Neuropathic Pain: From Mechanisms to Treatment.

Neuropathic pain caused by a lesion or disease of the somatosensory nervous system is a common chronic pain condition with major impact on quality of life. Examples include trigeminal neuralgia, painful polyneuropathy, postherpetic neuralgia, and central poststroke pain. Most patients complain of an ongoing or intermittent spontaneous pain of, for example, burning, pricking, squeezing quality, which may be accompanied by evoked pain, particular to light touch and cold. Ectopic activity in, for example, nerve-end neuroma, compressed nerves or nerve roots, dorsal root ganglia, and the thalamus may in different conditions underlie the spontaneous pain. Evoked pain may spread to neighboring areas, and the underlying pathophysiology involves peripheral and central sensitization. Maladaptive structural changes and a number of cell-cell interactions and molecular signaling underlie the sensitization of nociceptive pathways. These include alteration in ion channels, activation of immune cells, glial-derived mediators, and epigenetic regulation. The major classes of therapeutics include drugs acting on α2δ subunits of calcium channels, sodium channels, and descending modulatory inhibitory pathways.

Identification and targeting of a unique NaV1.7 domain driving chronic pain.

Small molecules directly targeting the voltage-gated sodium channel (VGSC) NaV1.7 have not been clinically successful. We reported that preventing the addition of a small ubiquitin-like modifier onto the NaV1.7-interacting cytosolic collapsin response mediator protein 2 (CRMP2) blocked NaV1.7 function and was antinociceptive in rodent models of neuropathic pain. Here, we discovered a CRMP2 regulatory sequence (CRS) unique to NaV1.7 that is essential for this regulatory coupling. CRMP2 preferentially bound to the NaV1.7 CRS over other NaV isoforms. Substitution of the NaV1.7 CRS with the homologous domains from the other eight VGSC isoforms decreased NaV1.7 currents. A cell-penetrant decoy peptide corresponding to the NaV1.7-CRS reduced NaV1.7 currents and trafficking, decreased presynaptic NaV1.7 expression, reduced spinal CGRP release, and reversed nerve injury-induced mechanical allodynia. Importantly, the NaV1.7-CRS peptide did not produce motor impairment, nor did it alter physiological pain sensation, which is essential for survival. As a proof-of-concept for a NaV1.7 -targeted gene therapy, we packaged a plasmid encoding the NaV1.7-CRS in an AAV virus. Treatment with this virus reduced NaV1.7 function in both rodent and rhesus macaque sensory neurons. This gene therapy reversed and prevented mechanical allodynia in a model of nerve injury and reversed mechanical and cold allodynia in a model of chemotherapy-induced peripheral neuropathy. These findings support the conclusion that the CRS domain is a targetable region for the treatment of chronic neuropathic pain.

High-Frequency Spinal Stimulation Suppresses Microglial Kaiso-P2X7 Receptor Axis-Induced Inflammation to Alleviate Neuropathic Pain in Rats.

OBJECTIVE: Neuropathic pain poses a persistent challenge in clinical management. Neuromodulation has emerged as a last-resort therapy. Conventional spinal cord stimulation (Con SCS) often causes abnormal sensations and provides short analgesia, whereas high-frequency spinal cord stimulation (HF SCS) is a newer therapy that effectively alleviates pain without paresthesia. However, the modes of action of 10kHz HF SCS (HF10 SCS) in pain relief remain unclear. To bridge this knowledge gap, we employed preclinical models that mimic certain features of clinical SCS to explore the underlying mechanisms of HF10 SCS. Addressing these issues would provide the scientific basis for improving and evaluating the effectiveness, reliability, and practicality of different frequency SCS in clinical settings. METHODS: We established a preclinical SCS model to examine its effects in a neuropathic pain rat model. We conducted bulk and single-cell RNA sequencing in the spinal dorsal horn (SDH) to examine cellular and molecular changes under different treatments. We employed genetic manipulations through intrathecal injection of a lentiviral system to explore the SCS-mediated signaling axis in pain. Various behavioral tests were performed to evaluate pain conditions under different treatments. RESULTS: We found that HF10 SCS significantly reduces immune responses in the SDH by inactivating the Kaiso-P2X7R pathological axis in microglia, promoting long-lasting pain relief. Targeting Kaiso-P2X7R in microglia dramatically improved efficacy of Con SCS treatment, leading to reduced neuroinflammation and long-lasting pain relief. INTERPRETATION: HF10 SCS could improve the immunopathologic state in the SDH, extending its benefits beyond symptom relief. Targeting the Kaiso-P2X7R axis may enhance Con SCS therapy and offer a new strategy for pain management. ANN NEUROL 2024;95:966-983.

Targeted ubiquitination of sensory neuron calcium channels reduces the development of neuropathic pain.

Neuropathic pain caused by lesions to somatosensory neurons due to injury or disease is a widespread public health problem that is inadequately managed by small-molecule therapeutics due to incomplete pain relief and devastating side effects. Genetically encoded molecules capable of interrupting nociception have the potential to confer long-lasting analgesia with minimal off-target effects. Here, we utilize a targeted ubiquitination approach to achieve a unique posttranslational functional knockdown of high-voltage-activated calcium channels (HVACCs) that are obligatory for neurotransmission in dorsal root ganglion (DRG) neurons. CaV-aßlator comprises a nanobody targeted to CaV channel cytosolic auxiliary ß subunits fused to the catalytic HECT domain of the Nedd4-2 E3 ubiquitin ligase. Subcutaneous injection of adeno-associated virus serotype 9 encoding CaV-aßlator in the hind paw of mice resulted in the expression of the protein in a subset of DRG neurons that displayed a concomitant ablation of CaV currents and also led to an increase in the frequency of spontaneous inhibitory postsynaptic currents in the dorsal horn of the spinal cord. Mice subjected to spare nerve injury displayed a characteristic long-lasting mechanical, thermal, and cold hyperalgesia underlain by a dramatic increase in coordinated phasic firing of DRG neurons as reported by in vivo Ca2+ spike recordings. CaV-aßlator significantly dampened the integrated Ca2+ spike activity and the hyperalgesia in response to nerve injury. The results advance the principle of targeting HVACCs as a gene therapy for neuropathic pain and demonstrate the therapeutic potential of posttranslational functional knockdown of ion channels achieved by exploiting the ubiquitin-proteasome system.

Insular cortex stimulation alleviates neuropathic pain through changes in the expression of collapsin response mediator protein 2 involved in synaptic plasticity.

In recent studies, brain stimulation has shown promising potential to alleviate chronic pain. Although studies have shown that stimulation of pain-related brain regions can induce pain-relieving effects, few studies have elucidated the mechanisms of brain stimulation in the insular cortex (IC). The present study was conducted to explore the changes in characteristic molecules involved in pain modulation mechanisms and to identify the changes in synaptic plasticity after IC stimulation (ICS). Following ICS, pain-relieving behaviors and changes in proteomics were explored. Neuronal activity in the IC after ICS was observed by optical imaging. Western blotting was used to validate the proteomics data and identify the changes in the expression of glutamatergic receptors associated with synaptic plasticity. Experimental results showed that ICS effectively relieved mechanical allodynia, and proteomics identified specific changes in collapsin response mediator protein 2 (CRMP2). Neuronal activity in the neuropathic rats was significantly decreased after ICS. Neuropathic rats showed increased expression levels of phosphorylated CRMP2, alpha amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor (AMPAR), and N-methyl-d-aspartate receptor (NMDAR) subunit 2B (NR2B), which were inhibited by ICS. These results indicate that ICS regulates the synaptic plasticity of ICS through pCRMP2, together with AMPAR and NR2B, to induce pain relief.

GT1b functions as a novel endogenous agonist of toll-like receptor 2 inducing neuropathic pain.

Spinal cord microglia contribute to nerve injury-induced neuropathic pain. We have previously demonstrated that toll-like receptor 2 (TLR2) signaling is critical for nerve injury-induced activation of spinal cord microglia, but the responsible endogenous TLR2 agonist has not been identified. Here, we show that nerve injury-induced upregulation of sialyltransferase St3gal2 in sensory neurons leads to an increase in expression of the sialylated glycosphingolipid, GT1b. GT1b ganglioside is axonally transported to the spinal cord dorsal horn and contributes to characteristics of neuropathic pain such as mechanical and thermal hypersensitivity. Spinal cord GT1b functions as an TLR2 agonist and induces proinflammatory microglia activation and central sensitization. Pharmacological inhibition of GT1b synthesis attenuates nerve injury-induced spinal cord microglia activation and pain hypersensitivity. Thus, the St3gal2-GT1b-TLR2 axis may offer a novel therapeutic target for the treatment of neuropathic pain.

Electroacupuncture Ameliorates Depression-Like Behaviors Comorbid to Chronic Neuropathic Pain via Tet1-Mediated Restoration of Adult Neurogenesis.

Although electroacupuncture (EA) stimulation is a widely used therapy for chronic pain and comorbid psychiatric disorders, its long-term effects on chronic neuropathic pain-induced depression and the underlying mechanisms remain elusive. In the present study, we found that EA stimulation was able to restore adult neurogenesis in the ventral dentate gyrus (DG), by both increasing neuronal differentiation and restoring the normal morphology of newborn dendrites, in mice with spared nerve injury surgery. By ablating the Nestin+ neural stem cells (NSCs) via diphtheria toxin fragment A expression, we further proved that neurogenesis in the ventral DG was crucial to the long-term, but not the immediate antidepressant effect of EA, nor was it associated with nociception. Furthermore, we found that the restoration of neurogenesis was dependent on Tet1-mediated epigenetic modification upon EA treatment. Tet1 could bind to the promoter of the Prox1 gene, thus catalyzing its demethylation and facilitating its expression, which finally contributed to the restoration of neurogenesis and amelioration of depression-like behaviors induced by chronic neuropathic pain. Thus, we conclude that EA stimulation restores inhibited Tet1 expression in hippocampal NSCs of mice with chronic neuropathic pain, and increased Tet1 expression ameliorates hypermethylation of Prox1 and restores normal adult neurogenesis in the ventral DG, which contributes to the long-term antidepressant effect of EA.

An extract of phase II and III trials on recent developments in managing neuropathic pain syndromes: diabetic peripheral neuropathy, trigeminal neuralgia, and postherpetic neuralgia.

INTRODUCTION: Neuropathic pain (NP) conditions involve lesions to the somatosensory nervous system leading to chronic and debilitating pain. Many patients suffering from NP utilize pharmacological treatments with various drugs that seek to reduce pathologic neuronal states. However, many of these drugs show poor efficacy as well as cause significant adverse effects. Because of this, there is a major need for the development of safer and more efficacious drugs to treat NP. AREAS COVERED: In this review, we analyzed current treatments being developed for a variety of NP conditions. Specifically, we sought drugs in phase II/III clinical trials with indications for NP conditions. Various databases were searched including Google Scholar, PubMed, and clinicaltrials.gov. EXPERT OPINION: All the mentioned targets for treatments of NP seem to be promising alternatives for existing treatments that often possess poor side effect profiles for patients. However, gene therapy potentially offers the unique ability to inject a plasmid containing growth factors leading to nerve growth and repair. Because of this, gene therapy appears to be the most intriguing new treatment for NP.

A sensory neuron-specific long non-coding RNA reduces neuropathic pain by rescuing KCNN1 expression.

Nerve injury to peripheral somatosensory system causes refractory neuropathic pain. Maladaptive changes of gene expression in primary sensory neurons are considered molecular basis of this disorder. Long non-coding RNAs (lncRNAs) are key regulators of gene transcription; however, their significance in neuropathic pain remains largely elusive.Here, we reported a novel lncRNA, named sensory neuron-specific lncRNA (SS-lncRNA), for its expression exclusively in dorsal root ganglion (DRG) and trigeminal ganglion. SS-lncRNA was predominantly expressed in small DRG neurons and significantly downregulated due to a reduction of early B cell transcription factor 1 in injured DRG after nerve injury. Rescuing this downregulation reversed a decrease of the calcium-activated potassium channel subfamily N member 1 (KCNN1) in injured DRG and alleviated nerve injury-induced nociceptive hypersensitivity. Conversely, DRG downregulation of SS-lncRNA reduced the expression of KCNN1, decreased total potassium currents and afterhyperpolarization currents and increased excitability in DRG neurons and produced neuropathic pain symptoms.Mechanistically, downregulated SS-lncRNA resulted in the reductions of its binding to Kcnn1 promoter and heterogeneous nuclear ribonucleoprotein M (hnRNPM), consequent recruitment of less hnRNPM to the Kcnn1 promoter and silence of Kcnn1 gene transcription in injured DRG.These findings indicate that SS-lncRNA may relieve neuropathic pain through hnRNPM-mediated KCNN1 rescue in injured DRG and offer a novel therapeutic strategy specific for this disorder.

Non-pharmacological management of neuropathic pain in older adults: a systematic review.

INTRODUCTION: Neuropathic pain encompasses multiple diagnoses with detrimental impacts on quality of life and overall health. In older adults, pharmacological management is limited by adverse effects and drug interactions, while surgical management involves perioperative risk. Prior reviews addressing non-pharmacological interventions for neuropathic pain have not focused on this demographic. Therefore, this systematic review synthesizes the evidence regarding the effectiveness of non-pharmacological interventions in reducing neuropathic pain severity in older adults. METHODS: PubMed, CINAHL, Web of Science, and PsycInfo were searched using key terms, with inclusion criteria of age ≥ 65, neuropathic pain, non-pharmacological intervention, pain severity measurement, English language, peer-reviewed, and either randomized controlled trial (RCT) or quasi-experimental design. In total, 2759 records were identified, with an additional 28 records identified by review of reference lists. After removal of duplicates, 2288 records were screened by title and abstract, 404 full-text articles were assessed, and 19 articles were critically reviewed and synthesized. RESULTS: Of the 14 RCTs and 5 quasi-experimental studies included in the review, the most common intervention was electric and/or magnetic therapy, followed by acupuncture, mindfulness meditation, exercise, and light therapy. Several studies revealed both statistical and clinical significance, but conclusions were limited by small sample sizes and methodological shortcomings. The interventions were generally safe and acceptable. CONCLUSIONS: Results should be interpreted with consideration of clinical vs statistical significance, mediators of pain severity, and individual variations in effectiveness. Further research should address multimodal and novel interventions, newer models of care, and technology-based interventions.

Effectiveness of combined dorsal root ganglion and spinal cord stimulation: a retrospective, single-centre case series for chronic focal neuropathic pain.

OBJECTIVE: This case series retrospectively reviewed the outcomes in patients implanted with combined, synchronous dorsal root ganglion stimulation (DRGS) and spinal cord stimulation (SCS) connected to a single implantable pulse generator (IPG) in a tertiary referral neuromodulation centre in the United Kingdom. METHODS: Twenty-six patients underwent a trial of DRGS+SCS for treating focal neuropathic pain between January 2016 and December 2019, with a follow-up in February 2022. A Transgrade approach was employed for DRGS. Patients were provided with 3 possible stimulation programs: DRGS-only, SCS-only, or DRGS+SCS. Patients were assessed for pain intensity, patients' global impression of change (PGIC), preferred lead(s) and complications. RESULTS: Twenty patients were successful and went on for full implantation. The most common diagnosis was Complex Regional Pain Syndrome. After an average of 3.1 years follow-up, 1 patient was lost to follow-up, and 2 were non-responders. Of the remaining 17 patients, 16 (94%) continued to report a PGIC of 7. The average pain intensity at Baseline was 8.5 on an NRS scale of 0-10. At the last follow-up, the average NRS reduction overall was 78.9% with no statistical difference between those preferring DRGS+SCS (n = 9), SCS-only (n = 3) and DRGS-only (n = 5). The combination of DRGS+SCS was preferred by 53% at the last follow-up. There were no serious neurological complications. CONCLUSIONS: This retrospective case series demonstrates the potential effectiveness of combined DRGS+SCS with sustained analgesia observed at an average follow-up of over 3 years. Implanting combined DRGS+SCS may provide programming flexibility and therapeutic alternatives.

Psychologically based interventions for adults with chronic neuropathic pain: a scoping review.

OBJECTIVE: As psychologically based interventions have been shown to have clinical utility for adults with chronic pain generally, a similar benefit might be expected in the management of chronic neuropathic pain (NeuP). However, to date, this has not been established, with existing systematic reviews on this topic being hampered by the scarcity of randomized controlled trials (RCTs). This review aimed to identify the type of psychologically based interventions studied for adults with chronic NeuP. It also aimed to assess whether there are enough RCTs to justify undertaking an updated systematic review. METHODS: Seven databases and 2 clinical trial registries were searched for NeuP and psychologically based interventions from database inception to December 2021, and the search was updated in February 2023. The search was broadened by reviewing the reference list of included studies and contacting field experts. Predetermined study characteristics were extracted. RESULTS: Of 4682 records screened, 33 articles (less than 1%) met the eligibility criteria. Four broad intervention approaches were observed, including cognitive-behavioral approaches (n = 16), mindfulness/meditation (n = 10), trauma-focused therapy (n = 4), and hypnosis (n = 3). Thirteen RCTs were identified, and of these, 9 retained 20 participants in each arm after treatment. CONCLUSIONS: Cognitive-behavioral therapy was the most common therapeutic approach identified, whereas mindfulness/meditation was the most frequently used technique. Almost half to two-thirds of the studies reported significant improvements in pain, disability, or distress, which suggests that psychologically based interventions are potentially beneficial for adults with chronic NeuP. An updated systematic review seems warranted. STUDY REGISTRATION: Open Science Framework (https://osf.io) (December 6, 2021; DOI: 10.17605/OSF.IO/WNSTM).

Efficacy of transauricular vagus nerve stimulation for the treatment of chemotherapy-induced painful peripheral neuropathy: a randomized controlled exploratory study.

BACKGROUND: Chemotherapy-induced painful peripheral neuropathy (CIPN) is a common adverse event in cancer patients, and there is still a lack of effective treatment. Transauricular vagal nerve stimulation (taVNS) is a minimally invasive treatment, but there are few reports regarding its efficacy for CIPN. OBJECTIVE: To investigate the efficacy and possible mechanism of taVNS in patients with CIPN. METHODS: Twenty-seven patients with CIPN were randomly divided into a taVNS group (n = 14) and a sham stimulation (SS) group (n = 13). A numerical rating scale (NRS) for pain, NCICTCAE 4.0 (neurotoxicity classification), quantitative sensory test (QST), Short-Form-Health Survey-12 (SF-12), and Athens Insomnia Scale (AIS) were administered before the intervention (D-10) and on the day after the intervention (D0), and the inflammatory cytokines in plasma were also measured. The NRS, NCI-CTCAE 4.0, SF-12, and AIS were administered again at D30 and D90. RESULTS: Compared with the SS group, the NRS and AIS in the taVNS group were significantly lower at D0. The impact lasted until D30. There were no statistically significant differences in the NRS and AIS between the 2 groups at D90. On D30, the mental component score of the SF-12 was significantly higher in the taVNS group than in the SS group. No adverse events were found. There was no significant difference in QST and plasma inflammatory cytokines between the 2 groups. CONCLUSION: taVNS can relieve chemotherapy-induced neuropathic pain in the short term, can improve sleep status and quality of life, and is expected to become a novel clinical treatment method for CIPN.

Effects of Computer-based Balance Exercises on Balance, Pain, Clinical Presentation and Nerve Function in Patients With Diabetic Peripheral Neuropathy: A Randomized Controlled Study.

OBJECTIVE: To evaluate the use of a computer-based biodex balance exercise system (BBS) on balance, neuropathic pain, clinical presentation and nerve function in patients with diabetic peripheral neuropathy (DPN). METHODS: A total of 32 participants with DPN were randomly assigned in a 1:1 ratio to an intervention group (IG) or control group (CG). The IG performed exercises using the BBS twice weekly for 8 weeks, while CG were informed regarding diabetes self-management. At baseline and after study completion, participants underwent balance (postural stability and fall risk) and neuropathic pain assessment (DN4 questionnaire) and were screened using the Michigan Neuropathy Screening Instrument and nerve conduction test. RESULTS: Among the baseline participants, 14 in the IG and 13 in the CG completed the study. Balance training improved postural stability (overall, p<0.001), fall risk (p<0.001), neuropathic pain (p=0.01) and symptoms (p<0.001), and clinical presentation (p=0.02), but not nerve function, within the IG. At follow-up, IG displayed significantly improved stability (p<0.001) and fall risk (p=0.02) and decreased neuropathic symptoms (p=0.01) compared to the CG. CONCLUSION: Computer-based balance exercises improve balance, pain, and clinical presentation of DPN, but not nerve function, in patients with DPN. CLINICALTRIALS: gov ID: NCT05255497.

Prevalence and Management of Chronic Pain, Including Neuropathic Pain, in Dialysis Patients with End-Stage Renal Disease.

BACKGROUND Chronic kidney disease (CKD) is a growing global health concern. Chronic pain, as a common symptom of CKD, particularly among patients with end-stage renal disease (ESRD), is influenced by complications, dialysis procedures, and comorbidities. We aimed to evaluate chronic pain and probable neuropathic pain in 96 dialysis patients with ESRD using the Douleur Neuropathique 4 (DN4) questionnaire. MATERIAL AND METHODS A total of 96 patients from a single dialysis center were enrolled for the purpose of this study. ESRD was caused by diseases causing kidney damage, such as diabetes. The average duration of maintenance dialysis was 4.6±5.67 years. Comorbidities, functional and mental assessment, and pharmacological treatment data were collected using a questionnaire. The satisfaction with life scale was also used. Chronic pain was defined as lasting more than 3 months. The DN4 was used to determine the neuropathic component of pain. RESULTS Chronic pain was observed in 63.5% of the study participants, with 47.5% of them reporting the presence of neuropathic pain accompanied by a neuropathic component. Significantly more patients with chronic pain reported mood disorders and reduced life satisfaction, but there was no difference in their activities of daily living-assessed functional status or duration of dialysis. Patients experiencing chronic pain received non-steroidal anti-inflammatory drugs, paracetamol, and opioids. CONCLUSIONS Chronic pain, especially with a neuropathic component, is highly prevalent in patients with CKD, and its treatment remains ineffective. Undiagnosed components of pain can contribute to underdiagnosis and inadequate therapy. Further studies and staff education are needed to address this important issue.

Electroacupuncture attenuates neuropathic pain via suppressing BIP-IRE-1α-mediated endoplasmic reticulum stress in the anterior cingulate cortex.

Studies have suggested that endoplasmic reticulum stress (ERS) is involved in neurological dysfunction and that electroacupuncture (EA) attenuates neuropathic pain (NP) via undefined pathways. However, the role of ERS in the anterior cingulate cortex (ACC) in NP and the effect of EA on ERS in the ACC have not yet been investigated. In this study, an NP model was established by chronic constriction injury (CCI) of the left sciatic nerve in rats, and mechanical and cold tests were used to evaluate behavioral hyperalgesia. The protein expression and distribution were evaluated using western blotting and immunofluorescence. The results showed that glucose-regulated protein 78 (BIP) and inositol-requiring enzyme 1α (IRE-1α) were co-localized in neurons in the ACC. After CCI, BIP, IRE-1α, and phosphorylation of IRE-1α were upregulated in the ACC. Intra-ACC administration of 4-PBA and Kira-6 attenuated pain hypersensitivity and downregulated phosphorylation of IRE-1α, while intraperitoneal injection of 4-PBA attenuated hyperalgesia and inhibited the activation of P38 and JNK in ACC. In contrast, ERS activation by intraperitoneal injection of tunicamycin induced behavioral hyperalgesia in naive rats. Furthermore, EA attenuated pain hypersensitivity and inhibited the CCI-induced overexpression of BIP and pIRE-1α. Taken together, these results demonstrate that EA attenuates NP by suppressing BIP- and IRE-1α-mediated ERS in the ACC. Our study presents novel evidence that ERS in the ACC is implicated in the development of NP and provides insights into the molecular mechanisms involved in the analgesic effect of EA.

Literature Review: Mechanism, Indications, and Clinical Efficacy of Peripheral Nerve Stimulators in Lower Extremity Pain.

PURPOSE OF REVIEW: Lower extremity pain is deemed by Center for Disease Control and Prevention (CDC) to be a significant source of chronic pain in adults. If not appropriately managed, patients are subjected to risks of prolonged musculoskeletal dysfunction, disruption to quality of life, and elevated healthcare expenditures. Peripheral nerve stimulation (PNS) has shown great potential in recent years demonstrating efficacy in multiple diagnoses ranging from acute post-surgical pain to complex regional pain syndrome (CRPS). This study seeks to delineate efficacy of peripheral neuromodulation in the context of chronic lower extremity pain. RECENT FINDINGS: Prevailing clinical studies demonstrate evidence levels ranging from II to V (Oxford Centre of Level of Evidence) in lower limb PNS, attaining positive outcomes in pain scores, opioid use, and quality of life measures. Nerves most frequently targeted are the sciatic and femoral nerves with post-amputation pain and CRPS most commonly investigated for efficacy. PNS is a promising therapeutic modality demonstrated to be effective for a variety of nociceptive and neuropathic pain conditions in the lower extremity. PNS offers chronic pain physicians a powerful tool in the multi-modal management of lower limb chronic pain.

Recent Advances in Management of Neuropathic, Nociceptive, and Chronic Pain: A Narrative Review with Focus on Nanomedicine, Gene Therapy, Stem Cell Therapy, and Newer Therapeutic Options.

PURPOSE OF REVIEW: This manuscript summarizes novel clinical and interventional approaches in the management of chronic, nociceptive, and neuropathic pain. RECENT FINDINGS: Pain can be defined as a feeling of physical or emotional distress caused by an external stimulus. Pain can be grouped into distinct types according to characteristics including neuropathic pain, which is a pain caused by disease or lesion in the sensory nervous system; nociceptive pain, which is pain that can be sharp, aching, or throbbing and is caused by injury to bodily tissues; and chronic pain, which is long lasting or persisting beyond 6 months. With improved understanding of different signaling systems for pain in recent years, there has been an upscale of methods of analgesia to counteract these pathological processes. Novel treatment methods such as use of cannabinoids, stem cells, gene therapy, nanoparticles, monoclonal antibodies, and platelet-rich plasma have played a significant role in improved strategies for therapeutic interventions. Although many management options appear to be promising, extensive additional clinical research is warranted to determine best practice strategies in the future for clinicians.

Platelet-rich plasma alleviates neuropathic pain in osteoarthritis by downregulating microglial activation.

BACKGROUND: The development of neuropathic pain (NP) is one of the reasons why the pain is difficult to treat, and microglial activation plays an important role in NP. Recently, platelet-rich plasma (PRP) has emerged as a novel therapeutic method for knee osteoarthritis (KOA). However, it's unclarified whether PRP has analgesic effects on NP induced by KOA and the underlying mechanisms unknown. PURPOSE: To observe the analgesic effects of PRP on NP induced by KOA and explore the potential mechanisms of PRP in alleviating NP. METHODS: KOA was induced in male rats with intra-articular injections of monosodium iodoacetate (MIA) on day 0. The rats received PRP or NS (normal saline) treatment at days 15, 17, and 19 after modeling. The Von Frey and Hargreaves tests were applied to assess the pain-related behaviors at different time points. After euthanizing the rats with deep anesthesia at days 28 and 42, the corresponding tissues were taken for subsequent experiments. The expression of activating transcription factor 3 (ATF3) in dorsal root ganglia (DRG) and ionized-calcium-binding adapter molecule-1(Iba-1) in the spinal dorsal horn (SDH) was detected by immunohistochemical staining. In addition, the knee histological assessment was performed by hematoxylin-eosin (HE) staining. RESULTS: The results indicated that injection of MIA induced mechanical allodynia and thermal hyperalgesia, which could be reversed by PRP treatment. PRP downregulated the expression of ATF3 within the DRG and Iba-1 within the SDH. Furthermore, an inhibitory effect on cartilage degeneration was observed in the MIA + PRP group only on day 28. CONCLUSION: These results indicate that PRP intra-articular injection therapy may be a potential therapeutic agent for relieving NP induced by KOA. This effect could be attributed to downregulation of microglial activation and reduction in nerve injury.

Current trends in the medical treatment of neuropathic low back pain: a Swedish registry-based study of 1.7 million people.

BACKGROUND: Low back pain, a common problem worldwide, causes more global disability than any other condition and is associated with high costs to society. This observational registry-based study describes the current trends in the medical treatment of neuropathic low back pain in the Swedish region of Västra Götaland, which has a population of 1.7 million. The study aims to; (1) identify the prevalence of neuropathic low back pain within the study population; (2) to explore the patterns of medical treatment utilization, including the prevalence and distribution of opioids (OG) and analgesics specified for neuropathic low back pain (NG) and (3) to evaluate the long-term trends and changes in medical treatment practice for neuropathic low back pain over the study period. METHODS: This study includes a descriptive analysis of aggregated data extracted from the Swedish primary care registry VEGA and the pharmaceutical prescription registry Digitalis between the years 2017 and 2021. The data were stratified by year, age, gender, pharmaceutical code (ATC), and sub-diagnoses and presented as the prevalence of unique patients retrieving prescribed medication within six months before or after a registered diagnosis of neuropathic low back pain. The pharmaceutical codes were furthermore grouped into two groups depending on their mechanism of action; opioid group (OG) and neuropathic group (NG). RESULTS: In all four diagnosis groups, more patients used opioid analgesics than neuropathic analgesics. The greatest difference between the opioid group and neuropathic group was in the lumbar spinal stenosis diagnosis group (67.1% vs. 40.6%), followed by the lumbar root canal stenosis diagnosis (65.9% vs. 44.2%), the nerve root and plexus compressions in intervertebral disc disorders diagnosis (57.5% vs. 40.8%), and lumbago with sciatica diagnosis (38.4% vs. 22.7%). CONCLUSIONS: The trends suggest a general increase in the prescription rate and therefore patients' use of neuropathic analgesics for neuropathic pain associated with the studied diagnoses. However, opioid treatment remains the most common. The results indicate that the treatment for neuropathic low back pain needs to be improved.