Reduction of allodynia in patients with complex regional pain syndrome: A double-blind placebo-controlled trial of topical ketamine

A double-blind placebo-controlled crossover trial was used to determine the effects of topical ketamine, an N-methyl-d-aspartate (NMDA) receptor antagonist, on the sensory disturbances in 20 patients with complex regional pain syndrome (CRPS). On two occasions separated by at least one week, sensory tests to light touch, pressure, punctate stimulation, light brushing and thermal stimuli were performed in the symptomatic and contralateral limb and on each side of the forehead before and 30 min after 10% ketamine cream was applied to the symptomatic or healthy limb. Venous blood for the plasma estimations of ketamine and norketamine was obtained 1 h after application of the creams. Ketamine applied to the symptomatic limb inhibited allodynia to light brushing and hyperalgesia to punctate stimulation. Systemic effects of the ketamine are unlikely to account for this as the plasma levels were below detectable limits. As touch thresholds were unchanged, NMDA receptors may contribute to the sensory disturbances in CRPS via actions at cutaneous nociceptors. Allodynia and hyperalgesia were detected in the ipsilateral forehead to a range of stimuli (brushing, pressure, punctate stimulation, cold, heat, and warmth). In several patients, ketamine treatment of the symptomatic limb inhibited allodynia to brushing the ipsilateral forehead, suggesting that the mechanism that mediates allodynia in the symptomatic limb contributed to allodynia at more remote sites. The present study shows promise for the use of topical ketamine as opposed to parenteral and oral forms which often result in undesirable side effects.     

Pupillary Reflexes in Complex Regional Pain Syndrome: Asymmetry to Arousal Stimuli Suggests an Ipsilateral Locus Coeruleus Deficit

Converging lines of evidence suggest that autonomic and nociceptive pathways linked with the locus coeruleus are disrupted in complex regional pain syndrome (CRPS). To investigate this, pupillary dilatation to arousal stimuli (which reflects neural activity in the locus coeruleus) and pupillary reflexes to light were assessed in a cross-sectional study of 33 patients with CRPS. Moderately painful electrical shocks were delivered to the affected or contralateral limb and unilateral 110 dB SPL acoustic startle stimuli were delivered via headphones. To determine whether the acoustic startle stimuli inhibited shock-induced pain, startle stimuli were also administered bilaterally 200 ms before or after the electric shock. The pupils constricted briskly and symmetrically to bright light (500 lux) and dilated symmetrically in dim light (5 lux). However, the pupil on the CRPS-affected side was smaller than the contralateral pupil before and after the delivery of painless and painful arousal stimuli. Auditory sensitivity was greater on the affected than unaffected side but acoustic startle stimuli failed to inhibit shock-induced pain. Together, these findings suggest that neural activity in pathways linked with the locus coeruleus is compromised on the affected side in patients with CRPS. This may contribute to autonomic disturbances, auditory discomfort and pain.PerspectiveThe locus coeruleus is involved not only in modulation of pain but also regulates sensory traffic more broadly. Hence, fatigue of neural activity in the ipsilateral locus coeruleus might not only exacerbate pain and hyperalgesia in CRPS but could also contribute more generally to hemilateral disturbances in sensory processing.     

Sensory changes in the forehead of patients with complex regional pain syndrome

The aim of this study was to investigate involvement of central mechanisms in complex regional pain syndrome (CRPS). In particular, we wished to determine whether hyperalgesia extends ipsilaterally from the affected limb to the forehead. The heat-pain threshold, pressure-pain threshold, and ratings of cold and sharpness were investigated on each side of the forehead and in the affected and unaffected limbs of 38 patients with features of CRPS. In addition, touch thresholds were investigated in the limbs. The pressure-pain threshold was lower on the ipsilateral forehead than contralaterally, consistent with the presence of static mechanical hyperalgesia. Although the heat-pain threshold and ratings of sharpness and cold did not differ between the two sides of the forehead in the group as a whole, the sharpness of pinprick sensations in the affected limb was mirrored by similar sensations in the ipsilateral forehead. Conversely, diminished sensitivity to light touch in the affected limb was associated with diminished sensitivity to sharpness, cold and heat-pain in the ipsilateral forehead. These findings suggest that central nociceptive processing is disrupted in CRPS, possibly due to disturbances in the thalamus or higher cortical centres.     

Altered Neurocognitive Processing of Tactile Stimuli in Patients with Complex Regional Pain Syndrome

Chronic pain in complex regional pain syndrome (CRPS) has been linked to tactile misperceptions and deficits in somatotopic representation of the affected limb. In this study, we identify altered cognitive processing of tactile stimuli in CRPS patients that we propose marks heterogeneity in tactile decision-making mechanisms. In a case-control design, we compared middle- and late-latency somatosensory evoked potentials in response to pseudorandomized mechanical stimulation of the digits of both hands (including CRPS-affected and nonaffected sides) between 13 CRPS patients and 13 matched healthy controls. During a task to discriminate the digit simulated, patients (compared with controls) had significantly lower accuracy and slowed response times but with high between-subject variability. At middle latencies (124–132?ms), tactile processing in patients relative to controls showed decrements in superior parietal lobe and precuneus (that were independent of task demands) but enhanced activity in superior frontal lobe (that were task-dependent). At late latencies, patients showed an augmented P300-like response under task demands that localized to the supplementary motor area. Source activity in the supplementary motor area correlated with slowed response times, although its scalp representation intriguingly correlated with better functioning of the affected limb, suggesting a compensatory mechanism. Future research should investigate the clinical utility of these putative markers of tactile decision-making mechanisms in CRPS.

Patterns of cortical reorganization parallel impaired tactile discrimination and pain intensity in complex regional pain syndrome

In the complex regional pain syndrome (CRPS), several theories proposed the existence of pathophysiological mechanisms of central origin. Recent studies highlighted a smaller representation of the CRPS-affected hand on the primary somatosensory cortex (SI) during non-painful stimulation of the affected side. We addressed the question whether reorganizational changes can also be found in the secondary somatosensory cortex (SII). Moreover, we investigated whether cortical changes might be accompanied by perceptual changes within associated skin territories. Seventeen patients with CRPS of one upper limb without the presence of peripheral nerve injuries (type I) were subjected to functional magnetic resonance imaging (fMRI) during electrical stimulation of both index fingers (IFs) in order to assess hemodynamic signals of the IF representation in SI and SII. As a marker of tactile perception, we tested 2-point discrimination thresholds on the tip of both IFs. Cortical signals within SI and SII were significantly reduced contralateral to the CRPS-affected IF as compared to the ipsilateral side and to the representation of age- and sex-matched healthy controls. In parallel, discrimination thresholds of the CRPS-affected IF were significantly higher, giving rise to an impairment of tactile perception within the corresponding skin territory. Mean sustained, but not current pain levels were correlated with the amount of sensory impairment and the reduction in signal strength. We conclude that patterns of cortical reorganization in SI and SII seem to parallel impaired tactile discrimination. Furthermore, the amount of reorganization and tactile impairment appeared to be linked to characteristics of CRPS pain.     

A CRPS-IgG-transfer-trauma model reproducing inflammatory and positive sensory signs associated with complex regional pain syndrome

The aetiology of complex regional pain syndrome (CRPS), a highly painful, usually post-traumatic condition affecting the limbs, is unknown, but recent results have suggested an autoimmune contribution. To confirm a role for pathogenic autoantibodies, we established a passive-transfer trauma model. Prior to undergoing incision of hind limb plantar skin and muscle, mice were injected either with serum IgG obtained from chronic CRPS patients or matched healthy volunteers, or with saline. Unilateral hind limb plantar skin and muscle incision was performed to induce typical, mild tissue injury. Mechanical hyperalgesia, paw swelling, heat and cold sensitivity, weight-bearing ability, locomotor activity, motor coordination, paw temperature, and body weight were investigated for 8 days. After sacrifice, proinflammatory sensory neuropeptides and cytokines were measured in paw tissues. CRPS patient IgG treatment significantly increased hind limb mechanical hyperalgesia and oedema in the incised paw compared with IgG from healthy subjects or saline. Plantar incision induced a remarkable elevation of substance P immunoreactivity on day 8, which was significantly increased by CRPS-IgG. In this IgG-transfer-trauma model for CRPS, serum IgG from chronic CRPS patients induced clinical and laboratory features resembling the human disease. These results support the hypothesis that autoantibodies may contribute to the pathophysiology of CRPS, and that autoantibody-removing therapies may be effective treatments for long-standing CRPS.     

Muscle hyperalgesia is widespread in patients with complex regional pain syndrome

Patients with complex regional pain syndrome (CRPS) frequently show prominent sensory abnormalities in their affected limb, which may extend proximally and even to unaffected body regions. This study examines whether sensory dysfunction is observed in unaffected body parts of CRPS patients, and investigates whether the extent of dysfunction is similar for the various sensory modalities. Quantitative sensory testing was performed in the unaffected extremities and cheeks of 48 patients with CRPS of the arm (31 with dystonia), and the results were compared with values obtained among healthy controls. The most prominent abnormality was the pressure pain threshold, which showed a consistent pattern of higher sensitivity in unaffected contralateral arms and unaffected legs, as well as the cheek, and demonstrated the largest effect sizes. The cheeks of CRPS patients showed thermal hypoesthesia and hyperalgesia as well as a loss of vibration detection. Except for a lower vibration threshold in the contralateral leg of CRPS patients with dystonia, no differences in sensory modalities were found between CRPS patients with and without dystonia. These results point to a general disturbance in central pain processing in patients with CRPS, which may be attributed to impaired endogenous pain control. Since pressure pain is the most deviant sensory abnormality in both unaffected and affected body regions of CRPS patients, this test may serve as an important outcome parameter in future studies and may be used as a tool to monitor the course of the disease.     

Evidence of focal small-fiber axonal degeneration in complex regional pain syndrome-I (reflex sympathetic dystrophy)

CRPS-I consists of post-traumatic limb pain and autonomic abnormalities that continue despite apparent healing of inciting injuries. The cause of symptoms is unknown and objective findings are few, making diagnosis and treatment controversial, and research difficult. We tested the hypotheses that CRPS-I is caused by persistent minimal distal nerve injury (MDNI), specifically distal degeneration of small-diameter axons. These subserve pain and autonomic function. We studied 18 adults with IASP-defined CRPS-I affecting their arms or legs. We studied three sites on subjects’ CRPS-affected and matching contralateral limb; the CRPS-affected site, and nearby unaffected ipsilateral and matching contralateral control sites. We performed quantitative mechanical and thermal sensory testing (QST) followed by quantitation of epidermal neurite densities within PGP9.5-immunolabeled skin biopsies. Seven adults with chronic leg pain, edema, disuse, and prior surgeries from trauma or osteoarthritis provided symptom-matched controls. CRPS-I subjects had representative histories and symptoms. Medical procedures were unexpectedly frequently associated with CRPS onset. QST revealed mechanical allodynia (P < 0.03) and heat-pain hyperalgesia (P < 0.04) at the CRPS-affected site. Axonal densities were highly correlated between subjects’ ipsilateral and contralateral control sites (r = 0.97), but were diminished at the CRPS-affected sites of 17/18 subjects, on average by 29% (P < 0.001). Overall, control subjects had no painful-site neurite reductions (P = 1.00), suggesting that pain, disuse, or prior surgeries alone do not explain CRPS-associated neurite losses. These results support the hypothesis that CRPS-I is specifically associated with post-traumatic focal MDNI affecting nociceptive small-fibers. This type of nerve injury will remain undetected in most clinical settings.     

Decreased perceptual learning ability in complex regional pain syndrome

Recently, several functional imaging studies have shown that sensorimotor cortical representations may be changed in complex regional pain syndromes (CRPS). Therefore, we investigated tactile performance and tactile learning as indirect markers of cortical changes in patients with CRPS type I and controls. Patients had significant higher spatial discrimination thresholds at CRPS-affected extremities compared to both unaffected sides and control subjects. Furthermore, in order to improve tactile spatial acuity we used a Hebbian stimulation protocol of tactile coactivation. This consistently improved tactile acuity, both in controls and patients. However, the gain of performance was significantly lower on the CRPS-affected side implying an impaired perceptual learning ability. Therefore, we provide further support for an involvement of the CNS in CRPS, which may have implications to future neurorehabilitation strategies for this disease.     

Complex Regional Pain Syndrome Is Associated With Structural Abnormalities in Pain-Related Regions of the Human Brain

Complex regional pain syndrome (CRPS) is a chronic condition that involves significant hyperalgesia of the affected limb, typically accompanied by localized autonomic abnormalities and frequently by motor dysfunction. Although central brain systems are thought to play a role in the development and maintenance of CRPS, these systems have not been well characterized. In this study, we used structural magnetic resonance imaging to characterize differences in gray matter volume between patients with right upper extremity CRPS and matched controls. Analyses were carried out using a whole brain voxel-based morphometry approach. The CRPS group showed decreased gray matter volume in several pain-affect regions, including the dorsal insula, left orbitofrontal cortex, and several aspects of the cingulate cortex. Greater gray matter volume in CRPS patients was seen in the bilateral dorsal putamen and right hypothalamus. Correlation analyses with self-reported pain were then performed on the CRPS group. Pain duration was associated with decreased gray matter in the left dorsolateral prefrontal cortex. Pain intensity was positively correlated with volume in the left posterior hippocampus and left amygdala, and negatively correlated with the bilateral dorsolateral prefrontal cortex. Our findings demonstrate that CRPS is associated with abnormal brain system morphology, particularly pain-related sensory, affect, motor, and autonomic systems.PerspectiveThis paper presents structural changes in the brains of patients with CRPS, helping us differentiate CRPS from other chronic pain syndromes and furthering our understanding of this challenging disease.     

Impaired spatial body representation in complex regional pain syndrome type 1 (CRPS I)

Recently, a shift of the visual subjective body midline (vSM), a correlate of the egocentric reference frame, towards the affected side was reported in patients with complex regional pain syndrome (CRPS). However, the specificity of this finding is as yet unclear. This study compares 24 CRPS patients to 21 patients with upper limb pain of other origin (pain control) and to 24 healthy subjects using a comprehensive test battery, including assessment of the vSM in light and dark, line bisection, hand laterality recognition, neglect-like severity symptoms, and motor impairment (disability of the arm, shoulder, and hand). Statistics: 1-way analysis of variance, t-tests, significance level: 0.05. In the dark, CRPS patients displayed a significantly larger leftward spatial bias when estimating their vSM, compared to pain controls and healthy subjects, and also reported lower motor function than pain controls. For right-affected CRPS patients only, the deviation of the vSM correlated significantly with the severity of distorted body perception. Results confirm previous findings of impaired visuospatial perception in CRPS patients, which might be the result of the involvement of supraspinal mechanisms in this pain syndrome. These mechanisms might accentuate the leftward bias that results from a right-hemispheric dominance in visuospatial processing and is known as pseudoneglect. Pseudoneglect reveals itself in the tendency to perceive the midpoint of horizontal lines or the subjective body midline left of the centre. It was observable in all 3 groups, but most pronounced in CRPS patients, which might be due to the cortical reorganisation processes associated with this syndrome.     

Cold‐induced limb pain decreases sensitivity to pressure‐pain sensations in the ipsilateral forehead

The aim of this study was to investigate the effect of unilateral limb pain on sensitivity to pain on each side of the forehead. In the first experiment, pressure‐pain thresholds and sharpness sensations were assessed on each side of the forehead in 45 healthy volunteers before and after a 10 °C cold pressor of the hand and in 18 controls who were not subjected to the cold pressor. In a second experiment, forehead sensitivity was assessed in 32 healthy volunteers before and after a 2 °C cold pressor. The assessments were repeated without the cold pressor, and before and after six successive 4 °C cold pressor tests. The 10 °C cold pressor did not influence forehead sensitivity, whereas the 2 °C cold pressor and the 4 °C cold pressor tests resulted in bilateral analgesia to sharpness and pressure. The analgesia to pressure was greater in the ipsilateral forehead. Stress‐induced analgesia and diffuse noxious inhibitory controls may have contributed to the analgesia to pressure‐pain and sharpness sensations bilaterally after the most painful cold pressor tests. The locus coeruleus inhibits ipsilateral nociceptive activity in dorsal horn neurons during limb inflammation, and thus may have mediated the ipsilateral component of analgesia. Pain‐evoked changes in forehead sensitivity differed for sharpness and pressure, possibly due to separate thalamic or cortical representations of cutaneous and deep tissue sensibility. These findings suggest that several mechanisms act concurrently to influence pain sensitivity at sites distant from a primary site of painful stimulation.     

Cognitive correlates of "neglect-like syndrome" in patients with complex regional pain syndrome

Patients with complex regional pain syndrome (CRPS) often show distinct neurocognitive dysfunctions, which were initially termed "neglect-like symptoms." So far, particularly the patients' feelings about the affected extremity, motor, and sensory aspects of the "neglect-like symptoms" have been investigated, possibly pointing to a disturbed body schema. Because patients with classical neurological neglect show diminished awareness regarding the perception of their body, as well as of the space around them, our hypothesis was that CRPS patients exhibit some signs of personal neglect and extrapersonal visuospatial problems over and beyond those seen in patients simply suffering from limb pain. We used quantitative sensory testing and motor assessment aimed at detecting motor and sensory loss, a standardized questionnaire calculating a neglect score, and applied a detailed neuropsychological test battery assessing different parietal lobe functions, including visual neglect. We examined 20 CRPS patients and 2 matched control groups, one consisting of healthy subjects and the other one of patients with limb pain other than CRPS. Results show significant higher neglect scores for CRPS patients and the pain control group, but interestingly, CRPS patients and pain patients were indistinguishable. The results of the neuropsychological test battery did not demonstrate systematic variances, which would be indicative of a classical neurological neglect in CRPS patients, even though there were 3 CRPS patients who differed ≥ 2 SD from the mean of our healthy control group, with poorer results in ≥ 3 different tests. We assume that the "neglect-like syndrome" in most CRPS patients is different from typical neglect.     

Activation of Cutaneous Immune Responses in Complex Regional Pain Syndrome

The pathogenesis of complex regional pain syndrome (CRPS) is unresolved, but tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) are elevated in experimental skin blister fluid from CRPS-affected limbs, as is tryptase, a marker for mast cells. In the rat fracture model of CRPS, exaggerated sensory and sympathetic neural signaling stimulate keratinocyte and mast cell proliferation, causing the local production of high levels of inflammatory cytokines leading to pain behavior. The current investigation used CRPS patient skin biopsies to determine whether keratinocyte and mast cell proliferation occur in CRPS skin and to identify the cellular source of the up-regulated TNF-α, IL-6, and tryptase observed in CRPS experimental skin blister fluid. Skin biopsies were collected from the affected skin and the contralateral mirror site in 55 CRPS patients and the biopsy sections were immunostained for keratinocyte, cell proliferation, mast cell markers, TNF-α, and IL-6. In early CRPS, keratinocytes were activated in the affected skin, resulting in proliferation, epidermal thickening, and up-regulated TNF-α and IL-6 expression. In chronic CRPS, there was reduced keratinocyte proliferation, leading to epidermal thinning in the affected skin. Acute CRPS patients also had increased mast cell accumulation in the affected skin, but there was no increase in mast cell numbers in chronic CRPS.PerspectiveThe results of this study support the hypotheses that CRPS involves activation of the innate immune system, with keratinocyte and mast cell activation and proliferation, inflammatory mediator release, and pain.     

Long-term skin temperature measurements - a practical diagnostic tool in complex regional pain syndrome

Despite the development of the IASP criteria, diagnosing complex regional pain syndrome (CRPS) remains a challenge because all symptoms vary interindividually, including the vascular abnormalities. Previous studies showed that skin temperature asymmetries between the affected and contralateral extremity around 2 degrees C are useful for diagnosing CRPS. However, they were either assessed only at one single point in time or during specific investigations including controlled thermoregulatory modulation of sympathetic activity which limits their practicability. The present study evaluated long-term skin temperature changes under everyday circumstances in 22 patients with CRPS, 18 patients with limb pain of other origin and 23 healthy controls. The asymmetries in skin temperature and oscillation number (Q Oscill), the percentage of assessed time with a-synchron temperature changes on both body sides and the determination coefficient of the individual regression (r2 id) were compared between the groups. Patients with CRPS differed significantly from healthy controls in nearly all parameters. Minor differences between both patient groups were found regarding the percentage of assessed time with side difference >2 degrees C (DeltaT2). However, both patient groups differed significantly in parameters characterizing the skin temperature dynamics. A sum score (2 *Q Oscill +r2 id +DeltaT2) allowed diagnosing CRPS with a specificity of 67% vs. patients with other painful diseases and 79% vs. healthy controls (sensitivity: 73%, respectively, 94%) and reflected the severity of the dysfunction in CRPS better than the mean skin temperature side differences alone. The applied skin temperature analysis can be easily applied in the clinical settings and serves as a further facet in the difficult diagnosis of CRPS.     

Quantitative sensory testing, neurophysiological and psychological examination in patients with complex regional pain syndrome and hemisensory deficits

Based on bed-side neurological testing, it has recently been shown that 33% of chronic complex regional pain syndrome (CRPS) type I patients exhibit sensory impairments, which extend past the painful area of the affected limb in a hemisensory distribution (Pain, 80 (1999) 95). In the present study, the clinically observed changes in touch and temperature sensations on the side of the body ipsilateral to the affected limb were investigated quantitatively. Neurophysiological and psychological examinations were conducted to detect changes in the peripheral and central nervous system as well as psychopathological abnormalities.In 40 patients with CRPS, a bed-side neurological examination was performed. Quantitative sensory testing was conducted at five locations on each side of the body. The evaluation of touch thresholds was performed using von Frey filaments (n=40). To measure cool, warm and heat pain thresholds quantitatively, a thermal stimulator using a Peltier-element was used (n=28). With respect to clinical findings, the initiating trauma and severity of abnormalities on nerve conduction testing, three patients were diagnosed as having a reliable CRPS II (causalgia) and five patients a possible CRPS II. Thirty-two patients were diagnosed as having a CRPS I.On clinical examination, 15 patients revealed generalized sensory deficits on the side of the body ipsilateral to the affected limb (hemisensory deficit, n=12; sensory impairment in the upper quadrant of the body, n=3). Patients with these generalized sensory deficits had a significantly longer illness duration (P<0.05) and a significantly higher percentage of mechanical allodynia/hyperalgesia than patients with spatially restricted sensory deficits (n=25) (P<0.05). In patients with generalized sensory impairment, thresholds for touch, warm and cold sensations, and for heat pain were significantly increased at all five locations tested ipsilaterally compared with the contralateral body side, except for the cool threshold on the chest and the heat pain threshold distally on the affected limb. In patients with sensory deficits limited to the affected limb, the touch threshold was significantly higher only in the distal part of the affected limb when compared with the contralateral limb. In these patients, thermal testing revealed almost no differences in cool, warm and heat pain thresholds when comparing both sides. Repeated thermal testing conducted in five patients with generalized sensory impairment reproduced the significant differences between both sides for cool, warm and heat pain thresholds. However, the correlation between the results obtained in the first and second examinations was poor.Neurophysiological recordings revealed pathological results in 46% for nerve conduction studies, 24% for somatosensory evoked potentials and 39% for sympathetic skin response. For all methods applied, there was no statistically significant difference in the incidence of pathological results between patients with generalized and patients with spatially restricted sensory abnormalities. Psychological examination using the structured clinical interview on DSM-IV (SKID) demonstrated a high frequency of affective and anxiety disorders, however, without significant differences between both groups.We conclude that hemisensory impairment in patients with CRPS Type I is probably related to functional disturbances in processing of noxious events in the thalamus and may be a clinical correlate of subcortical brain plasticity in chronic pain.     

Despite clinical similarities there are significant differences between acute limb trauma and complex regional pain syndrome I (CRPS I).

In order to analyze the pathophysiology behind the clinical similarity acutely after limb trauma and in acute stages of complex regional pain syndrome (CRPS), 20 patients with external fixation after distal radius fracture (3.5 days after surgery) without signs of CRPS and 24 patients suffering from acute CRPS I (without nerve lesion; duration, 5 weeks) were investigated. Hyperalgesia to heat was tested by a feedback-controlled thermode, and to mechanical stimuli by an impact stimulator. The sympathetic nervous system was examined by measuring skin temperature (infra-red thermography), testing different sympathetic vasoconstrictor reflexes (laser-Doppler flowmetry) and quantitative sudometry after thermal load (thermoregulatory sweat test). We found hyperalgesia to heat after trauma (P<0.001), but not in CRPS, whereas mechanical hyperalgesia was present in both patient groups (trauma: P<0.001; CRPS: P<0.005). Skin temperature was significantly increased on the affected side in both patient groups (acute trauma: P<0.001; CRPS: P<0.005). However, sympathetic failure, as indicated by impairment of sympathetic vasoconstrictor reflexes (P<0.02) and hyperhidrosis (P<0.01), was found exclusively in CRPS patients. Our results indicate that pain and vasomotor disturbances may be generated by different mechanisms acutely after trauma and in acute CRPS. Despite the clinical similarity, additional changes in the peripheral or central nervous system are required for CRPS. In the light of our observations, it seems unlikely that CRPS is a simple exaggeration of post-traumatic inflammation.     

Cortical Reorganization in Primary Somatosensory Cortex in Patients With Unilateral Chronic Pain

Bodily representations of the primary somatosensory (SI) cortex are constantly modified according to sensory input. Increased input due to training as well as loss of input due to deafferentation are reflected as changes in the extent of cortical representations. Recent studies in complex regional pain syndrome (CRPS) patients have indicated that the chronic pain itself is associated with cortical reorganization. However, it is unclear whether the observed reorganization is specific for CRPS or if it can be detected also in other types of chronic pain. We therefore searched for signs of cortical reorganization in a group of 8 patients who suffered from chronic pain associated with herpes simplex virus infections. The pain was widespread but restricted to unilateral side of the body and included the upper limb. We recorded neuromagnetic responses to tactile stimulation of fingers of both hands in patients and in a group of healthy, matched control subjects. In the patients, the distance between the thumb (D1) and little finger (D5) representations in SI cortex was statistically significantly smaller in the hemisphere contralateral to painful side than in the hemisphere contralateral to healthy side. In the control subjects, the D1–D5 distance was the same in both hemispheres.PerspectiveThe present results indicate that cortical reorganization occurs in chronic neuropathic pain patients even without peripheral nerve damage. It is possible that cortical reorganization is related to chronic pain, regardless of its etiology. Causality between reorganization and chronic pain should be examined further to develop therapeutic approaches for chronic pain.     

Cutaneous norepinephrine application in complex regional pain syndrome.

Patients with complex regional pain syndrome (CRPS) (n=20) were examined in order to evaluate cutaneous reactions to norepinephrine (NE) on both the affected and the unaffected limb in comparison to healthy controls. Sixteen female and four male patients suffering from very acute and therefore untreated CRPS with a mean duration of 5.5 weeks were included in this study. Two groups of healthy volunteers served as control groups: the first group (n=18) according to the same study protocol as CRPS patients, and the second group (n=10) after warming up one limb. Norepinephrine was iontophoresized (0.2 mA, 120 s) and vasoconstriction was recorded by laser-doppler flowmetry. Pain sensations were simultaneously rated on a visual analogue scale (VAS). Five patients underwent a second trial with higher intracutaneous NE concentrations in order to study possible dose-dependent effects of NE on pain sensation. After acclimatization, skin temperature was recorded by infra-red thermography. The NE-induced reduction of skin blood flow was significantly higher in the affected limb in the patient group (33.0 vs 11.2%, p<0.005). None of the patients reported pain or hyperalgesia. The skin temperature of CRPS patients was significantly higher in the affected limb (34.7 vs 32.5 degrees C, p<0.001). The first control group did not show any difference between left and right sides concerning NE-induced vasoconstriction or skin temperature. The second control group had an increased unilateral skin temperature after warming up (35.0 vs 34.3 degrees C, p<0.006) and demonstrated a significantly increased vasoconstriction on the warmer side (52.0 vs 20.2%, p<0.03) corresponding to findings in patients with acute CRPS. The present study proves that there are signs of decreased sympathetic activity in the affected limb in very acute CRPS. However, no indication was found for increased sensitivity of vascular alpha-receptors in the very acute stages of CRPS, and there was also no indication for a significant direct contribution of the sympathetic nervous system to pain in very acute CRPS.