Treatment Of Neuropathic Pain Research Articles

In-silico, in-vitro and in-vivo Biological Activities of Flavonoids for the Management of Type 2 Diabetes.

In spite of the fact that many medicinal plants have been truly utilized for the management of diabetes all through the world, very few of them have been reported scientifically. Recently, a diverse variety of animal models have been established to better understand the pathophysiology of diabetes mellitus, and new medications to treat the condition have been introduced in the market. Flavonoids are naturally occurring substances that can be found in plants and various foods and may have health benefits in the treatment of neuropathic pain. Flavonoids have also been shown to have an anti-inflammatory impact that is significant to neuropathic pain, as indicated by a decrease in several pro-inflammatory mediators such TNF-, NF-B IL-6, and IL-1. Flavonoids appear to be a viable novel therapy option for macrovasular complications in preclinical models; however, human clinical data is still inadequate. Recently, several in silico, in-vitro and in-vivo aproaches were made to evaluate mechanisms associated with the pathogenesis of diabetes in a better way. Screening of natural antidiabetic agents from plant sources can be analysed by utilizing advanced in-vitro techniques and animal models. Natural compounds, mostly derived from plants, have been studied in diabetes models generated by chemical agents in the majority of research. The aim of this work was to review the available in silico, in-vitro and animal models of diabetes for screening of natural antidiabetic agents. This review contributes to the scientist's design of new methodologies for the development of novel therapeutic agents having potential antihyperglycemic activity.

Restoration of peripheral neuropathy in Fabry mice via intrathecal administration of an adeno-associated virus vector encoding mGLA cDNA

Anderson-Fabry disease (FD) is an X-linked lysosomal storage disorder caused by a pathological variant of the α-galactosidase A (GLA) gene that results in deficient GLA activity. GLA deficiency leads to the accumulation of globotriaosylceramide (Gb3) and lyso-Gb3 in many tissues. A certain number of FD patients have burning pain or acroparesthesia in the feet and hands since childhood. Enzyme replacement therapy (ERT) is available for FD patients. However, ERT does not dramatically improve these FD-related peripheral neuropathic pain. We generated an adeno-associated virus serotype PHP.eB (AAV-PHP.eB) vector encoding mouse GLA cDNA, which was administered to FD mice intrathecally (it) or intravenously (iv). In the it-administered AAV (it-AAV) FD mice, the GLA enzyme activity in the lumbar dorsal root ganglion (DRG) was significantly greater than that in the untreated (NT) FD mice, and the level of activity was similar to that in wild-type (WT) B6 mice. However, in iv-administered AAV (iv-AAV) FD mice, GLA activity in the DRG did not increase compared to that in NT FD mice. Gb3 storage in the DRG of it-AAV FD mice was reduced compared to that in the DRG of NT FD mice. However, compared with NT FD mice, iv-AAV FD mice did not exhibit a significant reduction in the expression of the Gb3 substrate. Compared with WT mice, FD mice were thermally hyposensitive at 52 °C according to the hot plate test. The it-AAV FD mice showed significant recovery from thermal hyposensitivity. However, the iv-AAV FD mice did not exhibit significant improvement in thermal hyposensitivity. These results suggest that the intrathecal delivery of AAV-PHP.eB-mGLA may be a valuable tool for the treatment of FD-related peripheral neuropathic pain.

Mirogabalin: a novel gabapentinoid or another false dawn?

Mirogabalin is a novel gabapentinoid medication for the treatment of neuropathic pain. The purpose of this review is to discuss current evidence for its use. Gabapentinoids are widely prescribed for neuropathic pain. Mirogabalin offers theoretical advantages over traditional gabapentinoids due to its specificity for the α2δ-1 subunit of voltage-gated calcium channels. It is theorised that this specificity may reduce adverse drug reactions by minimising binding to the α2δ-2 subunit which is responsible for many of the gabapentinoid side effects. Mirogabalin's slower dissociation from the α2δ-1 compared with α2δ-2, and its higher potency may also impart an efficacy benefit over traditional gabapentinoids. These theoretical advantages of mirogabalin remain inconclusive in clinical practice, with mixed evidence regarding mirogabalin versus traditional gabapentinoids. Some studies suggest a reduced side effect profile yet, others fail to demonstrate significant differences. Regarding efficacy, mirogabalin may be superior to placebo for several neuropathic pain syndromes, but evidence of widespread benefit over traditional gabapentinoids is currently lacking. Mirogabalin offers theoretical promise, but large, independent studies are required to further assess its performance versus traditional gabapentinoids.

Single-cell sequencing reveals glial cell involvement in development of neuropathic pain via myelin sheath lesion formation in the spinal cord.

Neuropathic pain (NP), which results from injury or lesion of the somatosensory nervous system, is intimately associated with glial cells. The roles of microglia and astrocytes in NP have been broadly described, while studies on oligodendrocytes have largely focused on axonal myelination. The mechanisms of oligodendrocytes and their interactions with other glial cells in NP development remain uncertain. To explore the function of the interaction of the three glial cells and their interactions on myelin development in NP, we evaluated changes in NP and myelin morphology after a chronic constriction injury (CCI) model in mice, and used single-cell sequencing to reveal the subpopulations characteristics of oligodendrocytes, microglia, and astrocytes in the spinal cord tissues, as well as their relationship with myelin lesions; the proliferation and differentiation trajectories of oligodendrocyte subpopulations were also revealed using pseudotime cell trajectory and RNA velocity analysis. In addition, we identified chemokine ligand-receptor pairs between glial cells by cellular communication and verified them using immunofluorescence. Our study showed that NP peaked on day 7 after CCI in mice, a time at which myelin lesions were present in both the spinal cord and sciatic nerve. Oligodendrocytes, microglia, and astrocytes subpopulations in spinal cord tissue were heterogeneous after CCI and all were involved in suppressing the process of immune defense and myelin production. In addition, the differentiation trajectory of oligodendrocytes involved a unidirectional lattice process of OPC-1-Oligo-9, which was arrested at the Oligo-2 stage under the influence of microglia and astrocytes. And the CADM1-CADM1, NRP1-VEGFA interactions between glial cells are enhanced after CCI and they had a key role in myelin lesions and demyelination. Our study reveals the close relationship between the differentiation block of oligodendrocytes after CCI and their interaction with microglia and astrocytes-mediated myelin lesions and NP. CADM1/CADM1 and NRP-1/VEGFA may serve as potential therapeutic targets for use in the treatment of NP.

Mechanism of gabapentinoid potentiation of opioid effects on cyclic AMP signaling in neuropathic pain

Over half of spinal cord injury (SCI) patients develop opioid-resistant chronic neuropathic pain. Safer alternatives to opioids for treatment of neuropathic pain are gabapentinoids (e.g., pregabalin and gabapentin). Clinically, gabapentinoids appear to amplify opioid effects, increasing analgesia and overdose-related adverse outcomes, but in vitro proof of this amplification and its mechanism are lacking. We previously showed that after SCI, sensitivity to opioids is reduced by fourfold to sixfold in rat sensory neurons. Here, we demonstrate that after injury, gabapentinoids restore normal sensitivity of opioid inhibition of cyclic AMP (cAMP) generation, while reducing nociceptor hyperexcitability by inhibiting voltage-gated calcium channels (VGCCs). Increasing intracellular Ca2+ or activation of L-type VGCCs (L-VGCCs) suffices to mimic SCI effects on opioid sensitivity, in a manner dependent on the activity of the Raf1 proto-oncogene, serine/threonine-protein kinase C-Raf, but independent of neuronal depolarization. Together, our results provide a mechanism for potentiation of opioid effects by gabapentinoids after injury, via reduction of calcium influx through L-VGCCs, and suggest that other inhibitors targeting these channels may similarly enhance opioid treatment of neuropathic pain.

Interleukin-35 alleviates neuropathic pain and induces an anti-inflammatory shift in spinal microglia in nerve-injured male mice

Immune cells are critical in promoting neuroinflammation and neuropathic pain and in facilitating pain resolution, depending on their inflammatory and immunoregulatory cytokine response. Interleukin (IL)-35, secreted by regulatory immune cells, is a member of the IL-12 family with a potent immunosuppressive function. In this study, we investigated the effects of IL-35 on pain behaviors, spinal microglia phenotype following peripheral nerve injury, and in vitro microglial cultures in male and female mice. Intrathecal recombinant IL-35 treatment alleviated mechanical pain hypersensitivity prominently in male mice, with only a modest effect in female mice after sciatic nerve chronic constriction injury (CCI). IL-35 treatment resulted in sex-specific microglial changes following CCI, reducing inflammatory microglial markers and upregulating anti-inflammatory markers in male mice. Spatial transcriptomics analysis revealed that IL-35 suppressed microglial complement activation in the superficial dorsal horn in male mice after CCI. Moreover, in vitro studies showed that IL-35 treatment of cultured inflammatory microglia mitigated their hypertrophied morphology, increased their cell motility, and decreased their phagocytic activity, indicating a phenotypic shift towards homeostatic microglia. Further, IL-35 altered microglial cytokines/chemokines in vitro, suppressing the release of IL-9 and monocyte-chemoattractant protein-1 and increasing IL-10 in the supernatant of male microglial cultures. Our findings indicate that treatment with IL-35 modulates spinal microglia and alleviates neuropathic pain in male mice, suggesting IL-35 as a potential sex-specific targeted immunomodulatory treatment for neuropathic pain.

Exploring the high-quality ingredients and mechanisms of Da Chuanxiong Formula in the treatment of neuropathic pain based on network pharmacology, molecular docking, and molecular dynamics simulation

Da Chuanxiong Formula (DCXF) is a traditional herbal prescription used for pain management. It consists of Chuanxiong Rhizoma (CR) and Gastrodiae Rhizoma (GR). Despite its long history of use, the underlying therapeutic mechanism of DCXF remains insufficiently understood. Therefore, in this study, key target genes were obtained through network pharmacology research methods and molecular docking techniques, including transient receptor potential vanilloid 1 (TRPV1), adenosine A2a receptor (ADORA2A), nuclear receptor subfamily 3 group C member 1 (NR3C1), and protein kinase C beta (PRKCB). Molecular dynamics simulations demonstrated the favorable binding between all four key genes and their corresponding compounds. Notably, chronic constriction injury (CCI) treatment resulted in a significant decrease in mechanical threshold and thermal latency period for rat foot contraction, which was ameliorated upon administration of DCXF. Furthermore, real-time quantitative reverse transcription PCR (RT-qPCR) and western blot (WB) analyses indicated an upregulation of TRPV1, ADORA2A, NR3C1, and PRKCB expression in the rat dorsal root ganglion following CCI, which was attenuated by treatment with DCXF. The expressions of inflammatory factors, including tumor necrosis factor-α (TNF-α), interleukin 1 beta (IL-1β), and interleukin 6 (IL-6), in the rat dorsal root ganglion were assessed using ELISA, confirming consistent trends with the aforementioned findings. The results of this study offer a promising theoretical foundation for the utilization of DCXF in the treatment of neuropathic pain (NP).

Identification and validation of aging-related genes in neuropathic pain using bioinformatics.

Neuropathic pain (NP) is a debilitating and refractory chronic pain with a higher prevalence especially in elderly patients. Cell senescence considered a key pathogenic factor in NP. The objective of this research is to discover genes associated with aging in peripheral blood of individuals with NP using bioinformatics techniques. Two cohorts (GSE124272 and GSE150408) containing peripheral blood samples of NP were downloaded from the GEO database. By merging the two cohorts, differentially expressed aging-related genes (DE-ARGs) were obtained by intersection with aging-related genes. The potential biological mechanisms of DE-ARGs were further analyzed through GO and KEGG. Three machine learning methods, namely, LASSO, SVM-RFE, and Random Forest, were utilized to identify diagnostic biomarkers. A Nomogram model was developed to assess their diagnostic accuracy. The validation of biomarker expression and diagnostic effectiveness was conducted in three distinct pain cohorts. The CIBERSORT algorithm was employed to evaluate the immune cell composition in the peripheral blood of patients with NP and investigate its association with the expression of diagnostic biomarkers. This study identified a total of 24 DE-ARGs, mainly enriched in "Chemokine signaling pathway," "Inflammatory mediator regulation of TRP channels," "HIF-1 signaling pathway" and "FOXO signaling pathway". Three machine learning algorithms identified a total of four diagnostic biomarkers (CEBPA, CEACAM1, BTG3 and IL-1R1) with good diagnostic performance and the similar expression difference trend in different types of pain cohorts. The expression levels of CEACAM1 and IL-1R1 exhibit a positive correlation with the percentage of neutrophils. Using machine learning techniques, our research identified four diagnostic biomarkers related to aging in peripheral blood, providing innovative approaches for the diagnosis and treatment of NP.

Serotonin-Mediated Anti-Allodynic Effect of Yokukansan on Diabetes-Induced Neuropathic Pain.

Background: Diabetic neuropathic pain is a known complication of diabetes mellitus (DM) and results from the complex interaction of various factors affecting the nervous system. Yokuansan (YKS) is a versatile traditional Japanese herbal medicine with a wide range of applications, especially in pain management and neurological manifestations. YKS has analgesic properties for nerve damage and is a potential treatment for DM-induced neuropathic pain, especially in patients with diabetic neuropathy. Thus, we examined the anti-allodynic effect of YKS on DM-induced neuropathic pain. Methods: All experiments were performed on 6-week-old male Sprague-Dawley rats. DM and diabetic neuropathy were induced in rats with streptozotocin. Mechanical allodynia was assessed using dynamic plantar esthesiometry. Additionally, we conducted an immunological assessment of microglia cell changes in the spinal cord and an experiment to clarify the involvement of serotonin. Results: Diabetes significantly reduced withdrawal thresholds in rats during the initial two weeks of the experiment, which stabilized thereafter. However, this effect was not investigated in the control group. We assessed, using the dynamic plantar test, the anti-allodynic effects of orally administered YKS (1 g/kg). Daily YKS administration significantly increased the withdrawal threshold in DM animals. Additionally, oral YKS reduced the expression of Ibal-1-positive microglia. To elucidate the mechanism of action of YKS, we explored the involvement of serotonin (5-hydroxytryptamine [5-HT]) receptors in mediating its effects. Intrathecal administration of 5-HT receptor antagonists (WAY-100635, ketanserin, and ondansetron) inhibited the protective effects of YKS. Conclusions: YKS exhibited an anti-allodynic effect, suggesting that YKS may activate 5-HT receptors in the spinal cord, thereby alleviating diabetic neuropathic pain.

Methadone for Pain Management in Chemotherapy-Induced Peripheral Neuropathy: A Retrospective Review

Chemotherapy-Induced Peripheral Neuropathy (CIPN) refers to damage of peripheral nerve fibers due to the use of neurotoxic chemotherapy to treat various cancers. It occurs in more than 30% of patients and only duloxetine has currently been identified to show limited efficacy in symptomatic treatment of CIPN. Opioids have traditionally been used to treat cancer pain, and there is evidence for their use in treatment of peripheral neuropathic pain from other causes. With a similar mechanism of action to duloxetine, methadone has rationale for treating neuropathic pain. This study is a retrospective chart review to evaluate the outcomes of using methadone for CIPN pain. Out of 31 patients, 65% felt that methadone was an effective treatment, 19% felt that it was ineffective, and 16% felt that it was partially or temporarily effective. These results suggest that analgesic response to methadone varies between patients, but that it has a potential role in painful CIPN. Its advantages for long-term use include low cost and lack of metabolites. Potential risks include a long half-life, drug interactions, and potential for QT prolongation at high doses. Prospective studies should be conducted to evaluate the role of methadone in CIPN pain management more comprehensively.

NIR-Remote Selectively Triggered Buprenorphine Hydrochloride Release from Microneedle Patches for the Treatment of Neuropathic Pain.

Neuropathic pain is a prevalent form of intermittent chronic pain, affecting approximately 7-10% of the global population. However, the current clinical administration methods, such as injection and oral administration, are mostly one-time administration, which cannot achieve accurate control of pain degree and drug dose. Herein, we developed near-infrared (NIR) light-responsive microneedle patches (MNPs) to spatiotemporally control the drug dose released to treat neuropathic pain according to the onset state. The mechanism of action utilizes upconversion nanoparticles to convert NIR light into visible and ultraviolet light. This conversion triggers the rapid rotation of the azobenzene molecular motor in the mesoporous material, enabling the on-demand controlled release of a drug dose. Additionally, MNs are used to overcome the barrier of the stratum corneum in a minimally invasive and painless manner, effectively promoting the transdermal penetration of drug molecules. The effectiveness of these patches has been demonstrated through significant results. Upon exposure to NIR light for five consecutive cycles, with each cycle lasting 30 s, the patches achieved a precise release of 318 μg of medication. In a mouse model, maximum pain relief was observed within 1 h of one cycle of NIR light exposure, with the effects lasting up to 6 h. The same level of precise treatment efficacy was maintained for subsequent pain episodes with similar light exposure. The NIR-controlled drugs precision-released MNPs provide a novel paradigm for the treatment of intermittent neuropathic pain.

Potential analgesic effect of a novel cannabidiol nanocrystals powder for the treatment of neuropathic pain.

The current analgesics often prevent patients from getting effective treatment due to their adverse effects. Cannabidiol (CBD) is well tolerated, has few side effects and has been extensively investigated in analgesia. However, its oral bioavailability is extremely low. In order to solve this problem, we developed the cannabidiol nanocrystals (CBD-NC) in the earlier stage. In this study, we evaluated the nociceptive behaviours associated with neuropathic pain (NP) induced by the spared nerve injury (SNI) model. Assessment of pain threshold was evaluated by paw withdraw threshold (PWT) and paw withdrawal latency (PWL). The improving effect on the motor dysfunction was determined by rota-rod testing. To assess the neuroprotective effect, nerve demyelination and expression of peripheral myelin protein PMP22 were measured with myelin sheath staining and western blotting. Protein expressions in microglia of spinal cord were tested by western blot to explore the underlying mechanism. Compared with the CBD oil solution, CBD-NC significantly reduced mechanical allodynia and thermal hyperalgesia in rats. CBD-NC could improve motor dysfunction induced by SNI in rats, significantly reverse the demyelination and increase the expression of the marker protein of peripheral myelin. Underlying spinal analgesic mechanism of microglia and related factors were preliminarily confirmed. CBD-NC administration is an effective treatment for NP associated with SNI, and the analgesic effect of CBD-NC was significantly better than that of CBD oil sol. By contrast, CBD-NC has a fast-acting and long-term effect in the treatment of NP. Our study further supports the potential therapeutic effect of CBD-NC on NP. The absolute bioavailability of the CBD-NC intramuscular injection formulation can reach 203.31%, which can solve the problem of low oral bioavailability. This research evaluated the therapeutic effect of CBD-NC on NP associated with the SNI model for the first time. All available date showed that whatever the analgesic or neuroprotective effect of CBD-NC, it was significantly better than that of CBD oil sol., which was consistent with the results of the pharmacokinetic. This research supports the initiation of more trials testing the efficacy of CBD-NC for treating NP.

Diabetic Neuropathy: A Guide to Pain Management.

Diabetic neuropathy is a common complication of diabetes mellitus (DM) and can affect up to 50% of DM patients during their lifetime. Patients typically present with numbness, tingling, pain, and loss of sensation in the extremities. Since there is no treatment targeting the underlying mechanism of neuropathy, strategies focus on preventative care and pain management. Up to 69% of patients with diabetic neuropathy receive pharmacological treatment for neuropathic pain. The United States Food and Drug Administration (FDA) confirmed four drugs for painful diabetic neuropathy (PDN): pregabalin, duloxetine, tapentadol, and the 8% capsaicin patch. Nonpharmacological treatments such as spinal cord stimulation (SCS) and transcutaneous electrical nerve stimulation (TENS) both show promise in reducing pain in DM patients. Despite the high burden associated with PDN, effective management remains challenging. This update covers the background and management of diabetic neuropathy, including its epidemiology, pathogenesis, preventative care, and current therapeutic strategies.

Vortioxetine treatment for neuropathic pain in major depressive disorder: a three-month prospective study.

Several studies revealed the therapeutic potential of vortioxetine (Vo) for pain. In this context, we aimed to evaluate the efficacy of Vo as a safe and tolerable novel pharmacologic agent in treating neuropathic pain (NP) in patients with major depressive disorder (MDD). The population of this cross-sectional prospective study consisted of all consecutive patients who were newly diagnosed with MDD by a neurology doctor at a psychiatric clinic and had NP for at least 6 months. All patients included in the sample were started on Vo treatment at 10 mg/day. They were assessed with Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), Self-Reported Leeds Assessment of Neuropathic Symptoms and Signs (S-LANSS), Douleur Neuropathique 4 Questions (DN4), Montreal Cognitive Assessment (MoCA), and Neuropathic Pain Impact on Quality of Life (NePIQoL) at the beginning of treatment and during the follow visits conducted at the end of the first, second and third months of the treatment. During these follow-up visits, patients were also queried about any side effects of Vo. The mean age of 50 patients included in the sample, 76% of whom were female, was 45.8 ± 11.2 years. There was a significant reduction in patients' NP complaints based on DN4 and S-LANNS, the subscales of NePIQoL, and significant improvement in MoCA. There was a significant reduction in patients' NP complaints based on DN4 and S-LANNS scores and a significant improvement in scores of the subscales of NePIQoL and MoCA. The study's findings indicate that Vo, with its multiple mechanisms of action, can effectively treat NP independently of its mood-stabilizing effect. Future indication studies for Vo are needed to establish Vo's efficacy in treating NP.

Dexborneol Amplifies Pregabalin's Analgesic Effect in Mouse Models of Peripheral Nerve Injury and Incisional Pain.

Pregabalin is a medication primarily used in the treatment of neuropathic pain and anxiety disorders, owing to its gabapentinoid properties. Pregabalin monotherapy faces limitations due to its variable efficacy and dose-dependent adverse reactions. In this study, we conducted a comprehensive investigation into the potentiation of pregabalin's analgesic effects by dexborneol, a neuroprotective bicyclic monoterpenoid compound. We performed animal experiments where pain models were induced using two methods: peripheral nerve injury, involving axotomy and ligation of the tibial and common peroneal nerves, and incisional pain through a longitudinal incision in the hind paw, while employing a multifaceted methodology that integrates behavioral pharmacology, molecular biology, neuromorphology, and lipidomics to delve into the mechanisms behind this potentiation. Dexborneol was found to enhance pregabalin's efficacy by promoting its transportation to the central nervous system, disrupting self-amplifying vicious cycles via the reduction of HMGB1 and ATP release, and exerting significant anti-oxidative effects through modulation of central lipid metabolism. This combination therapy not only boosted pregabalin's analgesic property but also notably decreased its side effects. Moreover, this therapeutic cocktail exceeded basic pain relief, effectively reducing neuroinflammation and glial cell activation-key factors contributing to persistent and chronic pain. This study paves the way for more tolerable and effective analgesic options, highlighting the potential of dexborneol as an adjuvant to pregabalin therapy.

Acupuncture Modulation of Chronic Neuropathic Pain and Its Association With Brain Functional Properties

Chronic neuropathic pain has been one of the prominent causes of disability, and acupuncture has shown promise in treatment. The present study aimed to characterize acupuncture modulation of chronic neuropathic pain and explore the related functional brain changes. Sixty chronic sciatica patients were divided into acupuncture- or sham acupuncture groups and received 10 sessions of treatment during 4 weeks. The visual analog scale for leg pain, oswestry disability index (ODI), and resting-state functional magnetic resonance images were assessed at baseline and after treatment. Then, fractional amplitudes of low-frequency fluctuations (fALFF) and support vector regression analyses were performed. Compared with sham acupuncture, acupuncture significantly improved symptoms, including visual analog scale for leg pain and ODI. In addition, acupuncture exhibited increased fALFF of the right superior parietal lobule (SPL) and right postcentral gyrus. Furthermore, the actual 4-week ODI values were positively correlated with the support vector regression-predicted values based on the right SPL fALFF and baseline clinical measurements. These results indicate that the spontaneous neural activity of the right SPL and right postcentral gyrus may be involved in the modulation of acupuncture in chronic neuropathic pain. In addition, the spontaneous neural activity of the right SPL might be used as the predictor of response to acupuncture therapy. PerspectiveThis clinical neuroimaging study elucidated the neural basis of acupuncture in chronic sciatica. Neurological indicators and clinical measurements could be used as potential predictors of acupuncture response. This study combines neuroimaging and artificial intelligence techniques to highlight the potential of acupuncture for the treatment of chronic neuropathic pain. Trial registration numberChinese Clinical Trial Registry, ChiCTR2100044585, http://www.chictr.org.cn.

Improvements in Therapy Experience with Evoked Compound Action Potential Controlled, Closed-Loop Spinal Cord Stimulation – Primary Outcome of the ECHO-MAC Randomized Clinical Trial

Spinal cord stimulation (SCS) is a well-established treatment for chronic neuropathic pain. However, over- or under-delivery of the SCS may occur because the spacing between the stimulating electrodes and the spinal cord is not fixed; spacing changes with motion and postural shifts may result in variable delivery of the SCS dose, and in turn a sub-optimal therapy experience for the patient. The evoked compound action potential (ECAP)—a measure of neural activation — may be used as a control signal to adapt SCS parameters in real-time to compensate for this variability. In this prospective, multicenter, randomized, single-blind, crossover trial, reduction in overstimulation intensity was used as a perceptual measure to evaluate a novel ECAP-controlled, closed-loop (CL) SCS algorithm relative to traditional open-loop (OL) SCS. The primary outcome used a Likert scale to assess sensation during activities of daily living with CL versus OL SCS. Of the 42 subjects in the Intent-to-Treat Analysis set, 97.6% had a reduction in sensation with CL versus OL SCS. The primary objective was met as the lower confidence limit (87.4%) exceeded the performance goal of 50% (p < 0.001). A total of 88.1% (37/42) of subjects preferred CL and 11.9% (5/42) preferred OL SCS. SCS dose consistency during CL SCS was demonstrated by the reduced variability in ECAP amplitude with CL SCS (SD: 8.72 µV) relative to OL SCS (SD: 19.95 µV). Together, these results demonstrate that the ECAP-controlled, CL algorithm reduces or eliminates unwanted sensation, and thereby provides a more preferred and consistent SCS experience. PerspectivePatients with chronic pain need durable and dependable options for pain relief. SCS is an important therapy option, and new technology advancements could improve long-term therapy use. Closed-loop SCS offers a preferred and more consistent therapy experience for patients that could lead to increased therapy utilization and reliable therapy outcomes.

Pharmacokinetic Modeling of the Effect of Tariquidar on Ondansetron Disposition into the Central Nervous System

PurposeSerotonin (5-HT3) receptor antagonists are promising agents for treatment of neuropathic pain. However, insufficient drug exposure at the central nervous system (CNS) might result in lack of efficacy. The goal of this study was to evaluate the impact of administration of a Pgp inhibitor (tariquidar) on ondansetron exposure in the brain, spinal cord, and cerebrospinal fluid in a wild-type rat model.MethodsOndansetron (10 mg/kg) and tariquidar (7.5 mg/kg) were administered intravenously, plasma and tissue samples were collected and analyzed by HPLC. A mathematical model with brain, spinal cord, cerebrospinal fluid and two systemic disposition compartments was developed to describe the data.ResultsThe results demonstrate that tariquidar at 7.5 mg/kg resulted in a complete inhibition of Pgp efflux of ondansetron in the brain and spinal cord. The compartmental model successfully captured pharmacokinetics of ondansetron in wild type and Pgp knockout (KO) animals receiving the drug alone or in wild type animals receiving the ondansetron and tariquidar combination.ConclusionsThe study provided important quantitative information on enhancement of CNS exposure to ondansetron using co-administration of Pgp Inhibitor in a rat model, which will be further utilized in conducting a clinical study. Tariquidar co-administration resulted in ondansetron CNS exposure comparable to observed in Pgp KO rats. Results also highlighted the effect of tariquidar on plasma disposition of ondansetron, which may not be dependent on Pgp inhibition, and should be evaluated in future studies.

Evaluation of the Therapeutic Potential of Amantadine in a Vincristine-Induced Peripheral Neuropathy Model in Rats.

This study aimed to evaluate the therapeutic potential of amantadine in a vincristine-induced peripheral neuropathy model in rats. Forty-eight male Wistar rats were used. The treated groups received oral amantadine at doses of 2, 5, 12, 25 and 50 mg/kg, with daily applications for 14 days. The mechanical paw withdrawal threshold was measured using a digital analgesimeter. Immunohistochemical analysis of IL-6, TNFα, MIP1α, IL-10, CX3CR1, CXCR4, SOD, CAT and GPx, and enzymatic activity analysis of CAT, SOD and GPx were performed, in addition to quantitative PCR of Grp78, Chop, Ho1, Perk, Bax, Bcl-xL, Casp 3, Casp 9, IL-6, IL-10, IL-18 and IL-1β. The results showed an increase in nociceptive thresholds in animals that received 25 mg/kg and 50 mg/kg amantadine. Immunohistochemistry showed a decrease in the immunostaining of IL-6, TNFα, MIP1α and CX3CR1, and an increase in IL-10. CAT and SOD showed an increase in both immunochemistry and enzymatic analysis. qPCR revealed a reduced expression of genes related to endoplasmic reticulum stress and regulation in the expression of immunological and apoptotic markers. Amantadine demonstrated antinociceptive, anti-inflammatory and antioxidant effects in the vincristine-induced peripheral neuropathy model in rats, suggesting that amantadine may be considered an alternative approach for the treatment of vincristine-induced peripheral neuropathic pain.

Sex-Gender Differences Are Completely Neglected in Treatments for Neuropathic Pain.

As sex-gender differences have been described in the responses of patients to certain medications, we hypothesized that the responses to medications recommended for neuropathic pain may differ between men and women. We conducted a literature review to identify articles reporting potential sex-gender differences in the efficacy and safety of these medications. Only a limited number of studies investigated potential sex-gender differences. Our results show that women seem to achieve higher blood concentrations than men during treatment with amitriptyline, nortriptyline, duloxetine, venlafaxine, and pregabalin. Compared to men, higher rates of women develop side effects during treatment with gabapentin, lidocaine, and tramadol. Globally, the sex-gender differences would suggest initially administering smaller doses of these medications to women with neuropathic pain compared to those administered to men. However, most of these differences have been revealed by studies focused on the treatment of other diseases (e.g., depression). Studies focused on neuropathic pain have overlooked potential sex-gender differences in patient responses to medications. Despite the fact that up to 60% of patients with neuropathic pain fail to achieve an adequate response to medications, the potential role of sex-gender differences in the efficacy and safety of pharmacotherapy has not adequately been investigated. Targeted studies should be implemented to facilitate personalized treatments for neuropathic pain.