Anesth Analg 2004;99:816-822
© 2004 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000132995.35119.99
PAIN MEDICINE
The Effect of Intravenous Infusion of Adenosine on Electrically Evoked Hyperalgesia in a Healthy Volunteer Model of Central Sensitization
Boris A. Chizh, MD PhD*,
Martin Dusch
,
Martin Puthawala,
Martin Schmelz, MD PhD,
Louise M. Cookson*,
Reynaldo Martina
,
John Brown, MD*, and
Wolfgang Koppert, MD
*Translational Medicine and
Statistics, GlaxoSmithKline, Cambridge, United Kingdom; and
Department of Physiology, University of Erlangen, Erlangen, Germany
Address correspondence and reprint requests to Boris A. Chizh, MD, PhD, GlaxoSmithKline, Addenbrooke’s Centre for Clinical Investigation, Hills Rd., Cambridge CB2 2GG, UK. Address e-mail to Boris_A_Chizh{at}gsk.com
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Abstract
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Human pain models invoking central sensitization, one of the key mechanisms of chronic pain, may be useful for characterizing new analgesics. A new model of electrical hyperalgesia can detect the efficacy of several analgesic mechanisms. Because IV adenosine can alleviate neuropathic pain, we investigated its effect on experimental sensitization. This was a double-blinded, randomized, two-period crossover study in 20 healthy volunteers. Current pulses (0.5 ms; 1 Hz) were applied intracutaneously to achieve pain rating of 
5 on a 0–10 numeric rating scale. Pain, areas of pinprick hyperalgesia, and tactile allodynia were assessed during the 2.5-h stimulation period. Adenosine (50 µg · kg–1 · min–1) and placebo were infused IV over 60 min. Additional testing was performed 24 h after each treatment. Adenosine reduced the area of pinprick hyperalgesia during the infusion compared with placebo; there was no significant effect on tactile allodynia or pain rating. The effect on hyperalgesia developed over 15 min and was significant (P 
0.05) for the rest of the infusion period. There was no difference between treatments at 24 h. Thus, in accordance with reports on neuropathic pain, adenosine reduced central sensitization in the human model of electrical hyperalgesia. However, adenosine did not have the long-term effects seen in patients. The model can investigate mechanisms of drugs for the treatment of chronic pain.
IMPLICATIONS: A controlled study of IV adenosine in a healthy volunteer model of electrically evoked hyperalgesia demonstrated a reduction of measures of central sensitization, a key mechanism of neuropathic pain. Because adenosine can alleviate neuropathic pain in patients, the model may be useful for early characterization of new treatments for this indication in humans.
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Introduction
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Central sensitization plays a key role in the development and maintenance of a wide variety of chronic pain states (1,2). Human models of central sensitization may, therefore, help to ensure translation into humans of analgesic mechanisms discovered in animal models of pain. A model of electrically evoked pain and hyperalgesia has been developed that appears to have some advantages over other models of pronociceptive sensitization (3). It involves repetitive intracutaneous electrical stimulation over a few hours by highly localized current pulses. This stimulation is likely to activate a wide spectrum of primary afferents, including the populations of A- and C-fibers that are thought to play important roles in chronic pain and hyperalgesia (4,5). Furthermore, the frequency of this stimulation broadly mimics the frequencies of ectopic discharge observed in patients with neuropathic pain (6) and is known to be able to evoke temporal summation and windup in humans in a variety of experimental conditions (7). By way of model characterization, the efficacy of some important analgesic mechanisms has been studied and confirmed in this model (3). These include opioid agonism, N-methyl-D-aspartic acid (NMDA) antagonism, and sodium channel blockade, all of which are effective in neuropathic pain in patients. To further evaluate the utility of this model for development of compounds for neuropathic pain indications, it appeared important to study another analgesic mechanism with demonstrated efficacy in neuropathic pain. Several studies have reported that adenosine can alleviate symptoms of neuropathic pain in patients (8–11), as well as in animal models of mononeuropathy (12,13). However, the results of adenosine studies in volunteer models of persistent pain are somewhat discordant (14,15). One potential reason is different balances of central sensitization versus other mechanisms in these models. The aim of this study, therefore, was to investigate the effect of infusing a clinically effective dose of IV adenosine on measures of central sensitization evoked by afferent electrical stimulation in healthy volunteers. Furthermore, we sought to assess the potential long-lasting effects of adenosine as reported in some neuropathic pain patients (8–10). The results of this study have been published in abstract form (16,17).
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Methods
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Twenty healthy volunteers (10 women and 10 men; age range, 20–41 yr; mean ± SEM, 29 ± 1.14 yr) participated in this study. All subjects were familiar with the described stimulation procedures. Each subject gave written, informed consent before taking part in the study. The study was performed in accordance with good clinical practice guidelines and, where applicable, the 1996 version of the Declaration of Helsinki; the experimental protocol was approved by the Ethics Committee of the University of Erlangen-Nuremberg and an internal protocol review group of GlaxoSmithKline.
Electrical stimulation was performed as previously described (3), with some modifications. Two microdialysis probes fitted with an internal stainless-steel wire (Dermal Dialysis, Erlangen, Germany) were inserted intracutaneously (depth, 0.5 mm; length, 1 cm; 5–8 mm apart) into the central volar forearm of one arm. After a baseline period of 5 min, current pulses (0.5-ms width; 1 Hz) of alternating polarity were applied via a constant current stimulator (Digitimer DS7; Hertfordshire, UK). During the first 15 min of stimulation, the current was gradually increased to achieve a continuing pain rating of 5 on a 0–10 numeric rating scale (0 = no pain and 10 = maximum pain imaginable) and then was kept constant for the rest of the experiment. These settings were recorded during the first stimulation session and were used in all subsequent sessions.
Mechanical hyperalgesia was assessed with punctate (pinprick) stimulation by a 450-mN von Frey filament (Stoelting); tactile allodynia was measured by stroking the skin with a cotton bud at 1 cm/s. The borders of hyperalgesic and allodynic areas were delineated along eight radial axes with the stimulation site at the center. The testing began at distant points moving toward the center until the subject reported increased sharpness of the pinprick stimulus (mechanical hyperalgesia) or unpleasant sensations caused by the cotton bud (dynamic tactile allodynia). The areas of hyperalgesia and allodynia were assessed at regular intervals during the 2.5-h stimulation period (Table 1). The size of the areas was calculated as follows.
For the 8 vector lines a to h, 8 new vector lines were calculated on the basis of the distances along the original vector lines:
The area was then calculated as
The potential interaction of adenosine with nociceptors in the periphery was assessed by laser Doppler imaging of superficial cutaneous blood flow of the stimulated arm (LDI Moor Instruments Ltd., Devon, UK). An area of 16 x 8 cm around the stimulation site was scanned with a resolution of 22,400 pixels, with each pixel representing a separate Doppler flux measurement. Data were processed offline with dedicated software (MoorLDI Version 3.0; Moor Instruments Ltd). The flare area was calculated from all pixels around the stimulation site in which flux values exceeded the 95% percentile of the baseline distribution. Laser Doppler images were recorded as indicated in Table 1.
This was a double-blinded, randomized, two-period crossover study. Each subject participated in 2 experimental sessions separated by a 2-wk washout period; each session consisted of two assessment visits on consecutive days. On Days 1 and 14, subjects received 60-min IV infusions of either adenosine (Adrekar®; Sanofi Winthrop, France; 50 µg · kg–1 · min–1) or placebo (0.9% saline). The order in which they received the treatments was randomized (Table 1). The infusion was into the arm contralateral to the stimulated arm. The dose of adenosine was chosen on the basis of published data on safety and efficacy in neuropathic pain patients and volunteer models (8–10,14,18). An additional, shortened test (Days 2 and 15) was performed 24 h after each treatment to investigate the potential long-lasting effect of adenosine on experimental sensitization. No infusion was given during this test. Mean arterial blood pressure (MAP) and electrocardiogram were assessed at baseline and during the electrical stimulation (Table 1). The Bond and Lader mood rating scale (19) was used before, during, and after the infusion to assess the influence of adenosine on alertness and mood.
Comparisons of the areas of hyperalgesia, allodynia, and flare between treatment groups were performed by a mixed model repeated-measures analysis of variance (RM-ANOVA), fitting terms for period, treatment, and regimen. Subject was fitted as a random effect. The full model was used to investigate interactions. Treatment effects were based on the additive model. Pain ratings were analyzed by means of ANOVA. Measurements taken before the start of infusion on Days 1 and 14 were summarized per subject for each day (baseline). The baseline was added in the model as a covariate. The analysis was performed on absolute values; P values 0.05 were deemed significant. Throughout the article, the results are expressed as mean ± SEM; in figures, the data are expressed as mean absolute differences from the respective baseline (the last measurement before the infusion started).
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Results
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A total of 19 subjects were included in the analysis (1 subject did not develop any hyperalgesia). The mean current that was used in the first session to achieve a pain rating of 5 was 55.4 ± 5.9 mA (range, 16–99 mA). The same current was used in the subsequent sessions and produced very similar baseline pain ratings (data not shown). Consistent with the previous report on this model (3), pain ratings somewhat declined during the first 30 min of the stimulation (baseline), whereas the areas of hyperalgesia, allodynia, and flare increased over the same period (Fig. 1). The currents used in this study, as well as baseline values of hyperalgesia, allodynia, and flare, are similar to those reported in the previous study that used this model (Table 2) (3). There was no significant difference between the baseline values on Days 1 and 14.
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Figure 1. Areas of hyperalgesia (A) and allodynia (B) in the adenosine and placebo groups. The data are plotted as mean ± SEM changes from baseline for each time point; for each session, the values at the last time point before infusion (on Day 1) were taken as the baseline. The infusion period is indicated by the shaded area. *Statistically significant differences between groups (P 0.05; RM-ANOVA; n = 19; see text for details). Day 1 denotes the treatment session (adenosine or placebo, in a randomized order), and Day 2 corresponds to the additional test 24 h after the treatment.
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In the placebo group, the area of pinprick hyperalgesia continued to increase after the first 30 min of stimulation, reached a plateau during the first 5 min of the infusion, and remained relatively stable for the rest of this period (Fig. 1A). In the adenosine group, however, the area of hyperalgesia began to decline soon after the onset of infusion; the maximum effect was observed after 25 min of infusion (55 min after the start of stimulation; Fig. 1A). The difference between the adenosine and placebo groups was significant for the time points between 45 and 95 min after the onset of stimulation (P 0.05; F = 4.34; RM-ANOVA).
In the placebo group, the time course of the area of tactile allodynia was similar to that of pinprick hyperalgesia (i.e., increase during the first 30 min and plateau during the infusion; Fig. 1B). After the start of the infusion, there was a trend for a decline of the area of allodynia in the adenosine group (Fig. 1B). For this end-point, however, the difference between the treatment groups for the same time points (45–95 min after the stimulation started) was not significant (RM-ANOVA).
In both treatment groups, pain ratings declined slowly during the stimulation period. This time course was not changed by infusion of either adenosine or placebo (Fig. 2A); no significant difference was observed between the treatment groups for this end-point. With flare, the area also declined over the stimulation period after reaching a peak at baseline (Fig. 2B); there was no significant difference between groups. The flare intensity also did not differ between the groups (data not shown).
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Figure 2. Pain ratings (A) and areas of flare (B) in the adenosine and placebo groups. The data are plotted as mean ± SEM for each time point (n = 19). The infusion period is indicated by the shaded area. Day 1 denotes the treatment session (adenosine or placebo, in a randomized order), and Day 2 corresponds to the additional test 24 h after the treatment.
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When the electrical stimulation was repeated 24 h after the first session, the values for areas of hyperalgesia, allodynia, and flare and pain ratings at the beginning of the stimulation period (15- and 25-min time points) were similar to the baseline values (before the infusion) in the first session (Figs. 1 and 2 ). With both treatment groups, the time course of all these end points was also similar to that seen in the placebo group during the first session. None of the end points showed any difference between treatments at 24 h.
Adenosine infusion produced only minor changes in cardiovascular variables. Thus, the average MAP in the adenosine group increased from 87.6 ± 1.9 mm Hg at baseline to a maximum of 90.7 ± 1.9 mm Hg during the infusion; the respective values for the placebo group were 86.0 ± 2.1 mm Hg and 86.4 ± 2.3 mm Hg. Changes in heart rate were similarly minor in both groups (data not shown).
The composite alertness scores calculated from Bond and Lader mood rating scale were similar before, during, and after the infusion in both treatment groups (Table 3). One subject reported an episode of chest oppression during adenosine infusion. The intensity of this sensation was described as moderate. No other side effects were reported.
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Discussion
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To have a predictive value for patient conditions, healthy volunteer models must be able to mimic key mechanisms of chronic pain states. Central sensitization has been identified as the key contributor to pathophysiology of a broad variety of chronic pain conditions (1,2,20). The current view of neuropathic pain pathophysiology is that pain and hypersensitivity are largely driven by central sensitization, which is often maintained by peripheral input from injured nerves (21,22).
The electrical hyperalgesia model mimics the main symptoms of neuropathic pain—i.e., continuing pain, hyperalgesia, and allodynia—hyperalgesia and allodynia are viewed as measures of central sensitization (3,23). The main finding of this study is that IV adenosine can reduce measures of central sensitization in this model. The effect was related to the infusion of adenosine such that the reduction of the area of hyperalgesia was most pronounced and significant during the infusion (Fig. 2A). Although the reduction of the area of allodynia was not significant, there was a trend for an infusion-related effect (Fig. 2B). The less clear attenuation of allodynia may be explained by the higher variability of this end-point.
Our results are in accord with the published data from trials with adenosine in neuropathic pain patients. Thus, doses of IV adenosine similar to those used in our study attenuated hyperalgesia and allodynia in patients with various types of neuropathic pain (8–10). Analogous to our results, in a recent study in mixed-etiology neuropathic pain, pinprick hyperalgesia, but not touch-evoked allodynia, was significantly attenuated by adenosine (11). Although both of these sensory phenomena are centrally mediated, they involve activation of different types of sensory fibers in the periphery (5), thus suggesting a greater role of adenosine receptors in pathways activated by A
fibers.
Our results are in agreement with some, but not all, of the previously published data on adenosine in healthy volunteer models, which are somewhat discordant. Thus, in the heat/capsaicin model, no significant antihyperalgesic effect of IV infusion of adenosine (60 µg · kg–1 · min–1 over 85 min) was observed (15), whereas the same or smaller doses of this substance have been shown to have antihyperalgesic properties in the burn and mustard oil models of experimental hyperalgesia and allodynia (14). In the latter study, systemically administered adenosine appeared to inhibit central sensitization, because the area of secondary hyperalgesia was reduced without any change in spontaneous pain or primary hyperalgesia (14). This discrepancy may be related to different balances of central versus peripheral sensitization in different pain models. Thus, although the relative contribution of central and peripheral mechanisms has not been studied systematically across different models, there is evidence for peripheral mechanisms of sensitization in the capsaicin model (24). Adenosine is believed to reduce pronociceptive sensitization centrally by acting at A1 receptors in the central nervous system (CNS) (8,9,12), whereas it may be pronociceptive in the periphery (25). In the electrical hyperalgesia model, hyperalgesia and allodynia have been demonstrated to be mediated centrally (23). It is unlikely that adenosine could change the input into the CNS from peripheral fibers activated by the electrical stimulation, because no effect on electrically evoked flare was detected (Fig. 2B). Thus, it appears that the reduction of sensitization in the current study by IV adenosine was due to its central action. In line with this, studies with intrathecal administration of adenosine have also demonstrated antihyperalgesic and antiallodynic effects of the substance in other volunteer models of central sensitization (26,27).
On the basis of these findings, one can speculate that, although adenosine is known to be rapidly taken up from plasma by blood cells and tissues (28), sufficient amounts may be accumulated in the CNS after IV infusion to exert central effects. In previously published studies with IV adenosine, sensory testing was typically performed after 
45 minutes of infusion (14), and the time course of antihyperalgesic action of adenosine was not systematically examined. In this study, although some reduction of sensitization was apparent as early as 5 minutes after adenosine infusion, the maximum reduction of hyperalgesia during infusion was observed after 25 minutes (Fig. 1). The mechanisms by which adenosine may reach central sites after IV infusion are unclear. Several systems have been identified that transport nucleosides (including adenosine) across the blood-brain barrier (29). In addition, mechanisms dealing with efflux of endogenous adenosine from the brain have been described (30), and it is conceivable that exogenous adenosine may interfere with these mechanisms and lead to accumulation of adenosine in the brain and spinal cord. Given the nature of our study, we can only speculate that one or several of such mechanisms indeed take place; however, our data on the effects of adenosine on measures of central sensitization are best explained by this hypothesis.
One potential problem with studies of adenosine in pain models is that some of its central effects may change the subject’s assessment of pain and sensitization end-points. Thus, changes in alertness and sedation during adenosine infusion could have changed the reporting of pain, hyperalgesia, and allodynia and "unblinded" the subjects and/or operators. It seems unlikely, however, that this could have affected the results of this study. First, all volunteers were able to fully cooperate during the sensory testing. Second, no changes in the mood rating score (alertness, contentedness, or calmness) were observed during adenosine infusion compared with the saline-treated group. Third, only one subject reported a characteristic sensation of a moderate chest oppression during adenosine infusion. Last, a selective antihyperalgesic effect of adenosine makes generalized subjective bias due to unblinding implausible.
One of the objectives of our study was to investigate the potential long-term effects of a single adenosine infusion. Adenosine has an extremely short plasma half-life due to its rapid cellular uptake (28). Nevertheless, in a proportion of patients with neuropathic pain, the alleviation of pain and/or allodynia by short (40–60 minutes) IV infusion of adenosine has been reported to last for up to several weeks (8–11). A resetting of central hyperexcitability by centrally-acting adenosine has been suggested as a mechanism of this phenomenon (8,9). In the same vein, long-lasting pain relief of neuropathic pain has been reported after a single treatment with NMDA antagonists (31), and the short-acting NMDA antagonist (S)-ketamine was found to have a prolonged antihyperalgesic action in the electrical hyperalgesia model (3). In this study, although the maximum effect of adenosine was observed during the infusion, the time course did not appear to be as abrupt as could be expected from the known pharmacokinetics of adenosine (Fig. 1); a trend for antihyperalgesic action was noticeable for up to an hour after the infusion. However, when experimental sensitization was evoked 24 hours after the infusion, no difference was observed between the groups treated with adenosine and saline.
There are several potential explanations for the lack of long-term effects of adenosine in this study. The magnitude of the antihyperalgesic effect of adenosine in this study was apparently smaller compared with the effects of other antihyperalgesic mechanisms tested in this model (3). It is possible that the amount of adenosine that reaches the CNS after IV infusion was insufficient to bring about long-term downregulation of central hyperexcitability. With spinal adenosine, a long-lasting antiallodynic effect was observed after intrathecal administration of adenosine in rats with experimental neuropathy (12,13); the effect outlasted the duration of adenosine residence in the cerebrospinal fluid (13). In healthy volunteers, the alleviation of capsaicin-evoked tactile allodynia by spinal adenosine outlasted the duration of the increase of adenosine concentration in the cerebrospinal fluid (27). Another potential explanation for the lack of a long-lasting antihyperalgesic action of adenosine in our study is the relatively short duration of central sensitization in the electrical hyperalgesia model. In contrast to neuropathic pain conditions that last for years, experimental sensitization in this model is relatively short-lived (2.5 hours). It has been suggested that the continuing sensitization in neuropathic pain conditions takes a relatively long time to be reestablished after adenosine (8,9,12). Experimental sensitization, however, is evoked every time the electrical stimulation is applied, such that the level of hyperexcitability that develops 24 hours after adenosine is comparable to baseline. Interestingly, and in contrast to our findings, intrathecal adenosine was able to inhibit the development of capsaicin-evoked sensitization even 24 hours after the injection (27); the potential reasons for this discrepancy are a larger amount of adenosine in the CNS and a different intensity and time course of the sensitizing stimuli. It has also been suggested that the long duration of the antiallodynic action of adenosine could be due to repletion of internal adenosine stores in the pool of inhibitory interneurons (27). It is conceivable that any depletion of such inhibitory mechanisms by continuing nociceptive barrage will be greater in chronic pain states than in these relatively acute experimental conditions. Nevertheless, if the A1 receptor-mediated inhibition is responsible for a resetting of central hyperexcitability by centrally-acting adenosine, as has been suggested (8,9,12), then A1 receptor agonists with good central penetration can be expected to be effective in this model and can potentially exert longer-lasting antihyperalgesic effects.
In conclusion, in accordance with reports on neuropathic pain, IV adenosine reduced central sensitization in the healthy volunteer model of electrical hyperalgesia. However, adenosine did not have the long-term effects seen in patients. The model, therefore, mimics some of the mechanisms of sensitization in neuropathic pain and can be useful to characterize drugs for its treatment.
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Acknowledgments
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Supported by GlaxoSmithKline.
Sponsored by GlaxoSmithKline. We are grateful to Dr. Andrew Jackson for his help with the study.
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Accepted for publication March 12, 2004.
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Abstract
Introduction
