Spinal Cord Injury Neuropathic Pain Research Articles

ID: 204799 Failure of Spinal Cord Stimulation for Neuropathic Pain After Spinal Cord Injury: A Case Report

Besides motor, bowel, and bladder dysfunction, patients with spinal cord injury (SCI) often experience neuropathic pain (NP). NP can present at or below the level of the lesion, is alarmingly common (70-80%) and has a major impact on patient’s quality of life. There are few effective analgesics and no recommended interventional treatment options for NP in SCI.

ID: 211374 Spinal Cord Stimulation for Diffuse Neuropathic Pain After Spinal Cord Injury

Post spinal cord injury (SCI) patients often develop chronic neuropathic pain [1]. Management of pain in these complex patients is frequently inadequate leading to a significant negative impact on quality of life and rehabilitation. Neuropathic pain is usually diffuse, severely debilitating, and can affect 30-80% of SCI injury patients [2]. Current understanding of the mechanism for this pain is limited and broadly attributed to dysfunctional somatosensory pathways. Neuromodulation as a therapeutic option for SCI neuropathic pain has been poorly studied [3].

Potential novel therapeutic strategies for neuropathic pain.

To explore the potential therapeutic strategies of different types of neuropathic pain (NP) and to summarize the cutting-edge novel approaches for NP treatment based on the clinical trials registered on ClinicalTrials.gov. The relevant clinical trials were searched using ClinicalTrials.gov Dec 08, 2022. NP is defined as a painful condition caused by neurological lesions or diseases. All data were obtained and reviewed by the investigators to confirm whether they were related to the current topic. A total of 914 trials were included in this study. They were divided into painful diabetic neuropathy (PDN), postherpetic neuralgia (PHN), sciatica (SC), peripheral nerve injury-related NP (PNI), trigeminal neuralgia (TN), chemotherapy-induced NP (CINP), general peripheral NP (GPNP) and spinal cord injury NP (SCI-NP). Potential novel therapeutic strategies, such as novel drug targets and physical means, were discussed for each type of NP. NP treatment is mainly dominated by drug therapy, and physical means have become increasingly popular. It is worth noting that novel drug targets, new implications of conventional medicine, and novel physical means can serve as promising strategies for the treatment of NP. However, more attention needs to be paid to the challenges of translating research findings into clinical practice.

The mechanism of human neural stem cell secretomes improves neuropathic pain and locomotor function in spinal cord injury rat models: through antioxidant, anti-inflammatory, anti-matrix degradation, and neurotrophic activities.

Globally, spinal cord injury (SCI) results in a big burden, including 90% suffering permanent disability, and 60%-69% experiencing neuropathic pain. The main causes are oxidative stress, inflammation, and degeneration. The efficacy of the stem cell secretome is promising, but the role of human neural stem cell (HNSC)-secretome in neuropathic pain is unclear. This study evaluated how the mechanism of HNSC-secretome improves neuropathic pain and locomotor function in SCI rat models through antioxidant, anti-inflammatory, anti-matrix degradation, and neurotrophic activities. A proper experimental study investigated 15 Rattus norvegicus divided into normal, control, and treatment groups (30 μL HNSC-secretome, intrathecal in the level of T10, three days post-traumatic SCI). Twenty-eight days post-injury, specimens were collected, and matrix metalloproteinase (MMP)-9, F2-Isoprostanes, tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-β, and brain derived neurotrophic factor (BDNF) were analyzed. Locomotor recovery was evaluated via Basso, Beattie, and Bresnahan scores. Neuropathic pain was evaluated using the Rat Grimace Scale. The HNSC-secretome could improve locomotor recovery and neuropathic pain, decrease F2-Isoprostane (antioxidant), decrease MMP-9 and TNF-α (anti-inflammatory), as well as modulate TGF-β and BDNF (neurotrophic factor). Moreover, HNSC-secretomes maintain the extracellular matrix of SCI by reducing the matrix degradation effect of MMP-9 and increasing the collagen formation effect of TGF-β as a resistor of glial scar formation. The present study demonstrated the mechanism of HNSC-secretome in improving neuropathic pain and locomotor function in SCI through antioxidant, anti-inflammatory, anti-matrix degradation, and neurotrophic activities.

Coexistence of chronic hyperalgesia and multilevel neuroinflammatory responses after experimental SCI: a systematic approach to profiling neuropathic pain

BackgroundPeople with spinal cord injury (SCI) frequently develop neuropathic pain (NP) that worsens disability and diminishes rehabilitation efficacy. Chronic NP is presently incurable due to poor understanding of underlying mechanisms. We hypothesized that multilocus neuroinflammation (NIF) might be a driver of SCI NP, and tested it by investigating whether NP coexisted with central NIF, neurotransmission (NTM), neuromodulation (NML) and neuroplasticity (NPL) changes post-SCI.MethodsFemale Sprague–Dawley rats (230–250 g) with T10 compression or laminectomy were evaluated for physical conditions, coordinated hindlimb functions, neurological reflexes, and mechanical/thermal sensitivity thresholds at 1 day post-injury (p.i.) and weekly thereafter. Eight weeks p.i., central nervous system tissues were histochemically and immunohistochemically characterized for parameters/markers of histopathology and NIF/NTM/NML/NPL. Also analyzed was the correlative relationship between levels of selected biomarkers and thermosensitivity thresholds via statistical linear regression.ResultsSCI impaired sensorimotor functions, altered reflexes, and produced spontaneous pain signs and hypersensitivity to evoked nociceptive, mechanical, and thermal inputs. Only injured spinal cords exhibited neural lesion, microglia/astrocyte activation, and abnormal expression of proinflammatory cytokines, as well as NIF/NTM/NML/NPL markers. Brains of SCI animals displayed similar pathophysiological signs in the gracile and parabrachial nuclei (GrN and PBN: sensory relay), raphe magnus nucleus and periaqueduct gray (RMN and PAG: pain modulation), basolateral amygdala (BLA: emotional-affective dimension of pain), and hippocampus (HPC: memory/mood/neurogenesis). SCI augmented sensory NTM/NPL (GrN and PBN); increased GAD67 (PAG) level; reduced serotonin (RMN) and fear-off neuronal NTR2 (BLA) expressions; and perturbed neurogenesis (HPC).ConclusionT10 compression caused chronic hyperalgesia that coexisted with NIF/NTM/NML/NPL responses at multilevel neuroaxis centers. The data have provided multidimensional biomarkers as new mechanistic leads to profile SCI NP for therapeutic/therapy development.

Hsa-MiR-19a-3p and hsa-MiR-19b-3p Are Associated with Spinal Cord Injury-Induced Neuropathic Pain: Findings from a Genome-Wide MicroRNA Expression Profiling Screen.

Neuropathic pain in spinal cord injury (SCI) is associated with inflammation in both the peripheral and central nervous system (CNS), which may contribute to the initiation and maintenance of persistent pain. An understanding of factors contributing to neuroinflammation may lead to new therapeutic targets for neuropathic pain. Moreover, novel circulating biomarkers of neuropathic pain may facilitate earlier and more effective treatment. MicroRNAs (miRNAs) are short, non-coding single-stranded RNA that have emerged as important biomarkers and molecular mediators in physiological and pathological conditions. Using a genome-wide miRNA screening approach, we studied differential miRNA expression in plasma from 68 healthy, community-dwelling adults with and without SCI enrolled in ongoing clinical studies. We detected 2367 distinct miRNAs. Of these, 383 miRNAs were differentially expressed in acute SCI or chronic SCI versus no SCI and 71 were differentially expressed in chronic neuropathic pain versus no neuropathic pain. We selected homo sapiens (hsa)-miR-19a-3p and hsa-miR-19b-3p for additional analysis based on p-value, fold change, and their known role as regulators of neuropathic pain and neuroinflammation. Both hsa-miR-19a-3p and hsa-miR-19b-3p levels were significantly higher in those with chronic SCI and severe neuropathic pain versus those with chronic SCI and no neuropathic pain. In confirmatory studies, both hsa-miR-19a-3p and hsa-miR-19b-3p have moderate to strong discriminative ability to distinguish between those with and without pain. After adjusting for opioid use, hsa-miR-19b-3p levels were positively associated with pain interference with mood. Because hsa-miR-19 levels have been shown to change in response to exercise, folic acid, and resveratrol, these studies suggest that miRNAs are potential targets of therapeutic interventions.

Immersive interactive virtual walking reduces neuropathic pain in spinal cord injury: findings from a preliminary investigation of feasibility and clinical efficacy.

Chronic neuropathic pain (NP) is a common and often debilitating secondary condition for persons with spinal cord injury (SCI) and is minimally responsive to existing pharmacological and nonpharmacological treatments. The current preliminary investigation describes the feasibility and initial comparative efficacy of an interactive virtual reality walking intervention, which is a novel extension of visual feedback/illusory walking therapies shown to reduce SCI NP. Virtual reality walking intervention builds on previous research by, for the first time, allowing individuals with SCI NP to volitionally control virtual gait to interact with a fully immersive virtual environment. The current pilot study compared this interactive, virtual walking intervention to a passive, noninteractive virtual walking condition (analogous to previous illusory walking interventions) in 27 individuals with complete paraplegia (interactive condition, n = 17; passive condition, n = 10; nonrandomized design). The intervention was delivered over 2 weeks in individuals' homes. Participants in the interactive condition endorsed significantly greater reductions in NP intensity and NP-related activity interference preintervention to postintervention. Notable improvements in mood and affect were also observed both within individual sessions and in response to the full intervention. These results, although preliminary, highlight the potentially potent effects of an interactive virtual walking intervention for SCI NP. The current study results require replication in a larger, randomized clinical trial and may form a valuable basis for future inquiry regarding the mechanisms and clinical applications of virtual walking therapies.

Multimodal sensory evaluation of neuropathic spinal cord injury pain: an experimental study

Study designAn experimental study.ObjectivesTo investigate the changes in somatosensory functions using the combined application of quantitative sensory testing (QST), contact heat-evoked potentials (CHEPs) and laser-evoked potentials (LEPs) studies in individuals with spinal cord injury (SCI) in relation to neuropathic pain (NeP).SettingCentre for Pain Medicine, Swiss Paraplegic Centre, Nottwil, Switzerland.MethodsIndividuals with SCI were compared: 12 with NeP (SCI NeP) and 12 without NeP (SCI no NeP). Tools used were QST, CHEPs, LEPs and self-reported questionnaires. Tests were applied to the control (hand) and test (dermatome of altered sensation) sites, and compared to the able-bodied group.ResultsQST, LEPs and CHEPs assessments showed abnormalities both on the test and control sites, which did not differ between the groups with SCI. QST showed higher prevalence of allodynia in SCI NeP. CHEPs and LEPs demonstrated diminished amplitudes in both groups with SCI in comparison to able-bodied individuals. Only reaction time (RT) analysis revealed the difference of SCI NeP from the other two groups, expressed in partially preserved responses to the laser C-fibre stimulations.ConclusionsCombination of assessments in our study allowed to examine spinothalamic and dorsal column functions in individuals with SCI. Changes in QST, CHEPs and LEPs were detected below the level of injury independent of NeP and at the control site indicating modifications in sensory processing rostral to the spinal lesion. Analysis of RT during laser stimulation could be an essential component when evaluating the somatosensory functions related to NeP in persons with SCI.

Intensive Locomotor Training Provides Sustained Alleviation of Chronic Spinal Cord Injury-Associated Neuropathic Pain: A Two-Year Pre-Clinical Study.

Neuropathic pain often accompanies the functional deficits associated with spinal cord injury (SCI) and further reduces a patient's quality of life. Clinical and pre-clinical research is beginning to highlight the beneficial role that rehabilitative therapies such as locomotor training can have not only on functional recovery but also on chronic pain management. Our group has previously developed an intensive locomotor training (ILT) treadmill protocol on rats that reduced SCI neuropathic pain symptoms for at least 3 months. We have extended these findings in the current study to evaluate the ability of regular ILT regimen over a 2 year period post-SCI to maintain neuropathic pain reduction. To assess this, the rat clip compression SCI model (T7/8) was used and treadmill training was initiated starting 4 weeks after SCI and continuing through the duration of the study. Results showed continued suppression of SCI neuropathic pain responses (reduced mechanical, heat, and cold hypersensitivity throughout the entire time course of the study). In contrast, non-exercised rats showed consistent and sustained neuropathic pain responses during this period. In addition, prolonged survival and improved locomotor outcomes were observed in rats undergoing ILT as the study longevity progressed. Potential contributory mechanisms underlying beneficial effects of ILT include reduced inflammation and restoration of anti-nociceptive inhibitory processes as indicated by neurochemical assays in spinal tissue of remaining rats at 2 years post-SCI. The benefits of chronic ILT suggest that long-term physical exercise therapy can produce powerful and prolonged management of neuropathic pain, partly through sustained reduction of spinal pathological processes.

Motor cortical excitability behavior in chronic spinal cord injury neuropathic pain individuals submitted to transcranial direct current stimulation—case reports

Increased excitability of the motor cortex through transcranial direct current stimulation (tDCS) has been described as a non-pharmacological strategy for the treatment of Spinal Cord Injury neuropathic pain (SCINP). It is also believed that the ability to enhance motor cortex excitability (MCE) could be impaired within chronic SCINP individuals. The following case reports describe the MCE behavior in individuals with chronic SCINP submitted to electrical non-invasive neuromodulation. This article reports 11 cases with chronic SCINP in which each individual was submitted to a 5-day pre-post MCE analysis in order to evaluate its behavior after the anodal tDCS sessions. All cases maintained ongoing pharmacological treatment. Four individuals have shown negative variation of the MCE, two of which reported pain intensity reduction. Three other individuals had MCE-positive variation along 5 days, from which only one reported a VAS 0.5 pain reduction after the 5th day of observation. The other four individuals did not present significant variation of the MCE. The positive variation of MCE was significantly altered by adjunctive tDCS only in three individuals, though no clinically relevant reduction in pain intensity was reported among these participants. Key factors such as pain and injury duration, age, chronic medication use and underlying maladaptive neuroplasticity may influence responsiveness to brain stimulation within this population. These case reports try to add evidence for cautious recommendation of tDCS in chronic SCINP individuals and to the necessity of identifying groups of individuals that are most susceptible to neuromodulation.

The short-term effects of head-mounted virtual-reality on neuropathic pain intensity in people with spinal cord injury pain: a randomised cross-over pilot study.

Within-subject, randomised cross-over trial. To determine whether a commercially available 3D head-mounted (HMD) virtual reality (VR) device results in significant reductions in neuropathic pain compared to using a 2D screen device in people with spinal cord injury (SCI). Greenwich Hospital, Sydney, Australia. Sixteen men with established SCI and chronic neuropathic pain participated in a single-session randomised cross-over trial. We compared the effects of 3D HMD VR and a 2D screen application on SCI neuropathic pain intensity and levels of perceived presence. Participants reported significantly lower pain intensity after 3D HMD VR compared to 2D screen application (1.9 ± SD 1.8 versus 3.4 ± SD 1.6, mean 95% CI: 1.5, P < 0.0001). Participants reported significantly higher perceived levels of presence with the 3D HMD VR compared to 2D screen of (49.6 ± SD 8.9 versus 32.8 ± SD 11.1, mean 95% CI: 16.6, P < 0.0001). Increased perceived presence was associated with significantly lower pain intensity regardless of randomised sequencing of the two conditions (mean 95% CI: 0.06, P = 0.005). Effect size for pain reduction using 3D HMD VR was 0.80. We suggest that 3D HMD VR may provide neuropathic pain relief for people with SCI. Given the lack of cybersickness and ease of access, we propose that immersive VR could be a helpful adjunct to current pharmacotherapy. Further research is required to show that VR can be effective for more long-term reductions in SCI pain.

Mental Imagery as a Rehabilitative Therapy for Neuropathic Pain in People With Spinal Cord Injury: A Randomized Controlled Trial

Background Pain of neuropathic origin in spinal cord injury (SCI) is unbearable and challenging to treat. Research studies conducted in the past have shown that mental imagery (MI) techniques have a significant impact on the reduction of symptoms of central neuropathic pain in people with SCI. Objectives The objective of this study was to evaluate the effect of MI training on pain intensity, neuropathic pain symptoms, and interference of pain with function in SCI. Methods A total of 42 SCI participants with central neuropathic pain (duration 6-12 months) were recruited and randomly allocated to MI or control groups. A MI training protocol was administered to MI group and for 30 min/d for 5 days. Outcome measures were assessed at baseline and at the end of 4 weeks. Results There was significant reduction in differences of mean [95% CI] scores of numeric rating scale (−2.1 [CI −2.78 to −1.41]; P < .001) between groups. Mean [95% CI] total scores of Neuropathic Pain Symptom Inventory declined in MI group as compared with control group (−4.52 [CI −5.86 to −3.18]; P < .001). Similarly, Brief Pain Inventory interference scale total dropped significantly (P < .001) in MI group. Majority of participants in the MI group (55%) reported improvement in scores of Patients’ Global Impression of Change scale as compared with control group where most of the participants (52%) reported no change. Conclusions This study shows the effectiveness of the MI protocol developed as a rehabilitative approach in improving central neuropathic pain in SCI. Trial Registration. Clinical Trials Registry–India under Indian Council of Medical Research; CTRI/2018/07/014884. Registered July 16, 2018.

Evaluation of the Effectiveness of a Novel Brain-Computer Interface Neuromodulative Intervention to Relieve Neuropathic Pain Following Spinal Cord Injury: Protocol for a Single-Case Experimental Design With Multiple Baselines.

BackgroundNeuropathic pain is a debilitating secondary condition for many individuals with spinal cord injury. Spinal cord injury neuropathic pain often is poorly responsive to existing pharmacological and nonpharmacological treatments. A growing body of evidence supports the potential for brain-computer interface systems to reduce spinal cord injury neuropathic pain via electroencephalographic neurofeedback. However, further studies are needed to provide more definitive evidence regarding the effectiveness of this intervention.ObjectiveThe primary objective of this study is to evaluate the effectiveness of a multiday course of a brain-computer interface neuromodulative intervention in a gaming environment to provide pain relief for individuals with neuropathic pain following spinal cord injury.MethodsWe have developed a novel brain-computer interface-based neuromodulative intervention for spinal cord injury neuropathic pain. Our brain-computer interface neuromodulative treatment includes an interactive gaming interface, and a neuromodulation protocol targeted to suppress theta (4-8 Hz) and high beta (20-30 Hz) frequency powers, and enhance alpha (9-12 Hz) power. We will use a single-case experimental design with multiple baselines to examine the effectiveness of our self-developed brain-computer interface neuromodulative intervention for the treatment of spinal cord injury neuropathic pain. We will recruit 3 participants with spinal cord injury neuropathic pain. Each participant will be randomly allocated to a different baseline phase (ie, 7, 10, or 14 days), which will then be followed by 20 sessions of a 30-minute brain-computer interface neuromodulative intervention over a 4-week period. The visual analog scale assessing average pain intensity will serve as the primary outcome measure. We will also assess pain interference as a secondary outcome domain. Generalization measures will assess quality of life, sleep quality, and anxiety and depressive symptoms, as well as resting-state electroencephalography and thalamic γ-aminobutyric acid concentration.ResultsThis study was approved by the Human Research Committees of the University of New South Wales in July 2019 and the University of Technology Sydney in January 2020. We plan to begin the trial in October 2020 and expect to publish the results by the end of 2021.ConclusionsThis clinical trial using single-case experimental design methodology has been designed to evaluate the effectiveness of a novel brain-computer interface neuromodulative treatment for people with neuropathic pain after spinal cord injury. Single-case experimental designs are considered a viable alternative approach to randomized clinical trials to identify evidence-based practices in the field of technology-based health interventions when recruitment of large samples is not feasible.Trial RegistrationAustralian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12620000556943; https://bit.ly/2RY1jRx International Registered Report Identifier (IRRID)PRR1-10.2196/20979

"Challenges and facilitators-navigating in the landscape of spinal cord injury neuropathic pain"-a qualitative study on the use of prescribed drugs.

A qualitative study with an emergent design using semi-structured interviews in focus groups. To explore the expectations, experiences and desires among individuals who are prescribed drugs for spinal cord injury (SCI) neuropathic pain (NP). SCI rehabilitation centre. Eighteen informants with SCI and NP were enrolled. The informants originated from large and small cities in southern Sweden. Data were collected in focus groups consisting of 4-5 individuals in four separate sessions. An emergent design was employed using an interview guide containing open questions. The interviews were transcribed verbatim and data were analyzed according to qualitative content analysis. A model of three themes emerged: "Balancing between pain and side-effects" described the difficult choices the informants had to make between drugs and their unwanted side-effects and pain, "Desiring competence and structure in pain management" described the informants wishes regarding pain management and "From hope to personal solutions" described the process from hope of total pain relief from drugs to the development of personal strategies. There is a great need for improvement of SCI-related neuropathic pain management since recommended drugs are insufficiently effective and accompanied by severe side-effects that impact quality of life but also due to structural limitations and physicians' lack of competence in pain management.

Mutually beneficial effects of intensive exercise and GABAergic neural progenitor cell transplants in reducing neuropathic pain and spinal pathology in rats with spinal cord injury

Spinal cord injury (SCI) produces both locomotor deficits and sensory dysfunction that greatly reduce the overall quality of life. Mechanisms underlying chronic pain include increased neuro-inflammation and changes in spinal processing of sensory signals, with reduced inhibitory GABAergic signaling a likely key player. Our previous research demonstrated that spinal transplantation of GABAergic neural progenitor cells (NPCs) reduced neuropathic pain while intensive locomotor training (ILT) could reduce development of pain and partially reverse already established pain behaviors. Therefore, we evaluate the potential mutually beneficial anti-hypersensitivity effects of NPC transplants cells in combination with early or delayed ILT. NPC transplants were done at 4 weeks post-SCI. ILT, using a progressive ramping treadmill protocol, was initiated either 5 days post-SCI (early: pain prevention group) or at 5 weeks post-SCI (delayed: to reverse established pain) in male Sprague Dawley rats. Results showed that either ILT alone or NPCs alone could partially attenuate SCI neuropathic pain behaviors in both prevention and reversal paradigms. However, the combination of ILT with NPC transplants significantly enhanced neuropathic pain reduction on most of the outcome measures including tests for allodynia, hyperalgesia, and ongoing pain. Immunocytochemical and neurochemical analyses showed decreased pro-inflammatory markers and spinal pathology with individual treatments; these measures were further improved by the combination of either early or delayed ILT and GABAergic cellular transplantation. Lumbar dorsal horn GABAergic neuronal and process density were nearly restored to normal levels by the combination treatment. Together, these interventions may provide a less hostile and more supportive environment for promoting functional restoration in the spinal dorsal horn and attenuation of neuropathic pain following SCI. These findings suggest mutually beneficial effects of ILT and NPC transplants for reducing SCI neuropathic pain.

Prevalence of Spasticity and Below-Level Neuropathic Pain Related to Spinal Cord Injury Level and Damage to the Lower Spinal Segments.

ObjectiveTo evaluate spasticity and below-level spinal cord injury neuropathic pain after spinal cord injury in patients with, or without, damage to the lumbar spinal cord and roots.Design/patientsChart review of 269 patients with spinal cord injury from segments C1 to T11.MethodsPatients were interviewed concerning leg spasticity and below-level spinal cord injury neuropathic pain in the lower trunk and legs. Damage to the lumbar spinal cord and roots was inferred where there was radiological evidence of a vertebral fracture, spinal stenosis or the narrowing of spinal foramina of a vertebra from thoracic 11 to lumbar 5, or; magnetic resonance imaging showing evidence of damage to the lumbar spinal cord and roots.ResultsAmong 161 patients without damage to the lumbar spinal cord and roots, 87% of those with cervical spinal cord injury experienced spasticity, compared with 85% with thoracic spinal cord injury. The corresponding figures for patients in whom damage to the lumbar spinal cord and roots was present were 57% and 52%, respectively. Below-level spinal cord injury neuropathic pain was not associated with damage to the lumbar spinal cord and roots. In those patients with no damage to the lumbar spinal cord and roots, regression showed that neither outcome was significantly associated with the level of spinal cord injury.ConclusionThe lack of segmental dependency for spinal cord injury and spasticity suggests mechanisms restricted mainly to the lumbar spinal cord. For below-level spinal cord injury neuropathic pain, additional mechanisms, other than lesions of the spino-thalamic tract, must be considered.LAY ABSTRACTFollowing a spinal cord injury, symptoms of increased nerve cell activity in the central nervous system appear, e.g. involuntary muscle activity (spasticity), below level neuropathic pain and urinary leakage. The distribution of overactive neurons is still unresolved. This chart review showed that leg spasticity was more frequent in patients with a cervical or thoracic spinal cord injury if the patients had no signs of damage to the lumbar spinal cord and roots. The occurrence of leg spasticity and below level spinal cord injury neuropathic pain was unrelated to each other or to the level of the spinal cord injury. This suggests that the mechanisms behind leg spasticity are mainly restricted to the lumbar spinal cord. For this pain, additional mechanisms other than lesions of the spino-thalamic tract must be considered

Dopamine D1 and D3 receptor modulators restore morphine analgesia and prevent opioid preference in a model of neuropathic pain

A secondary consequence of spinal cord injury (SCI) is debilitating chronic neuropathic pain, which is commonly morphine resistant and inadequately managed by current treatment options. Consequently, new pain management therapies are desperately needed. We previously reported that dopamine D3 receptor (D3R) dysfunction was associated with opioid resistance and increases in D1 receptor (D1R) protein expression in the spinal cord. Here, we demonstrate that in a model of SCI neuropathic pain, adjuvant therapy with a D3R agonist (pramipexole) or D1R antagonist (SCH 39166) can restore the analgesic effects of morphine and reduce reward potential. Prior to surgery thermal and mechanical thresholds were tested in three groups of female rats (naïve, sham, SCI). After surgery, testing was repeated under the following drug conditions: 1) saline, 2) morphine, 3) pramipexole, 4) SCH 39166, 5) morphine + pramipexole, and 6) morphine + SCH 39166. Reward potential of morphine and both combinations was assessed using conditioned place preference. Following SCI, morphine + pramipexole and morphine + SCH 39166 significantly increased both thermal and mechanical thresholds. Morphine alone induced conditioned place preference, but when combined with either the D3R agonist or D1R antagonist preference was not induced. The data suggest that adjunct therapy with receptor-specific dopamine modulators can restore morphine analgesia and decrease reward potential and thus, represents a new target for pain management therapy after SCI.

Pain assessment in hospitalized spinal cord injured patients - a controlled cross-sectional study.

Background and aims Following spinal cord injury (SCI), a majority of individuals may develop neuropathic pain, which further reduces quality of life. Pain is difficult to treat by medication; in fact, medication overuse may aggravate neuropathic pain in SCI by causing central sensitization (CS): a mechanism of hyper-reactivity of the dorsal horn neurons in the spinal cord with amplified cerebral pain response. The purpose of this study was to examine the presence of neuropathic pain and CS above the spinal lesion in SCI, and to investigate whether injury characteristics or medication influenced pain response. Methods Twenty-four SCI patients with various injury characteristics (eight subacute, traumatic injuries, eight chronic, traumatic injuries, eight non-traumatic injuries) and 12 able-bodied controls underwent sensory testing:pressure algometry, Von Frey filaments (sensitivity), and repetitive pinprick stimulation (pain windup). SCI participants also fulfilled a modified version of the McGill Pain Questionnaire. Data were analyzed regarding (i) SCI patients compared with controlgroup and (ii) SCI subgroup comparison (grouped by a) injury characteristics and (b) intake of analgesics, where low-medicated subgroup were prescribed only non-opioids and high-medicated potent opioids). Results Neuropathic pain was present in 21 of 24 SCI patients. Chronic and non-traumatic SCI patients reported considerably higher present pain intensity than sub-acute traumatic SCI patients on a five-point scale (3.13±0.99, 1.75±1.75 and 0.13±0.35, respectively, p<0.005). Reduced pressure pain detection thresholds (PPDT) were found in SCI patients at several supra-lesional anatomical points compared to controls. Contrarily, tactile detection thresholds were higher in SCI. SCI subgroup analyses showed that i) the low-medicated SCI subgroup displayed significantly lower PPDT compared to the high-medicated subgroup, ii) pain-windup was present in all subgroups although the sub-acute and non-traumatic subgroups displayed lesser pain windup than controls, and the chronic SCI subgroup mainly displayed higher pain windup. Conclusions The reduced PPDT found above lesion suggests the presence of CS in SCI. However, findings regarding SCI subgroup comparison did not support our hypothesis that more medication leads to increased CS. Implications The development of CS may complicate diagnosis and pain treatment following SCI. Prospective studies of SCI with a healthy control group are needed.

Efficacy of Internet-Delivered Mindfulness for Improving Depression in Caregivers of People With Spinal Cord Injuries and Chronic Neuropathic Pain: A Randomized Controlled Feasibility Trial

ObjectivesTo explore the feasibility and efficacy of web-based mindfulness training for carers of people with spinal cord injury (SCI). DesignRandomized controlled feasibility study with 3-month follow-up. SettingCommunity setting. ParticipantsSpouses or family caregivers (N=55) of people with SCI and chronic neuropathic pain were recruited via the direct care team and advertisements. Participants were older than 18 years (no upper age limit), with Internet access for the duration of the study. Participants were randomly allocated to an 8-week online mindfulness training intervention (n=28), or to receive 8 weeks of psychoeducational materials on SCI and chronic pain (n=27). InterventionsAn established web-based, mindfulness training course was delivered over 8 weeks. Participants completed 10 minutes of mindfulness practices, twice per day, 6 days per week, totaling 960 minutes. The control group received a weekly e-mail with psychoeducational materials (based on the established elements) on SCI and pain for 8 weeks. Main Outcome MeasureDepression severity. ResultsMindfulness reduced depression severity more than psychoeducation at T2 (mean difference= −.891; 95% confidence interval,−1.48 to −.30) and T3 (mean difference=−1.96; 95% confidence interval, −2.94 to −.97). Mindfulness training also reduced anxiety at T2 (mean difference=−.888; 95% confidence interval, −1.40 to −.38) and T3 (mean difference=−2.44; 95% confidence interval, −3.20 to −1.69). ConclusionsResults indicate that Internet-delivered mindfulness training offers unique benefits and is viable for caregivers of people with SCI and chronic neuropathic pain. Further work should explore the feasibility of combined education and mindfulness training incorporating both patient and caregiver, for optimum benefit.

Neuropathic Pain After Spinal Cord Injury: Challenges and Research Perspectives.

Neuropathic pain is a debilitating consequence of spinal cord injury (SCI) that remains difficult to treat because underlying mechanisms are not yet fully understood. In part, this is due to limitations of evaluating neuropathic pain in animal models in general, and SCI rodents in particular. Though pain in patients is primarily spontaneous, with relatively few patients experiencing evoked pains, animal models of SCI pain have primarily relied upon evoked withdrawals. Greater use of operant tasks for evaluation of the affective dimension of pain in rodents is needed, but these tests have their own limitations such that additional studies of the relationship between evoked withdrawals and operant outcomes are recommended. In preclinical SCI models, enhanced reflex withdrawal or pain responses can arise from pathological changes that occur at any point along the sensory neuraxis. Use of quantitative sensory testing for identification of optimal treatment approach may yield improved identification of treatment options and clinical trial design. Additionally, a better understanding of the differences between mechanisms contributing to at- versus below-level neuropathic pain and neuropathic pain versus spasticity may shed insights into novel treatment options. Finally, the role of patient characteristics such as age and sex in pathogenesis of neuropathic SCI pain remains to be addressed.