary hyperalgesia The mechanism of secondary hyperalgesia is believed to Thermal thresholds be caused by central sensitization of wide dynamic range All sensory tests were carried out by the same investigator (WDR) neurones and subsequent dynamic changes in the (H. G.) in a quiet room (temperature C) with the central processing of mechanoreceptive input in A-beta subject comfortably lying in bed. fibres. 8 Thermal thresholds were measured using the Somedic Ketamine is a non-competitive NMDA receptor blocker Thermotest (Somedic AB, Sweden). A Peltier thermode which reduces the activity of sensitized WDR neurones in with an area of 12.5 cm 2 was applied to the skin with a the dorsal horn of the spinal cord and may also fixed application pressure at the site of injection. Baseline act peripherally Ketamine has been shown to block temperature was set at 30 C with a thermal rate of change experimentally induced pain and mechanical hyperalgesia of 1 Cs 1 and an inter-stimulus interval randomized between in the capsaicin model and the burn injury model and 6 s. The cut-off limit for warmth was 52 C. Heat In patients suffering from different types of neuropathic detection thresholds (HDT) and heat pain threshold (HPT) pain, ketamine has been reported to reduce both static22 23 were determined at the injection site before injection of capsaicin to ensure that capsaicin was not injected into In contrast, lidocaine is a sodium channel blocker which desensitized skin. Subjects indicated when perception reduces hyperalgesia induced by nerve injury and nociceptor changed to warm or hot pain by pressing a button. The produced central sensitization, with both a peripheral and thermode automatically returned to baseline temperature central action Lidocaine also reduces experimental when the button was pressed. One minute after injection of hyperalgesia in humans 29 and clinical hyperalgesia after capsaicin and at the end of each treatment, HPT at the nerve injury injection site was determined. Thresholds were defined as If dynamic and static hyperalgesia are mediated by the average of three measurements. different mechanisms, ketamine and lidocaine should modulate static and dynamic hyperalgesia differently. Assessment of pain and hyperalgesia The intradermal capsaicin model was used to test this Pain assessment hypothesis Spontaneous pain and evoked pain intensity were measured using a visual analogue scale (VAS mm; 0 no Subjects and methods pain, 100 unbearable pain). To assess brush-evoked pain, a cotton gauze was swept back and forth three times We studied 12 healthy male volunteers in a randomized, at the 3-cm point at a speed of 1 2 cms 1 and the intensity double-blind, placebo-controlled crossover study. Informed was scored on a VAS scale. Punctate-evoked pain was written consent was obtained from all participants and the assessed by bending a fixed von Frey hair (744.9 mn) study was approved by the Local Ethics Committee and (Semmes-Weinstein monofilaments, Stoelting, IL, USA) at the Danish National Board of Health. Before the first the 3-cm point twice, at a rate of 1 Hz, and was scored in experiment, capsaicin 50 µg was injected into the left volar a similar manner. All measurements were performed at forearm to familiarize subjects with capsaicin pain and specific times and in the following order: (1) spontaneous the tests performed during each experiment. One subject pain intensity, (2) brush-evoked pain intensity, (3) punctate- developed allodynia lasting only a few minutes at the evoked pain intensity, (4) area of brush-evoked hyperalgesia screening session and was not included in the study. and (5) area of punctate-evoked hyperalgesia. Intradermal capsaicin Capsaicin (8-methyl N-vanillyl 6-nonamide) (Sigma, USA) was dissolved in Tween 80 UPS by heating. 11 Saline was added under sterile conditions to obtain a concentration of 5mgml 1. Capsaicin 20 µl (100 µg) was injected using a 0.5-ml syringe fitted with a 27-gauge needle. Six radiating lines from the injection site with ticks at 1-cm intervals were drawn on the skin before injection of capsaicin. The Areas of secondary hyperalgesia The area of brush-evoked hyperalgesia was assessed by stroking a hand-held cotton gauze from the skin with normal sensation towards the injection site at a rate of approximately 1cms 1 and in steps of 1 cm. This was performed along the six radiating lines drawn on the skin before injection of capsaicin. Subjects were asked to report when the sensation changed to a sensation of tenderness or pain, and the distance from the injection site to this point was 156

3 Effects of ketamine and lidocaine on hyperalgesia measured. On basis of the marked distances along the lines where sensation changed, a hexagon was drawn and the area calculated. The area of punctate-evoked hyperalgesia was assessed by bending a hand-held von Frey hair (744.9 mn) towards the injection site in steps of 1 cm at a rate of 1 cm s 1. Subjects were asked to report when the sensation became increasingly painful. The area was measured as described above, by outlining the borders and calculated from a drawn hexagon. Drug infusion punctate-evoked hyperalgesia. Measurements were performed at specific times after injection of capsaicin. In each treatment session, a baseline was defined for each subject which was the measurement 15 min after injection of capsaicin (start of infusion). Subsequent measures were converted to percentage of baseline. For each treatment and each subject, the effect variables were plotted against time as a percentage of baseline values. Curves for each treatment group are presented in Figures 1B 5B in which median values at each time of measurement are shown. Area under the curve (AUC) for each subject was calculated for min after injection of capsaicin, corresponding to the measurements performed during infusion (t 15, 30, 45 min). Differences in AUC between treatment groups were analysed by non-parametric repeated analysis of variance on ranks (Friedmans test). AUC are presented as box plots, medians are indicated by horizontal lines and boxes show the 25th to 75th percentiles; 90% confidence intervals are presented as whiskers. P 0.05 was considered statistically significant. On each of 3 examination days, separated by at least 1 week, subjects received, in a double-blind randomized manner, an i.v. infusion of ketamine 50 mg ml 1 (Ketalar, Parke-Davis), lidocaine 20 mg ml 1 (Lidokain, SAD) or saline 9 mg ml 1 (NaCl, SAD) diluted in isotonic saline. I.v. infusion started 15 min after injection of capsaicin via an infusion pump (Ivac 598, Kivex A/S, Denmark); each treatment session consisted of infusion of NaCl ml, with or without drug, over 10, 20 and 20 min. The total infusion time did not exceed 55 min. Ketamine was given as Results a bolus infusion of 0.1 mg kg 1 over 10 min followed by The mean dose of ketamine administered was 28.4 (SD two infusions of 7 µg kg 1 min 1, each lasting 20 min. 4.2) mg and the mean dose of lidocaine was (58.4) mg. Lidocaine was given as a continuous infusion of The infusion was stopped temporarily for 2 min because of 1.67 mg kg 1 over 10 min, followed by one infusion of dizziness 26 min after onset in one individual receiving 3.33 mg kg 1 over 20 min and one infusion of NaCl 100 ml lidocaine and 16 min after onset in another individual over 20 min. Saline was infused in a similar manner with receiving ketamine. These data are included in the results NaCl 100 ml over 10 min followed by two infusions of NaCl because the infusion was stopped for only a short period 100 ml over 20 min. To ensure blinding, the investigator who and because both investigator and subjects were uninformed. carried out the measurements during the study (H. G.) was not involved in drug infusion or in collecting reports of Thermal thresholds in the primary hyperalgesic area side effects. Table 1 shows the effect of capsaicin on thermal thresholds. ECG, heart rate and arterial pressure were monitored There was no difference in heat detection threshold (HDT) until the end of each study session. or heat pain threshold (HPT) before injection of capsaicin in the three groups. There was a significant reduction in Side effects HPT 1 min after capsaicin and at the end of the study To ensure blinding, subjects were asked about side effects compared with before capsaicin in all three groups, but at specific times by a co-investigator (P. O. H.) who there were no differences between groups. administered the infusion and was responsible for the blinding procedure. The investigator responsible for sensory Pain relief testing (H. G.) was not informed of side effect reports. Median VAS scores for spontaneous pain at the beginning Reported side effects were graded on a three-point scale as of infusion were 33 (25th and 75th percentiles 23; 53) in weak, moderate or severe. the placebo group, 46 (39; 58) in the ketamine group and Statistical analysis The study was carried out in a crossover design. The number of subjects needed to document an effect was calculated as nine (α 0.05; β 0.80). Treatment Differences in HDT and HPT between treatment groups were analysed by one-way ANOVA. HPT values before Thermal threshold Lidocaine Ketamine Placebo and after injection of capsaicin were compared using a HDT before (0.321) 32.6 (0.480) (0.317) paired t test in each treatment group. HPT before (0.565) (0.507) (0.789) Effect variables were spontaneous pain, pain evoked by brush end punctate stimuli and areas of brush-evoked and Table 1 Heat detection threshold (HDT) and heat pain threshold (HPT) values in the lidocaine, ketamine and placebo groups. *P 0.05 (paired t test) from corresponding HPT value before capsaicin (cap.) (HPT before ). Values are mean (SEM) HPT 1 min after cap (0.962)* 37.5 (1.114)* (0.917)* HPT 105 min after cap (0.672)* (0.500)* (0.672)* 157

4 Gottrup et al. Fig 1 Spontaneous pain intensity in the lidocaine, ketamine and placebo groups, plotted as median AUC (A) and median VAS score (percentage of baseline) (B) from the start of infusion until the end of the experiment. The grey area indicates the infusion period (n 12). Fig 2 Intensity of brush-evoked pain in the lidocaine, ketamine and placebo groups, plotted as median AUC (A) and median VAS score (percentage of baseline) (B) from the start of infusion until the end of the experiment. The grey area indicates the infusion period (n 9). 41 (17; 55) in the lidocaine group. Lidocaine tended to Punctate-evoked pain reduce median VAS scores of spontaneous pain but this All 12 subjects felt pain to a bending von Frey hair was not significant. There was no effect of ketamine or (744.9 mn) at a single point 3 cm proximal from the placebo on spontaneous pain. (Fig. 1A, B). injection site. They were not asked to score the sensation before injection of capsaicin. VAS scores 15 min after Brush-evoked pain capsaicin were 37 (21; 47) in the placebo group, 37 (25; All subjects developed a short-lived brush-evoked pain 53) in the ketamine group and 29 (25; 50) in the lidocaine outside the capsaicin injection site. Nine of 12 subjects still group. VAS scores for punctate-evoked pain at the 3-cm complained of pain in all three groups when brushing the point were not reduced significantly by ketamine or lidocaine skin at the 3-cm point immediately before drug infusion compared with placebo (Fig. 3A, B). (15 min after capsaicin). The three subjects in whom brushevoked pain disappeared before infusion started are not included in the results. VAS scores of brush-evoked pain Area of hyperalgesia at the beginning of the infusion were 25 (14; 40) in the Area of brush-evoked hyperalgesia placebo group, 26 (15; 43) in the ketamine group and 24 Eleven of 12 subjects still had an area of allodynia in all (10; 38) in the lidocaine group. There was no effect of three experiments, 15 min after capsaicin. The subject lidocaine on brush-evoked pain whereas ketamine tended without an area of allodynia 15 min after capsaicin was not to reduce brush-evoked pain, although not significantly included in the results. The median area of brush-evoked (Fig. 2A, B). hyperalgesia at the beginning of the infusion was 26 (18; 158

5 Effects of ketamine and lidocaine on hyperalgesia Fig 3 Intensity of punctate-evoked pain in the lidocaine, ketamine and placebo groups, plotted as median AUC (A) and median VAS score (percentage of baseline) (B) from the start of infusion until the end of the experiment. The grey area indicates the infusion period (n 12). Fig 4 Area of brush-evoked hyperalgesia in the lidocaine, ketamine and placebo groups, plotted as median AUC (A) and median area (percentage of baseline) (B) from the start of infusion until the end of the experiment. The grey area indicates the infusion period (n 11). *Significant difference from corresponding placebo value (non-parametric repeated measures analysis of variance on ranks, Friedmans test, P 0.05). Fig 5 Area of punctate-evoked hyperalgesia in the lidocaine, ketamine and placebo groups, plotted as median AUC (A) and median area (percentage of baseline) (B) from the start of infusion until the end of the experiment. The grey area indicates the infusion period (n 12). *Significant difference from corresponding placebo value (non-parametric repeated measures analysis of variance on ranks, Friedmans test, P 0.05). 33) cm 2 in the placebo group, 22 (19; 35) cm 2 in the evoked hyperalgesia significantly (non-parametric repeated ketamine group and 40 (23; 46) cm 2 in the lidocaine group. measures analysis of variance on ranks, Friedmans test; P Ketamine, but not lidocaine, reduced the area of brush ketamine vs placebo) (Fig. 4A, B). 159

6 Gottrup et al. Table 2 Number of subjects with side effects after drug treatment Ketamine Lidocaine Placebo and lidocaine had no effect on VAS scores of punctateevoked pain. Thus these findings extend, but are also at variance with, those obtained by others with lidocaine 32 Paraesthesia and ketamine. 18 Dizziness Sleepiness Our findings suggested that: (1) central sensitization Nausea evoked by continuous noxious input from C-nociceptors Dry mouth was reduced by the NMDA antagonist ketamine; (2) a Blurred vision diminished noxious input, using a sodium channel blocker, Light-headedness Relaxed reduced neuronal sensitization but did not prevent A-beta Euphoria fibre input from driving already sensitized central neurones; Unreality and (3) the pharmacology of static and dynamic hyperalgesia Drunkenness Palpitations can be distinguished. Flying Side effects were observed with both ketamine and lidocaine. Although it may be argued that blinding was insufficient, we consider this possibility unlikely. The Area of punctate-evoked hyperalgesia All 12 subjects had an area of punctate-evoked hyperalgesia examiner responsible for sensory testing and pain assessin each experiment. The area of punctate-evoked hyperalgeof individuals with psychotropic side effects (sleepiness, ment was unaware of the reported side effects. The number sia at the beginning of the infusion was 22 (14; 45) cm 2 in light-headedness, relaxation, euphoria, unreality, flying the placebo group, 21 (15; 49) cm 2 in the ketamine group and drunkenness) was similar in the ketamine and lidocaine and 35 (29; 51) cm 2 in the lidocaine group. Both ketamine groups (Table 2). Finally, the differential effect of lidocaine and lidocaine significantly reduced the area of punctateand ketamine argues against systematic bias. evoked hyperalgesia during infusion (non-parametric Experimental and clinical observations indicate that repeated measures analysis of variance on ranks, Friedmans generation of pain in an injured area by mechanical input test, P 0.05 ketamine vs placebo; P 0.05 lidocaine vs reflects central sensitization of WDR and spinothalamic placebo) (Fig. 5A, B). tract neurones In our study, we measured two Side effects types of hyperalgesia: brush-evoked and punctate-evoked, which both reflect central sensitization, but which are During ketamine and lidocaine but not during saline treatprobably mediated by separate mechanisms. Ochoa and ment, subjects developed side effects. Table 2 shows the Yarnitsky, 2 in a group of neuropathic patients, showed that number of subjects reporting different types of side the brush-evoked form was mediated by A-beta fibres while effects. Lidocaine caused paraesthesia and palpitations the punctate form was mediated by C-fibres. Punctate more frequently than ketamine, which produced more a hyperalgesia outlasts capsaicin-induced pain and this hyperfeeling of relaxation, unreality, flying and euphoria. In the algesia cannot be blocked by local lidocaine infiltration. ketamine group, one subject had three or more side effects, 5 Finally, it has been shown recently in a series of neuropathic seven had two side effects and four had one side effect. In pain patients suffering from hyperalgesia that there was the lidocaine group, six subjects had three or more side no relationship between brush-evoked pain and punctateeffects, four had two side effects and two had one side evoked pain in the same patients. effect. After infusion of ketamine, the intensity of the 9 The effect of ketamine is suggested to be a result of a side effects were graded as weak in 19%, moderate in 67% central effect by non-competitive binding to NMDA recepand severe in 14% of subjects. After lidocaine infusion, tors and hence block of sensitized WDR neurones in the side effects were graded as weak in 36%, moderate in 50% spinal cord In our study, the areas of both brushand severe in 19% of subjects. evoked hyperalgesia and punctate-evoked hyperalgesia were Discussion reduced by ketamine. Previous studies in experimental human pain models showed that NMDA block before and The main finding of our study was a differential effect of after injury reduced or abolished symptoms of central i.v. infusion of ketamine and lidocaine on brush-evoked sensitization Our results are consistent with the hyperalgesia (dynamic hyperalgesia) and punctate-evoked findings of others in a burn injury model where the areas hyperalgesia (static hyperalgesia). of both brush-evoked hyperalgesia and punctate hyperalgesia We found that ketamine reduced the area of both brushevoked were reduced significantly after bolus infusion of and punctate-evoked hyperalgesia and tended to ketamine Punctate, but not brush-evoked, hyperalgesia reduce the VAS score of brush-evoked pain but had no (allodynia) was reduced by post-injury treatment in effect on spontaneous pain. Lidocaine reduced the area of the capsaicin model. 18 In our study, we failed to find a punctate-evoked hyperalgesia but had no effect on the reduction in spontaneous or evoked pain, although ketamine area of brush-evoked hyperalgesia or brush-evoked pain. tended to reduce brush-evoked pain. Differences in dose and Lidocaine tended to reduce spontaneous pain. Ketamine timing of capsaicin and ketamine may be one explanation 160

7 Effects of ketamine and lidocaine on hyperalgesia for this discrepancy. The fact that we used a very stiff C-fibre input, under these conditions, may block punctate von Frey hair when measuring evoked pain by punctate hyperalgesia. In contrast, it is conceivable that block of hyperalgesia may preclude us from finding an effect on central sensitized WDR neurones by the NMDA receptor punctate hyperalgesia. blocker ketamine reduces both dynamic and static hyper- Our study is consistent with clinical studies of ketamine algesia driven by A-beta and C-fibre input, respectively. showing relief of brush-evoked and punctate-evoked hyperalgesia In summary, our findings indicate that an ongoing C-fibre in patients suffering from different types of input induced central sensitization which was blocked by a neuropathic pain NMDA receptor antagonist. Reduction of afferent input Studies by Devor and colleagues indicated that lidocaine using a sodium channel blocker may reduce central sensitization. reduced ectopic discharges from distal neuromas and A rational approach for treatment of some types of from ectopic foci in dorsal root ganglion cells (DRG) pain may therefore be a combination of a sodium channel A central action has also been suggested because blocker and an NMDA receptor antagonist because of the systemic lidocaine blocks the nociceptive flexor reflex in differential effects of ketamine and lidocaine. Additional humans 29 and the C-fibre-evoked reflex in rats. 40 In our combination studies are necessary to test this hypothesis. study, lidocaine reduced the area of punctate hyperalgesia and tended to reduce spontaneous pain, but brush-evoked Acknowledgements pain and the area of brush-evoked allodynia were not This study was supported by grants from: Danish Pain Research Centre, affected. Our findings differ from those reported by Wallace Danish Cancer Society (No ), the Danish National Research and colleagues 32 in which lidocaine 3 µgml 1, administered Foundation and the Danish Medical Research Council (No ). We thank Dr Flemming W. Bach for helpful comments. before capsaicin, reduced heat hyperalgesia and the area of flare after intradermal capsaicin, but had no significant effect on the area of hyperalgesia to stroking or punctate References stimuli or spontaneous pain intensity. Again, differences in 1 Lindblom U, Verrillo RT. Sensory functions in chronic neuralgia. J Neurol Neurosurg Psychiatry 1979; 42: dose and timing of capsaicin and lidocaine may play a role 2 Ochoa JL, Yarnitsky D. Mechanical hyperalgesia in neuropathic in the differential effect. The tendency to reduce spontaneous pain patients: dynamic and static subtypes. 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