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Experimental pain models have been proposed as tools for potential new therapies for neuropathic pain . However, most work using experimental pain models has been in healthy volunteers [2, 3]. This makes their relevance questionable since the mechanisms by which chronic pain is maintained may not be active in pain-free people. Capsaicin, the hot constituent of the capsicum pepper, is a transient receptor potential vanilloid 1 (TRPV1) receptor agonist , expressed on C-fibre polymodal receptors . Altered central nociceptive signal processing, called central sensitization , is experimentally reproduced with intradermal (i.d.) capsaicin, through widening of the receptive field of dorsal horn neurons [7–9] to Aβ-fibre input, enabling innocuous touch stimuli to be perceived as painful in allodynia. Increased responsiveness to Aδ inputs [8–12] allows hyperalgesia to occur in the uninjured skin surrounding tissue injury [13, 14].
Local application of capsaicin has some attractions as a model for neuropathic pain as it reliably reproduces some of the key symptoms of neuropathic pain, i.e. allodynia and hyperalgesia. Allodynia is due to an increased central response to a given input from rapidly conducting low-threshold Aβ-mechanoreceptors  and hyperalgesia is mediated through C-fibres and high threshold, short-diameter Aδ-fibres . Additionally, surrounding the injection site there is an area of flare, or redness, lasting between 30–90 min, due to a local axon reflex .
Intradermal capsaicin has been found to have a dose-dependent relationship with flare, allodynia and hyperalgesia responses in pain-free volunteers , replicated in further studies [7, 12, 13, 17–22]. Intradermal rather than topical capsaicin is preferred because of superior spatial resolution of response. Intradermal capsaicin has been shown to detect the effects of a single dose of pregabalin in healthy volunteers . Hence the i.d. capsaicin model is potentially a useful tool to study the mechanisms of neuropathic-type symptoms [9, 11, 15, 24], and the efficacy of analgesic drugs in relieving these symptoms [7, 23, 25].
Despite the extensive literature on the use of capsaicin models in pain-free volunteers, little has been published using i.d. capsaicin in pain patients. In a previous study, increased allodynia and hyperalgesia in vulvodynia-afflicted women was observed compared with pain-free controls following 10 µg of i.d. capsaicin . A study in rheumatoid arthritis patients showed similar responses in patients and controls .
No study has compared the response of i.d. capsaicin in the affected and non-painful skin areas in patients with unilateral neuropathic limb pain. We have examined the response to i.d. capsaicin in patients with unilateral sciatica. Although the pathology of pain in sciatica is debated, and is certainly heterogeneous, it is a readily recruitable population and a poorly treated painful condition in which a component of neuropathic pain is present in many patients [28, 29]. We hypothesized that a) in patients with unilateral sciatica, the response to i.d. capsaicin would be amplified compared with pain-free controls and that b) responses in the affected and unaffected limbs may differ. We also wished to assess the acceptability of the technique in patients with chronic pain. Our hypothesis was that response would be greater in patients with pain.
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This study primarily aimed to determine if there was a difference in spontaneous pain, area of flare, hyperalgesia and allodynia responses between patients with unilateral sciatic pain and pain-free subjects in response to i.d. capsaicin and in the patients whether the response in the affected and unaffected limbs differed. In order to investigate this, it was necessary that sciatica patients could tolerate the capsaicin doses used and we were concerned that a higher response in patients would not be tolerated and hence dose selection was an important study design consideration.
The 1 µg and 10 µg doses chosen in this study were much lower than the maximum doses used in previous studies investigating pain-free volunteers [20, 21] and equal to the maximum dose used in one study investigating vulvodynia-afflicted women . The dose used in a previous study in rheumatoid arthritis patients was much higher (33-fold higher concentration and 333-fold higher dose) . Our previous work in healthy volunteers suggested that satisfactory responses would be observed in the controls at the doses used in the current study . Placebo was not used in the main study session as it has been previously reported that subjects could identify the characteristic initial burning sensation of the capsaicin injection compared with placebo , potentially introducing bias due to unblinding.
There was increased pain in both legs in sciatica patients compared with pain-free controls. Mean pre dose VAS scores of approximately 1 cm are consistent with negligible pain (31). However the mean peak post capsaicin values of approximately 4 cm following a 10 µg dose came within a range generally accepted as being at the lower level of clinically significant pain, used as an entry criterion for treatment studies . This is not due to high baseline levels and hence represents an exaggerated response compared with the controls confirming our hypothesis. This also confirms that the cautious approach in dose selection was appropriate and warranted.
Increased hyperalgesia responses in sciatica patients were significant at all time points, suggesting that chronic pain sufferers have central inputs that are more sensitive to Aδ-fibre input compared with pain-free volunteers. The reduction of hyperalgesia over time in pain-free volunteers is as expected from previous studies [20, 21]. However, in sciatica patients the hyperalgesia response increased steadily over time, particularly in the unaffected leg. This is a novel finding, and may suggest spinal cord wind-up mechanisms in subjects with chronic pain. Increased responses in sciatica patients compared with pain-free subjects have been previously demonstrated in the non-painful volar forearm skin areas of vulvodynia-afflicted women . An explanation proposed is that the sensitized spinal cord in chronic pain patients may be highly sensitive to contralateral inputs from Aδ-fibres following i.d. capsaicin. Contralateral hyperalgesia input is supported by a recent study which identified contralateral hyperalgesia and allodynia responses in both rheumatoid arthritis subjects, an inflammatory type pain, and pain-free volunteers lasting for up to 1 h following 1 µg i.d. capsaicin . The assessment of hyperalgesia response in the unaffected limb of neuropathic pain subjects may be a superior model of spinal cord wind-up using the i.d capsaicin model. Future studies should incorporate a longer duration of assessments following i.d. capsaicin, as the increasing trajectory of hyperalgesia in the unaffected leg of pain subjects may become significantly higher than the affected leg at greater than 1 post injection. Increasing the time between each injection may also reduce potential influences of the i.d. capsaicin in the contralateral leg.
In sciatica patients, allodynia response in the affected leg was significantly greater than in the unaffected leg at all time points, suggesting Aβ-fibres in chronic pain subjects may be received on the unilateral side of the sensitized dorsal horn neuron.
Flare responses showed the smallest differences between pain patients and controls. There were no differences in the affected limb at 10 µg and small differences in the other leg. As the flare is due to a local axon reflex, the small differences in this variable suggest that the differences observed with the other variables were not due to increase response at the level of peripheral nerve.
The strategic function of this study was to assess whether the i.d. capsaicin model in patients is worthy of further development as a screening model for the evaluation of novel analgesics in neuropathic pain. The key question is: What incremental response value does the injected capsaicin provide over standard quantitative sensory testing? This pain model is increasingly being evaluated as a biomarker for patient stratification and assessment of treatment response [32–37]. Firstly, although our patients reported significant functional interference with their daily living as a result of their sciatica, baseline pain scores on the treatment day were relatively low and would not generally qualify such patients for clinical trials. This enables recruitment of the patient population likely to be relatively representative of the true broad community of patients rather than selecting people at the severe end of the spectrum introducing potential bias. Secondly, daily baseline pain is likely to be affected by multiple environmental factors which will vary from day to day. The concept behind giving a standardized stimulus is to try to elicit more reproducibly a response in a controlled manner . Similar logic applies in other provocative stimulation models and it should be noted that provocation technically occurs during standard quantitative sensory testing to thermal and punctate stimuli. However, these are short lived and do not necessarily reflect the sensitization that occurs in neuropathic pain. In this study we have demonstrated enhanced slowly developing and long-lasting hyperalgesia to i.d. capsaicin which may more closely reflect the pathological state of sensitization, potentially suitable for detecting an analgesic drug effect . Future studies should compare the sensitivity of the i.d. capsaicin model to standard quantitative sensory testing to detect treatment responses.
In conclusion, this is the first study to investigate directly the i.d. capsaicin pain model in patients with unilateral sciatica. Capsaicin was well tolerated at 1 µg and 10 µg doses. Higher spontaneous pain and hyperalgesia responses were greatest in sciatica patients compared with pain-free controls, particularly in the unaffected leg. This suggests that patients with pre-existing neuropathic pain have fundamental differences in central nervous system processing compared with pain-free controls, and potentially limits the utility of neuropathic pain models in pain-free volunteers. Future studies using the i.d. capsaicin model should utilize neuropathic pain subjects to help identify neuropathic pain mechanisms and evaluate analgesic efficacy in clinical drug development.