Exposure to an Immersive Virtual Reality Environment can Modulate Perceptual Correlates of Endogenous Analgesia and Central Sensitization in Healthy Volunteers

Virtual reality (VR) has been shown to produce analgesic effects during different experimental and clinical pain states. Despite this, the top-down mechanisms are still poorly understood. In this study, we examined the influence of both a real and sham (ie, the same images in 2D) immersive arctic VR environment on conditioned pain modulation (CPM) and in a human surrogate model of central sensitization in 38 healthy volunteers. CPM and acute heat pain thresholds were assessed before and during VR/sham exposure in the absence of any sensitization. In a follow-on study, we used the cutaneous high frequency stimulation model of central sensitization and measured changes in mechanical pain sensitivity in an area of heterotopic sensitization before and during VR/sham exposure. There was an increase in CPM efficiency during the VR condition compared to baseline (P < .01). In the sham condition, there was a decrease in CPM efficiency compared to baseline (P < .01) and the real VR condition (P < .001). Neither real nor sham VR had any effect on pain ratings reported during the conditioning period or on heat pain threshold. There was also an attenuation of mechanical pain sensitivity during the VR condition indicating a lower sensitivity compared to sham (P < .05). We conclude that exposure to an immersive VR environment has no effect over acute pain thresholds but can modulate dynamic CPM responses and mechanical hypersensitivity in healthy volunteers.PerspectiveThis study has demonstrated that exposure to an immersive virtual reality environment can modulate perceptual correlates of endogenous pain modulation and secondary hyperalgesia in a human surrogate pain model. These results suggest that virtual reality could provide a novel mechanism-driven analgesic strategy in patients with altered central pain processing.     

Virtual Reality Hypnosis for Pain Associated With Recovery From Physical Trauma

Pain following traumatic injuries is common, can impair injury recovery and is often inadequately treated. In particular, the role of adjunctive nonpharmacologic analgesic techniques is unclear. The authors report a randomized, controlled study of 21 hospitalized trauma patients to assess the analgesic efficacy of virtual reality hypnosis (VRH)—hypnotic induction and analgesic suggestion delivered by customized virtual reality (VR) hardware/software. Subjective pain ratings were obtained immediately and 8 hours after VRH (used as an adjunct to standard analgesic care) and compared to both adjunctive VR without hypnosis and standard care alone. VRH patients reported less pain intensity and less pain unpleasantness compared to control groups. These preliminary findings suggest that VRH analgesia is a novel technology worthy of further study, both to improve pain management and to increase availability of hypnotic analgesia to populations without access to therapist-provided hypnosis and suggestion.     

Virtual Reality as a Clinical Tool for Pain Management

Purpose of Review

To evaluate the use of virtual reality (VR) therapies as a clinical tool for the management of acute and chronic pain.

Recent Findings

Recent articles support the hypothesis that VR therapies can effectively distract patients who suffer from chronic pain and from acute pain stimulated in trials. Clinical studies yield promising results in the application of VR therapies to a variety of acute and chronic pain conditions, including fibromyalgia, phantom limb pain, and regional specific pain from past injuries and illnesses.

Summary

Current management techniques for acute and chronic pain, such as opioids and physical therapy, are often incomplete or ineffective. VR trials demonstrate a potential to redefine the approach to treating acute and chronic pain in the clinical setting. Patient immersion in interactive virtual reality provides distraction from painful stimuli and can decrease an individual’s perception of the pain. In this review, we discuss the use of VR to provide patient distraction from acute pain induced from electrical, thermal, and pressure conditions. We also discuss the application of VR technologies to treat various chronic pain conditions in both outpatient and inpatient settings.

     

The Specificity and Mechanisms of Hemilateral Sensory Disturbances in Complex Regional Pain Syndrome

Hyperalgesia often extends from the affected limb to the ipsilateral forehead in patients with complex regional pain syndrome (CRPS). To investigate whether this is more common in CRPS than other chronic pain conditions, pressure-pain thresholds and sharpness to a firm bristle were assessed on each side of the forehead, at the pain site, and at an equivalent site on the contralateral side in 32 patients with chronic pain other than CRPS (neuropathic or nociceptive limb pain, radicular pain with referral to a lower limb or postherpetic neuralgia), and in 34 patients with CRPS. Ipsilateral forehead hyperalgesia to pressure pain was detected in 59% of CRPS patients compared with only 13% of patients with other forms of chronic pain. Immersion of the CRPS-affected limb in painfully cold water increased forehead sensitivity to pressure, especially ipsilaterally, whereas painful stimulation of the healthy limb reduced forehead sensitivity to pressure pain (albeit less efficiently than in healthy controls). In addition, auditory discomfort and increases in pain in the CRPS-affected limb were greater after acoustic startle to the ear on the affected than unaffected side. These findings indicate that generalized and hemilateral pain control mechanisms are disrupted in CRPS, and that multisensory integrative processes may be compromised.

Perspective

The findings suggest that hemilateral hyperalgesia is specific to CRPS, which could be diagnostically important. Disruptions in pain-control mechanisms were associated with the development of hyperalgesia at sites remote from the CRPS limb. Addressing these mechanisms could potentially deter widespread hyperalgesia in CRPS.     

Three-Month Follow-Up Results of a Double-Blind,Randomized Placebo-Controlled Trial of 8-Week Self-Administered At-Home Behavioral Skills-Based Virtual Reality (VR) for Chronic Low Back Pain

Prior work established post-treatment efficacy for an 8-week home-based therapeutic virtual reality (VR) program in a double-blind, parallel arm, randomized placebo-controlled study. Participants were randomized 1:1 to 1 of 2 56-day VR programs: 1) a therapeutic immersive pain relief skills VR program; or 2) a Sham VR program within an identical commercial VR headset. Immediate post-treatment results demonstrated clinically meaningful and superior reduction for therapeutic VR compared to Sham VR for average pain intensity, indices of pain-related interference (activity, mood, stress but not sleep), physical function, and sleep disturbance. The objective of the current report was to quantify treatment effects to post-treatment month 3 and describe durability of effects. Intention-to-treat analyses revealed sustained benefits for both groups and superiority for therapeutic VR for pain intensity and multiple indices of pain-related interference (activity, stress, and newly for sleep; effect sizes ranged from d_rm = .56–.88) and physical function from pre-treatment to post-treatment month 3. The between-group difference for sleep disturbance was non-significant and pain-interference with mood did not survive multiplicity correction at 3 months. For most primary and secondary outcomes, treatment effects for therapeutic VR showed durability, and maintained superiority to Sham VR in the 3-month post-treatment period.PerspectiveWe present 3-month follow-up results for 8-week self-administered therapeutic virtual reality (VR) compared to Sham VR in adults with chronic low back pain. Across multiple pain indices, therapeutic VR had clinically meaningful benefits, and superiority over Sham VR. Home-based, behavioral skills VR yielded enduring analgesic benefits; longer follow-up is needed.     

Prefrontal White Matter Abnormalities Associated With Pain Catastrophizing in Patients With Complex Regional Pain Syndrome

ObjectiveTo investigate altered prefrontal white matter integrity in complex regional pain syndrome (CRPS) and its relation with the degree of pain catastrophizing.DesignCross-sectional study.SettingUniversity hospital.ParticipantsTwenty-one CRPS patients and 49 patients without CRPS (N=70).InterventionsNot applicable.Main Outcome MeasuresThe fractional anisotropy values within the prefrontal regions reflecting the structural integrity of white matter were measured in CRPS patients and patients without CRPS using diffusion tensor imaging. The degree of pain catastrophizing was also evaluated in CRPS patients.ResultsThe structural integrity of the prefrontal white matter was lower in CRPS patients than in patients without CRPS (P=.03). In addition, lower structural integrity in the prefrontal cortex was correlated with a higher degree of pain catastrophizing among CRPS patients (r= ?0.54, P=.01).ConclusionsOur findings suggest that pain catastrophizing, which is frequently reported in patients with CRPS, may be associated with the dysfunction of the prefrontal white matter.     

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.     

Sensory signs in complex regional pain syndrome and peripheral nerve injury

This study determined patterns of sensory signs in complex regional pain syndrome (CRPS) type I and II and peripheral nerve injury (PNI). Patients with upper-limb CRPS-I (n=298), CRPS-II (n=46), and PNI (n=72) were examined with quantitative sensory testing according to the protocol of the German Research Network on Neuropathic Pain. The majority of patients (66%-69%) exhibited a combination of sensory loss and gain. Patients with CRPS-I had more sensory gain (heat and pressure pain) and less sensory loss than patients with PNI (thermal and mechanical detection, hypoalgesia to heat or pinprick). CRPS-II patients shared features of CRPS-I and PNI. CRPS-I and CRPS-II had almost identical somatosensory profiles, with the exception of a stronger loss of mechanical detection in CRPS-II. In CRPS-I and -II, cold hyperalgesia/allodynia (28%-31%) and dynamic mechanical allodynia (24%-28%) were less frequent than heat or pressure hyperalgesia (36%-44%, 67%-73%), and mechanical hypoesthesia (31%-55%) was more frequent than thermal hypoesthesia (30%-44%). About 82% of PNI patients had at least one type of sensory gain. QST demonstrates more sensory loss in CRPS-I than hitherto considered, suggesting either minimal nerve injury or central inhibition. Sensory profiles suggest that CRPS-I and CRPS-II may represent one disease continuum. However, in contrast to recent suggestions, small fiber deficits were less frequent than large fiber deficits. Sensory gain is highly prevalent in PNI, indicating a better similarity of animal models to human patients than previously thought. These sensory profiles should help prioritize approaches for translation between animal and human research.     

Intense Pain Soon After Wrist Fracture Strongly Predicts Who Will Develop Complex Regional Pain Syndrome: Prospective Cohort Study

Complex regional pain syndrome (CRPS) is a distressing and difficult-to-treat complication of wrist fracture. Estimates of the incidence of CRPS after wrist fracture vary greatly. It is not currently possible to identify who will go on to develop CRPS after wrist fracture. In this prospective cohort study, a nearly consecutive sample of 1,549 patients presenting with wrist fracture to 1 of 3 hospital-based fracture clinics and managed nonsurgically was assessed within 1 week of fracture and followed up 4 months later. Established criteria were used to diagnose CRPS. The incidence of CRPS in the 4 months after wrist fracture was 3.8% (95% confidence interval = 2.9–4.8%). A prediction model based on 4 clinical assessments (pain, reaction time, dysynchiria, and swelling) discriminated well between patients who would and would not subsequently develop CRPS (c index .99). A simple assessment of pain intensity (0–10 numerical rating scale) provided nearly the same level of discrimination (c index .98). One in 26 patients develops CRPS within 4 months of nonsurgically managed wrist fracture. A pain score of ≥5 in the first week after fracture should be considered a “red flag” for CRPS.PerspectiveThis study shows that excessive baseline pain in the week after wrist fracture greatly elevates the risk of developing CRPS. Clinicians can consider a rating of greater than 5/10 to the question “What is your average pain over the last 2 days?” to be a “red flag” for CRPS.     

Differences in Neuronal Representation of Mental Rotation in Patients With Complex Regional Pain Syndrome and Healthy Controls

Spatial integration of parts of the body is impaired in patients with complex regional pain syndrome (CRPS). Because the training of mental rotation (MR) has been shown to be among the effective therapy strategies for CRPS, impairment of MR is also important for the pathophysiological understanding of CRPS. The aim of this study was to evaluate whether differences in the neural representation of MR occur between patients with CRPS and healthy controls (HC). Therefore, we included 15 patients with chronic CRPS and 15 age- and gender-matched HC. We assessed behavioral (accuracy and reaction time for MR of both hands), clinical (Disabilities of Arm, Shoulder and Hand questionnaire) and magnetic resonance imaging (T1-weighted, function magnetic resonance imaging during MR) data. Reaction times in the patient group were delayed compared with HC without a lateralization effect for the affected hand side. Although both groups showed an activation pattern typical for MR, only HC showed a highly significant contrast for the rotated versus unrotated hands in the right intraparietal sulcus. Patients with CRPS showed a reduction of functional magnetic resonance imaging activation in areas including the subthalamic nucleus, nucleus accumbens, and putamen. Regression analysis for the CRPS group emphasized the importance of putamen and nucleus accumbens activation for MR performance. This study highlights the reduced access of patients with CRPS for mental resources modulating arousal, emotional response, and subcortical sensorimotor integration.PerspectiveThis study localized the underlying neural responses for impaired mental rotation in patients with complex regional pain syndrome as a decrease in basal ganglia (putamen) and nucleus accumbens activation.     

Lenalidomide for Complex Regional Pain Syndrome Type 1: Lack of Efficacy in a Phase II Randomized Study

Complex regional pain syndrome (CRPS) is a potentially debilitating chronic pain syndrome with a poorly understood but likely neuroimmune/multifactorial pathophysiology associated with axonal injury. Based on the potential contribution of proinflammatory cytokines to CRPS pathogenesis and prior research with thalidomide, we investigated lenalidomide, a thalidomide derivative, for CRPS treatment. We conducted a phase II, randomized, double-blind, placebo-controlled study to evaluate the efficacy of oral lenalidomide 10 mg once daily in consenting patients with unilateral or bilateral CRPS type 1. The study comprised 12 weeks of treatment followed by a long-term extension. The primary efficacy outcome was reduced pain in the index limb, defined as ≥30% improvement from baseline using an 11-point numeric rating scale. One hundred eighty-four subjects enrolled. The primary endpoint was not met because equal proportions of treated (16.1%) and control (16.1%) subjects achieved the outcome; however, lenalidomide was well tolerated, with no evidence of neuropathy or major adverse effects. This study is the largest controlled, blinded clinical trial in subjects with chronic CRPS using the Budapest research criteria. It demonstrates the feasibility of conducting high-quality clinical trials in CRPS type 1 and provides considerations for designing future trials.PerspectiveThis article reports an adequately powered, controlled clinical trial in subjects with CRPS. Treatment and placebo were equally effective, but the study demonstrated that lenalidomide treatment is feasible in this population. The study provides examples to consider in designing future CRPS trials.     

Patients with Ehlers Danlos syndrome and CRPS: a possible association?

Rare patients are left with chronic pain, vasodysregulation, and other symptoms that define complex regional pain syndrome (CRPS), after limb traumas. The predisposing factors are unknown. Genetic factors undoubtedly contribute, but have not yet been identified. We report four CRPS patients also diagnosed with the classical or hypermobility forms of Ehlers Danlos syndrome (EDS), inherited disorders of connective tissue. These patients had been diagnosed using standard diagnostic criteria for CRPS and for EDS. All had sustained joint injury; in three this had been surgically treated. The association of these two diagnoses leads us to hypothesize that EDS might contribute to the development of CRPS in one or more of the following ways: via stretch injury to nerves traversing hypermobile joints, increased fragility of nerve connective tissue, or nerve trauma from more frequent surgery. We review the clinical presentation of the different Ehlers Danlos syndromes and provide clinical criteria that can be used to screen CRPS patients for EDS for clinical or research purposes.     

Exploratory findings with virtual reality for phantom limb pain; from stump motion to agency and analgesia

Purpose. Phantom limb pain is chronic and intractable. Recently, virtual reality (VR) and motion capture technology has replicated the mirror box device of Ramachandran (Ramachandran et al. Nature 1995, 377, 489–490; Ramachandran and Rogers-Ramachandran Proc R Soc Biol Sci 1996, 263, 377–386) and led to reductions in this pain. We present results from a novel variation on this method which captures motion data directly from a patient's stump (rather than using the opposite remaining limb) and then transforms it into goal directed, virtual action enacted by an avatar in a VR environment.

Method. A sample of subjects with ‘arm’ (n = 7) and ‘leg’ (n = 7) amputations underwent trials of a virtual reality (VR) system, controlled by motion captured from their stump which was translated into movements of a virtual limb within the VR environment. Measures of pain in the phantom limb were elicited from patients before and during this exercise as they attempted to gain agency for the movement they saw, and feel embodied within the limb. After this each subject was interviewed about their experiences.

Results. Five subjects in each group felt the virtual limb to be moved by them and felt sensations of movement within it. With this they also reported reductions in their phantom limb pain greater than expected from distraction alone. No carry over effect was seen.

Conclusions. This technique, which has shown similar success rates to trials of a virtual mirror box, is relatively cheap and portable, and will allow further trials in a home environment.     

Local and Systemic Expression Pattern of MMP-2 and MMP-9 in Complex Regional Pain Syndrome

Matrix metalloproteinases (MMP)-2 and MMP-9 play important roles in inflammation as well as in pain processes. For this reason, we compared the concentrations of these enzymes in skin and serum of patients with complex regional pain syndrome (CRPS), other pain diseases and healthy subjects. We analyzed ipsi- and contralateral skin biopsies of 18 CRPS patients, as well as in 10 pain controls and 9 healthy subjects. Serum samples were analyzed from 20 CRPS, 17 pain controls and 17 healthy subjects. All samples were analyzed with ELISA. Concentrations were then compared to clinical data as well as to quantitative sensory testing data.MMP-2 was increased in both ipsi- and contralateral skin biopsies of CRPS patients compared to healthy subjects. While low ipsilateral MMP-2 was associated with trophic changes, contralateral MMP-2 inversely correlated with the CRPS severity. MMP-9 was also locally increased in ipsilateral CRPS skin, and higher ipsi- and contralateral MMP-9 levels correlated with CRPS severity.We conclude that MMP-2 and MMP-9 are differently expressed depending on the clinical phenotype in CRPS.PerspectiveThis article describes an upregulation of MMPs in CRPS and pain controls and shows different expression of MMP-2 and -9 depending on clinical phenotype in CRPS. These results provide evidence that MMP-2 and -9 play a key role in CRPS pathophysiology.     

Widespread Pressure Pain Hypersensitivity in Musculoskeletal and Nerve Trunk Areas as a Sign of Altered Nociceptive Processing in Unilateral Plantar Heel Pain

Our aim was to investigate the differences in pressure sensitivity over musculoskeletal and nerve symptomatic and distant areas between individuals with plantar heel pain and healthy subjects and to determine the relationship between sensitivity to pressure pain, foot pain, and fascia thickness. Thirty-five patients with unilateral chronic plantar heel pain and 35 matched healthy controls participated. Pressure pain thresholds (PPTs) were assessed bilaterally over several nerve trunks (median, radial, ulnar, common peroneal, tibial, and sural nerve trunks) and musculoskeletal structures (calcaneus, medial gastrocnemius, tibialis anterior, and second metacarpal) by an assessor blinded to the subject's condition. Pain was assessed with a numerical pain rating scale (0–10), impact of foot pain was assessed with the Foot Function Index, and plantar fascia thickness was measured via ultrasound imaging. Analysis of covariance revealed lower widespread and bilateral PPTs over both nerve trunks and musculoskeletal structures in individuals with plantar heel pain (P < .001). Female patients showed lower PPT than male patients in almost all points (P < .001). PPT over the peripheral nerve trunks of the lower extremity were significantly associated with the intensity of pain at first step in the morning and with the foot function disability scale of the Foot Function Index (P < .05). This study found widespread pressure pain hypersensitivity over both nerve trunks and musculoskeletal structures in individuals with unilateral chronic plantar heel pain, suggesting the presence of a central altered central nociceptive pain processing. Pressure hypersensitivity over nerve trunks on the lower extremity was associated with higher pain intensity and related disability.

Upregulation of α1-adrenoceptors on cutaneous nerve fibres after partial sciatic nerve ligation and in complex regional pain syndrome type II

After peripheral nerve injury, nociceptive afferents acquire an abnormal excitability to adrenergic agents, possibly due to an enhanced expression of α₁-adrenoceptors (α₁-ARs) on these nerve fibres. To investigate this in the present study, changes in α₁-AR expression on nerve fibres in the skin and sciatic nerve trunk were assessed using immunohistochemistry in an animal model of neuropathic pain involving partial ligation of the sciatic nerve. In addition, α₁-AR expression on nerve fibres was examined in painful and unaffected skin of patients who developed complex regional pain syndrome (CRPS) after a peripheral nerve injury (CRPS type II). Four days after partial ligation of the sciatic nerve, α₁-AR expression was greater on dermal nerve fibres that survived the injury than on dermal nerve fibres after sham surgery. This heightened α₁-AR expression was observed on nonpeptidergic nociceptive afferents in the injured sciatic nerve, dermal nerve bundles, and the papillary dermis. Heightened expression of α₁-AR in dermal nerve bundles after peripheral nerve injury also colocalized with neurofilament 200, a marker of myelinated nerve fibres. In each patient examined, α₁-AR expression was greater on nerve fibres in skin affected by CRPS than in unaffected skin from the same patient or from pain-free controls. Together, these findings provide compelling evidence for an upregulation of α₁-ARs on cutaneous nociceptive afferents after peripheral nerve injury. Activation of these receptors by circulating or locally secreted catecholamines might contribute to chronic pain in CRPS type II.     

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.     

Impaired Recognition of Social Emotion in Patients With Complex Regional Pain Syndrome

Multiple brain areas involved in nociceptive, autonomic, and social-emotional processing are disproportionally changed in patients with complex regional pain syndrome (CRPS). Little empirical evidence is available involving social cognitive functioning in patients with chronic pain conditions. We investigated the ability of patients with CRPS to recognize the mental/emotional states of other people. Forty-three patients with CRPS and 30 healthy controls performed the Reading Mind in the Eyes Test, which consists of photos in which human eyes express various emotional and mental states. Neuropsychological tests, including the Wisconsin Card Sorting Test, the stop-signal test, and the reaction time test, were administered to evaluate other cognitive functions. Patients with CRPS were significantly less accurate at recognizing emotional states in other persons, but not on other cognitive tests, compared with control subjects. We found a significant association between the deficit in social-emotion recognition and the affective dimension of pain, whereas this deficit was not related to the sensory dimension of pain. Our findings suggest a disrupted ability to recognize others' mental/emotional states in patients with CRPS.     

A substance P receptor (NK1) antagonist can reverse vascular and nociceptive abnormalities in a rat model of complex regional pain syndrome type II

Sciatic nerve section in rats evokes chronic hindlimb edema, pain behavior, and hyperalgesia, a syndrome resembling complex regional pain syndrome (CRPS II) in man. Furthermore, there is an increase in spontaneous protein extravasation in the hindpaw skin of rats after sciatic transection, similar to the increased protein extravasation observed in the edematous limbs of CRPS patients. Now we demonstrate that sciatic nerve section also generates chronic hindlimb warmth, distal articular tenderness, allodynia, and periarticular osteoporosis, sequelae of nerve injury resembling those observed in CRPS. We postulated that facilitated substance P signaling may contribute to these vascular and nociceptive abnormalities and attempted to reverse these changes with the long acting substance P receptor (NK(1)) antagonist LY303870. Hindpaw spontaneous extravasation was inhibited by LY303870. Systemic administration of LY303870 also reversed hindpaw edema and cutaneous warmth. Intrathecal, but not systemic administration of LY303870 reversed soft tissue and articular mechanical hyperalgesia in the hindpaw. Collectively, these data further support the hypothesis that the sciatic nerve transection model closely resembles CRPS and that substance P contributes to the spontaneous extravasation, edema, warmth, and mechanical hyperalgesia observed in this model.