Natural history of sensory function after herpes zoster

The natural history of sensory function in the first 6 months after herpes zoster (HZ) was determined in a cohort of 94 subjects at elevated risk for developing post-herpetic neuralgia (PHN). All four visits included ratings of pain and sensory symptoms, mapping areas of altered sensation and allodynia, and quantitative thermal and mechanical sensory testing. The last three visits included the capsaicin response test. Sensory thresholds in distant control skin were stable. Mirror-image skin was persistently hyperesthetic to warming and mechanical stimuli and hyperalgesic to heat compared to distant control skin. HZ skin showed deficits in all thermal modalities. Sensory recovery was limited and selective. Allodynia area and severity, hyperalgesia to von Frey hair, and cold detection threshold improved, but deficits to warmth and heat pain did not. Capsaicin on HZ skin significantly aggravated pain and allodynia in the majority of subjects at 6–8 weeks after HZ onset. At study entry, eventual PHN subjects had significantly more impairment in detecting warmth and cold, a larger area of altered sensation, a larger area of allodynia, and more severe allodynia. The results support the study hypothesis that severity of initial injury predicts PHN, especially impaired cold sensation in HZ skin. The hypothesis that PHN develops because of a failure to recover normal neural function was not supported. Sensory recovery proceeded at the same rate in eventual pain-free and eventual PHN subjects and is not a requirement for pain resolution. Early interventions that reduce neural injury or enhance recovery should be of benefit.     

Natural history of cutaneous innervation following herpes zoster

As part of a comprehensive study of the natural history of herpes zoster (HZ), 57 of 94 subjects in a cohort at elevated risk for post-herpetic neuralgia (PHN) consented to collection of 3-mm skin punch biopsies from affected, mirror-image, and distant control skin at baseline and followup visits. As cutaneous innervation is reduced in longstanding severe PHN, we tested the hypothesis that development of PHN is correlated with severity of initial neural injury and/or a failure of neural recovery. Quantitative analysis using single-label PGP9.5 immunofluorescence microscopy showed epidermal profiles were reduced in zoster skin by approximately 40% at study entry compared to control and mirror skin. The density of the subepidermal plexus was approximately 15% lower in zoster skin. Mirror skin was not denervated compared to control skin. Although not significant at all visits, correlations between epidermal nerve fiber density in HZ skin and thermal sensation, allodynia, capsaicin response, and average daily pain all associated more severe abnormalities with lower epidermal innervation. There was limited evidence that the initial neural injury was more severe in the 15 eventual PHN subjects. Overall, pain and pain-related disability resolved the fastest. Sensory abnormalities and symptom aggravation by focal capsaicin application showed partial and selective recovery over 6 months. In contrast, cutaneous innervation showed no recovery at all by 6 months, conclusive evidence that resolution of pain and allodynia does not require cutaneous reinnervation. A much longer period of observation is needed to determine if zoster-affected skin is ever reinnervated.     

Effect of adrenergic receptor activation on post-herpetic neuralgia pain and sensory disturbances

Patients with acute herpes zoster, and to a lesser extent post-herpetic neuralgia (PHN), have been reported to respond to local anesthetic blockade of the sympathetic nervous system. In animal models of nerve injury, local injection of adrenergic agonists after nerve injury, but not before, excites nociceptors. In some patients with chronic neuropathic pain, local application of norepinephrine evokes pain. In 15 subjects with PHN, the role of adrenergic receptors in PHN pain was assessed in a two-session double blind study comparing the response to cutaneous infiltration of epinephrine or phenylephrine (30 μg in 3 ml) with the response to normal saline in both the painfully affected skin and mirror-image normal skin. Two adjacent sites were studied on each side of the body, one site for injection and the other for measuring sensory effects of the injection. In the morning part of each session, mirror-image normal skin was injected. In the afternoon portion of each session, skin in the most painful area affected by PHN was injected. Injection of saline or the adrenergic agonist in normal skin produced mild and transient pain without development of allodynia and without affecting overall PHN pain intensity. In PHN skin, injection of saline and the adrenergic agonist produced an equivalent degree of transient pain that was slightly greater than injection into mirror-image normal skin. After injection of the adrenergic agonist into PHN skin, both overall PHN pain and allodynia severity were significantly greater than after saline injection, peaking at 10–15 min post-injection. Even when PHN has been present for years, adrenergic receptor stimulation in PHN skin increases pain, most likely through direct activation of C-nociceptors in the painful skin. Increased allodynia is most likely mediated centrally and driven by the increase in C-nociceptor input.     

Post-herpetic neuralgia: the relation of pain complaint, sensory disturbance, and skin temperature

Twelve otherwise healthy patients with longstanding postherpetic neuralgia (PHN) were prospectively studied using clinical examination, infrared thermography and response to local anesthetic skin infiltration. All had at least 2 of 3 possible components to their PHN pain: continuous, neuralgic, or allodynic. In patients with allodynia, maximal reported pain and the location of maximal allodynia on sensory examination were largely overlapping and were often warm thermographically. Areas of dense sensory loss and skin scarring without allodynia were usually cool thermographically. Local anesthetic skin infiltration produced substantial pain relief in all 9 patients (essentially complete relief in 7) with allodynia: the 3 patients with predominantly continuous pain were not relieved. In 7 of 8 skin infiltration responders, the same dose of lidocaine i.m. in the deltoid muscle also produced significant, though less complete pain relief. These results suggest that PHN patients can be divided into at least 2 clinical groups: those with predominantly continuous pain localized to a region of significant sensory loss and those in whom allodynia is the most prominent sensory disturbance. The latter group has pain localized to areas with relatively preserved sensation. The differences in clinical features and response to lidocaine suggest that there are at least 2 different mechanisms contributing to the pain of PHN.     

Relief of post-herpetic neuralgia by surgical removal of painful skin

We present a case of longstanding PHN treated by skin excision of the area of greatest pain (11.3 x 26.0 cm(2)). The operation reduced pain, eliminated tactile allodynia, and facilitated greatly reduced medication use over a 1-year follow-up period. Fourteen punch biopsies and 10 strips of skin (each 10 mm long) from the excised painful PHN skin were qualitatively assessed by double-label immunofluorescence using antibodies against protein-gene-product 9.5 (PGP9.5), 200 kDa neurofilament protein (NF), calcitonin gene-related peptide (CGRP) and vanilloid receptor-1 (VR-1). Compared with a punch biopsy from mirror image skin, the pattern of cutaneous innervation in PHN skin was consistently and substantially different. The results may explain the anatomical basis of the capsaicin-response test and have implications for our understanding of clinical mechanisms underlying PHN pain.     

Stimulation of Cutaneous Low Threshold Mechanoreceptors in Mice After Intracolonic Capsaicin Increases Spinal c-Fos Labeling in an NKCC1-Dependent Fashion

Stimulation of peripheral nociceptors results in increased c-Fos labeling in spinal cord regions associated with nociceptive processing. Accordingly, intracolonic capsaicin, which generates robust secondary (referred) allodynia on the abdomen of mice, also causes an increased spinal c-Fos labeling. In naïve rodents, low intensity innocuous stimulation does not affect c-Fos labeling in spinal nociceptive regions. However, after persistent noxious input, low intensity stimulation of the inflamed region further enhances c-Fos labeling, suggesting that low threshold mechanosensitive fibers gain access to the nociceptive channel after persistent inflammation. We have previously proposed that afferent activity in low threshold sensory fibers activates nociceptive sensory fibers through Na⁺-K⁺-Cl^? cotransporter 1 (NKCC1) -mediated enhanced primary afferent depolarization. Here, we show that intracolonic capsaicin enhances spinal c-Fos labeling and secondary allodynia in an NKCC1-dependent manner. Furthermore, we demonstrate that gently brushing the abdomen, the region of secondary allodynia, further increased spinal c-Fos levels, an effect that can be prevented by spinal NKCC1 blockade. These findings provide evidence that increased NKCC1 activity contributes to secondary allodynia and that innocuous touch can access the nociceptive channel in part through enhanced NKCC1 activity.PerspectiveWhile touch normally soothes acute pain, we demonstrate that following peripheral inflammation, touch evokes pain (allodynia) through the switching of a normally inhibitory spinal pathway into an excitatory pathway. Activation of low threshold mechanoreceptors activates spinal nociceptive neurons following inflammation-induced enhancement of NKCC1 expression, as measured by spinal c-Fos labeling.     

Painful neuropathy: altered central processing maintained dynamically by peripheral input.

We performed sensory assessments before and during diagnostic tourniquet-cuff and local anesthetic blocks in 4 patients diagnosed with reflex sympathetic dystrophy (RSD). All patients complained of mechano-allodynia; lightly touching the skin evoked an intense pain sensation. At detection levels, electrical stimuli were perceived as painful, suggesting that the mechano-allodynia was mediated by A beta low-threshold mechanoreceptor afferents. A beta-mediated allodynia was further supported by reaction time latencies to painful electrical stimuli at threshold for A-fiber activation and, in 1 patient, by differential cuff blocks which abolished A beta function and allodynia while thermal sensation (warm and cold) were preserved. Local anesthetic block of painful foci associated with previous trauma abolished mechano-allodynia, cold allodynia, and spontaneous pain in all patients and relieved the motor symptoms in 1 patient with tonic contractures of the toes. Tactile and thermal perception in the previously allodynic area was preserved. When the local anesthetic block waned, spontaneous pain, allodynia, and motor symptoms returned. We propose a model of neuropathic pain in which ongoing nociceptive afferent input from a peripheral focus dynamically maintains altered central processing that accounts for allodynia, spontaneous pain, and other sensory and motor abnormalities. Blocking the peripheral input causes the central processing to revert to normal, abolishing the symptoms for the duration of the block. The model accounts for sympathetically maintained (SMP) and sympathetically independent (SIP) pain. The peripheral input can be independent of sympathetic activity or driven completely or in part by activity in sympathetic efferents or by circulating catecholamines. The shared final common pathway may explain the common features of SMP and SIP.     

Early and late effects of prolonged topical capsaicin on cutaneous sensibility and neurogenic vasodilatation in humans.

Cutaneous sensibility and neurogenic vasodilatation (flare) were measured before, during and after long-term topical application of capsaicin in humans. Each subject applied a vehicle cream containing 0.075% capsaicin (Axsain, GalenPharma Inc.) to a 4 cm2 area of skin on one volar forearm and vehicle alone to an identical treatment area on the other forearm, according to a double-blind procedure. Each substance was applied 4 times/day for 6 weeks. Psychophysical measurements of sensory detection thresholds, magnitude of suprathreshold heat pain, magnitude and duration of histamine-induced itch and flare area were obtained before, at 1, 3 and 7 days after the first application, and once a week thereafter for a total of 8 weeks. Capsaicin produced mild burning in all subjects which diminished in magnitude and duration over several weeks. Capsaicin significantly altered detection thresholds for heat pain and the magnitude of pain produced by suprathreshold painful stimuli. Mean detection threshold for heat pain was lowered 1.6 degrees C following 1 day of capsaicin application but subsequently increased to become elevated 3.5 degrees C after 6 weeks of application. In addition, mean magnitude of suprathreshold heat pain diminished progressively after 1 week. Heat pain thresholds returned to or near pretreatment values within 2 weeks after discontinuing application. Detection thresholds for touch, cold sensation and pain induced by low temperature and by mechanical stimulation were not altered by capsaicin. Similarly, capsaicin did not alter the magnitude or duration of itch produced by intradermal injection of 1 microgram histamine. However, the area of flare produced by histamine was significantly reduced in capsaicin-treated skin. These studies demonstrate that prolonged application of capsaicin at low concentration selectively diminishes sensations of heat pain and neurogenic vasodilatation, presumably via desensitization of heat-sensitive nociceptors. It is also shown that the decrease in heat pain is temporary and is maintained with repeated capsaicin application. There appears to be a therapeutic role for capsaicin in cutaneous painful syndromes mediated, at least in part, by activity of heat-sensitive nociceptors.     

Randomized control trial of topical clonidine for treatment of painful diabetic neuropathy

A length-dependent neuropathy with pain in the feet is a common complication of diabetes (painful diabetic neuropathy). It was hypothesized that pain may arise from sensitized-hyperactive cutaneous nociceptors, and that this abnormal signaling may be reduced by topical administration of the α₂-adrenergic agonist, clonidine, to the painful area. This was a randomized, double-blind, placebo-controlled, parallel-group, multicenter trial. Nociceptor function was measured by determining the painfulness of 0.1% topical capsaicin applied to the pretibial area of each subject for 30 minutes during screening. Subjects were then randomized to receive 0.1% topical clonidine gel (n = 89) or placebo gel (n = 90) applied 3 times a day to their feet for 12 weeks. The difference in foot pain at week 12 in relation to baseline, rated on a 0–10 numerical pain rating scale (NPRS), was compared between groups. Baseline NPRS was imputed for missing data for subjects who terminated the study early. The subjects treated with clonidine showed a trend toward decreased foot pain compared to the placebo-treated group (the primary endpoint; P = 0.07). In subjects who felt any level of pain to capsaicin, clonidine was superior to placebo (P < 0.05). In subjects with a capsaicin pain rating ?2 (0–10, NPRS), the mean decrease in foot pain was 2.6 for active compared to 1.4 for placebo (P = 0.01). Topical clonidine gel significantly reduces the level of foot pain in painful diabetic neuropathy subjects with functional (and possibly sensitized) nociceptors in the affected skin as revealed by testing with topical capsaicin. Screening for cutaneous nociceptor function may help distinguish candidates for topical therapy for neuropathic pain.     

No effect of sympathetic sudomotor activity on capsaicin-evoked ongoing pain and hyperalgesia

BACKGROUND: Complex regional pain syndromes (causalgia and RSD) can be relieved by blockade of the sympathetic efferent activity. The mechanisms of sympathetically maintained pain (SMP) are unclear. So far an adrenergic interaction between sympathetic vasoconstrictor neurons and nociceptors has been proposed. Alternatively, a cholinergic coupling of sympathetic sudomotor neurons and nociceptors is possible. OBJECTIVE: To determine the effect of cutaneous sympathetic sudomotor activity on pain induced by primary afferent C-nociceptor activation with capsaicin in humans. METHODS: In 10 healthy volunteers capsaicin was injected into the forearm skin to induce ongoing pain and dynamic and punctate mechanical hyperalgesia. Intensity of pain and hyperalgesia and area of hyperalgesia (planimetry) were assessed. The local skin temperature at the application and measurement sites was kept constant at 35 degrees C. In each individual the analyses were performed during the presence of low and high sympathetic sudomotor skin activity induced by whole-body temperature changes with a thermal suit. By altering whole-body temperature from a moderately warm to an intensely warm state, sympathetic sudomotor activity is modulated selectively in the widest range that can be achieved physiologically while sympathetic vasoconstrictor activity is continuously inhibited. The degree of sudomotor discharge was monitored by measuring cutaneous sweat production at the forearm with the colour indicator ponso-red. The inhibition of vasocontrictor discharge was monitored by measuring cutaneous blood flow at the index finger with laser Doppler flowmetry. RESULTS: The intensity and spatial distribution of capsaicin-evoked ongoing pain and dynamic and punctate mechanical hyperalgesia were not significantly different during the presence of high and low sympathetic sudomotor discharge. Conclusions: Cutaneous sympathetic sudomotor activity does not influence capsaicin induced pain and mechanical hyperalgesia.     

Cannabinoid agonists attenuate capsaicin-induced responses in human skin

The induction of hyperalgesia upon capsaicin administration requires activation of specific sub-classes of nociceptive afferent C-fibres providing nociceptive input to the central nervous system.It has been demonstrated in animal models that the endocannabinoid anandamide has anti-hyperalgesic properties upon capsaicin stimulation, albeit it also binds to vanilloid receptors. In the present study we topically administered the cannabinoid receptor ligand HU210 to human skin and investigated its effects on capsaicin-induced pain and hyperalgesia.We demonstrated that pre-treatment with HU210 significantly reduced the perception of pain following the administration of capsaicin. Heat pain thresholds were significantly reduced by capsaicin application measured 5 and 30min after administration. In contrast, at the HU210 pre-treated skin sites capsaicin failed to induce heat hyperalgesia during the fifth minute of administration. Secondary mechanical hyperalgesia to touch (allodynia) was measured during the fifth, 15th and 30th minute after capsaicin administration. In comparison to the ethanol control site, the area of touch-evoked allodynia was significantly reduced at the HU210 skin site during the first two measures. However, 30min after the administration of capsaicin no significant differences of allodynia were observed between the HU210 and ethanol pre-treated skin.The present study provided evidence for analgesic and anti-hyperalgesic properties of a topically applied cannabinoid receptor ligand, which might have important therapeutic implications in humans.     

Altered C-tactile processing in human dynamic tactile allodynia

Human unmyelinated (C) tactile afferents signal the pleasantness of gentle skin stroking on hairy (nonglabrous) skin. After neuronal injury, that same type of touch can elicit unpleasant sensations: tactile allodynia. The prevailing pathophysiological explanation is a spinal cord sensitization, triggered by nerve injury, which enables Aβ afferents to access pain pathways. However, a recent mouse knockout study demonstrates that C-tactile afferents are necessary for allodynia to develop, suggesting a role for not only Aβ but also C-tactile afferent signaling. To examine the contribution of C-tactile afferents to the allodynic condition in humans, we applied the heat/capsaicin model of tactile allodynia in 43 healthy subjects and in 2 sensory neuronopathy patients lacking Aβ afferents. Healthy subjects reported tactile-evoked pain, whereas the patients did not. Instead, patients reported their C-touch percept (faint sensation of pleasant touch) to be significantly weaker in the allodynic zone compared to untreated skin. Functional magnetic resonance imaging in 18 healthy subjects and in 1 scanned patient indicated that stroking in the allodynic and control zones evoked different responses in the primary cortical receiving area for thin fiber signaling, the posterior insular cortex. In addition, reduced activation in the medial prefrontal cortices, key areas for C-tactile hedonic processing, was identified. These findings suggest that dynamic tactile allodynia is associated with reduced C-tactile mediated hedonic touch processing. Nevertheless, because the patients did not develop allodynic pain, this seems dependent on Aβ signaling, at least under these experimental conditions.     

Secondary hyperalgesia persists in capsaicin desensitized skin

Several lines of evidence suggest that secondary hyperalgesia to punctate mechanical stimuli arises from central sensitization to the input from primary afferent nociceptors. Conventional C-fiber nociceptors respond to heat stimuli and yet heat hyperalgesia is absent in the region of secondary hyperalgesia. This evidence suggests that the central sensitization to nociceptor input does not involve heat sensitive nociceptors. To test this hypothesis, we investigated whether desensitization of heat sensitive nociceptors by topical application of capsaicin led to an alteration in the secondary hyperalgesia. Two 2x2 cm areas on the volar forearm, separated by 1 cm, were treated in 10 healthy volunteers. One of the areas was desensitized by treatment with 10% topical capsaicin (6 h/day for 2 days). The other site served as vehicle control. Hyperalgesia was produced 2 days later by an intradermal injection of capsaicin (50 microg, 10 microl) at a point midway between the two treatment areas. Secondary hyperalgesia to noxious mechanical stimuli was investigated by using a blade probe (32 and 64 g) attached to a computer-controlled mechanical stimulator. In the area of topical capsaicin treatment, there was a marked increase in heat pain threshold and decrease in heat pain ratings indicating a pronounced desensitization of heat sensitive nociceptors. However, touch threshold and pain to pinching stimuli were not significantly altered. The intradermal capsaicin injection led to the development of a similar degree of secondary hyperalgesia at both the vehicle and capsaicin treatment areas. These results indicate that capsaicin insensitive nociceptive afferents play a dominant role not only in normal mechanical pain but also in secondary hyperalgesia to noxious mechanical stimuli.     

Tactile allodynia in patients with postherpetic neuralgia: lack of change in skin blood flow upon dynamic stimulation

Tactile allodynia is a common, troublesome feature of neuropathic pain. Allodynia has been proposed to involve abnormal Abeta-afferent coupling in the dorsal horn resulting in C-fibre activation and increased skin blood flow (SBF). Thus, changes in SBF could provide an objective measure of allodynia. We searched for this mechanism in patients with postherpetic neuralgia (PHN) with varying degrees of cutaneous sensory loss. We mapped the allodynic area in PHN patients using cotton buds and von Frey hairs. Quantitative thermal testing was performed to assess small fibre function in the affected and mirror-image areas. At a subsequent visit the area of allodynia was remapped. Then the SBF in the affected and control areas was quantified before and after allodynic stimulation using laser Doppler imaging and subsequent single point continuous monitoring to detect rapid changes. We enrolled 10 PHN patients (medians: age 77 yrs, duration 20 months, ongoing pain 5). The allodynic area (range 11-546 cm2) was stable across the sessions. Thermal testing showed similar (n=5) or reduced (n=5) warmth and pain sensation in the affected versus control area. Following allodynic stimulation (median evoked pain-5) we saw no changes in SBF using either imaging (repeated measures ANOVA, P=0.73) or single point monitoring. This was the case for all patients regardless of the degree of sensory impairment in the affected dermatome. In conclusion, in a representative population of PHN patients we found no evidence of changes in SBF in response to allodynic stimulation. Hence, SBF measurements are not suitable for assessing allodynia.     

Effects of intradermal foot and forearm capsaicin injections in normal and vulvodynia-afflicted women

Cutaneous response to capsaicin has been used to assess central sensitization in pain research. This study compared the response to intradermal capsaicin in the forearm and foot of vulvar vestibulitis (vestibulodynia)-afflicted cases and controls. We hypothesized that cases will experience greater spontaneous pain, larger cutaneous areas of punctate hyperalgesia and dynamic allodynia, and greater vascular flow than controls. We also hypothesized enhanced post-injection pain in the foot compared to the forearm based on dermatome proximity of the foot and vulva. Methods. Ten vulvar vestibulitis syndrome (VVS) cases and 10 age and ethnically matched controls underwent two randomized, cross-over trials with intra-dermal injections of capsaicin or a saline placebo in the forearm and foot. Outcome measures included spontaneous pain level, surface area of punctate hyperalgesia, surface area of dynamic allodynia, cutaneous blood flow, regional skin temperature and vital signs. Results. VVS cases experienced greater spontaneous pain, punctate hyperalgesia and dynamic allodynia than pain-free controls. Within the VVS group, post-capsaicin spontaneous pain, punctate hyperalgesia and dynamic allodynia were similar in the forearm and foot. Post-capsaicin blood flow did not differ between cases and controls by anatomic site. Measures of depression and anxiety correlated with spontaneous pain intensity but did not correlate with measures of hyperalgesia, allodynia, or blood flow. VVS cases had higher resting pulse rates and lower resting systolic blood pressures than in controls. Conclusion. VVS patients show enhancement of post-capsaicin pain response extending far beyond the anatomic location of the primary complaint.     

Natural history of herpes zoster: Late follow-up of 3.9 years (n = 43) and 7.7 years (n = 10)

Postherpetic neuralgia (PHN) is a common complication after herpes zoster (HZ). Subjects who completed a longitudinal observational 6-month study (4 visits) of the natural history of HZ were recontacted for 2 additional follow-up visits that included pain and sensory symptom assessment, quantitative sensory testing, capsaicin response test, and 3-mm punch skin biopsies in HZ-affected, mirror-image, and control skin sites. Forty-three subjects (14 with PHN at 6 months) of the original 94 subjects in the cohort were comprehensively assessed at a median 3.9 years after HZ onset (visit 5), and 10 subjects underwent a final assessment at a median 7.7 years after HZ onset (visit 6). At 3.9 years, none of the 29 subjects who had been pain free at 6 months had a recurrence of pain. Only 2 of the 14 subjects with PHN at 6 months still had pain at 3.9 years. One subject with PHN at 6 months was free of symptoms at 3.9 years but had very mild pain at 7.7 years. Sensory function continued on a path toward normalization, but was still abnormal in many subjects, especially those who met criteria for PHN at 6 months. Even at 7.7 years, reinnervation of HZ-affected skin was not apparent.     

Sensory responses to injection and punctate application of capsaicin and histamine to the skin

A punctate, cutaneous application of capsaicin or histamine by means of a cowhage spicule elicits itch accompanied by pricking/stinging, burning, and typically, one or more areas of dysesthesia (alloknesis, hyperalgesia, hyperknesis). When applied over a wider and deeper area of skin by means of intradermal injection, histamine evokes the same sensory effects, but capsaicin evokes pain and hyperalgesia with allodynia instead of alloknesis. To examine the sensory effects of the spatial spread, depth, and amount of capsaicin and histamine, we applied different amounts of capsaicin or histamine by intradermal injection or by single vs multiple spicules within a circular cutaneous region of ∼5 mm. Subjects rated the perceived intensity of itch, pricking/stinging, and burning for 20 minutes. Histamine injections or multiple spicules of capsaicin or histamine that resulted in a greater area of flare than a single spicule of each chemical evoked no greater magnitudes of sensation or areas of dysesthesia. Capsaicin injections elicited a dose-dependent increase in the magnitude of nociceptive sensations, areas of dysesthesia, and flare. However, there was little or no itch; and allodynia replaced alloknesis. Yet, hyperalgesia was typically accompanied by hyperknesis. We conclude that the pruritic sensory responses produced by capsaicin/histamine spicules and histamine injections may be due to activation of common nerve fibers, possibly different from those mediating the flare, and that capsaicin injections may activate additional fibers whose effects mask the sensory effects of fibers mediating itch and alloknesis but not hyperknesis.     

Dynamic mechanical allodynia in humans is not mediated by a central presynaptic interaction of A beta-mechanoreceptive and nociceptive C-afferents

Recently, Cervero and Laird (NeuroReport, 7 (1996) 526-528; Pain, 68 (1996) 13-23) proposed a new pathophysiological mechanism of dynamic mechanical allodynia in skin. Using the capsaicin pain model in humans, they showed that light mechanical stimulation within an area of secondary mechanical allodynia induces vasodilatation measured by laser-Doppler flowmetry. They suggested that the low-threshold A beta-mechanoreceptive fibres depolarize the central terminals of nociceptive primary afferent neurons via interneurons. Consequently, the vasodilatation is produced by impulses conducted antidromically in nociceptive C-axons. The allodynia was proposed to result from depolarization of central terminals of primary afferent neurons with C-fibres with activation of nociceptive dorsal horn neurons. In order to extend these findings, we used the same experimental approach but additionally stimulated the A beta-fibres electrically to evoke secondary allodynia during simultaneous monitoring skin blood flow. Twenty microlitres of a 0.5% capsaicin solution was injected intradermally into the dorsal forearm. Skin sites that demonstrated dynamic mechanical allodynia but were not located within the area of primary hyperalgesia and flare were investigated. Ten mm away from a laser-Doppler probe, dynamic mechanical allodynia was induced for 1 min (1) by moving a cotton swab and (2) by electrically stimulating the afferent nerve endings transdermally. Increasing stimulus intensities were applied (0.3-4 mA, 40 Hz, pulse duration 0.2 ms). After intracutaneous injection of capsaicin, light mechanical stimulation elicited a burning painful sensation (numeric analogue scale (NAS) 1.5-3) and concomitant movement artefacts at the laser signal. Antidromic vasodilatation was never observed. In this area of dynamic allodynia, electrical stimulation at stimulus intensities that were not painful before capsaicin injection (A beta-stimulation) was now able to elicit a burning painful sensation (NAS 1.5-3). No change in blood flow was detected. When the stimulus intensities were increased reaching levels that were also painful before capsaicin treatment (C-fibre stimulation), an increase in blood flow could be induced showing the time course of an axon reflex vasodilatation. In conclusion, electrical stimulation of A beta-fibres in allodynic skin does not induce antidromic vasodilatation. Consequently, interaction of A beta-mechanoreceptive fibres and nociceptive C-fibres at a presynaptic level is unlikely to produce antidromically conducted impulses and therefore cannot explain the pathophysiology of mechanical allodynia. Alternatively, it is much more likely that under pathophysiological conditions, activity in A beta-fibres may activate nociceptive second-order neurons, i.e. in the spinal cord.     

Pathophysiology and diagnosis in patients with sympathetically dependent pain

Chronic pain in a distal extremity that is accompanied by autonomic dysfunction in the same region is taken to indicate reflex sympathetic dystrophy. Typically, hyperalgesia to light touch is present in addition to the spontaneous pain. The absence of heat hyperalgesia indicates that the underlying mechanism is central rather than peripheral sensitization. This mechanism is similar to that of secondary hyperalgesia in the intact skin surrounding an injury site. Sympathetically maintained pain (SMP) is diagnosed, when these sensory symptoms are reversible under sympathetic blockade. SMP is not due to hyperactivity of sympathetic efferents but to receptor supersensitivity, probably by overexpression of alpha(1)-adrenergic receptors on nociceptive primary afferents. This way normal levels of norepinephrine can cause pathological spontaneous activity of nociceptors which maintains the central sensitization. Chronic burning pain and cutaneous hyperalgesia may also be independent of the sympathetic innervation of the skin. In this case, central sensitization is maintained by other mechanisms. A role of the sympathetic nervous system in the pathogenesis of pain cannot be deduced simply from the simultaneous presence of sensory and autonomic clinical signs and symptoms. Therefore, sympathetic blockade in a patient initially is a diagnostic procedure, aiming to demonstrate the presence of the symptom SMP. Therapeutic blockade is only indicated after this demonstration. For the substantial number of patients with sympathetically independent pain, other treatment modalities are needed which may for example attack central sensitization.