Mechanisms of Below-Level Pain Following Spinal Cord Injury (SCI).

Mechanisms of below-level pain are discoverable as neural adaptations rostral to spinal injury. Accordingly, the strategy of investigations summarized here has been to characterize behavioral and neural responses to below-level stimulation over time following selective lesions of spinal gray and/or white matter. Assessments of human pain and the pain sensitivity of humans and laboratory animals following spinal injury have revealed common disruptions of pain processing. Interruption of the spinothalamic pathway partially deafferents nocireceptive cerebral neurons, rendering them spontaneously active and hypersensitive to remaining inputs. The spontaneous activity among these neurons is disorganized and unlikely to generate pain. However, activation of these neurons by their remaining inputs can result in pain. Also, injury to spinal gray matter results in a cascade of secondary events, including excitotoxicity, with rostral propagation of excitatory influences that contribute to chronic pain. Establishment and maintenance of below-level pain results from combined influences of injured and spared axons in the spinal white matter and injured neurons in spinal gray matter on processing of nociception by hyperexcitable cerebral neurons that are partially deafferented. A model of spinal stenosis suggests that ischemic injury to the core spinal region can generate below-level pain. Additional questions are raised about demyelination, epileptic discharge, autonomic activation, prolonged activity of C nocireceptive neurons, and thalamocortical plasticity in the generation of below-level pain. PERSPECTIVE: An understanding of mechanisms can direct therapeutic approaches to prevent development of below-level pain or arrest it following spinal cord injury. Among the possibilities covered here are surgical and other means of attenuating gray matter excitotoxicity and ascending propagation of excitatory influences from spinal lesions to thalamocortical systems involved in pain encoding and arousal.

Clinical Features of Pediatric Complex Regional Pain Syndrome: A 5-Year Retrospective Chart Review.

OBJECTIVES: Complex regional pain syndrome (CRPS) is a painful condition of a limb characterized by a constellation of symptoms. Little is known about the clinical features of pediatric CRPS, with fewer than a dozen studies published to date. The aim of this study was to explore the clinical course of pediatric CRPS, with emphasis on clinical features and disease outcomes. A secondary aim was to discern differences in clinical features of pediatric CRPS with and without related movement disorders, and between children who had a favorable and unfavorable outcome. MATERIALS AND METHODS: We carried out a retrospective chart review of children with CRPS who presented to a pediatric Chronic Pain Clinic in Canada over a 5-year period (2012 to 2016). RESULTS: The study identified 59 children with CRPS (mean age: 12.7±2.5; 74.6% female; 72.9% lower extremity). In total, 87% (n=48) of children experienced complete resolution or significant improvement of CRPS, with a relapse rate of 15%. Overall, 25% (n=15) had a CRPS-related movement disorder. There were no differences in the clinical features of pediatric CRPS with or without related movement disorders. Children who experienced a favorable outcome had a significantly shorter symptom duration at the initial visit in comparison with children who experienced an unfavorable outcome. DISCUSSION: In this cohort, pediatric CRPS was most common in girls around the age of 12, usually in the lower extremity, and most experienced a favorable outcome. Further research is needed to better understand the prognosis and relapse rate of pediatric CRPS.

Effect of pain on deafferentation-induced modulation of somatosensory evoked potentials.

There is a large body of evidence showing substantial sensorimotor reorganizations after an amputation. These reorganizations are believed to contribute to the development of phantom limb pain, but alternatively, pain might influence the plasticity triggered by the deafferentation. The aim of this study was to test whether pain impacts on deafferentation-induced plasticity in the somatosensory pathways. Fifteen healthy subjects participated in 2 experimental sessions (Pain, No Pain) in which somatosensory evoked potentials (SSEPs) associated with electrical stimulation of the ulnar nerve were assessed before and after temporary ischemic deafferentation induced by inflation of a cuff around the wrist. In the Pain session capsaicin cream was applied on the dorsum of the hand 30 minutes prior to cuff inflation. Results show that pain decreased the amplitude of the N20 (main effect of condition, p = 0.033), with a similar trend for the P25. Temporary ischemic deafferentation had a significant effect on SSEPs (main effect of time), with an increase in the P25 (p = 0.013) and the P45 amplitude (p = 0.005), together with a reduction of the P90 amplitude (p = 0.002). Finally, a significant time x condition interaction, reflecting state-dependent plasticity, was found for the P90 only, the presence of pain decreasing the reduction of amplitude observed in response to deafferentation. In conclusion, these results show that nociceptive input can influence the plasticity induced by a deafferentation, which could be a contributing factor in the cortical somatosensory reorganization observed in chronic pain populations.

Dental deafferentation and brain damage: A review and a hypothesis.

In the last few decades, neurobiological and human brain imaging research have greatly advanced our understanding of brain mechanisms that support perception and memory, as well as their function in daily activities. Knowledge of the neurobiological mechanisms behind the deafferentation of stomatognathic systems has also expanded greatly in recent decades. In particular, current studies reveal that the peripheral deafferentations of stomatognathic systems may be projected globally into the central nervous system (CNS) and become an associated critical factor in triggering and aggravating neurodegenerative diseases. This review explores basic neurobiological mechanisms associated with the deafferentation of stomatognathic systems. Further included is a discussion on tooth loss and other dental deafferentation (DD) mechanisms, with a focus on dental and masticatory apparatuses associated with brain functions and which may underlie the changes observed in the aging brain. A new hypothesis is presented where DD and changes in the functionality of teeth and the masticatory apparatus may cause brain damage as a result of altered cerebral circulation and dysfunctional homeostasis. Furthermore, multiple recurrent reorganizations of the brain may be a triggering or contributing risk factor in the onset and progression of neurodegenerative conditions such as Alzheimer's disease (AD). A growing understanding of the association between DD and brain aging may lead to solutions in treating and preventing cognitive decline and neurodegenerative diseases.

Multicenter study on the asymmetry of skin temperature in complex regional pain syndrome: An examination of temperature distribution and symptom duration.

According to the International Association for the Study of Pain (IASP) and American Medical Association (AMA), the diagnostic criteria for complex regional pain syndrome (CRPS) require the presence of skin temperature asymmetry. In CRPS, it is generally accepted that the temperature of skin of affected limbs changes from warm to cold; however, in our clinical practice, we have experienced many cases with different thermographic characteristics. Therefore, we conducted a retrospective multicenter study that examined the distribution of skin temperature in patients with CRPS and skin temperature asymmetry versus symptom duration.Patients diagnosed with type 1 or 2 CRPS were recruited. After confirming CRPS according to the IASP diagnostic criteria, infrared thermographic images were evaluated for skin temperature differences (ΔT) between the affected and unaffected limbs.A total of 296 patients with CRPS were included in this study. The median duration of symptoms was 6 months and the mean ±â€Šstandard deviation of ΔT was -0.72 ±â€Š1.65°C. A skin temperature difference between bilateral limbs (|ΔT|) of 1°C or less was seen in 131 patients (44.3%); thus, these 131 patients did not meet the IASP criteria for CRPS. Further, cool skin temperature was not observed in 88 patients (29.7%), meaning that these patients did not meet the AMA criteria for CRPS. There was no correlation between the symptom duration and ΔT (Spearman's rho = -0.075, P = 0.196) and there was no significant difference in the average ΔT among the 4 symptom duration groups (0-3 months, 4-6 months, 7-12 months, >12 months, P = 0.08).In conclusion, a considerable proportion of the patients that participated in this study did not meet the thermal criteria set forth by the IASP and AMA. Further, there was no correlation between symptom duration and skin temperature difference.

Antiallodynic effect through spinal endothelin-B receptor antagonism in rat models of complex regional pain syndrome.

Complex regional pain syndrome (CRPS) is a very complicated chronic pain disorder that has been classified into two types (I and II). Endothelin (ET) receptors are involved in pain conditions at the spinal level. We investigated the role of spinal ET receptors in CRPS. Chronic post-ischemia pain (CPIP) was induced in male Sprague-Dawley rats as a model for CRPS-I by placing a tourniquet (O-ring) at the ankle joint for 3h, and removing it to allow reperfusion. Ligation of L5 and L6 spinal nerves to induce neuropathic pain was performed as a model for CRPS-II. After O-ring application and spinal nerve ligation, the paw withdrawal threshold was significantly decreased at injured sites. Intrathecal administration of the selective ET-B receptor antagonist BQ 788 dose-dependently increased the withdrawal threshold in both CRPS-I and CRPS-II. In contrast, ET-A receptor antagonist BQ 123 did not affect the withdrawal threshold in either CRPS type. The ET-1 levels of plasma and spinal cord increased in both CRPS types. Intrathecal BQ 788 decreased the spinal ET-1 level. These results suggest that ET-1 is involved in the development of mechanical allodynia in CRPS. Furthermore, the ET-B receptor appears to be involved in spinal cord-related CRPS.

Pathological mechanism of musculoskeletal manifestations associated with CRPS type II: an animal study.

Patients with complex regional pain syndrome (CRPS) often complain of abnormal sensations beyond the affected body part, but causes of this spread of musculoskeletal manifestations into contiguous areas remain unclear. In addition, immobilization can predispose to the development of CRPS. We examined functional, biochemical, and histological alterations in affected parts, including contiguous zones, using an animal model. Ten-week-old male Wistar rats were assigned to 5 groups: a normal group receiving no treatment, a sham operation group with surgical exploration, an immobilization group with surgical exploration plus internal knee joint immobilization, a surgical neuropathy group prepared by spinal nerve ligation (SNL) of the left L5 nerve root, and a surgical neuropathy+immobilization group with simultaneous SNL and knee joint immobilization. Mechanical allodynia and knee contracture were compared between groups, and tissues were harvested for histological assessments and gene and protein expression analyses. Neither surgical procedures nor immobilization induced detectable mechanical sensitivity. However, the addition of nerve injury resulted in detectable mechanical allodynia, and immobilization not only accelerated hyperalgesia, but also resulted in muscle fibrosis. Nerve growth factor (NGF) and other mediators of neurogenic inflammation were highly expressed not only in denervated muscles, but also in innervated muscles in contiguous areas, suggesting the spread of NGF production beyond the myotome of the injured nerve. Transforming growth factor ß was involved in the development of contracture in CRPS. These findings imply that neuroinflammatory components play major roles in the progression and dispersion of both sensory pathologies and pathologies that are exacerbated by immobilization.

The changes of c-Fos expression by motor cortex stimulation in the deafferentation pain model.

The effect of motor cortex stimulation (MCS) therapy for deafferentation pain was evaluated based on c-Fos, a known pain marker. Nineteen mature cats weighing 1.5-3.5 kg were used. Cats were divided into three groups: a deafferentation pain group in which the left trigeminal ganglion was destroyed, an MCS group in which MCS was used following destruction of the trigeminal ganglion, and a control group. Sites and levels of c-Fos expression were examined immunohistochemically. The percentage of c-Fos-positive cells in the left spinal nucleus of the trigeminus, the bilateral insula, and the bilateral operculum increased in both the deafferentation pain and the MCS groups. There were no statistically significant differences between these groups. In the cingulate gyrus, the percentage of c-Fos-positive cells increased bilaterally in the deafferentation pain group and the MCS group, but the increase was greater in the MCS group. The increase in c-Fos-positive cells in the left spinal nucleus of the trigeminus in the deafferentation group may reflect reported electrical hyperactivity. The cingulate gyrus, insula, and parietal operculum were activated after deafferentation. This change (increase in c-Fos positive cells) is related to the development of deafferentation pain. Pain relief due to MCS is not dependent on the suppression of the activated left spinal nucleus of the trigeminus or the descending analgesic mechanism of the brain stem. Activation of the cingulate gyrus appears to be a factor in the analgesic mechanism of MCS.

Atypical odontalgia: an up-to-date view.

Atypical odontalgia (AO) is a little known chronic pain condition. It usually presents as pain in a site where a tooth was endodontically treated or extracted, in the absence of clinical or radiographic evidence of tooth pathology. It is a rare clinical challenge for most clinicians, which leads to the patients being referred to several specialists and sometimes undergoing unnecessary surgical procedures. The pain mechanisms involved in AO are far from clear, and numerous potential mechanisms have been suggested. Currently, the most accredited hypothesis is that AO is a neuropathic pain condition caused by deafferentation. The differential diagnosis of AO remains difficult, because it shares symptoms with many others pathologies affecting this area. Patients have difficulties accepting the AO diagnosis and treatment. As a result, they frequently change physicians, and may potentially also receive several invasive treatments, usually resulting in an aggravation of the pain. Although some patients do get complete pain relief following treatment, for most patients the goal should be to achieve adequate pain management. Currently, most management is based on expert opinion and case reports. More research and high quality randomized controlled trials are needed in order to develop evidence-based treatments, currently based on expert opinion or carried over from other neuropathic pain conditions in the orofacial region.

Type II complex regional pain syndrome of the hand resulting from repeated arterial punctures during transradial coronary intervention.

Coronary catheterization using a transradial approach has become a common procedure, as the risks of local complications are low and this procedure affords relatively expeditious postprocedural patient mobilization. Access site complications--such as radial artery spasm, hematoma, and compartment syndrome--have been reported in the literature; however, cases of complex regional pain syndrome (CRPS) of the hand related to the procedure are extremely rare. We describe a case of type II CRPS affecting the hand after a transradial coronary intervention that was complicated by repeated periprocedural arterial punctures. In this case, a 55-year-old woman underwent a percutaneous coronary intervention for the treatment of unstable angina. After successful completion of the procedure, the patient complained of severe pain along the median and radial nerve distributions and resulting disability of the right hand. Although subsequent duplex sonography showed no abnormalities, a nerve conduction study uncovered injury to multiple nerves on the right. A diagnosis of type II CRPS was then made and the patient was treated with a nerve block as well as multiple medical modalities. This case demonstrates a very unusual complication resulting from the transradial approach to percutaneous coronary intervention.

[Complex regional pain syndrome--pathophysiology, clinical presentation and treatment]. / Kompleksni regionalni bolni sindrom--patofiziologija, klinicka slika i lijecenje.

In 1994, a consensus group of experts gathered by the International Association for the Study of Pain (IASP) agreed on new diagnostic criteria for the reflex sympathetic dystrophy (RSD) and causalgia, and renamed them complex regional pain syndrome (CRPS) types I and II, respectively. CRPS is a complex pathophysiological entity characterised by pain, trophic and vasomotoric changes, limited function of affected body part and relatively fast development of osteoporosis of affected region. We described possible pathophysiological mechanisms which caused the pain, clinical presentation of the disease and treatment which includes all available pharmacological modalities as well as interventional procedures.

Testing the link between sympathetic efferent and sensory afferent fibers in neuropathic pain.

The diagnosis of sympathetically maintained pain (SMP) is typically established by assessment of pain relief during local anesthetic blockade of the sympathetic ganglia that innervate the painful body part. To determine if systemic α-adrenergic blockade with phentolamine can be used to diagnose SMP, we compared the effects on pain of local anesthetic sympathetic ganglion blocks (LASB) and phentolamine blocks (PhB) in 20 patients with chronic pain and hyperalgesia that were suspected to be sympathetically maintained. The blocks were done inrandom order on separate days. Patients rated the intensity of ongoing and stimulus-evoked pain every 5 min before, during, and after the LASB and PhB. Patients and the investigator assessing pain levels were blinded to the time of intravenous administration of phentolamine (total dose 25-35 mg). The pain relief achieved by LASB and PhB correlated closely (r = 0.84), and there was no significant difference in the maximum pain relief achieved with the two blocks (t = 0.19, P > 0.8). Nine patients experienced a greater than 50% relief of pain and hyperalgesia from both LASB and PhB and were considered to have a clinically significant component of SMP. We conclude that α-adrenergic blockade with intravenous phentolamine is a sensitive alternative test to identify patients with SMP.

Changes in plasma cytokines and their soluble receptors in complex regional pain syndrome.

UNLABELLED: Complex Regional Pain Syndrome (CRPS) is a chronic and often disabling pain disorder. There is evidence demonstrating that neurogenic inflammation and activation of the immune system play a significant role in the pathophysiology of CRPS. This study evaluated the plasma levels of cytokines, chemokines, and their soluble receptors in 148 subjects afflicted with CRPS and in 60 gender- and age-matched healthy controls. Significant changes in plasma cytokines, chemokines, and their soluble receptors were found in subjects with CRPS as compared with healthy controls. For most analytes, these changes resulted from a distinct subset of the CRPS subjects. When the plasma data from the CRPS subjects was subjected to cluster analysis, it revealed 2 clusters within the CRPS population. The category identified as most important for cluster separation by the clustering algorithm was TNFα. Cluster 1 consisted of 64% of CRPS subjects and demonstrated analyte values similar to the healthy control individuals. Cluster 2 consisted of 36% of the CRPS subjects and demonstrated significantly elevated levels of most analytes and in addition, it showed that the increased plasma analyte levels in this cluster were correlated with disease duration and severity. PERSPECTIVE: The identification of biomarkers that define disease subgroups can be of great value in the design of specific therapies and of great benefit to the design of clinical trials. It may also aid in advancing our understanding of the mechanisms involved in the pathophysiology of CRPS, which may lead to novel treatments for this very severe condition.

Self-mutilation in patients after nerve injury may not be due to deafferentation pain: a case report.

OBJECTIVE: Animals with transected nerves may develop self-mutilating behavior (autotomy) directed at the denervated body part. Autotomy is often thought to be a response to deafferentation pain produced by pathological changes in the dorsal horn, and self-mutilation after dorsal rhizotomy has consequently been used as an outcome measure for the investigation of chronic pain in animal models. A less recognized hypothesis suggests that autotomy is simply an animal's efforts to remove the useless part. We report a case of self-mutilation of the thumb and fingers in a patient with loss of all sensory modalities in the arm after brachial plexus avulsion. CONCLUSION: Asking the patient about the reasons for his self-mutilation provides insights into the cause of autotomy which cannot be established from animal studies. We suggest that autotomy may not be a result of chronic pain, and discuss the human experience and alternative underlying pathological processes.

Motor cortex stimulation for trigeminal neuropathic or deafferentation pain: an institutional case series experience.

BACKGROUND: Trigeminal neuropathy is a rare, devastating condition that can be intractable and resistant to treatment. When medical treatment fails, invasive options are limited. Motor cortex stimulation (MCS) is a relatively recent technique introduced to treat central neuropathic pain. The use of MCS to treat trigeminal neuropathic or deafferentation pain is not widespread and clinical data in the medical literature that demonstrate efficacy are limited. METHOD: We retrospectively reviewed patients with trigeminal neuropathic or trigeminal deafferentation pain who were treated at the Oregon Health & Science University between 2001 and 2008 by 1 neurosurgeon using MCS. RESULTS: Eight of 11 patients (3 male, 8 female) underwent successful permanent implantation of an MCS system. All 8 patients reported initial satisfactory pain control. Three failed to experience continued pain control (6 months of follow-up). Five continued to experience long-term pain control (mean follow-up, 33 months). Average programming sessions were 2.2/year (all 8 patients) and 1.55/year (5 patients who sustained long-term pain control). Patients with anesthesia dolorosa or trigeminal deafferentation pain who had previously undergone ablative trigeminal procedures responded poorly to MCS. We encountered no perioperative complications. CONCLUSION: MCS is a safe and potentially effective therapy in certain patients with trigeminal neuropathy.

[Small fiber sensory neuropathies: contribution of laser evoked potentials]. / Neuropathies sensitives des petites fibres : intérêt des potentiels évoqués laser.

Standard neurophysiological techniques evaluate exclusively large myelinated fibers, but are not useful to explore sensory small fibers. Quantitative sensory tests have been developed to explore the thermal nociceptive function but this exploration is only subjective. Laser evoked potentials (LEPs) represent a noninvasive and objective test to explore thermal and nociceptive pathways. The clinical interest of LEPs have been assessed recently in the diagnosis of small fibers sensory neuropathies. In routine, the determination of detection and nociceptive thresholds, the analysis of N2P2 latencies and amplitudes enable demonstration of a dysfunction of A delta nerve fibers, to quantify these lesions and to determine whether the neuropathies are length-dependent or not. The LEP amplitude is negatively correlated to deafferentation. The interest of LEPs remained to be studied compared to skin biopsy.