The effect of intra spinal administration of cerium oxide nanoparticles on central pain mechanism: An experimental study.

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.

Site matters: Central neuropathic pain characteristics and somatosensory findings after brain and spinal cord lesions.

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.

Transient Reflexive Pain Responses and Chronic Affective Nonreflexive Pain Responses Associated with Neuroinflammation Processes in Both Spinal and Supraspinal Structures in Spinal Cord-Injured Female Mice.

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.

Effective Connectivity in Spinal Cord Injury-Induced Neuropathic Pain.

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.

[Pain in multiple sclerosis and neuromyelitis optica spectrum disorders]. / Schmerzen bei multipler Sklerose und Neuromyelitis-optica-Spektrum-Erkrankungen.

Multiple sclerosis and neuromyelitis optica spectrum disorders are autoimmune inflammatory diseases of the central nervous system, which can lead to a multitude of neurological complaints and pain syndromes. Pain may be an acute symptom during disease exacerbation as well as a chronic symptom, whereby the latter sometimes substantially reduces the quality of life. The etiology of pain is very heterogeneous but the rapid differential diagnostic classification is decisive in order to be able to initiate a differentiated treatment strategy. Chronic pain must be differentiated from pain as a possible (early) symptom of an acute disease exacerbation, classified in more detail and individually treated. These include central neuropathic pain, pain associated with spasticity, musculoskeletal pain due to excess loading and pain as a side effect of immunotherapy and in the context of comorbidities. The treatment strategies are often insufficiently evidence-based due to the lack of data.

Analgesic Effects of Directed Repetitive Transcranial Magnetic Stimulation in Acute Neuropathic Pain After Spinal Cord Injury.

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 (10 Hz, 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.

Transcutaneous Electrical Nerve Stimulation in Relieving Neuropathic Pain: Basic Mechanisms and Clinical Applications.

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.

Repetitive percutaneous radiofrequency thermocoagulation for persistent idiopathic facial pain and central neuropathic pain attributed to multiple sclerosis-a retrospective monocentric analysis.

BACKGROUND: Persistent idiopathic facial pain (PIFP) is a debilitating chronic pain condition with pain radiating to trigeminal dermatomes. Typically, there are no pathological findings that can be identified during workup and therapy is symptomatic. Facial pain is common in patients with multiple sclerosis (central neuropathic pain attributed to MS). Our aim was to evaluate the effectiveness of percutaneous radiofrequency thermocoagulation (PRTC) of the gasserian ganglion and the duration of pain relief, as well as the identification of factors associated with its outcome. METHODS: Data on all the above-mentioned patients that have been treated with PRTC between 2009 and 2019 were included into the study. The outcome was assessed with a six-tiered score from 1 (complete remission) to 6 (no benefit). Univariate and multivariate analyses were performed in order to obtain factors associated with the outcome. RESULTS: A total of 52 patients were included. The total number of procedures performed was 114. 61.5% of patients who experienced temporary pain relief that lasted for a median of 60 days (range 3-1490 days). In patients with recurrence, the fraction of successful interventions was higher, and also transient, with successful pain amelioration in over 80% of patients. Successful responses to PRTC were observed in 27.9% after 1 year, 19.4% after 2 years, and 8.3% after 3 years. The only independent variable predicting pain relief was a repeat intervention with a history of ≥ 2 interventions (OR: 4.36, 95%-CI: 1.34-14.34, p = 0.015). No severe complications occurred. CONCLUSIONS: Our data showed good and immediate pain relief after PRTC in the majority of our patients. PRTC is a low-risk procedure that can be discussed as an option in case of failure of medical treatment even in critically ill patients and can be repeated with good results when necessary. Long-term pain amelioration, even with repeated procedures, was not possible and no patient was permanently cured.

Home used, patient self-managed, brain-computer interface for the management of central neuropathic pain post spinal cord injury: usability study.

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.

Dronabinol use in France between 2004 and 2017.

OBJECTIVES: To investigate prescription practices for dronabinol, a pure extract of delta-9-tetrahydrocannabinol, prescribed for refractory chronic pain in France since 2004. DESIGN: A descriptive study based on answers to a questionnaire sent to dronabinol prescribers throughout metropolitan France between June and July 2017. MAIN OUTCOMES MEASURES: We assessed the type of prescribers including place of work (hospital, clinic or private practice) and their specialty. We also collected information about the patient profiles, diseases or symptoms initiating dronabinol prescription, its efficacy and side effects. RESULTS: We received completed questionnaires from 26 prescribers in 17 different areas throughout 12 regions. This represented a total of 191 patients of the 377 indexed since 1st January 2006: the sex ratio was 1:1, with an average age of 51 years for men and of 45 for women. The reason for dronabinol prescription was: multiple sclerosis (49.7%); central neuropathic pain from other causes (36.6%); peripheral neuropathic pain (8%); Parkinson's disease (2.9%); and other causes (around 1%). The duration of dronabinol treatment ranged from 1 month to 6 years and the dose from 2.5mg to 30mg per day (in one or several intakes). 59% of the patients declared experiencing a 30 to 50% reduction in pain. CONCLUSION: This first investigation into dronabinol in France underlines the need to further investigate prescription practices and efficacy so as to define conditions of good use and the place of dronabinol in pain management.

Tactile hallucinations in dementia with Lewy bodies.

BACKGROUND: Visual hallucinations (VH) are one of the most common psychological symptoms of dementia with Lewy bodies (DLB). It is generally considered that the VH that occur in DLB usually disappear when patients try to touch imaginary objects. However, DLB patients also sometimes experience tactile hallucinations (TH). To the best of my knowledge, this is the first report to comprehensively describe the TH experienced by DLB patients. METHODS: I searched the literature for case reports that described TH in Parkinson's disease (PD), PD dementia, or DLB. There were four reports regarding TH in PD, one of which was a review article published in 2017. I described the clinical courses of five representative cases of DLB in which TH were associated with VH, and then compared the characteristics of the TH experienced in DLB with those of the TH encountered in previously reported cases of PD. RESULTS: The TH experienced by the DLB patients had very similar characteristics to the TH experienced by PD patients. However, the TH of the DLB patients differed from those of PD patients in the following respects: (i) when the DLB patients tried to touch the imaginary objects, they often did not disappear; (ii) the imaginary objects experienced by the DLB patients sometimes exhibited characteristic hardness and temperature; and (iii) the imaginary objects experienced by the DLB patients were often influenced by the patients' behaviour, which in turn led to further hallucinations. CONCLUSIONS: Based on the abovementioned characteristics of the hallucinations of DLB patients, I propose that these phenomena represent a novel psychopathological entity, which I shall temporarily refer to as, 'strengthening of VH by TH'.

Long-Term Outcomes in the Management of Central Neuropathic Pain Syndromes: A Prospective Observational Cohort Study.

BACKGROUND: Central neuropathic pain syndromes are a result of central nervous system injury, most commonly related to stroke, traumatic spinal cord injury, or multiple sclerosis. These syndromes are distinctly less common than peripheral neuropathic pain, and less is known regarding the underlying pathophysiology, appropriate pharmacotherapy, and long-term outcomes. The objective of this study was to determine the long-term clinical effectiveness of the management of central neuropathic pain relative to peripheral neuropathic pain at tertiary pain centers. METHODS: Patients diagnosed with central (n=79) and peripheral (n=710) neuropathic pain were identified for analysis from a prospective observational cohort study of patients with chronic neuropathic pain recruited from seven Canadian tertiary pain centers. Data regarding patient characteristics, analgesic use, and patient-reported outcomes were collected at baseline and 12-month follow-up. The primary outcome measure was the composite of a reduction in average pain intensity and pain interference. Secondary outcome measures included assessments of function, mood, quality of life, catastrophizing, and patient satisfaction. RESULTS: At 12-month follow-up, 13.5% (95% confidence interval [CI], 5.6-25.8) of patients with central neuropathic pain and complete data sets (n=52) achieved a ≥30% reduction in pain, whereas 38.5% (95% CI, 25.3-53.0) achieved a reduction of at least 1 point on the Pain Interference Scale. The proportion of patients with central neuropathic pain achieving both these measures, and thus the primary outcome, was 9.6% (95% CI, 3.2-21.0). Patients with peripheral neuropathic pain and complete data sets (n=463) were more likely to achieve this primary outcome at 12 months (25.3% of patients; 95% CI, 21.4-29.5) (p=0.012). CONCLUSION: Patients with central neuropathic pain syndromes managed in tertiary care centers were less likely to achieve a meaningful improvement in pain and function compared with patients with peripheral neuropathic pain at 12-month follow-up.

Early transplantation of mesenchymal stem cells after spinal cord injury relieves pain hypersensitivity through suppression of pain-related signaling cascades and reduced inflammatory cell recruitment.

Bone marrow-derived mesenchymal stem cells (BMSC) modulate inflammatory/immune responses and promote motor functional recovery after spinal cord injury (SCI). However, the effects of BMSC transplantation on central neuropathic pain and neuronal hyperexcitability after SCI remain elusive. This is of importance because BMSC-based therapies have been proposed for clinical treatment. We investigated the effects of BMSC transplantation on pain hypersensitivity in green fluorescent protein (GFP)-positive bone marrow-chimeric mice subjected to a contusion SCI, and the mechanisms of such effects. BMSC transplantation at day 3 post-SCI improved motor function and relieved SCI-induced hypersensitivities to mechanical and thermal stimulation. The pain improvements were mediated by suppression of protein kinase C-γ and phosphocyclic AMP response element binding protein expression in dorsal horn neurons. BMSC transplants significantly reduced levels of p-p38 mitogen-activated protein kinase and extracellular signal-regulated kinase (p-ERK1/2) in both hematogenous macrophages and resident microglia and significantly reduced the infiltration of CD11b and GFP double-positive hematogenous macrophages without decreasing the CD11b-positive and GFP-negative activated spinal-microglia population. BMSC transplants prevented hematogenous macrophages recruitment by restoration of the blood-spinal cord barrier (BSCB), which was associated with decreased levels of (a) inflammatory cytokines (tumor necrosis factor-α, interleukin-6); (b) mediators of early secondary vascular pathogenesis (matrix metallopeptidase 9); (c) macrophage recruiting factors (CCL2, CCL5, and CXCL10), but increased levels of a microglial stimulating factor (granulocyte-macrophage colony-stimulating factor). These findings support the use of BMSC transplants for SCI treatment. Furthermore, they suggest that BMSC reduce neuropathic pain through a variety of related mechanisms that include neuronal sparing and restoration of the disturbed BSCB, mediated through modulation of the activity of spinal-resident microglia and the activity and recruitment of hematogenous macrophages.

Evaluating Sativex® in Neuropathic Pain Management: A Clinical and Neurophysiological Assessment in Multiple Sclerosis.

OBJECTIVE: The aim of our study was to better investigate the role of Sativex(®) in improving pain in multiple sclerosis (MS) patients by means of either clinical or neurophysiological assessment. SETTING: Pain is a common symptom of MS, affecting up to 70% of patients. Pain treatment is often unsatisfactory, although emerging drugs (including cannabinoids) are giving encouraging results. Clinical pain assessment in MS is very difficult, and more objective tools are necessary to better quantify this symptom and its potential response to the treatments. SUBJECTS AND METHODS: We enrolled 20 MS patients (10 with and 10 without neuropathic pain), who underwent a specific clinical (such as visual analog scale) and neurophysiological assessment (by means of laser-evoked potentials and transcranial magnetic stimulation), before and after 4 weeks of Sativex administration. RESULTS: One month of drug administration in MS patients with neuropathic pain successfully reduced pain rating and improved quality of life. Interestingly, such effects were paralleled by an increase of fronto-central γ-band oscillation and of pain-motor integration strength. CONCLUSIONS: Our data suggest that Sativex may be effective in improving MS-related neuropathic pain, maybe through its action on specific cortical pathways.

Chronic pain in "probable" vascular dementia: preliminary findings.

BACKGROUND: In a previous study, the levels of pain reported by patients with "possible" vascular dementia (VaD) were higher than those reported by older individuals without dementia. OBJECTIVE: To examine experienced pain in patients with "probable" VaD, confirmed by brain imaging. STUDY DESIGN: Observational, cross sectional. SETTING: Nursing home. METHODS: The participants were 20 nursing home residents (14 females, 6 males) who met the NINDS-AIREN criteria for "probable" VaD and 22 nursing home residents with a normal mental status (18 females, 4 males). The patients were in a mild to moderate stage of dementia. All of the participants were suffering from arthritis/arthrosis or osteoporosis. Global cognitive functioning was measured by the Mini-Mental State Examination. Pain was assessed by the Coloured Analogue Scale (CAS: original and modified version) and the Faces Pain Scale. The Geriatric Depression Scale and the Symptom Checklist-90 were used to assess mood. RESULTS: The main finding was that, after controlling for mood, the pain levels indicated by patients with "probable" VaD (M = 102.32; standard deviation [SD] = 53.42) were significantly higher than those indicated by the control group (M = 59.17; SD = 38.75), only according to the CAS modified version (F[1,29]) = 5.62, P = 0.01, η2 = 0.16). CONCLUSION: As VaD patients may experience greater pain than controls, it is essential for prescribers to be aware of the presence of this neuropathology if these patients are to receive adequate treatment.

A randomized, double-blind, placebo-controlled trial of duloxetine for the treatment of pain in patients with multiple sclerosis.

BACKGROUND: Patients with multiple sclerosis (MS) often report neuropathic pain (NP-MS). The purpose of this study was to assess the efficacy and tolerability of duloxetine as treatment for NP-MS. METHODS: In this study, 239 adults with NP-MS (duloxetine = 118, placebo = 121) were randomized to duloxetine 60 mg (30 mg for 1 week, then 60 mg for 5 weeks) or placebo once daily for a 6-week acute therapy phase, followed by a 12-week open-label extension phase (duloxetine 30 to 120 mg/day). Eligible patients had MS for ≥ 1 year and a score ≥ 4 on daily average pain intensity (API) ratings for ≥ 4 of 7 days immediately before randomization. Patients rated API daily on an 11-point numeric scale (0 [no pain] to 10 [worst possible pain]) in an electronic diary. The primary efficacy measure, change in weekly API ratings, was analyzed longitudinally with a mixed-model repeated-measures analysis. Completion, reasons for discontinuation, and treatment-emergent adverse event incidence were compared by Fisher's exact test. RESULTS: Duloxetine-treated patients had statistically greater mean improvement in API vs. placebo at Week 6 (-1.83 vs. -1.07, P = 0.001). Treatment completion did not significantly differ between groups. Discontinuation due to adverse events was statistically greater for duloxetine vs. placebo (13.6% vs. 4.1%, P = 0.012). Decreased appetite was reported significantly more often by duloxetine-treated patients (5.9% vs. 0%, P = 0.007). CONCLUSIONS: This study found analgesic efficacy of duloxetine for NP-MS. Duloxetine is not approved for treatment of this condition. The duloxetine safety profile of this study was consistent with the known profile in other patient populations.

Emotional burden among MS patients: associations between specific chronic pain diagnoses and psychological features.

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.

Inhibition of aquaporin-4 and its subcellular localization attenuates below-level central neuropathic pain by regulating astrocyte activation in a rat spinal cord injury model.

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.

Spinal Cord Stimulation for Central Neuropathic Pain After Spinal Cord Injury: A Single-Center Case Series.

Purpose: 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.

Usefulness of Mirogabalin in Central Neuropathic Pain After Stroke: Post Hoc Analysis of a Phase 3 Study by Stroke Type and Location.

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.