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Background: The objective was to test the generalisability of electroencephalography (EEG) markers of future pain using two independent datasets. Methods: Datasets, A [N = 20] and B [N = 35], were collected from participants with subacute spinal cord injury who did not have neuropathic pain at the time of recording. In both datasets, some participants developed pain within six months, (PDP) will others did not (PNP). EEG features were extracted based on either band power or Higuchi fractal dimension (HFD). Three levels of generalisability were tested: (1) classification PDP vs. PNP in datasets A and B separately; (2) classification between groups in datasets A and B together; and (3) classification where one dataset (A or B) was used for training and testing, and the other for validation. A novel normalisation method was applied to HFD features. Results: Training and testing of individual datasets achieved classification accuracies of >80% using either feature set, and classification of joint datasets (A and B) achieved a maximum accuracy of 86.4% (HFD, support vector machine (SVM)). With normalisation and feature reduction (principal components), the validation accuracy was 66.6%. Conclusions: An SVM classifier with HFD features showed the best robustness, and normalisation improved the accuracy of predicting future neuropathic pain well above the chance level. [ABSTRACT FROM AUTHOR]

Neuropathic pain (NP) is often caused by diabetic neuropathy, chemotherapy, or spinal cord lesions and is associated with significant economic burden and poor quality of life. Sophisticated etiology and pathology recognized different pharmacologic interventions, and hitherto, the reported analgesic efficacy and safety of guideline-recommended drugs are not satisfactory. Overall, this article reviews the mechanism of α2δ ligand, the clinical pharmacokinetics, efficacy, safety and cost-effectiveness of mirogabalin for the treatment of NP, offering clinical perspectives into potential benefits of NP-related syndrome or comorbidities. Mirogabalin, a novel voltage-gated Ca2+ channel (VGCC) α2δ ligand with selective binding affinities to α2δ-1 than α2δ-2 subunit, exhibited a wider safety margin and a relatively lower incidence of adverse events compared with other gabapentinoids. Randomized-controlled trials and open-label studies have demonstrated the efficacy and long-term safety of mirogabalin in Asian patients with diabetic peripheral neuropathic pain (DPNP), postherpetic neuralgia (PHN), and central NP. Analgesic effects of mirogabalin for the single or add-on treatment on chemotherapy-induced peripheral neuropathy and orthopedic disease/postoperation-related NP were also evidenced. To date, mirogabalin is approved for the general indication of NP in Japan, PNP in South Korea, and DPNP in the Chinese Mainland and DPNP, PHN in Taiwan (China). In summary, mirogabalin emerges as a promising option for NP; further research is warranted to refine wider treatment strategies, flexible dosing in real-world setting. [ABSTRACT FROM AUTHOR]

Introduction: Central post-stroke pain (CPSP) is a common type of central neuropathic pain (CNeP) that can occur following the onset of stroke. The oral gabapentinoid mirogabalin besylate (mirogabalin) is a selective α2δ ligand that is effective for the treatment of CNeP, including CPSP. However, it is unknown whether the analgesic effect of mirogabalin on CPSP varies in patients with different background factors. Methods: This was a post hoc subgroup analysis of a multinational, open-label, long-term phase 3 study of mirogabalin for the treatment of CNeP conducted between March 2019 and December 2020. Data from patients with CPSP were stratified by type of stroke (ischemic or hemorrhagic), stroke location (thalamus, putamen, brainstem, or other), presence/absence of motor weakness, median time since stroke (≥ 59 or < 59 months), and median duration of CPSP (≥ 55.5 or < 55.5 months). Efficacy was assessed with the short-form McGill Pain Questionnaire (SF-MPQ), and treatment-emergent adverse events (TEAEs) and adverse drug reactions (ADRs) were recorded. Results: This subanalysis included all 94 patients with CPSP from the phase 3 study; all were Japanese, and the mean age was 65.3 years. The least squares mean change [95% confidence interval] in SF-MPQ visual analog scale (VAS) score from baseline at week 52 (last observation carried forward) was − 17.0 [− 22.1, − 11.9] mm. Among the subgroups, least squares mean changes in SF-MPQ VAS scores were not different. Most TEAEs were mild or moderate; severe TEAEs occurred in six patients (6.4%). Somnolence (25.5%), peripheral edema (13.8%), dizziness (11.7%), and weight gain (6.4%) were the most common ADRs, and the types and frequencies of ADRs were similar among subgroups. Conclusion: Mirogabalin was generally effective and well tolerated in patients with CPSP, regardless of background factors such as stroke type or location, presence/absence of motor weakness, time since stroke, and duration of CPSP. Trial Registration: Trial registration number NCT03901352. [ABSTRACT FROM AUTHOR]

This study investigated Cerium oxide nanoparticles (CeONPs) effect on central neuropathic pain (CNP). The compressive method of spinal cord injury (SCI) model was used for pain induction. Three groups were formed by a random allocation of 24 rats. In the treatment group, CeONPs were injected above and below the lesion site immediately after inducing SCI. pain symptoms were evaluated using acetone, Radian Heat, and Von Frey tests weekly for six weeks. Finally, we counted fibroblasts using H&E staining. We evaluated the expression of Cx43, GAD65 and HDAC2 proteins using the western blot method. The analysis of results was done by PRISM software. At the end of the study, we found that CeONPs reduced pain symptoms to levels similar to those observed in normal animals. CeONPs also increased the expression of GAD65 and Cx43 proteins but did not affect HDAC2 inhibition. CeONPs probably have a pain-relieving effect on chronic pain by potentially preserving GAD65 and Cx43 protein expression and hindering fibroblast infiltration. The effects of CeONPs on intracellular homeostasis in CNP. Upon neuronal entry, CeONPs mitigate the negative effects of inflammation and oxidative stress associated with CNP and conditions like SCI. They help maintain levels of GAD65 and Cx43 proteins, while also combating and minimizing ROS levels within the cell. [ABSTRACT FROM AUTHOR]

Pawe&lstrok; Sokal,1 Damian Palus,1 Magdalena Jab&lstrok;o&nacute;ska,2 Oskar Puk,2 Sara Kieronska-Siwak1 1Department of Neurosurgery and Neurology, Faculty of Health Sciences, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, 85-168, Poland; 2Doctoral School Collegium Medicum Nicolaus Copernicus University, Bydgoszcz, 85-168, PolandCorrespondence: Pawe&lstrok; Sokal, Department of Neurosurgery and Neurology, Faculty of Health Sciences, Collegium Medicum Nicolaus Copernicus University, Ujejskiego 75, Bydgoszcz, 85-168, Poland, Email pawel.sokal@cm.umk.plPurpose: Central neuropathic pain (CNP) following spinal cord injury (SCI) presents a formidable therapeutic challenge, affecting over 50% of the patients post-SCI. For those who experience CNP, conventional treatments often prove insufficient. Spinal cord stimulation (SCS) emerges as a potential intervention for chronic pain after SCI that is unresponsive to pharmacotherapy and supportive measures. However, the efficacy of SCS in alleviating CNP is notably limited. The objective of our study was to evaluate novel stimulation paradigms in SCS for patients with severe CNP after SCI, based on our extensive experience.Patients and Methods: From a pool of 112 patients treated with SCS for chronic neuropathic pain in the Department of Neurosurgery and Neurology, we selected eight individuals (4 males and 4 females) with CNP for our case series. Burst and high frequency SCS was applied. The assessment involved utilizing the Numeric Rating Scale (NRS), the Neuropathic Pain Symptom Inventory (NPSI), and the EQ-5D quality of life scale before surgery and during a 12-month follow-up period.Results: Over the course of the one-year follow-up, only two patients experienced satisfactory relief from pain, demonstrating the effectiveness of the stimulation. Moreover, high-frequency and burst SCS failed to show improvement in the remaining six patients.Conclusion: Our findings suggest that, despite the incorporation of new stimulation paradigms such as burst stimulation and high-frequency stimulation, SCS does not exhibit significant effectiveness in treating neuropathic pain in patients after SCI. These findings highlight the ongoing challenge of treating CNP and emphasize the importance of investigating alternative therapeutic strategies for this group.Keywords: spinal cord stimulation, central neuropathic pain, spinal cord injury, burst stimulation, high-frequency stimulation

Neuropathic pain (NP) is often caused by diabetic neuropathy, chemotherapy, or spinal cord lesions and is associated with significant economic burden and poor quality of life. Sophisticated etiology and pathology recognized different pharmacologic interventions, and hitherto, the reported analgesic efficacy and safety of guideline-recommended drugs are not satisfactory. Overall, this article reviews the mechanism of α2δ ligand, the clinical pharmacokinetics, efficacy, safety and cost-effectiveness of mirogabalin for the treatment of NP, offering clinical perspectives into potential benefits of NP-related syndrome or comorbidities. Mirogabalin, a novel voltage-gated Ca2+ channel (VGCC) α2δ ligand with selective binding affinities to α2δ-1 than α2δ-2 subunit, exhibited a wider safety margin and a relatively lower incidence of adverse events compared with other gabapentinoids. Randomized-controlled trials and open-label studies have demonstrated the efficacy and long-term safety of mirogabalin in Asian patients with diabetic peripheral neuropathic pain (DPNP), postherpetic neuralgia (PHN), and central NP. Analgesic effects of mirogabalin for the single or add-on treatment on chemotherapy-induced peripheral neuropathy and orthopedic disease/postoperation-related NP were also evidenced. To date, mirogabalin is approved for the general indication of NP in Japan, PNP in South Korea, and DPNP in the Chinese Mainland and DPNP, PHN in Taiwan (China). In summary, mirogabalin emerges as a promising option for NP; further research is warranted to refine wider treatment strategies, flexible dosing in real-world setting.

Background: The objective was to test the generalisability of electroencephalography (EEG) markers of future pain using two independent datasets. Methods: Datasets, A [N = 20] and B [N = 35], were collected from participants with subacute spinal cord injury who did not have neuropathic pain at the time of recording. In both datasets, some participants developed pain within six months, (PDP) will others did not (PNP). EEG features were extracted based on either band power or Higuchi fractal dimension (HFD). Three levels of generalisability were tested: (1) classification PDP vs. PNP in datasets A and B separately; (2) classification between groups in datasets A and B together; and (3) classification where one dataset (A or B) was used for training and testing, and the other for validation. A novel normalisation method was applied to HFD features. Results: Training and testing of individual datasets achieved classification accuracies of >80% using either feature set, and classification of joint datasets (A and B) achieved a maximum accuracy of 86.4% (HFD, support vector machine (SVM)). With normalisation and feature reduction (principal components), the validation accuracy was 66.6%. Conclusions: An SVM classifier with HFD features showed the best robustness, and normalisation improved the accuracy of predicting future neuropathic pain well above the chance level.

Central neuropathic pain (CNP) and musculoskeletal pain (MSP) are often comorbid with multiple sclerosis (MS), yet data on the emotional burden entailed by this comorbidity are very limited. We studied whether MS patients with CNP exhibited greater emotional burden and pain severity than those with MSP and whether this emotional burden was attributed to the MS, the chronic pain, or both. Participants were 125 MS patients (55 with CNP; 30 with MSP; 40 MS pain-free) and 30 healthy controls (HCs). Participants completed questionnaires assessing pain interference, pain catastrophizing, depression, anxiety, stress, hypervigilance, and chronic pain. Group comparisons and a two-step cluster analysis were performed, and the association between cluster membership and clinical group membership was evaluated. Chronic pain was stronger and more widespread in the CNP group than in the MSP group. Both pain groups had higher pain interference, pain catastrophizing, and stress compared to MS pain-free and HC groups. All MS groups had greater depression levels compared to HCs, and the CNP group had the highest anxiety level. The "high psychological distress" cluster comprised mainly participants with CNP (57%), and the "minimal psychological distress" cluster comprised mainly the MS pain-free and HC groups. In conclusion, CNP seems to induce greater emotional burden and pain severity than does MSP. Whereas depression may be attributed to MS, and anxiety to CNP, enhanced pain interference, catastrophizing, and stress may be attributed to the comorbidity of MS and chronic pain. Identifying these traits among MS patients and targeting them in management programs may contribute to more effective, individually based care. [ABSTRACT FROM AUTHOR]

Chronic pain is a common problem among stroke patients, resulting from neurological damage to the central nervous system. This discomfort is primarily caused by the improper use of unaffected limbs or musculoskeletal issues. It can be challenging to differentiate neuropathic pain resulting from central nervous system damage. To address these challenges, researchers have developed a cutting‐edge technology called a Brain‐Computer Interface (BCI) based on electroencephalogram (EEG) data. In this paper, a novel BCI classifier has been developed using the Weighted Incremental‐Decremental Support Vector Machine (WIDSVM) classification method. The classifier has been trained using EEG‐based motor images from patients with central nervous system damage. The Quantum Chaos Butterfly Optimization Algorithm (QCBOA) has been used to enhance the performance of the WIDSVM classifier by creating a new dataset. The efficiency of the proposed model has been evaluated by comparing the results obtained from normal participants and those who developed chronic pain. The classification accuracy has been calculated for different regions, including the left hand, right hand, and feet, among the different participant groups. A total of 28 participants have been separated into three groups with pain in different regions, such as the lower abdomen and legs. The classifier has been tested using both 3‐channel bipolar montages and Common Spatial Patterns (CSPs). The results have shown that the proposed model offers higher classification accuracy and statistical significance in identifying the patient's risk of developing central neuropathic pain. However, it is important to note that further studies with larger sample sizes and different types of chronic pain are needed to validate the efficacy of the proposed model. [ABSTRACT FROM AUTHOR]

Abstract Introduction Central neuropathic pain (CNeP) is difficult to treat and has diverse etiology, including spinal cord injury (CNePSCI), Parkinson’s disease (CNePPD), and central post-stroke pain (CPSP). The safety and efficacy of mirogabalin have been demonstrated in short-term trials, including patients with CNePSCI. The objective of our study was to confirm the safety/efficacy of mirogabalin in patients with CNePPD and CPSP, and obtain long-term data for CNePSCI. Methods This 52-week, open-label extension of a previous randomized controlled study was conducted across Japan, Korea, and Taiwan. Patients with CNePSCI, CNePPD, or CPSP received twice daily (BID) 5–10 mg mirogabalin for a 4-week titration period, after which the dosage was maintained for 47 weeks at a maximum of 15 mg BID, followed by a 1-week taper period receiving the same dose but only administered once daily. The primary endpoint was safety, assessed primarily by incidence and severity of treatment-emergent adverse events (TEAEs). Efficacy was assessed in a post hoc analysis of data obtained by the short-form McGill Pain Questionnaire (SF-MPQ). Results Of the 210 patients enrolled, 106, 94, and 10 had CNePSCI, CPSP, and CNePPD, respectively. The mean overall age of patients was 62.9 years, and most patients were male and of Japanese ethnicity. TEAEs occurred in 84.8% of patients, the most common being somnolence (16.7%), peripheral edema (12.4%), edema (11.4%), nasopharyngitis (11.0%), and dizziness (7.6%). Most TEAEs were mild. Severe and serious TEAEs occurred in 6.2% and 13.3% of patients, respectively. All patient groups experienced reductions in SF-MPQ visual analog scores for pain: mean ± standard deviation changes from baseline at week 52 were −2.3 ± 21.13 mm (CNePSCI), −17.0 ± 24.99 mm (CPSP), and −17.1 ± 35.32 mm (CNePPD). Conclusion Mirogabalin was generally safe, well tolerated, and effective for treatment of CNeP in this long-term study. Trial registration ClinicalTrials.gov identifier, NCT03901352.

Introduction: Central neuropathic pain (CNeP) is difficult to treat and has diverse etiology, including spinal cord injury (CNePSCI), Parkinson's disease (CNePPD), and central post-stroke pain (CPSP). The safety and efficacy of mirogabalin have been demonstrated in short-term trials, including patients with CNePSCI. The objective of our study was to confirm the safety/efficacy of mirogabalin in patients with CNePPD and CPSP, and obtain long-term data for CNePSCI. Methods: This 52-week, open-label extension of a previous randomized controlled study was conducted across Japan, Korea, and Taiwan. Patients with CNePSCI, CNePPD, or CPSP received twice daily (BID) 5–10 mg mirogabalin for a 4-week titration period, after which the dosage was maintained for 47 weeks at a maximum of 15 mg BID, followed by a 1-week taper period receiving the same dose but only administered once daily. The primary endpoint was safety, assessed primarily by incidence and severity of treatment-emergent adverse events (TEAEs). Efficacy was assessed in a post hoc analysis of data obtained by the short-form McGill Pain Questionnaire (SF-MPQ). Results: Of the 210 patients enrolled, 106, 94, and 10 had CNePSCI, CPSP, and CNePPD, respectively. The mean overall age of patients was 62.9 years, and most patients were male and of Japanese ethnicity. TEAEs occurred in 84.8% of patients, the most common being somnolence (16.7%), peripheral edema (12.4%), edema (11.4%), nasopharyngitis (11.0%), and dizziness (7.6%). Most TEAEs were mild. Severe and serious TEAEs occurred in 6.2% and 13.3% of patients, respectively. All patient groups experienced reductions in SF-MPQ visual analog scores for pain: mean ± standard deviation changes from baseline at week 52 were −2.3 ± 21.13 mm (CNePSCI), −17.0 ± 24.99 mm (CPSP), and −17.1 ± 35.32 mm (CNePPD). Conclusion: Mirogabalin was generally safe, well tolerated, and effective for treatment of CNeP in this long-term study. Trial registration: ClinicalTrials.gov identifier, NCT03901352. [ABSTRACT FROM AUTHOR]

Background: It is unknown if different etiologies or lesion topographies influence central neuropathic pain (CNP) clinical manifestation. Methods: We explored the symptom–somatosensory profile relationships in CNP patients with different types of lesions to the central nervous system to gain insight into CNP mechanisms. We compared the CNP profile through pain descriptors, standardized bedside examination, and quantitative sensory test in two different etiologies with segregated lesion locations: the brain, central poststroke pain (CPSP, n = 39), and the spinal cord central pain due to spinal cord injury (CPSCI, n = 40) in neuromyelitis optica. Results: Results are expressed as median (25th to 75th percentiles). CPSP presented higher evoked and paroxysmal pain scores compared to CPSCI (p < 0.001), and lower cold thermal limen (5.6°C [0.0–12.9]) compared to CPSCI (20.0°C [4.2–22.9]; p = 0.004). CPSCI also had higher mechanical pain thresholds (784.5 mN [255.0–1078.0]) compared to CPSP (235.2 mN [81.4–1078.0], p = 0.006) and higher mechanical detection threshold compared to control areas (2.7 [1.5–6.2] vs. 1.0 [1.0–3.3], p = 0.007). Evoked pain scores negatively correlated with mechanical pain thresholds (r = −0.38, p < 0.001) and wind‐up ratio (r = −0.57, p < 0.001). Conclusions: CNP of different etiologies may present different pain descriptors and somatosensory profiles, which is likely due to injury site differences within the neuroaxis. This information may help better design phenotype mechanism correlations and impact trial designs for the main etiologies of CNP, namely stroke and spinal cord lesions. This study provides evidence that topography may influence pain symptoms and sensory profile. The findings suggest that CNP mechanisms might vary according to pain etiology or lesion topography, impacting future mechanism‐based treatment choices. [ABSTRACT FROM AUTHOR]

• Both subacute spinal cord injury (SCI) and central neuropathic pain (CNP) affect motor imagery (MI) activity and lateralization. • MI activity is greater in SCI with upcoming CNP compared to SCI with no CNP. • MI activity is more bilateral in SCI with upcoming CNP and more contralateral in SCI with existing CNP. The aim of this study is to explore whether cortical activation and its lateralization during motor imagery (MI) in subacute spinal cord injury (SCI) are indicative of existing or upcoming central neuropathic pain (CNP). Multichannel electroencephalogram was recorded during MI of both hands in four groups of participants: able-bodied (N = 10), SCI and CNP (N = 11), SCI who developed CNP within 6 months of EEG recording (N = 10), and SCI who remained CNP-free (N = 10). Source activations and its lateralization were derived in four frequency bands in 20 regions spanning sensorimotor cortex and pain matrix. Statistically significant differences in lateralization were found in the theta band in premotor cortex (upcoming vs existing CNP, p = 0.036), in the alpha band at the insula (healthy vs upcoming CNP, p = 0.012), and in the higher beta band at the somatosensory association cortex (no CNP vs upcoming CNP, p = 0.042). People with upcoming CNP had stronger activation compared to those with no CNP in the higher beta band for MI of both hands. Activation intensity and lateralization during MI in pain-related areas might hold a predictive value for CNP. The study increases understanding of the mechanisms underlying transition from asymptomatic to symptomatic early CNP in SCI. [ABSTRACT FROM AUTHOR]

Central neuropathic pain is not only characterized by reflexive pain responses, but also emotional or affective nonreflexive pain responses, especially in women. Some pieces of evidence suggest that the activation of the neuroimmune system may be contributing to the manifestation of mood disorders in patients with chronic pain conditions, but the mechanisms that contribute to the development and chronicity of CNP and its associated disorders remain poorly understood. This study aimed to determine whether neuroinflammatory factor over-expression in the spinal cord and supraspinal structures may be associated with reflexive and nonreflexive pain response development from acute SCI phase to 12 weeks post-injury in female mice. The results show that transient reflexive responses were observed during the SCI acute phase associated with transient cytokine overexpression in the spinal cord. In contrast, increased nonreflexive pain responses were observed in the chronic phase associated with cytokine overexpression in supraspinal structures, especially in mPFC. In addition, results revealed that besides cytokines, the mPFC showed an increased glial activation as well as CX3CL1/CX3CR1 upregulation in the neurons, suggesting the contribution of neuron-glia crosstalk in the development of nonreflexive pain responses in the chronic spinal cord injury phase. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) represents a major cause of chronic neurological disability in young adults and can result in upper limb sensorimotor impairment with a huge impact on manual dexterity and activities of daily living. Moreover, pain is common in MS and a large proportion of patients suffer from central neuropathic pain. To date, no rehabilitative treatment has been described as useful for these patients. A 46-year-old woman, affected by relapsing-remittent MS, described a one-year history of right shoulder pain (Visual Analogue Scale = 8) that started gradually and without trauma. The patient also presented balance and gait impairments, upper limb strength deficit, and fatigue (Expanded Disability Status Scale = 5.5). A multidisciplinary treatment was proposed, including three intra-articular corticosteroid injections and one month of manual therapy, three sessions/week, based on proprioceptive neuromuscular facilitation for the upper limb. At the end of the rehabilitative treatment, pain relief and an improvement in the range of motion of the affected shoulder, upper limb muscle strength, and hand dexterity were observed. The present paradigmatic case report with literature review demonstrated that a multidisciplinary approach seems to be effective in pain relief in a patient with central neuropathic shoulder pain and relapsing-remitting MS. [ABSTRACT FROM AUTHOR]

Aim: The aim of this study was to differentiate the effects of spinal cord injury (SCI) and central neuropathic pain (CNP) on effective connectivity during motor imagery of legs, where CNP is typically experienced. Methods: Multichannel EEG was recorded during motor imagery of the legs in 3 groups of people: able-bodied (N = 10), SCI with existing CNP (N = 10), and SCI with no CNP (N = 20). The last group was followed up for 6 months to check for the onset of CNP. Source reconstruction was performed to obtain cortical activity in 17 areas spanning sensorimotor regions and pain matrix. Effective connectivity was calculated using the directed transfer function in 4 frequency bands and compared between groups. Results: A total of 50% of the SCI group with no CNP developed CNP later. Statistically significant differences in effective connectivity were found between all groups. The differences between groups were not dependent on the frequency band. Outflows from the supplementary motor area were greater for the able-bodied group while the outflows from the secondary somatosensory cortex were greater for the SCI groups. The group with existing CNP showed the least differences from the able-bodied group, appearing to reverse the effects of SCI. The connectivities involving the pain matrix were different between able-bodied and SCI groups irrespective of CNP status, indicating their involvement in motor networks generally. Significance: The study findings might help guide therapeutic interventions targeted at the brain for CNP alleviation as well as motor recovery post SCI. [ABSTRACT FROM AUTHOR]

The research and clinical application of the noninvasive brain stimulation (NIBS) technique in the treatment of neuropathic pain (NP) are increasing. In this review article, we outline the effectiveness and limitations of the NIBS approach in treating common central neuropathic pain (CNP). This article summarizes the research progress of NIBS in the treatment of different CNPs and describes the effects and mechanisms of these methods on different CNPs. Repetitive transcranial magnetic stimulation (rTMS) analgesic research has been relatively mature and applied to a variety of CNP treatments. But the optimal stimulation targets, stimulation intensity, and stimulation time of transcranial direct current stimulation (tDCS) for each type of CNP are still difficult to identify. The analgesic mechanism of rTMS is similar to that of tDCS, both of which change cortical excitability and synaptic plasticity, regulate the release of related neurotransmitters and affect the structural and functional connections of brain regions associated with pain processing and regulation. Some deficiencies are found in current NIBS relevant studies, such as small sample size, difficulty to avoid placebo effect, and insufficient research on analgesia mechanism. Future research should gradually carry out large-scale, multicenter studies to test the stability and reliability of the analgesic effects of NIBS. [ABSTRACT FROM AUTHOR]

Abstract: Several different reporting biases cited in scientific literature have raised concerns about the overestimation of effects and the subsequent potential impact on the practice of evidence-based medicine and human health. Up to 7% to 8% of the population experiences neuropathic pain (NP), and established treatment guidelines are based predominantly on published clinical trial results. Therefore, we examined published randomized controlled trials (RCTs) of first-line drugs for NP and assessed the relative proportions with statistically significant (ie, positive) and nonsignificant (ie, negative) results and their rates of citation. We determined the relationships between reported study outcome and the frequency of their citations with journal impact factor, sample size, time to publication after study completion, and study quality metrics. We also examined the association of study outcome with maximum study drug dosage and conflict of interest. We found that of 107 published RCTs, 68.2% reported a statistically significant outcome regarding drug efficacy for chronic peripheral and central NP. Positive studies were cited nearly twice as often as negative studies in the literature (P = 0.01), despite similar study sample size, quality metrics, and publication in journals with similar impact factors. The time to publication, journal impact factor, and conflict of interest did not differ statistically between positive and negative studies. Our observations that negative and positive RCTs were published in journals with similar impact at comparable time-lags after study completion are encouraging. However, the citation bias for positive studies could affect the validity and generalization of conclusions in literature and potentially influence clinical practice. [ABSTRACT FROM AUTHOR]

The research and clinical application of the noninvasive brain stimulation (NIBS) technique in the treatment of neuropathic pain (NP) are increasing. In this review article, we outline the effectiveness and limitations of the NIBS approach in treating common central neuropathic pain (CNP). This article summarizes the research progress of NIBS in the treatment of different CNPs and describes the effects and mechanisms of these methods on different CNPs. Repetitive transcranial magnetic stimulation (rTMS) analgesic research has been relatively mature and applied to a variety of CNP treatments. But the optimal stimulation targets, stimulation intensity, and stimulation time of transcranial direct current stimulation (tDCS) for each type of CNP are still difficult to identify. The analgesic mechanism of rTMS is similar to that of tDCS, both of which change cortical excitability and synaptic plasticity, regulate the release of related neurotransmitters and affect the structural and functional connections of brain regions associated with pain processing and regulation. Some deficiencies are found in current NIBS relevant studies, such as small sample size, difficulty to avoid placebo effect, and insufficient research on analgesia mechanism. Future research should gradually carry out large-scale, multicenter studies to test the stability and reliability of the analgesic effects of NIBS.

Introduction: Central neuropathic pain (CNP) commonly develops in patients after spinal cord injury (SCI), causing debilitating symptoms and sensory abnormalities to mechanical and thermal stimuli. The biological variability of pain phenotypes in individuals has limited the number of positive outcomes. Thus, it is necessary to investigate the physiological processes contributing to sensory changes that develop over time., Objective: To investigate the physiological processes contributing to neuropathic pain sensory changes and locomotor impairments with sensory phenotypes that develop over time., Methods: Using the tail flick and von Frey tests, we performed hierarchical clustering to determine the subpopulation of rats that developed thermal and mechanical sensory abnormalities. To measure inflammation as a potential mediator of CNP phenotypes, we used flow cytometry and immunohistochemistry. Finally, to assess the secondary effects on locomotor recovery, up to 8 weeks after injury, we used the CatWalk test to assess multiple parameters of gait., Results: The von Frey test showed a subpopulation of SCI rats that were hyposensitive to mechanical stimuli from 6 to 8 weeks after injury. The tail flick test showed a subpopulation of SCI rats that were hypersensitive to thermal stimuli at 1 week and 3 to 8 weeks after injury. Although there were no differences in inflammatory cells between subpopulations, we did see significant changes in locomotor recovery between rats with and without sensory abnormalities., Conclusion: The myeloid cell population at large is not affected by mechanical or thermal phenotypes of pain in this model; however, locomotor recovery is impaired depending on the pain phenotype present. Further investigation into acute inflammatory cells may be insightful for predicting the development of pain phenotypes., Competing Interests: The authors have no conflict of interest to declare., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The International Association for the Study of Pain.)

ObjectiveEhlers-Danlos syndrome frequently causes acute and chronic pain because of joint subluxations and dislocations secondary to hypermobility. Current treatments for pain related to Ehlers-Danlos syndrome and central pain syndrome are inadequate. This case report discusses the therapeutic use of ketamine intravenous infusion as an alternative.Case reportA 27-year-old Caucasian female with a history of Ehlers-Danlos syndrome and spinal cord ischemic myelopathy resulting in central pain syndrome, presented with severe generalized body pain refractory to multiple pharmacological interventions. After a 7-day course of ketamine intravenous infusion under controlled generalized sedation in the intensive care unit, the patient reported a dramatic reduction in pain levels from 7-8 out of 10 to 0-3 out of 10 on a numeric rating scale and had a significant functional improvement. The patient tolerated a reduction in her pain medication regimen, which originally included opioids, gabapentin, pregabalin, tricyclic antidepressants, and nonsteroidal anti-inflammatory drugs.ConclusionKetamine infusion treatment has been used in various pain syndromes, including central neuropathic pain, ischemic pain, and regional pain syndrome. Reports have suggested that ketamine modulates pain by the regression of N-methyl-D-aspartate receptor to a resting state. As such, propagation of nociceptive signal to brain is interrupted allowing for the restoration of physiological balance between pain inhibition and facilitation. The present report shows that this treatment option can be used in patients with refractory central pain syndrome in the setting of spinal cord myelopathy secondary to Ehlers-Danlos syndrome. In addition, as seen in this case, this protocol can potentially decrease the chronic use of pain medication, such as opioids.

Abstract: A severe and debilitating consequence of a spinal cord injury (SCI) is central neuropathic pain (CNP). Our aim was to investigate the processes leading to CNP emergence and chronification by analyzing causal relationship over time between spinothalamic function, pain excitability, and pain inhibition after SCI. This longitudinal follow-up study included 53 patients with acute SCI and 20 healthy controls. Spinothalamic, pain excitability, and intrasegmental and extrasegmental pain inhibition indices were repeatedly evaluated at 1.5, 3, and 6 months post-SCI. Between- and within-group analyses were conducted among those patients who eventually developed CNP and those who did not. Healthy controls were evaluated twice for repeatability analysis. Patients who developed CNP, compared with those who did not, exhibited increased thermal thresholds (P < 0.05), reduced pain adaptation (P < 0.01), and conditioned pain modulation (P < 0.05), early post-injury, and the CNP group's manifestations remained worse throughout the follow-up. By contrast, allodynia frequency was initially similar across SCI groups, but gradually increased in the subacute phase onward only among the CNP group (P < 0.001), along with CNP emergence. Early worse spinothalamic and pain inhibition preceded CNP and predicted its occurrence, and early worse pain inhibition mediated the link between spinothalamic function and CNP. Crossover associations were observed between early and late pain inhibition and excitability. Inefficient intrasegmental and extrasegmental inhibition, possibly resulting from spinothalamic deafferentation, seems to ignite CNP chronification. Pain excitability probably contributes to CNP maintenance, possibly via further exhaustion of the inhibitory control. Preemptive treatment promoting antinociception early post-SCI may mitigate or prevent CNP. [ABSTRACT FROM AUTHOR]

Abstract Background Central Neuropathic Pain (CNP) is a frequent chronic condition in people with spinal cord injury (SCI). Previously, we showed that using laboratory brain-computer interface (BCI) technology for neurofeedback (NFB) training, it was possible to reduce CNP in people with SCI. In this study, we show results of patient self-managed treatment in their homes with a BCI-NFB using a consumer EEG device. Methods Users: People with chronic SCI (17 M, 3 F, 50.6 ± 14.1 years old), and CNP ≥4 on a Visual Numerical Scale. Location: Laboratory training (up to 4 sessions) followed by home self-managed NFB. User Activity: Upregulating the EEG alpha band power by 10% above a threshold and at the same time downregulating the theta and upper beta (20-30 Hz) band power by 10% at electrode location C4. Technology: A consumer grade multichannel EEG headset (Epoch, Emotiv, USA), a tablet computer and custom made NFB software. Evaluation: EEG analysis, before and after NFB assessment, interviews and questionnaires. Results Effectiveness: Out of 20 initially assessed participants, 15 took part in the study. Participants used the system for 6.9 ± 5.5 (median 4) weeks. Twelve participants regulated their brainwaves in a frequency specific manner and were most successful upregulating the alpha band power. However they typically upregulated power around their individual alpha peak (7.6 ± 0.8 Hz) that was lower than in people without CNP. The reduction in pain experienced was statistically significant in 12 and clinically significant (greater than 30%) in 8 participants. Efficiency: The donning was between 5 and 15 min, and approximately 10–20% of EEG data recorded in the home environment was noise. Participants were mildly stressed when self-administering NFB at home (2.4 on a scale 1–10). User satisfaction: Nine participants who completed the final assessment reported a high level of satisfaction (QUESQ, 4.5 ± 0.8), naming effectiveness, ease of use and comfort as main priorities. The main factors influencing frequency of NFB training were: health related issues, free time and pain intensity. Conclusion Portable NFB is a feasible solution for home-based self-managed treatment of CNP. Compared to pharmacological treatments, NFB has less side effects and provides users with active control over pain. Trial registration GN15NE124, Registered 9th June 2016.

Central neuropathic pain (CNP) negatively impacts the quality of life in a large proportion of people with spinal cord injury (SCI). With no cure at present, it is crucial to improve our understanding of how CNP manifests, to develop diagnostic biomarkers for drug development, and to explore prognostic biomarkers for personalised therapy. Previous work has found early evidence of diagnostic and prognostic markers analysing Electroencephalogram (EEG) oscillatory features. In this paper, we explore whether non-linear non-oscillatory EEG features, specifically Higuchi Fractal Dimension (HFD), can be used as prognostic biomarkers to increase the repertoire of available analyses on the EEG of people with subacute SCI, where having both linear and non-linear features for classifying pain may ultimately lead to higher classification accuracy and an intrinsically transferable classifier. We focus on EEG recorded during imagined movement because of the known relation between the motor cortex over-activity and CNP. Analyses were performed on two existing datasets. The first dataset consists of EEG recordings from able-bodied participants (N = 10), participants with chronic SCI and chronic CNP (N = 10), and participants with chronic SCI and no CNP (N = 10). We tested for statistically significant differences in HFD across all pairs of groups using bootstrapping, and found significant differences between all pairs of groups at multiple electrode locations. The second dataset consists of EEG recordings from participants with subacute SCI and no CNP (N = 20). They were followed-up 6 months post recording to test for CNP, at which point (N = 10) participants had developed CNP and (N = 10) participants had not developed CNP. We tested for statistically significant differences in HFD between these two groups using bootstrapping and, encouragingly, also found significant differences at multiple electrode locations. Transferable machine learning classifiers achieved over 80% accuracy discriminating between groups of participants with chronic SCI based on only a single EEG channel as input. The most significant finding is that future and chronic CNP share common features and as a result, the same classifier can be used for both. This sheds new light on pain chronification by showing that frontal areas, involved in the affective aspects of pain and believed to be influenced by long-standing pain, are affected in a much earlier phase of pain development.

Central neuropathic pain (CNP) negatively impacts the quality of life in a large proportion of people with spinal cord injury (SCI). With no cure at present, it is crucial to improve our understanding of how CNP manifests, to develop diagnostic biomarkers for drug development, and to explore prognostic biomarkers for personalised therapy. Previous work has found early evidence of diagnostic and prognostic markers analysing Electroencephalogram (EEG) oscillatory features. In this paper, we explore whether non-linear non-oscillatory EEG features, specifically Higuchi Fractal Dimension (HFD), can be used as prognostic biomarkers to increase the repertoire of available analyses on the EEG of people with subacute SCI, where having both linear and non-linear features for classifying pain may ultimately lead to higher classification accuracy and an intrinsically transferable classifier. We focus on EEG recorded during imagined movement because of the known relation between the motor cortex over-activity and CNP. Analyses were performed on two existing datasets. The first dataset consists of EEG recordings from able-bodied participants (N = 10), participants with chronic SCI and chronic CNP (N = 10), and participants with chronic SCI and no CNP (N = 10). We tested for statistically significant differences in HFD across all pairs of groups using bootstrapping, and found significant differences between all pairs of groups at multiple electrode locations. The second dataset consists of EEG recordings from participants with subacute SCI and no CNP (N = 20). They were followed-up 6 months post recording to test for CNP, at which point (N = 10) participants had developed CNP and (N = 10) participants had not developed CNP. We tested for statistically significant differences in HFD between these two groups using bootstrapping and, encouragingly, also found significant differences at multiple electrode locations. Transferable machine learning classifiers achieved over 80% accuracy discriminating between groups of participants with chronic SCI based on only a single EEG channel as input. The most significant finding is that future and chronic CNP share common features and as a result, the same classifier can be used for both. This sheds new light on pain chronification by showing that frontal areas, involved in the affective aspects of pain and believed to be influenced by long-standing pain, are affected in a much earlier phase of pain development. [ABSTRACT FROM AUTHOR]

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Abstract Introduction Due to side effects of medications used for chronic pain, combination therapy seems to be an appropriate solution for alleviation of chronic pain and reducing the side effects. The role of inhibitory GABA system is well proven in reducing neuropathic pain. Also, special attention has been focused on endogenous morphine (endomorphins) in reducing chronic pain originates from damage to the nervous system. The purpose of this study is to investigate the analgesic effect of simultaneous administration of GABA agonist and endomorphin‐1 on neuropathic pain in rat model of spinal cord injury (SCI). The role of oxidative stress, NR1 subunits of NMDA receptors, and α2 subunits of GABA receptors in the spinal cord has also been investigated. Methods Spinal cord at level of T6–T8 was compressed. Three weeks after spinal cord injury, muscimol and endomorphin‐1 were injected (intrathecally once a day for 7 days) individually or in combination. Mechanical and cold allodynia, thermal and mechanical hyperalgesia were evaluated before injection and 15 and 60 min after injection. At the end of behavioral experiments, histological and biochemical evaluations were done on prepared spinal cord samples. Results Isobologram results showed that combination therapy significantly increased the pain threshold comparing to injection of endomorphin‐1 (EM) or muscimol alone. Histological studies indicated the increased expression of α2 subunits of GABA receptors, and NR1 subunits of NMDA receptors in the spinal cord. The combination therapy also increased the glutathione (GSH) and superoxide dismutase (SOD) level and decreased the malondialdehyde (MDA) levels in the spinal cord. Conclusion Simultaneous administration of muscimol and endomorphine‐1 could be a new candidate for alleviation of pain resulting from spinal cord injury.

Inmaculada Failde,1,2 María Dueñas,2,3 Maria Victoria Ribera,4 Rafael Gálvez,5 Juan A Mico,2,6,7 Alejandro Salazar,2,3 Helena de Sola,1,2 Concepción Pérez8 1Department of Biomedicine, Biotechnology and Public Health, Faculty of Medicine, University of Cádiz, Cádiz, Spain; 2Institute of Research and Innovation in Biomedical Sciences of the Province of Cadiz, Spain; 3Department of Statistics and Operational Research, Faculty of Sciences, University of Cádiz, Cádiz, Spain; 4Pain Clinic, Hospital Vall d’Hebrón, Barcelona, Spain; 5Pain Clinic, Hospital Virgen de las Nieves, Granada, Spain; 6Department of Neuroscience, Pharmacology and Psychiatry, Faculty of Medicine, University of Cádiz, Cádiz, Spain; 7CIBER of Mental Health, CIBERSAM, Instituto de Salud Carlos III, Madrid, Spain; 8Pain Unit, Hospital de la Princesa, Madrid, Spain Background: The objective of the study was to estimate the prevalence of pure central neuropathic pain (CNP) and peripheral neuropathic pain (PNP) among patients attending pain clinics in Spain. The study also aimed to analyze factors associated with pain intensity and quality of life (QoL). Methods: A cross-sectional study was performed including 53 patients with pure CNP and 281 with pure PNP attending in 104 pain clinics in Spain. The revised grading system proposed in 2008 to determine a definite, probable or possible diagnosis of NP was used. Pain features, psychological variables and QoL were assessed. Descriptive, bivariate and multivariate analyses were performed. Results: The prevalence of pure CNP and PNP amongst neuropathic pain patients was 2.4% (95% CI: 1.7;3.1) and 12.9% (95% CI: 1.5;14.3), respectively. Comorbid anxiety, depression or sleep disorders were high in both groups, but higher in CNP patients (51.1%, 71.4%, respectively). Pain intensity in PNP patients was associated with the presence of depression and sleep disturbances. However, in CNP patients, it was related with pain in the lower limbs. The impairment of QoL was greater in CNP patients than in PNP patients; pain location, presence of depression and sleep disturbance were the factors that most negatively affected QoL. Among PNP patients, women and those with higher pain intensity had worse QoL. Conclusion: Pain intensity and QoL are affected by different factors in patients suffering from CNP or PNP. Identifying these factors could serve to guide therapeutic strategies and improve the QoL of patients. Keywords: central neuropathic pain, peripheral neuropathic pain, pain intensity, quality of life

Background and aims: The pathophysiology of spinal cord injury is very complex. One of the debilitating aspects of spinal cord injury in addition to pain is a defect in motor function below the lesion surface. In this study, we tried to assess the modulatory effect of (S)-3,4-Dicarboxyphenylglycine (DCPG), a metabotropic glutamate receptor subtype 8 (mGluR8) agonist, on animal's locomotor functions in a model of compression spinal cord injury. Methods: We used a contusion method (T6-T8) for induction of spinal cord injury. Male Wistar rats were randomly assigned to five equal groups (n = 10 per group). Clips compression injury model was used to induce spinal cord injury. Three weeks post injury DCPG, siRNA (small interfering Ribonucleic Acid) and normal saline (vehicle) were administered intra-ventrolaterally to the periaqueductal gray (PAG) region. Motor function, were assessed through BBB (Basso, Beattie, and Bresnahan Locomotor Rating Scale) and ladder walking test. In addition, the effects of DCPG on axonal regeneration in corticospinal tract were evaluated. Results: We found that DCPG could improve motor function and axonal regeneration in corticospinal tract when compared to siRNA group. Conclusions: The results revealed that activation of mGluR8 in PAG is capable to improve motor function and of axonal regeneration due to the inhibitory effect on glutamate transmission on the spinal cord surface and also the elimination of the deleterious effect of glutamate on the regeneration of the injured area as an excitatory neurotransmitter. Implications: Our findings in this study showed that, more attention should be paid to glutamate and its receptors in spinal cord injury studies, whether at the spinal or cerebral level, especially in the field of motor function after spinal cord injury. [ABSTRACT FROM AUTHOR]

Introduction: Central post-stroke pain (CPSP) is defined as the neuropathic pain that arises either acutely or in the chronic phase of a cerebrovascular event and is a result of central lesions of the somatosensory tract. The aim of this systematic review and meta-analysis was to establish the prevalence of CPSP, to describe its characteristics, and to discuss the associated management challenges.Methods: After a systematic Medline search, we identified 69 papers eligible to be included.Results: The pooled prevalence of CPSP in patients with stroke at any location was 11% (95% CI 7-18%), which can increase to more than 50% in the subgroups of patients with medullary or thalamic strokes. CPSP onset coincides with stroke occurrence in 26% of patients (95% CI 18-35%); CPSP manifests within a month since symptom onset in 31% of patients (95% CI 22-42%), and occurs between the first month and the first year in 41% of patients (95% CI 33.9-49.0%). CPSP develops more than 12 months after stroke onset in 5% of patients (95% CI 3-8%).Conclusions: Clinicians should look for any evidence of central neuropathic pain for at least 12 months after stroke. Both pharmacological and non-pharmacological interventions can be used for the management of CPSP. Lamotrigine has the strongest evidence (Level II of evidence, derived from small randomized controlled trials) for being effective in the management of CPSP. Future research should focus on well-designed trials of pharmacological and non-pharmacological interventions aiming to relief CPSP, which is a very common but often neglected pain syndrome. [ABSTRACT FROM AUTHOR]

Objectives. Central neuropathic pain (CNP) often appears following spinal cord injury (SCI), but current treatments are not always successful. In this study, we evaluated the analgesic effects of repetitive transcranial magnetic stimulation (rTMS) applied over the hand area of the motor cortex in patients with acute CNP after SCI. Methods. A total of 48 patients with complete or incomplete SCI and acute CNP participated in this study and were randomized to receive either rTMS (10Hz, 1,500 stimuli; N=24) or a sham intervention (N=24) for three weeks. The numeric rating scale (NRS) and Short-Form McGill Pain Questionnaire-2 (Chinese Edition; SF-MPQ-2-CN) were analyzed to assess the degree of pain. Brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) were collected to explore expression influenced by rTMS. Motor-evoked potential (MEP) latency and maximal amplitude were measured to determine neurophysiological changes. The assessments were carried out at baseline (T0), three days (T1), one week (T2), two weeks (T3), and three weeks (T4) after onset of treatment. Results. The analysis showed significant treatment–time interactions for the quality and intensity of pain, as measured by NRS (P < 0.001, η2 = 0.441) and SF-MPQ-2 (P < 0.001, η2 = 0.590). Compared with the sham group, the NRS and SF-MPQ2-CN scores were significantly lower on the third day (P < 0.001, Cohen’s d=1.135; P=0.006, Cohen’s d=0.616) and after one week (P < 0.001, Cohen’s d=0.846; P=0.012, Cohen’s d=0.557) of treatment. In addition, the serum levels of BDNF and NGF were significantly higher in the treated group after three weeks (P=0.015, Cohen’s d=0.539; P=0.009, Cohen’s d=0.580), and the MEP amplitude increased by 109.59% (P=0.033, Cohen’s d=0.464). Conclusions. These findings indicate that 10 Hz rTMS over the hand area of the motor cortex could alleviate acute CNP in the early phase of SCI and could enhance MEP parameters and modulate BDNF and NGF secretion. [ABSTRACT FROM AUTHOR]

The pathophysiology of neuropathic pain is very complex. It involves several environmental and central mechanisms. In this study, we tried to assess the modulatory effect of (S)-3,4-Dicarboxyphenylglycine (DCPG), a metabotropic glutamate receptor subtype 8 (mGluR8) agonist, in a model of chronic central neuropathic pain in male rats. We used a spinal cord contusion method (T6-T8) for the induction of chronic central neuropathic pain. Male Wistar rats were randomly assigned to 5 equal groups (n = 10 per group). Clips compression injury model was used to induce chronic central neuropathic pain. Three weeks after spinal cord injury DCPG, siRNA and normal saline were administered intra-ventrolaterally to the periaqueductal gray (PAG) region. Paw withdrawal response to acetone (cold allodynia) was assessed through acetone test. In addition, the effects of DCPG on rostral ventromedial medulla (RVM) off-cells activity were evaluated with immunohistochemistry. mGluR8 expressions were also measured. We found that treatment with DCPG increased pain threshold in acetone test. In addition, immunohistochemical evaluation of RVM off-cells showed that DCPG increased the suppressive function of these cells. The results revealed that activation of mGluR8 in PAG is capable to improve pain threshold via modulation of RVM off-cells activity. Abbreviations SCI: spinal cord injury; DCPG: (S)-3,4-dicarboxyphenylglycine; PAG: periaqueductal gray; siRNA: small interfering ribonucleic acid; RVM: rostral ventromedial medulla; mGluR: metabotropic glutamate receptor [ABSTRACT FROM AUTHOR]

Central neuropathic pain is a common untreated symptom in progressive multiple sclerosis (PMS) and is associated with poor quality of life and interference with patients' daily activities. The neuroinflammation process and mitochondrial dysfunction in the PMS lesions generate reactive species. The transient potential receptor ankyrin 1 (TRPA1) has been identified as one of the major mechanisms that contribute to neuropathic pain signaling and can be activated by reactive compounds. Thus, the goal of our study was to evaluate the role of spinal TRPA1 in the central neuropathic pain observed in a PMS model in mice. We used C57BL/6 female mice (20–30 g), and the PMS model was induced by the experimental autoimmune encephalomyelitis (EAE) using mouse myelin oligodendrocyte glycoprotein (MOG35–55) antigen and CFA (complete Freund's adjuvant). Mice developed progressive clinical score, with motor impairment observed after 15 days of induction. This model induced mechanical and cold allodynia and heat hyperalgesia which were measured up to 14 days after induction. The hypersensitivity observed was reduced by the administration of selective TRPA1 antagonists (HC-030031 and A-967079, via intrathecal and intragastric), antioxidants (α-lipoic acid and apocynin, via intrathecal and intragastric), and TRPA1 antisense oligonucleotide (via intrathecal). We also observed an increase in TRPA1 mRNA levels, NADPH oxidase activity, and 4-hydroxinonenal (a TRPA1 agonist) levels in spinal cord samples of PMS-EAE induced animals. In conclusion, these results support the hypothesis of the TRPA1 receptor involvement in nociception observed in a PMS-EAE model in mice. [ABSTRACT FROM AUTHOR]

Purpose: This is a comprehensive review of the current literature on central neuropathic pain mechanisms that is secondary to spinal cord injury. It reviews recent and seminal findings on the pathophysiology, diagnosis, and treatment and compares treatment options and recommendations.Recent Findings: Neuropathic pain (NP) is a common complication of spinal cord injury (SCI). Chronicity of NP is attributed to increased abundance of inflammatory mediators and ion channel dysfunction leading to afferent nerve sensitization; nerve damage and nerve-glia cross talk have also been implicated. Conventional treatment is medical and has had limited success. Recent studies have made headway in identifying novel biomarkers, including microRNA and psychosocial attributes that can predict progress from SCI to chronic NP (CNP). Recent advances have provided evidence of efficacy for two promising drugs. Baclofen was able to provide good, long-lasting pain relief. Ziconotide, a voltage-gated calcium channel blocker, was studied in a small trial and was able to provide good analgesia in most participants. However, several participants had to be withdrawn because of worrisome creatine phosphokinase (CPK) elevations, and further studies are required to define its safety profile. Non-medical interventions include brain sensitization and biofeedback techniques. These methods have recently had encouraging results, albeit preliminary. Case reports of non-conventional techniques, such as hypnosis, were also reported. CNP is a common complication of SCI and is a prevalent disorder with significant morbidity and disability. Conventional medical treatment is limited in efficacy. Recent studies identified baclofen and ziconotide as possible new therapies, alongside non-medical interventions. Further research into the pathophysiology is required to identify further therapy candidates. A multidisciplinary approach, including psychosocial support, medical and non-medical interventions, is likely needed to achieve therapeutic effects in this difficult to treat syndrome. [ABSTRACT FROM AUTHOR]

Repetitive transcranial magnetic stimulation (rTMS) is a procedure increasingly used to treat patients with central neuropathic pain, but its efficacy is still under debate. Patients with medically refractory chronic central neuropathic pain were included in 2 randomized phases (active/sham), separated by a wash-out period of 8 weeks. Each phase consisted of 4 consecutive rTMS sessions and a final evaluation session, all separated from one another by 3 weeks. High-frequency (20 Hz) rTMS was delivered over the primary motor cortex (M1) contralateral to the patient's pain using a neuronavigated robotic system. Patients and clinicians assessing outcomes were blinded to treatment allocation during the trial. The primary outcome measured the percentage of pain relief (%R) from baseline. Secondary outcomes were VAS score, Neuropathic Pain Symptom Inventory, analgesic drug consumption, and quality of life (EQ-5D). Thirty-six patients performed the entire study with no adverse effects. The analgesic effect for the main criterion (%R) was significantly higher in the active (33.8% confidence interval [CI]: [23.88-43.74]) than in the sham phase (13.02% CI: [6.64-19.76]). This was also the case for the secondary outcome VAS (-19.34% CI: [14.31-25.27] vs -4.83% CI: [1.96-8.18]). No difference was observed for quality of life or analgesic drug consumption. Seventeen patients (47%) were identified as responders, but no significant interaction was found between clinical and technical factors considered here and the analgesic response. These results provide strong evidence that 3 weeks spaced high-frequency rTMS of M1 results in a sustained analgesic effect and support the clinical interest of this stimulation paradigm to treat refractory chronic pain. [ABSTRACT FROM AUTHOR]

Purpose Of Review: Transcutaneous electrical nerve stimulation (TENS) is widely used as a non-pharmacological approach for pain relief in a variety of clinical conditions. This manuscript aimed to review the basic mechanisms and clinical applications regarding the use of TENS for alleviating the peripheral (PNP) and central neuropathic pain (CNP).Recent Findings: Basic studies on animal models showed that TENS could alleviate pain by modulating neurotransmitters and receptors in the stimulation site and its upper levels, including the spinal cord, brainstem, and brain. Besides, many clinical studies have investigated the efficacy of TENS in patients with CNP (caused by spinal cord injury, stroke, or multiple sclerosis) and PNP (induced by diabetes, cancer, or herpes zoster). Most clinical trials have demonstrated the efficacy of TENS in attenuating neuropathic pain and suggested that appropriate stimulation parameters (e.g., stimulation frequency and intensity) were critical to improving the analgesic effects of TENS. However, there are some conflicting findings related to the efficacy of TENS in relieving neuropathic pain. With optimized stimulation parameters, TENS would be effective in attenuating neuropathic pain. To obtain sufficient evidence to support the use of TENS in the clinic, researchers recommended performing multicenter clinical trials with optimized TENS protocols for the treatment of various CNP and PNP. [ABSTRACT FROM AUTHOR]

Central neuropathic pain (CNP) after spinal cord injury (SCI) is debilitating and immensely impacts the individual. Central neuropathic pain is relatively resistant to treatment administered after it develops, perhaps owing to irreversible pathological processes. Although preemptive treatment may overcome this shortcoming, its administration necessitates screening patients with clinically relevant biomarkers that could predict CNP early post-SCI. The aim was to search for such biomarkers by measuring pronociceptive and for the first time, antinociceptive indices early post-SCI. Participants were 47 patients with acute SCI and 20 healthy controls. Pain adaptation, conditioned pain modulation (CPM), pain temporal summation, wind-up pain, and allodynia were measured above, at, and below the injury level, at 1.5 months after SCI. Healthy control were tested at corresponding regions. Spinal cord injury patients were monitored for CNP emergence and characteristics at 3 to 4, 6 to 7, and 24 months post-SCI. Central neuropathic pain prevalence was 57.4%. Central neuropathic pain severity, quality, and aggravating factors but not location somewhat changed over 24 months. Spinal cord injury patients who eventually developed CNP exhibited early, reduced at-level pain adaptation and CPM magnitudes than those who did not. The best predictor for CNP emergence at 3 to 4 and 7 to 8 months was at-level pain adaptation with odds ratios of 3.17 and 2.83, respectively (∼77% probability) and a cutoff value with 90% sensitivity. Allodynia and at-level CPM predicted CNP severity at 3 to 4 and 24 months, respectively. Reduced pain inhibition capacity precedes, and may lead to CNP. At-level pain adaptation is an early CNP biomarker with which individuals at risk can be identified to initiate preemptive treatment. [ABSTRACT FROM AUTHOR]

The mechanisms of central neuropathic pain (CNP) caused by spinal cord injury have not been sufficiently studied. We have found that the upregulation of astrocytic aquaporin-4 (AQP4) aggravated peripheral neuropathic pain after spinal nerve ligation in rats. Using a T13 spinal cord hemisection model, we showed that spinal AQP4 was markedly upregulated after SCI and mainly expressed in astrocytes in the spinal dorsal horn (SDH). Inhibition of AQP4 with TGN020 suppressed astrocyte activation, attenuated the development and maintenance of below-level CNP and promoted motor function recovery in vivo. In primary astrocyte cultures, TGN020 also changed cell morphology, diminished cell proliferation and suppressed astrocyte activation. Moreover, T13 spinal cord hemisection induced cell-surface abundance of the AQP4 channel and perivascular localization in the SDH. Targeted inhibition of AQP4 subcellular localization with trifluoperazine effectively diminished astrocyte activation in vitro and further ablated astrocyte activation, attenuated the development and maintenance of below-level CNP, and accelerated functional recovery in vivo. Together, these results provide mechanistic insights into the roles of AQP4 in the development and maintenance of below-level CNP. Intervening with AQP4, including targeting AQP4 subcellular localization, might emerge as a promising agent to prevent chronic CNP after SCI. [ABSTRACT FROM AUTHOR]

Introduction: The pathophysiology of neuropathic pain is very complex. It involves several environmental and central mechanisms. In this study, we tried to assess the modulatory effect of (S)-3,4-Dicarboxyphenylglycine (DCPG), a metabotropic glutamate receptor subtype 8 (mGluR8) agonist, in a model of chronic central neuropathic pain in male rats. Methods and Materials: In this study, a total of 50 Wistar rats were used, which were randomly divided into 5 groups of 10; Three weeks after the induction of spinal cord injury (in order to induce central neuropathic pain, we used the spinal cord compression model in T6-T8 spinal cord cut), DCPG, siRNA and normal saline (solvent drugs) were injected into the periaqueductal gray area by stereotaxic surgery. Before the injection of drugs and 30 and 60 minutes after injection, Paw's withdrawal response to acetone (cold allodynia) was assessed through an acetone test. The brains of some animals were removed for immunohistochemical examination of the activity level of Off cells in the RVM region after transcardial perfusion, and several samples were also used for western blotting analysis of the expression level of mGluR8. Results: Intracerebral administration (PAG) of metabotropic receptor agonist No. 8 increased the pain threshold of animals when exposed to the non-painful cold stimulus; In addition, immunohistochemical examination of Off cells in the RVM area showed that DCPG injection can increase the inhibitory activity of these cells. Also, there was a decrease in the expression of 8 mGluR in SCI and siRNA group animals and a relative increase in the expression of these receptors after treatment. Conclusion: The results of this study showed that increasing the activity of mGluR8 in the periaqueductal gray area will be able to improve some central neuropathic pain symptoms (including cold allodynia) by modulating the activity of inhibitory cells in the RVM region to an acceptable extent. Finally, by observing the increased expression of mGluR8, we came to the conclusion that the activation of these receptors can have an inhibitory role on cell death caused by damage to the central nervous system. [ABSTRACT FROM AUTHOR]

Pain has a significant impact on the quality of life of patients with multiple sclerosis (MS). However, the neurophysiological mechanisms of central neuropathic pain in a MS course are not known. We hypothesized that changes in power spectral density (PSD) that take place in the electroencephalography (EEG) of MS patients with and without the central neuropathic pain (CNP) would differ. The study aimed to assess the features of quantitative EEG using the PSD indicator along with peak frequencies in the standard frequency bands in MS patients with and without CNP. We have analyzed the quantitative spectral content of the EEG at a resting state in 12 MS patients with CNP, 12 MS patients without CNP, and 12 gender- and age-matched healthy controls using fast Fourier transformation. Based on the ANOVA, at the group level, the theta band absolute and relative PSD showed an increase, whereas alpha band relative PSD showed a decrease in MS patients both with and without CNP. However, only in MS with CNP group, the absolute and relative PSD in the beta1 and beta2 bands increased and exceeded that in patients without pain. Only MS patients with CNP demonstrated the significantly increased absolute PSD for the theta, beta1, and beta2 frequency bands in most regions of interest. In the theta band, MS patients with CNP displayed the increase in absolute spectral power for the mid-temporal derivation of the right hemisphere and the increase in relative spectral power for the prefrontal derivation of this hemisphere. In the beta1 band, the increase in absolute spectral power was observed for the three temporal derivations of the right hemisphere, whereas in the beta2 band, for the occipital, parietal, and temporal lobes of both hemispheres. In the alpha band, only a relative spectral power decrease was revealed for the occipital lobes of both hemispheres and parietal lobe of the right hemisphere. In MS patients with CNP, the frequencies of the dominant spectral power (peak frequencies) in the high-frequency beta band were higher than in the healthy control in posterior areas of the left hemisphere. Data could represent central nervous system alterations related to central neuropathic pain in MS patients that lead to the disturbances in cortical communication.