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© 1999 International Anesthesia Research Society
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Abstract |
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Adenosine and adenosine analogs decrease pain-like behavior in animal models of both acute nociceptive and neuropathic pain via adenosine receptor activation at spinal and/or supraspinal levels. This open study is the first in a series of intrathecal (IT) adenosine administration studied for the evaluation of efficacy and side effects in 14 patients. All had chronic neuropathic pain with tactile hyperalgesia and/or allodynia primarily of traumatic origin. The effects of IT adenosine (500 µg [n = 9] or 1000 µg [n = 5]) were evaluated. Approximate areas of tactile pain were mapped. Spontaneous and evoked pain (visual analog scale score 0–100) and tactile pain thresholds were assessed before and 60 min after injection. The injection caused transient pain (<60 min) in the lumbar region in five patients. There were no other side effects. Spontaneous and evoked pain was reduced (median score from 65 to 24 [P < 0.01] and from 71 to 12 [P < 0.01], respectively) in parallel with increased tactile pain thresholds in allodynic areas. Areas of tactile hyperalgesia/allodynia were reduced (median reduction 90%; P < 0.001). Twelve patients experienced pain relief (median 24 h). We conclude that IT adenosine transiently causes lumbar pain in a subgroup of patients and may reduce various aspects of chronic neuropathic pain.
Implications: This is the first series of patients with chronic neuropathic pain in which tolerability to spinal adenosine administration has been evaluated. A subset of patients reported transient low back pain as the only side effect. Spontaneous and evoked pain intensity decreased in most patients, an effect lasting for a median of 24 h.
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Introduction |
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Experimental research has demonstrated pain modulatory effects of the endogenous nucleoside adenosine and its adenosine receptor analogs (1), probably by activation of the antinociceptive adenosine A1-receptor within the central nervous system (CNS) (1–4). Animal studies using intrathecally (IT) administrated adenosine and adenosine receptor analogs in chronic models of neuropathic pain-like behavior have demonstrated that these drugs have antinociceptive effects, i.e., decrease in pain-like behavior, most likely mediated by activation of spinal adenosine receptors. The antinociceptive effects of IT administrated adenosine analogs (A1-receptor agonists) are seen in animal models of both peripheral nerve damage, such as incomplete sciatic nerve ligation (3–5), and central neuropathic pain states in a model of spinal cord ischemia (6). In addition, spinal adenosine A1-receptor activation potentiates spinal cord stimulation in mononeuropathic rats (4). A long-term toxicological test with adenosine (100 µg twice daily for 2 wk) has been performed in rats without morphological spinal cord damage (unpublished data).
Adenosine reduces pain symptoms in clinical pain states in humans by IV administration (7–10) and in experimental pain by IT administration (11). One healthy volunteer receiving IT adenosine (2000 µg) reported transient lumbar pain (11). There is only one published case report regarding IT adenosine injection, which describes a patient with secondary erythromelalgia and severe pain caused by polyneuropathy (12). The adenosine analog R-PIA has also been shown to reduce neuropathic pain symptoms in one patient (13). In the present study, the first in a series, patients were examined to evaluate tolerability and possible pain modulatory effects of IT adenosine on chronic intractable neuropathic pain involving tactile hyperalgesia and/or allodynia.
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Methods |
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The investigation was approved by the local human research ethics committee at the Karolinska Institute. The Swedish Medical Product Agency suggested the open study design because it was the first IT tolerability-safety study in patients, corresponding to a Phase I-II trial in the United States Food and Drug Administration nomenclature. Fourteen patients with chronic intractable neuropathic pain were included after obtaining written, informed consent. Demographic data are given in Table 1. The pain duration varied from 8 mo to 27 yr. The etiology of the chronic (duration >6 mo) neuropathic pain was posttraumatic, including entrapment and radiculopathy. The inclusion criteria were chronic neuropathic pain with documented tactile allodynia, dysesthesia or hyperalgesia for pinprick, and inadequate pain relief with conventional treatment, i.e., antidepressant and anticonvulsant drugs, as well as opioids, paracetamol, nonsteroidal antiinflammatory drugs,
-amino-butyric acid agonists, local anesthetic blockades, IV guanethidine blocks, acupuncture, transcutaneous electric nerve stimulation, and dorsal column stimulation. IV tests with ketamine and adenosine had been performed in some cases. When appropriate, the patients had been involved in physiotherapy programs. All patients had spontaneous (resting) pain, as well as different types of stimulus-evoked (provoked) pain. Twelve patients suffered from pain symptoms outside the distribution of the primary damaged nerve structure, indicating centralization. Patients 6 and 10 had marked loss of muscle strength (duration 1–2 yr) of the right arm and hand, most likely due to pain-induced motor inhibition. None of the patients had received caffeinated beverages within the 12 h before the IT injection. The patients were allowed concomitant drug treatment at a stable and regular dose for at least 3 wk before the study. Transcutaneous electric nerve stimulation and dorsal column stimulation were not used during the test period.
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Spontaneous and stimulus-evoked pain intensity were assessed using a visual analog scale (VAS). The scale consisted of a 100-mm horizontal line with 0 = "no pain" and 100 = "worst imaginable pain." The patients were instructed to move a vertical line placed on a transparent plastic lever sliding along the scale to a point representing their present pain intensity. Before each scoring event, the level was set at a VAS score of 50 by the investigator, thereby reducing the influence of preceding recordings (carry-over effect). The patients were informed that their pain could either increase, decrease, or be uninfluenced by the IT adenosine injection.
The tests were performed in a nonstressful environment by the same investigators. The painful procedures (evoked pain and tactile pain threshold) were performed after spontaneous pain assessment. The control regions were examined before the neuropathic area for sensory testing procedures. The patients was unable to observe assessments of the hypersensitive neuropathic skin areas and tactile pain thresholds (TPT). Before and approximately 60 min after the IT injection, the patients rated their pain and were subjected to examination of somatosensory functions (as described below). A camel hair brush (touch), disposable pins and 12-g von Frey filaments (pinprick), and metallic rollers (20°C and 40°C for temperature) were used for bedside sensory examination and as stimuli for evoked pain. The sensation in the neuropathic area was compared with a contralateral homologous area. In Patient 2, who had bilateral sensory disturbances, the abdomen was used as the control area. The sensation was graded as unaltered, hypoesthesia, hyperesthesia, hypoalgesia, hyperalgesia, allodynia, and dysesthesia (terms defined according to the International Association for the Study of Pain). Approximate areas with sensory disturbances, i.e., dysesthesia-allodynia-hyperalgesia, were obtained by mapping the regions with the bedside sensory testing procedures. The areas were measured with a tape measure, and the approximate surface was calculated in squared centimeters. Evoked pain intensity by tactile or other pain-inducing stimuli was recorded. Calibrated von Frey filaments were used to obtain thresholds for TPT. The filaments were applied to the skin in alternating ascending and descending order. The threshold is calculated from the average of the first stimulus in an ascending series of four to be felt as painful and the first stimulus in each of four descending series not to be felt as painful (i.e., mean of eight values).
Before the IT injection, an IV line was inserted into the cubital vein. IT adenosine was administered through a spinal needle (pencil-point type, 27-gauge) at the lumbar level, L2-3 to L4-5. A dose of 500 µg (n = 9) or 1000 µg (n = 5) was given (Item Development AB, Stocksund, Sweden) (adenosine 5000 µg/mL in isotonic mannitol diluted with isotonic saline to a final concentration of 250 or 500 µg/mL). The injected volume was 2 mL. Patients remained in a supine position for at least 0.5 h after the IT injection. Subjective symptoms of any kind were actively asked for and recorded. Follow-up data for pain relief and side effects were obtained by regular interviews (mostly by telephone). Duration of effects was based on patient reports that the pain condition had returned to its habitual state.
Data are presented as medians (range) for the VAS (spontaneous and evoked pain) and TPT, as well as for treatment-induced changes (in percentages) of VAS, TPT, and areas of hyperphenomena. Clinical treatment effect was defined as: 1) a reduction of VAS pain intensity by 
50%; 2) reduction of dysesthetic-allodynic-hyperalgesic area of 50%; and 3) a increase of TPT by 100%. Statistical evaluation of the data, before and after treatment, was performed by using Wilcoxon's matched pairs test.
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Results |
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Spontaneous pain before treatment was 65 (22–80) (n = 14), whereas evoked pain was 71 (33–100) (n = 12) (Fig. 1). TPT within allodynic and/or dysesthetic areas were 0.5 g (0.03–4.2 g) (n = 10) (Fig. 2). Approximate skin areas of sensory dysfunction ranged from 15 to 700 cm2 (data not shown).
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After the IT adenosine injection, there were no reports of nonspecific subjective symptoms such as tiredness, sedation, nausea, or malaise. Five patients (four receiving 500 µg and one receiving 1000 µg) (Table 2) experienced pain (maximal pain intensity VAS score 40–70) early after injection, starting within 5 min, then tapering off and vanishing within 30 (n = 4) and 60 (n = 1) min. The dull type of pain was clearly distinguishable from the patients' habitual neuropathic pain experience, and it occurred in a circular distribution around the lumbar part of the trunk and in the back of both legs. During the follow-up period, there was no report of any late side effects. There was no report of postspinal headache.
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Regarding spontaneous pain, no patient reported any influence of the IT adenosine injection during the first 15–20 min. Thereafter, patients indicated gradually reduced spontaneous pain over a period of approximately 30 min. Approximately 1 h after the injection, spontaneous and evoked pain and sensory testing were reassessed. As shown in Figure 1, most patients reported reduced spontaneous and evoked pain. According to the criteria for response, 9 of 14 reported
50% reduction of spontaneous pain (65 [22–80] vs 24 [0–70]; P < 0.01), and 9 of 12 had reduced evoked pain (71 [33–100] vs 12 [0–55]; P < 0.01). TPT increased in 9 of 10 patients with low thresholds (<10 g) (Fig. 2) (0.5 [0.03–4.2] vs 8.45 [0.2–100] g; P < 0.01). Approximate areas of allodynia-dysesthesia-hyperalgesia were reduced by 50% in 13 of 14 patients (Patient 9 had a 30% reduction) (Table 2) (100% vs 10% [0%–70%]; P < 0.001). Patients 4 and 9 reported lack of any beneficial effect with respect to both spontaneous and evoked pain, although Patient 4 had a reduced area of tactile allodynia (Table 2). Patients 6 and 10, both of whom had pain-induced inhibition of motor function of the right arm, experienced fully restored muscle strength and mobility after the administration of adenosine, an effect that lasted during the period of pain relief. In those 12 patients who responded with pain relief and improved motor function, the duration of reported clinical effect ranged from 10 h to 6 days, with a median of approximately 24 h (Table 2). |
Discussion |
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The major finding of this tolerability study was that IT adenosine 500-1000 µg induced a transient lumbar pain reaction in a subset of patients. This reaction occurred without an apparent dose-response relationship. Further, the IT adenosine injection was associated with reduced spontaneous and evoked pain intensity in most patients. In parallel, adenosine also increased TPT, as assessed by using von Frey filaments, and reduced the area of allodynia-dysesthesia-hyperalgesia.
In five patients, the adenosine injection was associated with transient pain symptoms localized to the lumbar region. In patients who experienced a painful side effect, there was no apparent dose relationship because most had received the smaller dose. This transient pain in patients, along with the earlier finding of lumbar pain symptoms after an IT adenosine injection in one healthy volunteer receiving 2000 µg (11), suggests that adenosine has some direct influence on the nervous system at high concentrations in the cerebrospinal fluid (CSF) early after injection. The mechanism for this pain reaction is not evident. Because it is a transient effect localized to the spinal segments adjacent to the site of injection, exogenous adenosine may locally stimulate primary afferents of the dorsal root ganglia or may act by direct influence at superficial layers of the spinal cord. Adenosine A2-receptors may be involved in the peripheral algogenic effect of adenosine (1), and adenosine action at this receptor might also be involved in the transient pain-inducing effect at the spinal cord level. Another possibility could be that adenosine produces a meningeal vasodilatation via A2-receptor activation, leading to transient, migraine-equivalent pain. It has been reported that the IT injection of an adenosine A1-receptor agonist (R-PIA) causes vasodilation of the spinal cord in rats (14). Finally, because rodent toxicological safety data suggest a lack of nerve damage after long-term IT adenosine administration (at a dose that, on a weight basis, would correspond to 20,000 µg twice daily in humans; unpublished data), the current transient pain symptom is less likely to represent a direct toxic effect.
Because this study had an open design, it is likely that treatment responses, especially regarding VAS scores, involved placebo effects. However, several aspects suggest that these patients had more than a placebo response. Most patients had undergone several different regimens without clear-cut effects (Table 1). The criteria for "responders" were also set high to minimize misinterpretation of intraindividual variability. We assessed both spontaneous and evoked pain, and both estimates clearly indicated reduced pain in most cases. In responders reporting reduced spontaneous pain, none reported any relief of neuropathic pain within the first 15 min after injection. Thereafter, pain intensity was gradual reduced during a period of 
30 min. This pattern was reproducible, which indicates that the patients experienced a pharmacological effect that required some time to be activated. Of those five patients who experienced lumbar pain during the first hour after injection, four had significantly reduced pain (spontaneous and evoked) that was long-lasting. Nevertheless, because a placebo response may be a significant factor for the perception of chronic pain, the current observation of prominent pain relief in most patients must be confirmed in a placebo-controlled, cross-over study.
The mechanisms by which IT adenosine may modify neuropathic pain and reduce hypersensitivity are not clearly understood. Animal studies in chronic models of both central and peripheral neuropathic pain have shown a decrease in pain-like behavior after the IT administration of adenosine A1-receptor selective analogs (3–6), which activate the receptor believed to mediate pain inhibition (1). The adenosine receptor-mediated hyperpolarization of interneurons (15) and inhibition of presynaptic transmission by modulation of calcium flux (16) in animal models may be involved in the observed depression of spontaneous and evoked pain ratings in humans. It is not known whether IT adenosine penetrates into the spinal cord. Because adenosine is water-soluble but rapidly eliminated by tissue uptake (17), it could diffuse into the tissue along a concentration gradient. Determinations of CSF content of adenosine after 500- to 2000-µg injections in healthy volunteers demonstrated a 1000-fold increase, which rapidly declined over a period of approximately 2 h (11). Therefore, it is likely that the IT doses of adenosine used in the present study can penetrate into the spinal cord.
With respect to pain rating after experimental provocation of the static stimuli (TPT), increased thresholds were often observed after adenosine (Fig 2). A similar response pattern was reported when IV adenosine was infused in patients with peripheral neuropathic pain (10). Further, IT adenosine given to healthy volunteers before experimental skin inflammation can prevent the reduction of TPT that otherwise occurs (11). Consequently, different etiology of skin hypersensitivity and modes of adenosine administration all indicate that adenosine receptor activation can depress hypersensitivity to static tactile stimuli, possibly involving the mechanisms of action discussed above.
Drugs that inhibit central upregulation of spinal wide dynamic range neurons (such as N-methyl-D-aspartic acid receptor antagonists) are believed to depress the central sensitization mechanism (18). Our finding of marked reduction of areas of skin hypersensitivity after the administration of IT adenosine indicate that mechanisms of central sensitization were inhibited. Reduction of the tactile secondary hyperalgesic areas surrounding experimental skin inflammation has been previously reported after the IV and IT adenosine administration in healthy volunteers (8,11). We therefore believe that a mechanism of reduced central sensitization was involved when adenosine modified tactile hypersensitivity in the responders in the present study. It is, however, unclear how the adenosine-induced reduction of the resting pain component is mediated. Therefore, more detailed information as to the mechanism(s) of action, as well as to what structures may be reached by exogenous adenosine, remains to be elucidated.
This group of patients includes those with severe pain in both the upper and lower part of the body (Table 1). IT adenosine had similar effects regardless of the pain localization. The onset time for pain relief was not different in those patients with pain in the arms, which could imply that the adenosine solution readily diffuses in the rostral direction all the way to cervical segments, even with patients in the supine position. It further suggests that a spinal site of action is involved in the pain-relieving effect. This is also supported by animal studies, which report the rapid onset (5–15 min) of presumed inhibition of pain behavior in rats (4,6). The approximate 10-hour to 6-day duration of pain relief in the 12 responders in the present study outlasted the theoretical time for increased CSF levels of adenosine (a few hours; unpublished data) unless neuropathic pain patients have markedly different CSF turnover of adenosine. Analogous to the long-lasting pain relief after an adenosine infusion (hours to days) (10), it is likely that adenosine receptor activation somewhere in the central nervous system (at spinal and/or supraspinal levels) exerts an interaction at more persistent pain modulator control system(s). Such persistent effects of adenosine at the spinal dorsal horn level have been demonstrated by the involvement of endogenous adenosine in vibration-induced analgesia of the cat (19).
These preliminary observations of an analgesic effect of IT adenosine are limited to patients with neuropathic pain involving hyperalgesia-dysesthesia-allodynia. Additional placebo-controlled studies are needed in the present, as well as other, groups of chronic pain patients. Further, it must be established whether repeated IT adenosine administration can provide reproducible pain relief. The current and previous studies indicate that both IV and IT adenosine can be used diagnostically to assess signs of central sensitization. Because IT adenosine administration may be associated with postinjection side effects, e.g., transient pain, this must be considered before repeated or long-term IT administration. Further, additional safety toxicology data are required before repeated IT treatment should be considered in patients.
In conclusion, this first series of chronic pain patients receiving IT adenosine administration indicates significant long-lasting pain relief. A subset of patients also reported transient postinjection lumbar pain. Further clinical evaluation is therefore warranted.
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Acknowledgments |
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This study was supported by grants from the Swedish Medical Research Council (Project No. 7485) and Karolinska Institute.
We thank technicians Anette Ebberyd and Ringvor Hägglöf for excellent assistance.
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