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 SensoryMotor Interaction, Aalborg University, Denmark
Accepted for publication: March 29, 2000
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Abstract |
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Br J Anaesth 2000; 85: 5208.
Keywords: pain, capsaicin; hyperalgesia; anaesthetics local, lidocaine; anaesthetics i.v., ketamine
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Introduction |
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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.
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Materials and methods |
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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 ml1. 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 2022°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 (SemmesWeinstein 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 0100, 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 12 cm s1 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 s1. 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 s1. 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 KolmogorovSmirnov 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 Dunnetts method. Data are presented as mean (SEM). P-values less than 0.05 were considered to be statistically significant.
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Results |
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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.
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Discussion |
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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 primary sensory neurones, and a recent study suggests that punctate hyperalgesia is mediated by capsaicin-insensitive A
-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.
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Acknowledgements |
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Footnotes |
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References |
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