Peripheral lidocaine but not ketamine inhibits capsaicin-induced hyperalgesia in humans

H. Gottrup1,*, F. W. Bach2, L. Arendt-Nielsen3 and T. S. Jensen1

1Department of Neurology, University Hospital of Aarhus, DK-8000 Aarhus and Danish Pain Research Center, Aarhus University, Aarhus, Denmark. 2Department of Neurology, University Hospital of Aarhus, DK-8000 Aarhus, Denmark. 3Center for Sensory–Motor Interaction, Aalborg University, Denmark

Accepted for publication: March 29, 2000


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
We examined the effect of the subcutaneous infiltration of ketamine, lidocaine and saline before injury on capsaicin-induced pain and hyperalgesia. Twelve healthy volunteers participated in two separate, randomized, double-blind, placebo-controlled crossover experiments. In experiment 1, 100 µg capsaicin was injected intradermally in one volar forearm 10 min after the skin had been pretreated with lidocaine 20.0 mg in 2.0 ml or 0.9% saline 2.0 ml at the capsaicin injection site. In experiment 2, a similar capsaicin test was given 10 min after the skin had been pretreated with ketamine 5 mg in 2.0 ml or 0.9% saline 2.0 ml. To control for possible systemic effects, the capsaicin injection site was pretreated by injection of saline into the skin and the contralateral arm was treated with active drug, and vice versa. Outcome measures were spontaneous pain, pain evoked by punctate and brush stimuli, and areas of brush-evoked and punctate-evoked hyperalgesia. Lidocaine reduced all measures compared with placebo (P<0.001), whereas ketamine failed to change any measures. Pain scores and areas of hyperalgesia were not affected when the contralateral site was infiltrated with ketamine or lidocaine. Lidocaine produced no side-effects, whereas ketamine produced paraesthesia, dizziness and sleepiness in six out of 24 (25%) cases. Blocking peripheral sodium channels with locally administered lidocaine reduces spontaneous pain and capsaicin-induced hyperalgesia but local block with the NMDA-type glutamate receptor antagonist ketamine has no effect on capsaicin-induced pain and hyperalgesia.

Br J Anaesth 2000; 85: 520–8.

Keywords: pain, capsaicin; hyperalgesia; anaesthetics local, lidocaine; anaesthetics i.v., ketamine


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Intradermally or topically applied capsaicin is a widely used model of experimental hyperexcitability in humans. Previous studies have shown that capsaicin-induced hyperexcitability involves peripheral and central hyperexcitability16 and that this hyperexcitability is amenable to block with N-methyl-D-aspartate (NMDA)-type glutamate receptor antagonists and sodium channel blockers. Ketamine, a non-competitive NMDA receptor antagonist, reduces the excitatory responses of wide dynamic range neurones in the spinal cord and mechanical hyperalgesia in animals79 and reduces spontaneous pain and hyperalgesia in experimental and clinical pain states in humans.1017 The modulating effects of systemic ketamine on pain and hyperalgesia were previously attributed to an action on the NMDA receptor system in the central nervous system18 19 (the spinal cord or more centrally), but the recent anatomical demonstration of NMDA receptors in the peripheral nervous system has raised the possibility that the pain-relieving effect of ketamine is also mediated peripherally. For example, Carlton and colleagues20 demonstrated glutamate receptors on peripheral unmyelinated axons in rats, and these authors also showed that activation of these receptors gave rise to mechanical hyperalgesia that could be inhibited by local treatment with NMDA receptor antagonists.2022

Reports of the effects of locally administered ketamine on human experimental pain are not consistent. In a burn injury model, Warncke and colleagues23 showed that local treatment with ketamine before injury inhibits the development of mechanical hyperalgesia. As the effect of ketamine was compared directly with that of saline in the same session, it is possible that the effect observed was systemic and not local alone. In a recent human study by Pedersen and colleagues,24 peripheral ketamine treatment reduced spontaneous pain during the induction of burn injury and increased the threshold for heat pain. However, the number of side-effects reported was similar regardless of which side was treated with ketamine. Saline on both sides produced markedly fewer side-effects. Therefore, the observed effect of ketamine could be peripheral as well as systemic.

Pre-injury block with local anaesthetics may prevent or reduce central alterations after a peripheral injury.25 26 Lidocaine is a use-dependent sodium channel blocker. Pre-injury infiltration with lidocaine has been shown to inhibit the development of mechanical hyperalgesia in the capsaicin model3 and in a burn injury model27 in humans, indicating that hyperalgesia can be blocked by a peripherally acting analgesic.

Therefore, this study examined the analgesic effect of local treatment before injury with the NMDA receptor antagonist ketamine, the sodium channel blocker lidocaine and saline on the pain and hyperalgesia induced by intradermally applied capsaicin. We used a study design that permitted control for a possible systemic effect of local ketamine and lidocaine.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Subjects
Twelve healthy male volunteers participated in two separate experiments and 11 participated in both experiments. The primary effect parameters were the areas of brush-evoked and punctate-evoked hyperalgesia and the secondary effect parameters were spontaneous pain and evoked pain, scored on a visual analogue scale (VAS). The number of subjects needed to detect an effect on the area of hyperalgesia was calculated as 10 (SD 15) cm2 (the expected reduction of 50% of a mean area of 36–40 cm2; {alpha}=0.05, ß=0.80). To detect an effect on VAS scores, a smaller number of subjects was needed. Each experiment was performed in a randomized, double-blind, placebo-controlled crossover design. Informed written consent was obtained from all participants before the start of the study, and the study was approved by the local Ethics Committee and by the Danish National Board of Health.

Intradermal capsaicin and drug administration
Capsaicin (8-methyl N-vanillyl 6-nonamide) (Sigma, St. Louis, MO, USA) was dissolved in Tween 80 by heating.28 Saline was added under sterile conditions to obtain a concentration of 5 mg ml–1. To familiarize the subjects with capsaicin pain and the tests performed during each trial, 50 µg of capsaicin was injected in the left volar forearm at least 1 week before the first trial. Subjects who failed to develop allodynia at the screening session were not included in the study. In each experiment, capsaicin was injected in the right forearm in half of the subjects and in the left forearm in the remaining subjects, in random order. A person not involved in the testing prepared the randomization codes and the drugs used for injection, which were in identical syringes.

Experiment 1
On each of two examination days, separated by at least 1 week, subjects received pre-injury subcutaneous infiltration with lidocaine 20 mg in 2.0 ml (Lidokain, SAD, Copenhagen, Denmark, pH=5.5) or isotonic 0.9% saline in 2.0 ml (NaCl, SAD, pH=6.0) at the site where capsaicin was to be injected. The subcutaneous infiltration was done over an area of approximately 3 cm2 around the capsaicin injection site. To examine for a possible systemic effect of the active drug, capsaicin was injected into saline-pretreated skin and the contralateral arm was injected with active drug, and in other tests capsaicin was injected into skin pretreated with the active drug and saline into the contralateral arm in random order. Bilateral infiltration lasted about 2 min. Capsaicin (100 µg, 20 µl) was injected into the centre of the pretreated skin of one arm 10 min after infiltration. In the first trial the injection of capsaicin was carried out 5 cm proximal to the wrist, and in the second trial the injection site was moved 1 cm proximal to the preceding injection site to prevent injection at the same site.

Experiment 2
This experiment was similar to experiment 1, but the skin at the injection site was pretreated by subcutaneous infiltration with ketamine hydrochloride 5.0 mg in 2.0 ml (Ketalar®, Warner-Lambert/Parke-Davis, Ballerup, Denmark) (pH=5.2) or 0.9% saline in 2.0 ml (NaCl, SAD) (pH=6.0). As in experiment 1, the contralateral arm was infiltrated with ketamine if the capsaicin site had been pretreated with saline and vice versa. Capsaicin was injected in one forearm 10 min after the skin had been pretreated. The site of injection of capsaicin was 7 cm proximal to the wrist in this first trial and was moved 1 cm more proximally in the second trial to prevent injection at the same site.

Tactile threshold
The same investigator (HG) carried out all measurements, in a quiet room (temperature 20–22°C) with the subject comfortably resting in a supine position. The tactile pain threshold (TPT) was measured on the forearm contralateral to the capsaicin injection site. It was defined as the least force necessary to bend a von Frey hair that was felt as painful. The TPT was determined before and 9 min after subcutaneous infiltration by bending a von Frey hair (Semmes–Weinstein monofilaments; Stoelting, IL, USA, graded from 0.004 to 446.68 g) on the skin at the subcutaneous infiltration site. The von Frey hairs were calibrated once at the start of the study, and the same von Frey hairs were used in both experiments.

Assessment of pain and hyperalgesia
Six radiating lines (60° between adjacent lines) from the injection site with ticks at 1 cm intervals were drawn on the skin before the start of the experiment. A point was marked 3 cm proximal to the injection site. Spontaneous and evoked pain intensities were measured using a VAS with a range of range 0–100, with 0=no pain and 100=unbearable pain. To assess brush-evoked pain, cotton gauze was swept back and forth three times at the 3 cm point at a speed of 1–2 cm s–1 and pain intensity was scored on a VAS. Punctate-evoked pain was assessed by bending a fixed von Frey hair (75.86 g) twice at the 3 cm point at a rate of 1 Hz, and was scored in a similar fashion. All measurements were done at specific time intervals and in the following order: (1) spontaneous pain intensity; (2) brush-evoked pain intensity; (3) punctate-evoked pain intensity; (4) area of brush-evoked hyperalgesia; (5) area of punctate-evoked hyperalgesia.

The area of brush-evoked hyperalgesia was assessed by moving a hand-held cotton gauze along each of the six radiating vector lines, starting in skin areas with normal sensation and moving towards the injection centre in 1 cm steps at a rate of approximately 1 cm s–1. Subjects were asked to report when the sensation changed to a sensation of tenderness or pain. The area was calculated from the drawn hexagon.

The area of punctate-evoked hyperalgesia was assessed by bending a hand-held von Frey hair (75.86 g) 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 more painful. The area was calculated as described above.

Side-effects
Subjects were asked about side-effects at specific intervals. Reported side-effects were graded as weak, moderate or severe.

Statistical analysis
Statistical analysis was carried out using Jandel Sigmastat for Windows, version 2.0. The normality of the distribution of the data was tested with the Kolmogorov–Smirnov test. After the normal distribution of the data had been confirmed, the data were analysed by parametric methods. VAS scores for pain induced by subcutaneous injection of lidocaine, ketamine and saline were compared by the paired t-test in each experiment. TPTs before and after subcutaneous injection of saline, lidocaine and ketamine were analysed with the paired t-test. Data are presented as mean (SEM). Effect parameters were spontaneous capsaicin pain, pain evoked by brush and punctate stimuli, and areas of brush-evoked and punctate-evoked hyperalgesia. Differences in spontaneous pain, evoked pain and areas of hyperalgesia between treatment groups were analysed by parametric two-way analysis of variance with repeated measures (ANOVA RM) followed, in the case of significance, by multiple comparison using Dunnett’s method. Data are presented as mean (SEM). P-values less than 0.05 were considered to be statistically significant.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
As a result of the randomization, seven subjects received capsaicin on different sides in experiments 1 and 2. Four subjects received capsaicin on the same side and one subject in each experiment participated in only one experiment.

There was a significant increase in the TPT (Table 1) after infiltration of lidocaine (P<0.01, paired t-test). Ketamine did not change the TPT, whereas saline increased it significantly (P<0.05, paired t-test) in experiment 2.


View this table:
[in this window]
[in a new window]
 
Table 1 Tactile pain threshold (TPT/g; mean (SEM)). *P<0.05 (paired t-test), before versus after subcutaneous infiltration (n=12)
 
Mean VAS scores for spontaneous pain (Table 2) immediately after subcutaneous infiltration of lidocaine were significantly lower than after saline infiltration in experiment 1 (P<0.01, paired t-test). Mean VAS scores after subcutaneous infiltration of ketamine were significantly higher than those after saline infiltration in experiment 2 (P<0.01, paired t-test). There were no significant differences in mean VAS scores after subcutaneous saline in experiments 1 and 2. Pain induced by infiltration was short-lasting and disappeared in most cases before injection of capsaicin. Ketamine gave rise to slight pain when capsaicin was injected (VAS scores 7 and 8) in only two out of 24 subjects. Lidocaine gave rise to pain in one subject out of 24 (VAS score 28), whereas saline-induced pain ceased in all subjects before the injection of capsaicin.


View this table:
[in this window]
[in a new window]
 
Table 2 VAS pain score (0–100) after subcutaneous infiltration of lidocaine, ketamine and saline. *P<0.05 (paired t-test), active drug versus saline
 
Lidocaine, but not ketamine, reduced the VAS score for spontaneous pain induced by intradermal capsaicin significantly (ANOVA RM, P<0.001; Dunnett’s test, P<0.05, lidocaine versus saline) (Fig. 1).



View larger version (16K):
[in this window]
[in a new window]
 
Fig 1 Spontaneous pain intensity plotted as mean VAS pain score±SEM. Pain was reduced by pretreating the capsaicin injection site with local s.c. infiltration of lidocaine (A), but s.c. infiltration of ketamine (B) did not reduce pain (ANOVA RM, P<0.001; P<0.05 lidocaine vs saline).

 
Lidocaine reduced the VAS score for brush-evoked pain significantly (ANOVA RM, P<0.001; Dunnett’s test, P<0.05, lidocaine versus saline), whereas ketamine produced no effect on brush-evoked pain (Fig. 2).



View larger version (15K):
[in this window]
[in a new window]
 
Fig 2 Brush-evoked pain intensity plotted as mean VAS pain score±SEM. Pain was reduced by pretreating the capsaicin injection site with local s.c. infiltration of lidocaine (A), but s.c. infiltration of ketamine (B) did not reduce pain (ANOVA RM, P<0.001; P<0.05 lidocaine vs saline).

 
The VAS score for punctate-evoked pain at the 3 cm point were reduced significantly by lidocaine (ANOVA RM, P<0.001; Dunnett’s test, P<0.05, lidocaine versus saline). The effect of ketamine was similar to saline (Fig. 3).



View larger version (15K):
[in this window]
[in a new window]
 
Fig 3 Punctate-evoked pain intensity plotted as mean VAS pain score±SEM. Pain was reduced by pretreating the capsaicin injection site with local s.c. infiltration of lidocaine (A), but s.c. infiltration of ketamine (B) did not reduce pain (ANOVA RM, P<0.001; P<0.05 lidocaine vs saline).

 
Lidocaine, but not ketamine, reduced the area of brush-evoked hyperalgesia significantly (ANOVA RM, P<0.001; Dunnett’s test, P<0.05, lidocaine versus saline) (Fig. 4).



View larger version (16K):
[in this window]
[in a new window]
 
Fig 4 The area of brush-evoked hyperalgesia (mean±SEM) was reduced by pretreatment of the capsaicin injection site with local s.c. infiltration of lidocaine (A), but s.c. infiltration of ketamine (B) did not reduce the area (ANOVA RM, P<0.001; P<0.05 lidocaine vs saline).

 
Lidocaine reduced the area of punctate-evoked hyperalgesia significantly, whereas ketamine had no effect (ANOVA RM, P<0.001; Dunnett’s test, P<0.05, lidocaine versus saline) (Fig. 5).



View larger version (17K):
[in this window]
[in a new window]
 
Fig 5 The area of punctate-evoked hyperalgesia (mean±SEM) was reduced by pretreating the capsaicin injection site with local s.c. infiltration of lidocaine (A), but s.c. infiltration of ketamine (B) did not reduce the area (ANOVA RM, P<0.001; P<0.05 lidocaine vs saline).

 
Because 11 of 12 subjects participated in both trials, it was possible to look for systemic effects of ketamine and lidocaine. There were no differences in capsaicin-induced pain and evoked pain scores when the capsaicin injection site was pretreated with saline and the contralateral injection was of either ketamine or lidocaine. Mean values of both brush-evoked pain (ANOVA RM, P=0.33) and punctate-evoked pain tended to be lower when the contralateral side was pretreated with ketamine than when it was treated with lidocaine, although the difference did not reach significance (Fig. 6).



View larger version (15K):
[in this window]
[in a new window]
 
Fig 6 The effects of local infiltration of lidocaine and ketamine contralateral to the capsaicin injection site on VAS pain scores (mean±SEM). Placebo (saline) was injected at the capsaicin injection site. (A) Spontaneous pain. (B) Brush-evoked pain. (C) Punctate-evoked pain.

 
There were no differences in mean areas of brush-evoked and punctate-evoked hyperalgesia when the side contralateral to the capsaicin site was pretreated with ketamine or lidocaine. Mean areas of brush-evoked hyperalgesia (ANOVA RM, P=0.20) and punctate-evoked hyperalgesia (ANOVA RM, P=0.21) tended to be lower when ketamine was injected contralateral to the capsaicin site than when lidocaine was injected, but none of the differences reached significance (Fig. 7).



View larger version (18K):
[in this window]
[in a new window]
 
Fig 7 The effects of local s.c. infiltration of lidocaine and ketamine contralateral to the capsaicin injection site on the area of hyperalgesia (mean±SEM). Placebo (saline) was injected at the capsaicin injection site. (A) Brush-evoked hyperalgesia. (B) Punctate-evoked hyperalgesia.

 
Lidocaine and saline produced no side-effects, whereas paraesthesia, dizziness and sleepiness were seen in six out of 24 cases (25%) after ketamine. Side-effects occurred 5–10 min after subcutaneous injection and lasted up to 30 min.


    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Hyperexcitability has peripheral and central components, and it is well established that central hyperexcitability is mediated partly by NMDA receptor-linked systems.1 36 30 The recent anatomical demonstration of NMDA receptors in the peripheral nervous system in animals has raised the possibility that peripheral NMDA receptors, in addition to centrally located NMDA receptors, are involved in pain and hyperalgesia.2022 31 Using a burn injury model, Warncke and colleagues23 found that the non-competitive NMDA receptor antagonist ketamine blocked the development of punctate hyperalgesia and wind-up phenomena. In a similar human burn injury model, Pedersen and colleagues24 showed that ketamine had a transient antinociceptive effect. In the present study, using a capsaicin model, we failed to find an effect on pain and secondary hyperalgesia after local infiltration of the skin with ketamine before injury. Our finding confirms the observations of others.32 Hence, under these conditions peripheral NMDA receptor systems do not seem to be involved in pain and hyperalgesia. In contrast to the effect of ketamine, local infiltration of lidocaine into the skin before injury blocked spontaneous pain and evoked pain and almost abolished areas of hyperalgesia, indicating that the capsaicin model is a sensitive model and is amenable to modulation by a peripherally acting agent.

All three treatments (ketamine, lidocaine and saline) had a slight pain-inducing effect after skin infiltration. Lidocaine produced the lowest and ketamine the highest pain rating, but all mean pain scores were below 30 and the pain disappeared after a few minutes. Thus, it is unlikely that the different effects of ketamine and lidocaine on hyperalgesia found in this study can be explained by different pain-inducing effects of each treatment. Similarly, it is unlikely that the different pain response produced by each treatment could have violated the blinding of the study, because saline was used as a separate control in both experiments and saline gave rise to a mean VAS pain rating between 17 and 20. Furthermore, all pain scores were in the lower third of the VAS scale, precluding the possibility that the subjects and examiner distinguished between the treatments.

In accordance with previous studies,27 infiltration with lidocaine increased TPT while infiltration with ketamine did not change TPT. Previous reports on tactile thresholds in the burn injury model differ. Warncke and colleagues23 found unchanged tactile thresholds after local infiltration with ketamine. This finding was in contrast to the increased tactile thresholds reported by Pedersen and colleagues.24 Differences in pain models, dosage and timing of injury and ketamine may explain this discrepancy. In experiment 2, saline increased TPT. The reason for elevation in the pain threshold is unclear, but a DNIC (diffuse noxious inhibitory controls) effect33 34 is a possibility. Alternatively, it is possible that the assessment was done in a slightly different area. Some variation in TPT between experiments 1 and 2 before subcutaneous infiltration seems to be present. In experiment 1 the first injection site was 5 cm proximal to the wrist. The injection site was moved 1 cm at each session in order to prevent injection at the same site. It is therefore unlikely that desensitization of the skin can account for the difference in TPT found in the present study. A prolonged effect of subcutaneous lidocaine is also an unlikely explanation for the difference in TPT, because the subcutaneous injection evoked a pain score similar to that reported by others.24 It is possible that the skin closer to the wrist is more sensitive to punctate stimuli than more proximal skin.

Locally administered lidocaine inhibits afferent nerve conduction, including nociceptor activity.35 In the present study, secondary hyperalgesia was almost abolished by lidocaine. This observation is in line with earlier findings reported by LaMotte and colleagues3 in the capsaicin model and with later observations in the burn injury model.23 27 The peripheral activation required to develop hyperalgesia is not clear. The observation that both brush and punctate hyperalgesia were abolished despite ongoing pain suggests that a prerequisite for secondary hyperalgesia is an afferent nociceptive drive of sufficient magnitude to generate secondary hyperalgesia (in this case punctate- and brush-evoked hyperalgesia). Our findings are in contrast to findings reported by Cervero and colleagues,36 who observed the development of mechanical hyperalgesia to punctate and stroking stimuli after the application of prolonged non-painful heat stimuli in healthy subjects, whereas others suggest that hyperalgesia to brush but not punctate stimuli depend critically on persistent nociceptive activity of C fibres.2 37

In addition to its opioid interaction38 and sodium channel-blocking properties,39 40 ketamine also has affinity for the NMDA receptor complex, where it exerts a non-competitive block. Experimental12 13 15 17 and clinical10 11 14 16 studies have clearly documented the ability of systemically administered ketamine to block various manifestations of central sensitization. Previous studies have suggested that peripherally administered ketamine, with an action that is presumably limited to the periphery, can also block pain and sensitization.23 24 The failure to see an effect of peripherally administered ketamine in the present study is in accordance with a preliminary report by Koppert and colleagues32 in the capsaicin model, but at variance from those reported by others in a burn model.23 24 The explanation for the transient reduction in spontaneous pain24 and more prolonged reduction of evoked pain23 and the failure to see an effect in the present study is not clear. However, there are important differences between these studies. First, differences in the method of eliciting pain and hyperalgesia is one possibility. Mild painful heat stimuli activate C-mechano-heat (CMH) nociceptors.41 The increased nociceptive input induces central sensitization, which is reflected in secondary hyperalgesia to mechanical stimuli. In contrast, capsaicin activates capsaicin-sensitive CMH nociceptors and capsaicin-sensitive A{delta} primary sensory neurones, and a recent study suggests that punctate hyperalgesia is mediated by capsaicin-insensitive A{delta}-fibres.42 These findings suggest that the mechanisms underlying the central sensitization induced by burn injury and capsaicin may be different. We measured four parameters of secondary hyperalgesia (scores for pain evoked by brush and punctate stimuli and areas of brush- and punctate-evoked hyperalgesia) and did not find any effect of ketamine. In the study by Warncke and colleagues,23 in which punctate-evoked hyperalgesia and wind-up-like pain were reduced, pain was induced in both calves simultaneously, but it may be difficult to distinguish stimuli when pain is felt in two regions. Their design was sensitive to a systemic effect of ketamine. Since saline-treated injuries were compared directly with ketamine-treated injuries in the same session, the effect observed may be systemic as well as peripheral. With the present study design, it was possible to control for a systemic effect of ketamine by comparing capsaicin-induced hyperalgesia in two separate sessions.

It may be argued that a reduced capsaicin response with repeated dosing and lack of counterbalance influenced the present results. We consider this unlikely. Capsaicin injections and drug infiltration were moved 1 cm in each session to prevent injection into the same site. In a recent study, we found an unchanged capsaicin response after repeated doses.43 Finally, the pain intensity in experiment 2 was similar to that reported by Pedersen and colleagues.24 It may be argued that the greater area of hyperalgesia induced by capsaicin injected into saline-pretreated skin in the lidocaine group than by injection into saline-pretreated skin in the ketamine group may have biased our results in favour of lidocaine. Our study design was sensitive to a systemic effect of ketamine, and we suggest that the smaller area induced in saline-pretreated skin in the ketamine group may have been caused by the systemic effect of ketamine. Despite an almost similar VAS score in the two sessions in experiment 2, one possibility is that local treatment with ketamine 5 mg may produce a systemic plasma concentration that is not sufficient to reduce the intense pain induced by capsaicin but is adequate to reduce the manifestations of central hyperexcitability.

In our study, dizziness, paraesthesia and sleepiness were reported in 25% of all cases after local ketamine, symptoms that are similar to those reported after i.v. ketamine.10 12 14 16 17 No subjects reported side-effects in the study by Warncke and colleagues,24 but in the study by Pedersen and colleagues24 the frequency of side-effects was high. Our dose of ketamine was similar to the dose used by Warncke and colleagues,23 whereas a higher dose was used by Pedersen and colleagues,24 which may explain the higher frequency of side-effects in the latter study. It is unlikely that the lack of effect of ketamine in our study can be explained by the use of a dose of ketamine that was too low, because it was sufficient to produce slight systemic side-effects. Furthermore, we did find a reduction, albeit insignificant, in capsaicin-induced pain and hyperalgesia in skin pretreated with saline and ketamine contralaterally to the capsaicin site compared with lidocaine contralateral to the capsaicin site. Taking these results together, it is likely that in the capsaicin model peripherally administered ketamine exerts its antinociceptive and antihyperalgesic actions by a systemic mechanism when it is injected s.c.


    Acknowledgements
 
This study was supported by grants from the Danish Pain Research Center, the Danish Cancer Society (grant 78400) and the Danish Medical Research Council (grant 120828-1).


    Footnotes
 
* Corresponding author: Danish Pain Research Center, Building 1C, Aarhus Kommunehospital, DK-8000 Aarhus C, Denmark Back


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
1 Kilo S, Schmelz M, Koltzenburg M, Handwerker HO. Different patterns of hyperalgesia induced by experimental inflammation in human skin. Brain 1994; 117: 385–96[Abstract]

2 Koltzenburg M, Torebjörk HE, Wahren LK. Nociceptor modulated central sensitization causes mechanical hyperalgesia in acute chemogenic and chronic neuropathic pain. Brain 1994; 117: 579–91[Abstract]

3 LaMotte RH, Shain CN, Simone DA, Tsai E-FP. Neurogenic hyperalgesia: psychophysical studies of underlying mechanisms. J Neurophysiol 1991; 66: 190–211[Abstract/Free Full Text]

4 Simone DA, Baumann TK, Collins JG, LaMotte RH. Sensitisation of cat dorsal horn neurons to innocuous mechanical stimulation after intradermal capsaicin. Brain Res 1989; 486: 185–9[ISI][Medline]

5 Simone DA, Sorkin LS, Oh U, Chung JM, LaMotte RH, Willis WD. Neurogenic hyperalgesia: central neural correlates in responses of spinothalamic tract neurones. J Neurophysiol 1991; 66: 228–45[Abstract/Free Full Text]

6 Torebjörk HE, Lundberg LER, LaMotte RH. Central changes in processing of mechanoreceptive input in capsaicin-induced secondary hyperalgesia in humans. J Neurophysiol 1992; 448: 765–80

7 Davidson EM, Coggeshall RE, Carlton SM. Peripheral NMDA and non-NMDA glutamate receptors contribute to nociceptive behaviours in rat formalin test. Neuroreport 1997; 8: 941–6[ISI][Medline]

8 Mao J, Price DD, Hayes RL, Lu J, Mayer DJ, Frenk H. Intrathecal treatment with dextrorphan or ketamine potently reduces pain-related behaviours in rat models of peripheral mononeuropathy. Brain Res 1993; 605: 164–8[ISI][Medline]

9 Nagasaka H, Nagasaka I, Sato I, Matsumoto N, Matsumoto I, Hori T. The effect of ketamine on the excitation and inhibition of dorsal WDR neuronal activity induced by bradykinin injection into femoral artery in cats after spinal cord transection. Anesthesiology 1993; 78: 722–32[ISI][Medline]

10 Eide PK, Jørum E, Stubhaug A, Bremnes J, Breivik H. Relief of post-herpetic neuralgia with the N-methyl-D-aspartic acid receptor antagonist ketamine: a double-blind, cross-over comparison with morphine and placebo. Pain 1994; 58: 347–54[ISI][Medline]

11 Felsby S, Nielsen J, Arendt-Nielsen L, Jensen TS. NMDA receptor blockade in chronic neuropathic pain: a comparison of ketamine and magnesium chloride. Pain 1995; 64: 283–91[ISI]

12 Gottrup H, Hansen PO, Arendt-Nielsen L, Jensen TS. Differential effects of systemic administered ketamine and lidocaine on dynamic and static hyperalgesia induced by intradermal capsaicin in humans. Br J Anaesth 2000; 85: 155–63

13 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[Abstract/Free Full Text]

14 Max MB, Byas-Smith MG, Gracely RH, Bennett GJ. Intravenous infusion of the NMDA antagonist, ketamine, in chronic posttraumatic pain with allodynia: a double-blind comparison to alfentanil and placebo. Clin Neuropharmacol 1995; 18: 360–8[ISI][Medline]

15 Park KM, Max MB, Robinovitz E, Gracely RH, Bennett GJ. Effects of intravenous ketamine, alfentanil, or placebo on pain, pinprick hyperalgesia, and allodynia produced by intradermal capsaicin in human subjects. Pain 1995; 63: 163–72[ISI][Medline]

16 Nikolajsen L, Hansen CL, Nielsen J, Keller J, Arendt-Nielsen L, Jensen TS. The effect of ketamine on phantom pain: a neuropathic disorder maintained by peripheral input. Pain 1996; 67: 69–77[ISI][Medline]

17 Warncke T, Stubhaug A, Jørum E. Ketamine, an NMDA receptor antagonist, suppresses spatial and temporal properties of burn-injured secondary hyperalgesia in man: a double-blind, cross-over comparison with morphine and placebo. Pain 1997; 72: 99–106[ISI][Medline]

18 Chaplan SR, Malmberg AB, Yaksh TL. Efficacy of spinal NMDA receptor antagonism in formalin hyperalgesia and nerve injury evoked allodynia in the rat. J Pharmacol Exp Ther 1997; 280: 829–38[Abstract/Free Full Text]

19 Woolf CJ, Thompson SWN. The induction and maintenance of central sensitisation is dependent on N-methyl-D-aspartic acid receptor activation; implications for the treatment of post-injury pain hypersensitivity states. Pain 1991; 44: 293–9[ISI][Medline]

20 Carlton SM, Hargett GL, Coggeshall RE. Localization and activation of glutamate receptors in unmyelinated axons of rat glabrous skin. Neurosci Lett 1995; 197: 25–8[ISI][Medline]

21 Lawand NB, Willis WD, Westlund KN. Excitatory amino acid receptor involvement in peripheral nociceptive transmission in rats. Eur J Pharmacol 1997; 324: 169–77[ISI][Medline]

22 Zhou S, Bonasera L, Carlton SM. Peripheral administration of NMDA, AMPA or KA results in pain behaviours in rats. Neuroreport 1996; 7: 895–90[ISI][Medline]

23 Warncke T, Jørum E, Stubhaug A. Local treatment with N-methyl-D-aspartate receptor antagonist ketamine inhibits development of secondary hyperalgesia in man by a peripheral action. Neurosci Lett 1997; 227: 1–4[ISI][Medline]

24 Pedersen JL, Galle TS, Kehlet H. Peripheral analgesic effect of ketamine in acute inflammatory pain. Anesthesiology 1998; 89: 58–66[ISI][Medline]

25 Coderre TJ, Melzack R. Cutaneous hyperalgesia: contributions of the peripheral and central nervous system to the increase in pain sensitivity after injury. Brain Res 1987; 404: 95–106[ISI][Medline]

26 Coderre TJ, Vaccarino AL, Melzack R. Central nervous system plasticity in the tonic pain response to subcutaneous formalin injection. Brain Res 1990; 535: 155–8[ISI][Medline]

27 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[ISI][Medline]

28 Simone DA, Baumann TK, LaMotte RH. Dose-dependent pain and mechanical hyperalgesia in humans after intradermal injection of capsaicin. Pain 1989; 38: 99–107[ISI][Medline]

29 Dixon WJ. The up-and-down method for small samples. Am Stat Assoc J 1965; 60: 967–78

30 Koltzenburg M, Lundberg LER, Torebjörk HE. Dynamic and static components of mechanical hyperalgesia in human hairy skin. Pain 1992; 51: 207–19[ISI][Medline]

31 Davies SN, Lodge D. Evidence for involvement of N-methylaspartate receptors in ‘wind-up’ class 2 neurones in the dorsal horn of the rat. Brain Res 1987; 42: 402–6

32 Koppert W, Likar R, Zeck S. Intracutaneous fentanyl and ketamine do not alter capsaicin induced hyperalgesia. Anesthesiology 1998; 89: abstract 1101

33 Le Bars D, Dickenson AH, Besson JM. Diffuse noxious inhibitory controls (DNIC): II. Effect on dorsal horn convergent neurones in the rat. Pain 1979; 6: 283–304[ISI][Medline]

34 Le Bars D, Dickenson AH, Besson JM. Diffuse noxious inhibitory controls (DNIC): I. Lack of effect on non-convergent neurones, supraspinal involvement and theoretical implications. Pain 1979; 6: 305–27[ISI][Medline]

35 Butterworth JF, Strichartz GR. Molecular mechanisms of local anaesthesia: a review. Anesthesiology 1990; 72: 711–34[ISI][Medline]

36 Cervero F, Gilbert R, Hammond RGE, Tanner J. Development of secondary hyperalgesia following non-painful thermal stimulation of the skin: a psychophysical study in man. Pain 1993; 54: 181–9[ISI][Medline]

37 Gracely RH, Lynch SA, Bennett GJ. Painful neuropathy: altered central processing maintained dynamically by peripheral input. Pain 1992; 51: 175–94[ISI][Medline]

38 Husveit O, Maurset A, Oye I. Interaction of chiral forms of ketamine with opioid, phencyclidine, sigma and muscarinic receptors. Pharmacol Toxicol 1995; 77: 355–9[ISI][Medline]

39 Dowdy EG, Kaya K, Gocho Y. Some pharmacologic similarities of ketamine, lidocaine and procaine. Anesth Analg 1973; 52: 839–42[ISI][Medline]

40 Frenkel C, Urban BW. Molecular actions of racemic ketamine on human CNS sodium channels. Br J Anaesth 1992; 69: 292–7[Abstract]

41 LaMotte RH, Thalhammer JG. Peripheral neural mechanisms of cutaneous hyperalgesia following mild injury by heat. J Neurosci 1982; 2: 765–81[Abstract]

42 Magerl W, Fuchs PN, Meyer RA, Treede R-D. Secondary hyperalgesia to punctate stimuli in humans is mediated by capsaicin-insensitive A-fiber nociceptors. 9th World Congress on Pain 1999: abstract 102

43 Witting N, Svensson P, Arendt-Nilesen L, Jensen TS. Repetitive intradermal capsaicin: differential effect on pain and areas of allodynia and punctate hyperalgesia. Somatosens Mot Res. In press