A role for peripheral afferents in the pathophysiology and treatment of at-level neuropathic pain in spinal cord injury? A case report

At-level neuropathic pain is a frequent symptom following spinal cord injury, but the underlying pathophysiology is not completely understood. We report a patient suffering from treatment-resistant at-level pain characterized by ongoing pain and mechanical allodynia for three years after an incomplete spinal lesion. Quantitative sensory testing revealed severe thermosensory deficits in the neuropathic pain area. However, topical application of capsaicin in the neuropathic pain area induced a burning pain sensation, a marked decrease in heat pain threshold and an increase in mechanical allodynia. Treatment with topical lidocaine patches (5%) led to considerable pain relief. These results indicate a functional connection between peripheral, spinal and supraspinal nociceptive pathways and that peripheral afferents may contribute to at-level neuropathic pain after spinal cord injury in this patient. Lesioned peripheral afferents in combination with central neuronal hyperexcitability are discussed as a likely underlying pain mechanism.     

Spinal Cord Stimulation in the Treatment of Cancer-Related Pain: “Back to the Origins”

Spinal cord stimulation (SCS) has been used in the treatment of chronic pain for more than 40 years. The most common indication for SCS in the USA is failed back surgery syndrome (FBSS). Interestingly, the first two spinal cord stimulators ever implanted were in patients suffering from bronchogenic carcinoma and pelvic cancer, respectively. While cancer accounts for millions of deaths each year in the USA, pain is often the first sign of malignancy. An increasing number of people suffer from cancer-related pain each year and many receive suboptimal relief. Given the demonstrated value of spinal cord stimulation in the treatment of neuropathic pain, spinal cord stimulation should be considered "earlier" as an adjunct to the treatment of cancer-related pain. In addition, with the improving survival rates associated with advances in cancer treatment, spinal cord stimulation may help reduce the risk of development of chronic neuropathic pain in survivors.     

Different underlying pain mechanisms despite identical pain characteristics: a case report of a patient with spinal cord injury

Pain following spinal cord injury has been classified as nociceptive (musculoskeletal, visceral) or neuropathic (above, at, below level). There is no clear relation between the etiology and reported symptoms. Thus, due to different underlying mechanisms, the treatment is often ineffective. We report on a patient with spinal cord injury with neurological level of injury at T8 suffering from bilateral burning and prickling pain in the T9-11 dermatomes bilaterally (at-level pain), as well as diffusely in both legs from below the torso (below-level pain), accompanied by musculoskeletal low back pain. Bilateral comparison of quantitative sensory testing (QST) and skin biopsy revealed completely different findings in the dermatome T9 despite identical at-level pain characteristics. On the right side, QST revealed a normal sensory profile; the intraepidermal nerve fiber density (IENFD) was reduced, but not as severe as the contralateral side. On the left side there was a severe sensory loss with a stronger reduction of the IENDF, similar to the areas below the neurological level. These findings were significantly related to the treatment results. Pregabalin induced unilateral pain relief only in the area with remaining sensory function, whereas the left-sided at-level pain was unchanged. Thus, 2 different underlying mechanisms leading to bilaterally neuropathic pain with identical symptoms and with different treatment success were demonstrated in a single patient. The at-level pain in areas with remaining sensory function despite IENFD reduction could be relieved by pregabalin. Thus, in an individual case, QST may be helpful to better understand pain-generating mechanisms and to initiate successful treatment.     

Effect of antioxidant treatment on spinal GABA neurons in a neuropathic pain model in the mouse

One feature of neuropathic pain is a reduced spinal gamma-aminobutyric acid (GABA)-ergic inhibitory function. However, the mechanisms behind this attenuation remain to be elucidated. This study investigated the involvement of reactive oxygen species in the spinal GABA neuron loss and reduced GABA neuron excitability in spinal nerve ligation (SNL) model of neuropathic pain in mice. The importance of spinal GABAergic inhibition in neuropathic pain was tested by examining the effects of intrathecally administered GABA receptor agonists and antagonists in SNL and naïve mice, respectively. The effects of SNL and antioxidant treatment on GABA neuron loss and functional changes were examined in transgenic GAD67-enhanced green fluorescent protein positive (EGFP+) mice. GABA receptor agonists transiently reversed mechanical hypersensitivity of the hind paw in SNL mice. On the other hand, GABA receptor antagonists made naïve mice mechanically hypersensitive. Stereological analysis showed that the numbers of enhanced green fluorescent protein positive (EGFP+) GABA neurons were significantly decreased in the lateral superficial laminae (I–II) on the ipsilateral L5 spinal cord after SNL. Repeated antioxidant treatments significantly reduced the pain behaviors and prevented the reduction in EGFP+ GABA neurons. The response rate of the tonic firing GABA neurons recorded from SNL mice increased with antioxidant treatment, whereas no change was seen in those recorded from naïve mice, which suggested that oxidative stress impaired some spinal GABA neuron activity in the neuropathic pain condition. Together the data suggest that neuropathic pain, at least partially, is attributed to oxidative stress, which induces both a GABA neuron loss and dysfunction of surviving GABA neurons.     

Pain therapy after spinal cord lesion

An important part of patients with spinal cord disorder suffers chronic pain. Especially the neuropathic pain syndrome is a problem. The pain lost his function of a protective warning sign, it can reduce the quality of life dramatically. We show the diagnosis and pharmacotherapy in neuropathic pain syndromes in patients with spinal cord disorder.     

Central Pain

ABSTRACT

Questions from patients about pain conditions and analgesic pharmacotherapy and responses from authors are presented to help educate patients and make them more effective self-advocates. The topic addressed in this issue is central pain, a neuropathic pain syndrome caused by a lesion in the brain or spinal cord that sensitizes one's perception of pain. It is a debilitating condition caused by various diseases such as multiple sclerosis, strokes, spinal cord injuries, or brain tumors. Varied symptoms and the use of pharmacological medicines and nonpharmacological therapies will be addressed.     

Spinal Cord Stimulation as a Novel Approach to the Treatment of Refractory Neuropathic Mediastinal Pain

Spinal cord stimulation (SCS) offers new hope for patients with neuropathic pain. SCS "neuromodulates" the transmission and response to "painful" stimuli. The efficacy of SCS has been established in the treatment of a variety of neuropathic pain conditions and more recently in refractory angina pectoris, peripheral vascular disease, and failed back surgery syndrome. Recent publications suggest that visceral pain could be successfully treated with SCS. We report the first successful use of a spinal cord stimulator in the treatment of refractory neuropathic mediastinal, esophageal, and anterior neck pain following esophagogastrectomy.     

Characterization of cell proliferation in rat spinal cord following peripheral nerve injury and the relationship with neuropathic pain

Glial activation is a typical response of the central nervous system to nerve injury. In the current investigation, we characterized the temporal and spatial pattern of glial proliferation, one of the most conspicuous features of glial activation, in relation to nerve injury-induced neuropathic pain. Using bromodeoxyuridine (BrdU) as a mitotic marker, we analyzed cell proliferation in the spinal cord, identified the phenotype of dividing cells, traced their fate, and correlated these phenomena with behavioural assays of the neuropathic pain syndrome. Our results demonstrated that peripheral nerve injury induced an early and transient cell proliferation, on the spinal cord ipsilateral to the nerve lesion which peaked at day 3 post-surgery. The majority of the proliferating cells were Iba-1(+) microglia, together with some NG2(+) oligodendrocyte progenitors, and GFAP(+) astrocytes. These newly generated cells continued to divide over time with the response peaking at day 14 post-injury. Microglia were always the predominant phenotype which made up over 60% of activated microglia derived from this newly generated cell population. There was a close temporal correlation between microglial proliferation in the spinal cord dorsal horn and the abnormal pain responses, suggesting a contribution of the new microglia to the genesis of the neuropathic pain symptoms.     

Injury discharges regulate calcium channel alpha-2-delta-1 subunit upregulation in the dorsal horn that contributes to initiation of neuropathic pain

Previous studies have shown that peripheral nerve injury in rats induces increased expression of the voltage gated calcium channel (VGCC) alpha-2-delta-1 subunit (Ca v alpha2 delta1) in spinal dorsal horn and sensory neurons in dorsal root ganglia (DRG) that correlates to established neuropathic pain states. To determine if injury discharges trigger Ca v alpha2 delta1 induction that contributes to neuropathic pain initiation, we examined allodynia onset and Ca v alpha2 delta1 levels in DRG and spinal dorsal horn of spinal nerve ligated rats after blocking injury induced neural activity with a local brief application of lidocaine on spinal nerves before the ligation. The lidocaine pretreatment blocked ligation-induced discharges in a dose-dependent manner. Similar pretreatment with the effective concentration of lidocaine diminished injury-induced increases of the Ca v alpha2 delta1 in DRG and abolished that in spinal dorsal horn specifically, and resulted in a delayed onset of tactile allodynia post-injury. Both dorsal horn Ca v alpha2 delta1 upregulation and tactile allodynia in the lidocaine pretreated rats returned to levels similar to that in saline pretreated controls 2 weeks post the ligation injury. In addition, preemptive intrathecal Ca v alpha2 delta1 antisense treatments blocked concurrently injury-induced allodynia onset and Ca v alpha2 delta1 upregulation in dorsal spinal cord. These findings indicate that injury induced discharges regulate Ca v alpha2 delta1 expression in the spinal dorsal horn that is critical for neuropathic allodynia initiation. Thus, preemptive blockade of injury-induced neural activity or Ca v alpha2 delta1 upregulation may be a beneficial option in neuropathic pain management.     

CXCL13 drives spinal astrocyte activation and neuropathic pain via CXCR5

Recent studies have implicated chemokines in microglial activation and pathogenesis of neuropathic pain. C-X-C motif chemokine 13 (CXCL13) is a B lymphocyte chemoattractant that activates CXCR5. Using the spinal nerve ligation (SNL) model of neuropathic pain, we found that CXCL13 was persistently upregulated in spinal cord neurons after SNL, resulting in spinal astrocyte activation via CXCR5 in mice. shRNA-mediated inhibition of CXCL13 in the spinal cord persistently attenuated SNL-induced neuropathic pain. Interestingly, CXCL13 expression was suppressed by miR-186-5p, a microRNA that colocalized with CXCL13 and was downregulated after SNL. Spinal overexpression of miR-186-5p decreased CXCL13 expression, alleviating neuropathic pain. Furthermore, SNL induced CXCR5 expression in spinal astrocytes, and neuropathic pain was abrogated in Cxcr5^–/– mice. CXCR5 expression induced by SNL was required for the SNL-induced activation of spinal astrocytes and microglia. Intrathecal injection of CXCL13 was sufficient to induce pain hypersensitivity and astrocyte activation via CXCR5 and ERK. Finally, intrathecal injection of CXCL13-activated astrocytes induced mechanical allodynia in naive mice. Collectively, our findings reveal a neuronal/astrocytic interaction in the spinal cord by which neuronally produced CXCL13 activates astrocytes via CXCR5 to facilitate neuropathic pain. Thus, miR-186-5p and CXCL13/CXCR5-mediated astrocyte signaling may be suitable therapeutic targets for neuropathic pain.     

Pain report and the relationship of pain to physical factors in the first 6 months following spinal cord injury.

A prospective, longitudinal study of 100 people with traumatic spinal cord injury (SCI) was performed to determine the time of onset. prevalence and severity of different types of pain (musculoskeletal, visceral, neuropathic at level, neuropathic below level) at 2, 4, 8, 13 and 26 weeks following SCI. In addition, we sought to determine the relationship between physical factors such as level of lesion, completeness and clinical SCI syndrome and the presence of pain. At 6 months following SCI, 40% of people had musculoskeletal pain, none had visceral pain, 36% had neuropathic at level pain and 19% had neuropathic below level pain. When all types of pain were included, at 6 months following injury, 64% of people in the study had pain, and 21% of people had pain that was rated as severe. Those with neuropathic below level pain were most likely to report their pain as severe or excruciating. There was no relationship between the presence of pain overall and level or completeness of lesion, or type of injury. Significant differences were found, however, when specific types of pain were examined. Musculoskeletal pain was more common in people with thoracic level injuries. Neuropathic pain associated with allodynia was more common in people who had incomplete spinal cord lesions, cervical rather than thoracic spinal cord lesions, and central cord syndrome. Therefore, this study suggests that most people continue to experience pain 6 months following spinal cord injury and 21% of people continue to experience severe pain. While the presence or absence of pain overall does not appear to be related to physical factors following SCI, there does appear to be a relationship between physical factors and pain when the pain is classified into specific types.     

Spread of excitation across modality borders in spinal dorsal horn of neuropathic rats

Under physiological conditions, nociceptive information is mainly processed in superficial laminae of the spinal dorsal horn, whereas non-nociceptive information is processed in deeper laminae. Neuropathic pain patients often suffer from touch-evoked pain (allodynia), suggesting that modality borders are disrupted in their nervous system. We studied whether excitation evoked in deep dorsal horn neurons either via stimulation of primary afferent Abeta-fibres, by direct electrical stimulation or via glutamate microinjection leads to activation of neurons in the superficial dorsal horn. We used Ca(2+)-imaging in transversal spinal cord slices of neuropathic and control animals to monitor spread of excitation from the deep to the superficial spinal dorsal horn. In neuropathic but not control animals, a spread of excitation occurred from the deep to the superficial dorsal horn. The spread of excitation was synaptically mediated as it was blocked by the AMPA receptor antagonist CNQX. In contrast, block of NMDA receptors was ineffective. In control animals, the violation of modality borders could be reproduced by bath application of GABA(A) and glycine receptor antagonists. Furthermore, we could show that neuropathic animals were more prone to synchronous network activity than control animals. Thus, following peripheral nerve injury, excitation generated in dorsal horn areas which process non-nociceptive information can invade superficial dorsal horn areas which normally receive nociceptive input. This may be a spinal mechanism of touch-evoked pain.     

miR-338-5p Levels and Cigarette Smoking are Associated With Neuropathic Pain Severity in Individuals With Spinal Cord Injury: Preliminary Findings From a Genome-Wide microRNA Expression Profiling Screen

ObjectiveTo identify microRNA biomarkers and clinical factors associated with neuropathic pain after spinal cord injury.DesignCross-sectional, secondary analysis of baseline data collected from ongoing clinical studies. Using a genome-wide microRNA screening approach, we studied differential microRNA expression in serum from 43 adults with spinal cord injury enrolled in ongoing clinical studies. Least squares regression was used to identify associations between microRNA expression, clinical factors, and neuropathic pain severity.SettingCommunity-dwelling individuals with spinal cord injury.ParticipantsParticipants (N=43) were at least 18 years old with spinal cord injury, with 28 reporting neuropathic pain and 15 reporting no neuropathic pain.InterventionsNot applicable.Main Outcome MeasuresPain presence, type, and intensity were assessed with the International Spinal Cord Injury Pain Basic Data Set. Serum microRNA normalized deep sequencing counts were quantified from blood samples. Participant demographic factors, injury characteristics, medication use, and health habits were collected via questionnaire.ResultsmiR-338-5p expression and history of cigarette smoking were associated with and explained 37% of the variance in neuropathic pain severity (R²=0.37, F_2,18=5.31, P=.02) independent of other clinical factors. No association was identified between miR-338-5p levels and nociceptive pain severity.ConclusionsOur findings suggest that miR-338-5p and cigarette smoking may both play a role in the development or maintenance of neuropathic pain after spinal cord injury. While additional work is needed to confirm these findings, validated target analysis suggests a neuroprotective role of miR-338-5p in modulating neuroinflammation and neuronal apoptosis and that its downregulation may result in maladaptive neuroplastic mechanisms contributing to neuropathic pain after spinal cord injury.     

A comprehensive pain management programme comprising educational, cognitive and behavioural interventions for neuropathic pain following spinal cord injury.

OBJECTIVE: To assess whether a comprehensive multidisciplinary pain management programme could contribute to improvement regarding sleep quality, mood, life satisfaction, health-related quality of life, sense of coherence and pain for patients with a spinal cord injury and neuropathic pain.Design: A prospective intervention study. PATIENTS: Twenty-seven patients with spinal cord injury and neuropathic pain participated in a pain management programme in parallel with 11 patients in a control group. METHODS: A comprehensive pain management programme comprising educational, cognitive, and behavioural interventions was created for patients with spinal cord injury and neuropathic pain. The pain management programme consisted of 20 sessions over a 10-week period and included educational sessions, behavioural therapy, relaxation, stretching, light exercise and body awareness training. All patients were followed-up 3, 6 and 12 months after completion of the programme. RESULTS: At the 12-month follow-up, levels of anxiety and depression in the treatment group decreased compared with baseline values, and a tendency towards better quality of sleep was seen. In comparison with the control group, patients in the treatment group improved regarding sense of coherence and depression. CONCLUSION: This study implies that a multidimensional pain management programme can be a valuable complement in the treatment of spinal cord injured patients with neuropathic pain.     

Methylprednisolone worsening neuropathic pain in non‐traumatic thoracic myelopathy

Methylprednisolone (MP) is the only neuroprotective medication currently in widespread use for the treatment of spinal cord injury. Increasingly, published studies challenge its clinical effects in view of its serious side‐effects including wound infection, pneumonia, sepsis and steroid myopathy. Most cases with spontaneous spinal epidural haematoma (SSEH) need emergency evacuation, and typically show good neurologic recovery. Some patients with SSEH given preoperative or postoperative MP within hours of the onset of symptoms, and have had good motor recovery, although no mention was made of sensory function. Severe, intractable neuropathic pain has not been reported in patients with SSEH. We present a case of SSEH treated with a high‐dose MP 16 h after onset of symptoms. Surgical decompression was performed 1 h after MP treatment. Motor recovery was good; however, intractable neuropathic pain developed 5 weeks postoperatively. We discuss the factors contributing to intractable pain. We speculate that the severe, intractable pain might be due to misuse of large‐dose steroids in this case of non‐traumatic spinal myelopathy, and not because of the injury per se.     

Systemic lidocaine for neuropathic pain relief

The effectiveness of systemic lidocaine in relieving acute and chronic pain has been recognized for over 35 years. In particular, systemic lidocaine has been utilized both as a diagnostic and therapeutic tool for intractable neuropathic pain during the last decade. The introduction of oral lidocaine congeners such as mexiletine has significantly extended the usage of lidocaine therapy in chronic pain settings. However, a number of clinical issues remain to be addressed including (1) an effective, meaningful dose range for the clinical lidocaine test, (2) the predictive value of the lidocaine test for an oral trial of lidocaine congeners, (3) identification of pain symptoms and signs relieved by systemic lidocaine, (4) comparisons of therapeutic effects between systemic lidocaine and its oral congeners, and (5) long-term outcomes of systemic lidocaine and its oral congeners. Mechanisms of neuropathic pain relief from lidocaine therapy are yet to be understood. Both central and peripheral mechanisms have been postulated. Systemic lidocaine is thought to have its suppressive effects on spontaneous ectopic discharges of the injured nerve without blocking normal nerve conduction. However, there remain inconsistencies in the scientific basis underlying the clinical application of lidocaine therapy. Recent demonstration of changes in tetrodotoxin (TTX)-sensitive and TTX-resistant sodium channels following nerve injury and their link to certain neuropathic pain symptoms may lead to the development of subtype-specific sodium channel blockers. The thoughtful use of lidocaine therapy and the potential application of subtype-specific sodium channel blockers could provide better management of distinctive neuropathic pain symptoms.     

嗅鞘细胞移植治疗脊髓损伤后顽固性神经性疼痛17例报道

目的探讨嗅鞘细胞移植对脊髓损伤后顽固性神经性疼痛的治疗效果。方法对细胞学治疗后获得疗效的脊髓损伤合并顽固性神经性疼痛患者的临床资料进行总结。2004年11月～2007年11月间的17例患者,其中男性15例,女性2例,年龄18～68岁,平均40.4岁。受伤6～312个月,平均105.9个月,受伤原因包括车祸、坠落、放射性损伤、机器挤压伤、枪伤、跳水。疼痛持续时间6～309个月,平均102.2个月。嗅球嗅鞘细胞胰蛋白酶消化成单细胞后培养12～14 d。细胞移植到损伤段的上下两端。疼痛评价使用国际神经修复学会脊髓损伤日常生活功能评价量表：0分为极度疼痛,止痛药无效;1分为中度疼痛,需用强效止痛药;2分为轻度疼痛,普通止痛药有效;3分为无疼痛。结果随访时间0.5～88个月,平均17.5个月,疼痛平均改善1.2分。结论嗅鞘细胞移植对脊髓损伤后神经性疼痛有一定治疗作用。     

Experiences with Spinal Cord Stimulator in Patients with Chronic Neuropathic Back Pain

Neuropathic pain is a complex, chronic, and disabling condition that has physical, functional, and psychosocial repercussions. Although the estimated prevalence of neuropathic pain in the general population ranges from 1.5% to 8%, neuropathic pain is frequently underdiagnosed and undertreated. The aims of this study were to examine the experience of patients treated with spinal cord stimulation as a pain-relieving treatment and how this may influence the patient’s ability to participate in everyday life activities. A qualitative approach based on seven telephone interviews was performed. The participants were recruited from a university hospital in Norway, and all used spinal cord stimulation as a pain-relieving treatment. Qualitative content analysis was used. Two thematic findings emerged: (1) pain relief with spinal cord stimulation as a complex and individual experience and (2) challenges in adaptations in everyday life with spinal cord stimulation. Findings indicate that spinal cord stimulation can offer pain relief that can help patients achieve a meaningful life despite chronic pain. Spinal cord stimulation also may have disadvantages that should be considered before offering this treatment. It seems evident that extended information needs about working mechanism of SCS and precautions as well as follow-up are required to meet unexpected challenges in adaptation. Here the nurse has an important role when informing and following this patient group.     

Regulatory T cells attenuate neuropathic pain following peripheral nerve injury and experimental autoimmune neuritis

Neuroimmune crosstalk in neuropathic pain is a key contributor to pain hypersensitivity following nervous system injury. CD4+CD25+Foxp3+ regulatory T cells (Tregs) are endogenous immune suppressors, reducing T-cell proliferation and proinflammatory cytokine production. Currently, the role of Tregs in neuropathic pain is unknown. In this study, we tested the effects of expanding Tregs on pain hypersensitivity and neuroinflammation in 2 models of neuropathy; sciatic nerve chronic constriction injury and experimental autoimmune neuritis in rats. Following chronic constriction injury, treatment with CD28 superagonist (CD28SupA), a Treg population expander, significantly increased Tregs in the lymphoid tissues, injured sciatic nerve, and lumbar spinal cord of rats. CD28SupA treatment led to a significant reduction in mechanical pain hypersensitivity, alongside a decrease in the numbers of infiltrating T cells, macrophages, and antigen-presenting cells in the sciatic nerve and dorsal root ganglia. In experimental autoimmune neuritis-affected rats, CD28SupA treatment resulted in a significant improvement in disease severity and in mechanical pain hypersensitivity. This was associated with a reduction in the numbers of T cells, macrophages, and antigen-presenting cells in the sciatic nerve and dorsal root ganglia, and reduced activation of microglia and infiltration of T cells in the spinal cord. Furthermore, depletion of Tregs by a CD25 antibody in mice with a partial sciatic nerve ligation resulted in prolonged mechanical pain hypersensitivity. These findings suggest that Tregs play a role in endogenous recovery from neuropathy-induced pain. Thus, this T-cell subset may be specifically targeted to alleviate chronic neuropathic pain.     

Epileptiform activity in rat spinal dorsal horn in vitro has common features with neuropathic pain

Neuropathic pain and epileptic seizures bear several similarities, among them is the response to anticonvulsant drugs. It has therefore been hypothesized that epileptiform activity of nociceptive spinal dorsal horn neurons may contribute to paroxysmal forms of neuropathic pain. We used patch-clamp and field potential recordings from young rat spinal cord slices to test if nociceptive dorsal horn structures are indeed able to sustain epileptiform activity. Application of the convulsant 4-aminopyridine (100 microM) evoked epileptiform activity that was most pronounced in superficial dorsal horn and involved nociceptive lamina I neurons with a projection to the brain. The epileptiform activity was dependent on fast excitatory and inhibitory synaptic transmission through ionotropic glutamate receptors and GABA(A) receptors. During epileptiform activity, previously silent polysynaptic pathways from primary afferent C-fibers to superficial dorsal horn neurons were opened. Stimulation of primary afferents at Adelta- and C-fiber intensity interfered with the epileptiform rhythm, suggesting that both affect the same dorsal horn structures. Similar to neuropathic pain, spinal dorsal horn epileptiform activity was much less reduced by classical analgesics than by anticonvulsant agents.