Targeting inflammation as a treatment modality for neuropathic pain in spinal cord injury: a randomized clinical trial.
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ABSTRACT:
SUBMITTER: Allison DJ
PROVIDER: S-EPMC4912827 | biostudies-literature | 2016 Jun
REPOSITORIES: biostudies-literature
Publications
Targeting inflammation as a treatment modality for neuropathic pain in spinal cord injury: a randomized clinical trial.
Allison David J DJ Thomas Aysha A Beaudry Kayleigh K Ditor David S DS
Journal of neuroinflammation 20160617 1
<h4>Background</h4>The purpose of the present study was to examine the effectiveness of an anti-inflammatory intervention as a treatment for neuropathic pain following spinal cord injury (SCI).<h4>Methods</h4>This randomized, parallel-group, controlled clinical trial (NCT02099890) examined 20 participants with varying levels and severities of SCI, randomized (3:2) to either a 12-week anti-inflammatory diet, or control group. Outcome measures consisted of self-determined indices of pain as assess ...[more]
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Project description:Background: Heart rate variability (HRV), the physiological variance in the heart's R-R interval length, can be analyzed to produce various parameters reflective of one's autonomic balance. HRV analysis may be used to capture those autonomic aberrations associated with chronic neuropathic pain (NP) in spinal cord injury (SCI). This study assesses the capacity of HRV parameters to diagnose NP in an SCI cohort. Methods: An electrocardiogram (ECG) was collected at rest from able bodied participants (AB, n = 15), participants with SCI only (SCI-NP, n = 11), and those with SCI and NP (SCI+NP, n = 20). HRV parameters were analyzed using conventional time and frequency analysis. Results: At rest, there were no heart rate differences amongst groups. However, SCI+NP participants demonstrated lower overall HRV, as determined by the SDNN time domain parameter, compared to either AB (p < 0.01) or SCI-NP (p < 0.05) groups. Moreover, AB and SCI-NP participants were statistically comparable for all HRV time and frequency domain parameters. Additional analyses demonstrated no differences in HRV parameters between T4, above vs. T5, below SCI groups (for all parameters: p > 0.15) or between C8, above vs. T1, below SCI groups (p > 0.30). Conclusions: Participants with SCI and NP exhibit a lower overall HRV, which can be determined by HRV time domain parameter SDNN. HRV analysis is an innovative modality with the capacity for objective quantification of chronic NP in participants with SCI.
| S-EPMC5513934 | biostudies-literature
Project description:To assess the efficacy and tolerability of pregabalin for the treatment of central neuropathic pain after spinal cord injury (SCI).Patients with chronic, below-level, neuropathic pain due to SCI were randomized to receive 150 to 600 mg/d pregabalin (n = 108) or matching placebo (n = 112) for 17 weeks. Pain was classified in relation to the neurologic level of injury, defined as the most caudal spinal cord segment with normal sensory and motor function, as above, at, or below level. The primary outcome measure was duration-adjusted average change in pain. Key secondary outcome measures included the change in mean pain score from baseline to end point, the percentage of patients with ?30% reduction in mean pain score at end point, patient global impression of change scores at end point, and the change in mean pain-related sleep interference score from baseline to end point. Additional outcome measures included the medical outcomes study-sleep scale and the Hospital anxiety and depression scale.Pregabalin treatment resulted in statistically significant improvements over placebo for all primary and key secondary outcome measures. Significant pain improvement was evident as early as week 1 and was sustained throughout the treatment period. Adverse events were consistent with the known safety profile of pregabalin and were mostly mild to moderate in severity. Somnolence and dizziness were most frequently reported.This study demonstrates that pregabalin is effective and well tolerated in patients with neuropathic pain due to SCI.This study provides class I evidence that pregabalin, 150 to 600 mg/d, is effective in reducing duration-adjusted average change in pain compared with baseline in patients with SCI over a 16-week period (p = 0.003, 95% confidence interval = -0.98, -0.20).
| S-EPMC3589291 | biostudies-literature
Project description:The purpose of the present study was to examine the efficacy of targeting inflammation as a means of improving mood following spinal cord injury (SCI) and explore the potential mechanisms of action.The study was a randomized, parallel-group, controlled, clinical trial (NCT02099890) whereby 20 participants with varying levels and severities of SCI were randomized (3:2) to either the treatment group, consisting of a 12-week anti-inflammatory diet, or control group. Outcome measures were assessed at baseline, 1 and 3 months, and consisted of CES-D scores of depression, markers of inflammation as assessed by various pro- and anti-inflammatory cytokines and several amino acids related to depression.A significant group × time interaction was found for CES-D (Center for Epidemiologic studies Depression Scale) score (p?=?0.01), the TRP/LNAA (tryptophan/large neutral amino acid) ratio (p?=?0.04), the composite score of pro-inflammatory cytokines (p?=?0.04), IL-1? (interleukin-1 beta) (p?=?0.04), and IFN-? (interferon gamma) (p?=?0.03). Pearson's r correlation showed significance between the ?IL-1? and both the ?CES-D score (r?=?0.740, p?<?0.01) and the ?KYN/TRP (kynurenine/tryptophan) ratio (r?=?0.536, p?=?0.02). The ?KYN/TRP ratio was also significantly correlated with the ?CES-D score (r?=?0.586, p?=?0.01). Mediation analysis showed that the relationship between the ?KYN/TRP ratio and the ?CES-D score was mediated by the ?IL-1?. Subgroup analysis showed that participants with high CES-D scores had significantly higher concentrations of IL-1?, and all correlations were maintained or strengthened within this subgroup.Overall, the results demonstrated the effectiveness of targeting inflammation as a means of improving mood in SCI, with potential mechanisms relating to the reduction in IL-1? and improvements in levels of neuroactive compounds related to the kynurenine pathway. Due to the limited sample size, results should be interpreted with caution; however, they are worthy of further examination due to the potential impact of inflammation on depression.ClinicalTrials.gov ID: NCT02099890 .
| S-EPMC4636770 | biostudies-literature
Project description:Neuropathic pain is a well-known type of chronic pain caused by damage to the nervous system. Until recently, many researchers have primarily focused on identifying cellular or chemical sources of neuropathic pain or have approached neuropathic pain via the basis of biological study. We investigated whether both mmu-mir-23b (miR23b) and NADPH oxidase 4 (NOX4) antibody infusion can alleviate neuropathic pain by compensating for abnormally downregulated miR23b via reducing the expression of its target gene, NOX4, a reactive oxygen species (ROS) family member overexpressed in neuropathic pain. Ectopic miR23b expression effectively downregulated NOX4 and finally normalized glutamic acid decarboxylase 65/67 expression. Moreover, animals with neuropathic pain showed significantly improved paw withdrawal thresholds (PWTs) following miR23b infusion. Normalizing miR23b expression in tissue lesions, caused by neuropathic pain induction, reduced inflammatory mediators and increased several ROS scavengers. Moreover, ?-aminobutyric acid (GABA)ergic neurons coexpressed suboptimal levels of miR23b and elevated NOX4/ROS after pain induction at the cellular level. MiR23b finally protects GABAergic neurons against ROS/p38/c-Jun N-terminal kinase (JNK)-mediated apoptotic death. By evaluating the functional behavior of mice receiving pain/miR23b, normal/anti-miR23b, anti-miR23b/si-NOX4, pain/NOX4 antibody, pain/ascorbic acid, and pain/ascorbic acid/NOX4 antibody, the positive role of miR23b and the negative role of NOX4 in neuropathic pain were confirmed. Based on this study, we conclude that miR23b has a crucial role in the amelioration of neuropathic pain in injured spinal cord by inactivating its target gene, NOX4, and protection of GABAergic neurons from cell death. We finally suggest that infusion of miR23b and NOX4 antibody may provide attractive diagnostic and therapeutic resources for effective pain modulation in neuropathic pain.
| S-EPMC3542604 | biostudies-literature
Project description: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.
| S-EPMC6095789 | biostudies-other
Project description:Neuropathic pain represents a primary detrimental outcome of spinal cord injury. A major challenge facing effective management is a lack of surrogate measures to examine the physiology and anatomy of neuropathic pain. To this end, we investigated the relationship between psychophysical responses to tonic heat stimulation and neuropathic pain rating after traumatic spinal cord injury. Subjects provided a continuous rating to 2 min of tonic heat at admission to rehabilitation and again at discharge. Adaptation, temporal summation of pain, and modulation profile (i.e., the relationship between adaptation and temporal summation of pain) were extracted from tonic heat curves for each subject. There was no association between any of the tonic heat outcomes and neuropathic pain severity at admission. The degree of adaptation, the degree of temporal summation of pain, and the modulation profile did not change significantly from admission to discharge. However, changes in modulation profiles between admission and discharge were significantly correlated with changes in neuropathic pain severity (p = 0.027; R 2 = 0.323). The modulation profile may represent an effective measure to track changes in neuropathic pain severity from early to later stages of spinal cord injury.
| S-EPMC6382744 | biostudies-literature
Project description:Neuropathic pain following spinal cord injury involves plastic changes along the whole neuroaxis. Current neuroimaging studies have identified grey matter volume (GMV) and resting-state functional connectivity changes of pain processing regions related to neuropathic pain intensity in spinal cord injury subjects. However, the relationship between the underlying neural processes and pain extent, a complementary characteristic of neuropathic pain, is unknown. We therefore aimed to reveal the neural markers of widespread neuropathic pain in spinal cord injury subjects and hypothesized that those with greater pain extent will show higher GMV and stronger connectivity within pain related regions. Thus, 29 chronic paraplegic subjects and 25 healthy controls underwent clinical and electrophysiological examinations combined with neuroimaging. Paraplegics were demarcated based on neuropathic pain and were thoroughly matched demographically. Our findings indicate that (a) spinal cord injury subjects with neuropathic pain display stronger connectivity between prefrontal cortices and regions involved with sensory integration and multimodal processing, (b) greater neuropathic pain extent, is associated with stronger connectivity between the posterior insular cortex and thalamic sub-regions which partake in the lateral pain system and (c) greater intensity of neuropathic pain is related to stronger connectivity of regions involved with multimodal integration and the affective-motivational component of pain. Overall, this study provides neuroimaging evidence that the pain phenotype of spinal cord injury subjects is related to the underlying function of their resting brain.
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Project description:Most persons living with a spinal cord injury experience neuropathic pain in the months following their lesion, at the moment where they receive intensive gait rehabilitation. Based on studies using animal models, it has been proposed that central sensitization in nociceptive pathways (maladaptive plasticity) and plasticity related to motor learning (adaptive plasticity) share common neural mechanisms and compete with each other. This article aims to address the discrepancy between the growing body of basic science literature supporting this hypothesis and the general belief in rehabilitation research that pain and gait rehabilitation represent two independent problems. First, the main findings from basic research showing interactions between nociception and learning in the spinal cord will be summarized, focusing both on evidence demonstrating the impact of nociception on motor learning and of motor learning on central sensitization. Then, the generalizability of these findings in animal models to humans will be discussed. Finally, the way potential interactions between nociception and motor learning are currently taken into account in clinical research in patients with spinal cord injury will be presented. To conclude, recommendations will be proposed to better integrate findings from basic research into future clinical research in persons with spinal cord injury.
| S-EPMC5405804 | biostudies-literature
Project description:OBJECTIVE:To investigate changes in body ownership and chronic neuropathic pain in patients with spinal cord injury (SCI) using multisensory own body illusions and virtual reality (VR). METHODS:Twenty patients with SCI with paraplegia and 20 healthy control participants (HC) participated in 2 factorial, randomized, repeated-measures design studies. In the virtual leg illusion (VLI), we applied asynchronous or synchronous visuotactile stimulation to the participant's back (either immediately above the lesion level or at the shoulder) and to the virtual legs as seen on a VR head-mounted display. We tested the effect of the VLI on the sense of leg ownership (questionnaires) and on perceived neuropathic pain (visual analogue scale pain ratings). We compared illusory leg ownership with illusory global body ownership (induced in the full body illusion [FBI]), by applying asynchronous or synchronous visuotactile stimulation to the participant's back and the back of a virtual body as seen on a head-mounted display. RESULTS:Our data show that patients with SCI are less sensitive to multisensory stimulations inducing illusory leg ownership (as compared to HC) and that leg ownership decreased with time since SCI. In contrast, we found no differences between groups in global body ownership as tested in the FBI. VLI and FBI were both associated with mild analgesia that was only during the VLI specific for synchronous visuotactile stimulation and the lower back position. CONCLUSIONS:The present findings show that VR exposure using multisensory stimulation differently affected leg vs body ownership, and is associated with mild analgesia with potential for SCI neurorehabilitation protocols.
| S-EPMC5664293 | biostudies-literature
Project description:Study designReview of the literature and semi-structured interviews.ObjectiveTo explore the possible use of topical analgesics for the treatment of neuropathic pain (NP) in spinal cord injury (SCI).SettingInstitute for Neuropathic Pain, Soest, The Netherlands.MethodsA review was performed of studies on topical analgesics for SCI-related NP published up to May 2019. In addition, eight persons with SCI-related NP who were treated with topical analgesics were interviewed in a semi-structured interview on their experience with topical analgesics.ResultsSeven studies (five case reports and two case series) were found that evaluated the use of topical analgesics for SCI-related NP. None of the studies used a control treatment. Topical analgesics included baclofen, ketamine, lidocaine, capsaicin, and isosorbide dinitrate. All studies reported a decrease in NP over time. Persons interviewed were 49-72 years of age and all but one had an incomplete SCI. They used topical agents containing phenytoin, amitriptyline, baclofen, ketamine or loperamide. All showed a decrease in pain of at least 3 points on the 11-point numeric rating scale during this treatment.Discussion/conclusionsEvidence on the use of topical analgesics in SCI is scarce. Case reports, case series and interviews suggest that the use of topical analgesics can be beneficial in treating SCI-related NP. Placebo-controlled studies are required to investigate the effect of topical analgesics on SCI-related NP.
| S-EPMC7426910 | biostudies-literature