Is the Capsaicin 179 mg (8% w/w) Cutaneous Patch an Appropriate Treatment Option for Older Patients with Peripheral Neuropathic Pain?

Introduction: Capsaicin 179 mg (8% weight per weight) cutaneous patch ("capsaicin patch") is a recommended topical treatment for peripheral neuropathic pain (PNP). In older patients, topical treatments may be preferred over systemic treatments, but data specific to the older population are scarce. Methods: We conducted pooled analyses of multiple clinical trials to evaluate efficacy and safety of capsaicin patch in older patients. The analysis of efficacy included four randomized, double-blind, 12-week studies with similar trial design comparing a single treatment of capsaicin 179 mg cutaneous patch vs low-dose control patch in post-herpetic neuralgia. For the safety evaluation, data were pooled from 18 interventional studies in which capsaicin patch was used in PNP with varying etiologies. Results: Capsaicin patch had similar analgesic efficacy in elderly (n=582) and non-elderly patients (n=545) in terms of change from baseline to 2-12 weeks in the 11-point numeric pain rating scale (NPRS) score for average pain over the previous 24 hours. In both age groups, decrease in NPRS score was significantly greater with capsaicin patch vs control. Older patients treated with capsaicin patch were significantly more likely than those in the control group to achieve responder status (ie mean decrease in NPRS score from baseline to week 2-12 of at least 30% or ≥2 points): 36.1% vs 27.1% (odds ratio [OR] [95% CI] 1.52 [1.06, 2.18]; P=0.0231) and 33.1% vs 20.9% (OR [95% CI] 1.90 [1.30, 2.78]; P=0.0009) for active treatment vs control group, respectively. Similar proportions of non-elderly patients (n=2,311) and elderly patients (n=537) treated with capsaicin patch experienced treatment-emergent adverse events (TEAEs) (81.6% and 78.1%, respectively) and serious TEAEs (8.2% and 7.2%), with application-site reactions the most common TEAEs in both groups. Conclusion: The capsaicin patch was equally efficacious and well tolerated in older patients as in younger patients.

Peripheral neuropathic pain is a common challenge among the elderly, yet effective treatments for this age group remain underexplored. This research focuses on the use of a high-concentration capsaicin patch, a specialized treatment for this type of pain. The patch, which is applied directly to the affected skin area, has been shown to reduce pain significantly for up to 12 weeks. This analysis of multiple clinical trials showed that the high-concentration capsaicin patch significantly reduced pain intensity and was well tolerated in older patients with peripheral neuropathic pain.

Modeling an evaluation of the efficacy of the novel neuroanalgesic drug mirogabalin for diabetic peripheral neuropathic pain and postherpetic neuralgia therapy.

Diabetic peripheral neuropathic pain (DPNP) and postherpetic neuralgia (PHN) are challenging and often intractable complex medical conditions, with a substantial impact on the quality of life. Mirogabalin, a novel voltage-gated Ca2+ channel α2δ ligand, was approved for the indication of DPNP and PHN. However, the time course of effects has not yet been clarified.We aimed to establish pharmacodynamic and placebo effect models of mirogabalin and pregabalin in DPNP and PHN, and to quantitatively compare the efficacy characteristics (maximum efficacy, onset time, and other pharmacodynamic parameters) and safety of mirogabalin and pregabalin. Public databases were comprehensively searched for randomized placebo-controlled clinical trials. A model-based meta-analysis (MBMA) was developed to describe the time course of drug efficacy and placebo effects. Adverse events were compared using a fixed-effects meta-analysis. Sixteen studies including 5,147 participants were eligible for this study. The placebo effect was relatively high and gradually increased with time, and it required at least eight weeks to reach a plateau. The pharmacodynamic model revealed that the maximum pure efficacy for mirogabalin and pregabalin was approximately -7.85% and -8.86%, respectively; the efficacy of mirogabalin to relieve DPNP and PHN was not superior to that of pregabalin, and both drugs had similar safety. While the rate constant of the onset rate of pregabalin was approximately thrice as high as that of mirogabalin. In addition, the baseline level of pain was an important factor affecting pregabalin efficacy. These findings are helpful in evaluating the clinical extension value of mirogabalin. They suggest that the high placebo effect and the baseline level of pain should be considered when grouping patients in future research and development of voltage-gated Ca2+ channel neuroanalgesic.

Transient Compression Injury Triggers Neuroinflammation in a New Rat Model of Acute Peripheral Neuropathic Pain.

BACKGROUND: Peripheral neuropathic pain (NeP), induced by surgical intervention, is a well-known complication or sequela that remains a clinical challenge with few effective treatments. Ideal animal models that can recapitulate surgery-associated NeP remain to be established for both mechanistic studies and drug discovery. OBJECTIVES: We aimed to establish a new rat model of postsurgical NeP and describe its characteristics, as well as screen-promising therapeutic analgesics. STUDY DESIGN: Experimental research in rats. SETTING: The research took place in the laboratory of Xinqiao Hospital of the Third Military Medical University. METHODS: To mimic the surgical procedure associated with peripheral nerve injury (PNI), we established a transient compression injury (TCI) in the sciatic nerve. Behavioral tests of nociception were used to confirm the effect and the time course of this pain model. Histological assessments (transmission electron microscopy evaluation and immunohistochemistry) were performed to observe the neuropathological and immunological features. RNA sequencing (RNA-seq) of injured nerves and dorsal root ganglia (DRGs) was conducted to reveal the underlying mechanism in the newly established animal model and screen promising therapeutic targets. RESULTS: We established a rat model of TCI of the PN and detected nociceptive hypersensitivity of the injured (ipsilateral) nerve by behavioral tests. This animal model of NeP was further confirmed by observing time-dependent changes in mechanical allodynia and thermal hyperalgesia, as well as by examining the activation of microglia in the ipsilateral spinal dorsal horn. Pathophysiologically, TCI induced macroscopic nerve swelling and demyelination, which resulted in inflammatory responses in ipsilateral nerves. We also found inflammatory cell infiltration in the ipsilateral nerve that was sustained for several weeks, which further exacerbated local inflammation and oxidative stress. Moreover, RNA-seq revealed remarkably upregulated inflammatory reactions in PNs and the DRGs. Notably, the overexpression of inflammatory mediators and the infiltration of macrophages and microglia triggered remote immune responses in DRGs. Based on the RNA-seq results, we also confirmed that gabapentin (GBP) exerts therapeutic effects in TCI-induced NeP by regulating alpha2delta-1. LIMITATIONS: We did not compare the new rat model with the classical pain model (like chronic constriction injury or spared nerve injury) in histology or transcriptomics. CONCLUSIONS: We established a new rat model of NeP and thoroughly characterized neuroinflammation in the injured nerve and DRGs. Based on the upregulated genes in DRGs in this model, we screened a promising analgesic (GBP) capable of reducing pain hypersensitivity in surgery-associated NeP.

A narrative review of pulsed radiofrequency for the treatment of carpal tunnel syndrome.

OBJECTIVE: Carpal tunnel syndrome (CTS), which is the most common peripheral nerve entrapment syndrome, can commonly persist despite conservative treatment modalities such as wrist splinting or medications. Pulsed radiofrequency represents a minimally invasive pain intervention technique to alleviate pain. The literature was reviewed to establish the effectiveness of PRF therapy for CTS. STUDY DESIGN: This is a narrative review of relevant articles on the effectiveness of PRF for CTS. METHOD: Four databases, MEDLINE, Cochrane Central Register of Controlled Trials, Embase, OVID Emcare, and Web of Science, were systematically searched. 804 records were screened, and the reference lists of eligible articles were examined. For this review, eight extracted studies were narratively explored. RESULTS: One case report, three retrospective cohorts, one observational prospective study, and three randomized-controlled trials were included. PRF likely provides both an analgesic and functional benefit in patients with mild to severe CTS, and it also shows benefit as an adjunct to carpal tunnel release surgery. Long-term data is limited. It also appears likely that steroid injection may represent a comparable treatment modality to PRF, and there have been positive results when these modalities are used together. Notably, all studies differed in their methodology, making direct comparisons between studies challenging. CONCLUSIONS: The evidence for PRF in the treatment of CTS, across the range of spectrum of severity or peri-operative to CTS surgery, appears favorable and avoids known side effects of steroid injections. Potential mechanisms for PRF and future directions for research are explored.

Ropivacaine-loaded hydrogels for prolonged relief of chemotherapy-induced peripheral neuropathic pain and potentiated chemotherapy.

Chemotherapy can cause severe pain for patients, but there are currently no satisfactory methods of pain relief. Enhancing the efficacy of chemotherapy to reduce the side effects of high-dose chemotherapeutic drugs remains a major challenge. Moreover, the treatment of chemotherapy-induced peripheral neuropathic pain (CIPNP) is separate from chemotherapy in the clinical setting, causing inconvenience to cancer patients. In view of the many obstacles mentioned above, we developed a strategy to incorporate local anesthetic (LA) into a cisplatin-loaded PF127 hydrogel for painless potentiated chemotherapy. We found that multiple administrations of cisplatin-loaded PF127 hydrogels (PFC) evoked severe CIPNP, which correlated with increased pERK-positive neurons in the dorsal root ganglion (DRG). However, incorporating ropivacaine into the PFC relieved PFC-induced CIPNP for more than ten hours and decreased the number of pERK-positive neurons in the DRG. Moreover, incorporating ropivacaine into the PFC for chemotherapy is found to upregulate major histocompatibility complex class I (MHC-I) expression in tumor cells and promote the infiltration of cytotoxic T lymphocytes (CD8+ T cells) in tumors, thereby potentiating chemotherapy efficacy. This study proposes that LA can be used as an immunemodulator to enhance the effectiveness of chemotherapy, providing new ideas for painless cancer treatment.

Peripheral mechanisms of peripheral neuropathic pain.

Peripheral neuropathic pain (PNP), neuropathic pain that arises from a damage or disease affecting the peripheral nervous system, is associated with an extremely large disease burden, and there is an increasing and urgent need for new therapies for treating this disorder. In this review we have highlighted therapeutic targets that may be translated into disease modifying therapies for PNP associated with peripheral neuropathy. We have also discussed how genetic studies and novel technologies, such as optogenetics, chemogenetics and single-cell RNA-sequencing, have been increasingly successful in revealing novel mechanisms underlying PNP. Additionally, consideration of the role of non-neuronal cells and communication between the skin and sensory afferents is presented to highlight the potential use of drug treatment that could be applied topically, bypassing drug side effects. We conclude by discussing the current difficulties to the development of effective new therapies and, most importantly, how we might improve the translation of targets for peripheral neuropathic pain identified from studies in animal models to the clinic.

Exploring Cholinergic Compounds for Peripheral Neuropathic Pain Management: A Comprehensive Scoping Review of Rodent Model Studies.

Neuropathic pain affects about 7-8% of the population, and its management still poses challenges with unmet needs. Over the past decades, researchers have explored the cholinergic system (muscarinic and nicotinic acetylcholine receptors: mAChR and nAChR) and compounds targeting these receptors as potential analgesics for neuropathic pain management. This scoping review aims to provide an overview of studies on peripheral neuropathic pain (PNP) in rodent models, exploring compounds targeting cholinergic neurotransmission. The inclusion criteria were original articles on PNP in rodent models that explored the use of compounds directly targeting cholinergic neurotransmission and reported results of nociceptive behavioral assays. The literature search was performed in the PubMed and Web of Science databases (1 January 2000-22 April 2023). The selection process yielded 82 publications, encompassing 62 compounds. The most studied compounds were agonists of α4ß2 nAChR and α7 nAChR, and antagonists of α9/α10 nAChR, along with those increasing acetylcholine and targeting mAChRs. Studies mainly reported antinociceptive effects in traumatic PNP models, and to a lesser extent, chemotherapy-induced neuropathy or diabetic models. These preclinical studies underscore the considerable potential of cholinergic compounds in the management of PNP, warranting the initiation of clinical trials.

Potentiation of PIEZO2 mechanically-activated currents in sensory neurons mediates vincristine-induced mechanical hypersensitivity.

Vincristine, a widely used chemotherapeutic agent for treating different cancer, often induces severe peripheral neuropathic pain. A common symptom of vincristine-induced peripheral neuropathic pain is mechanical allodynia and hyperalgesia. However, mechanisms underlying vincristine-induced mechanical allodynia and hyperalgesia are not well understood. In the present study, we show with behavioral assessment in rats that vincristine induces mechanical allodynia and hyperalgesia in a PIEZO2 channel-dependent manner since gene knockdown or pharmacological inhibition of PIEZO2 channels alleviates vincristine-induced mechanical hypersensitivity. Electrophysiological results show that vincristine potentiates PIEZO2 rapidly adapting (RA) mechanically-activated (MA) currents in rat dorsal root ganglion (DRG) neurons. We have found that vincristine-induced potentiation of PIEZO2 MA currents is due to the enhancement of static plasma membrane tension (SPMT) of these cells following vincristine treatment. Reducing SPMT of DRG neurons by cytochalasin D (CD), a disruptor of the actin filament, abolishes vincristine-induced potentiation of PIEZO2 MA currents, and suppresses vincristine-induced mechanical hypersensitivity in rats. Collectively, enhancing SPMT and subsequently potentiating PIEZO2 MA currents in primary afferent neurons may be an underlying mechanism responsible for vincristine-induced mechanical allodynia and hyperalgesia in rats. Targeting to inhibit PIEZO2 channels may be an effective analgesic method to attenuate vincristine-induced mechanical hypersensitivity.

Stress specifically deteriorates working memory in peripheral neuropathic pain and fibromyalgia.

This study aimed to explore the influence of chronic stress, measured through hair cortisol, on executive functions in individuals with chronic pain. We expected that there would be significant differences in chronic stress and executive functioning between pain patients and healthy controls, as well as between primary and secondary pain classifications. We also hypothesized that hair cortisol concentration was predictive of worse performance on tests of executive functions, controlling for objective and subjective covariates. For this study, 122 participants provided a hair sample (n = 40 with fibromyalgia; n = 24 with peripheral neuropathic pain; n = 58 matched healthy controls). Eighty-four of these participants also completed highly detailed testing of executive functions (n = 40 with fibromyalgia; n = 24 with peripheral neuropathic pain; n = 20 healthy controls). To assess differences in stress levels and executive functions, t-tests were used to compare patients with controls as well as fibromyalgia with peripheral neuropathic pain. Then, univariate regressions were used to explore associations between stress and executive functioning in both chronic pain classifications. Any significant univariate associations were carried over to hierarchical multivariate regression models. We found that patients with chronic pain had significantly higher cortisol levels than healthy controls, but all groups showed similar executive functioning. Hierarchical multiple regression analyses disclosed that in a model controlling for age, sex and pain medication usage, hair cortisol levels explained 8% of the variance in spatial working memory strategy in individuals with chronic pain. The overall model explained 24% of the variance in spatial working memory. In a second model using imputed data, including both objective and subjectively reported covariates, hair cortisol levels explained 9% of the variance, and the full model 31% of the variance in spatial working memory performance. Higher levels of cortisol indicated worse performance. In this study, an applied measure of chronic stress, namely hair cortisol, explained a substantial part of the variance on a spatial working memory task. The current results have important implications for understanding and treating cognitive impairments in chronic pain.

People's experiences living with peripheral neuropathy: a qualitative study.

Introduction: Peripheral neuropathy is a neurological disorder characterised by pain, numbness, or tingling due to nerve damage. Peripheral neuropathy is one of the main health issues in Kuwait and is a rising concern which affects a large proportion of the population, therefore the lived experience needs to be explored to identify areas for improvement in care. This qualitative study explored the experiences of people living with peripheral neuropathy in Kuwait. Methods: Semi-structured interviews were conducted with 25 participants recruited from the Neurology Outpatient Clinic of the Ibn Sina Hospital in Kuwait. The interview questions explored their experiences and understanding of pain along with the impact on their daily life. The interviews were audio recorded, transcribed and translated into English then coded using NVivo 12. Thematic analysis was conducted to identify patterns and themes in the data. Results: Three major themes were identified including treatment beliefs (perceived effectiveness of treatment and seeking alternative treatments), the barriers to pain management (medication side effects, relationships with healthcare professionals and lack of information and access to healthcare), and the impact on quality of life (impact on work and social, physical, and psychological consequences). Self-efficacy was a key construct and over-arching theme that was discussed in all aspects, which finds reflection in the protection motivation theory. Discussion: This paper presents the experiences of people living with peripheral neuropathy and highlights there is scope for improvement of current treatments in Kuwait. Self-management strategies are recommended alongside prescribed medication and healthcare professionals are encouraged to use a patient-centered approach. More importantly, information and support on the condition to promote coping strategies and self-efficacy should be adopted to improve quality of life. These findings can be implemented locally and globally to improve the quality of care provided to people living with peripheral neuropathy.

The efficacy of a whole foods, plant-based dietary lifestyle intervention for the treatment of peripheral neuropathic pain in leprosy: a randomized control trial protocol.

Introduction: Despite effective treatment of leprosy via WHO-approved multi-drug therapy (MDT), patients still suffer from debilitating neuropathic sequelae, including peripheral neuropathic pain (PNP), and continue to develop intercurrent etiologies (such as diabetes), and progressive existing neuropathy over time. Strategies seeking to improve physiological and metabolic wellness, including those that reduce systemic inflammation and enhance immune responsiveness to neurotoxic factors may influence underlying neuropathic etiologies. A whole food plant-based diet (WFPBD) has been shown to be effective in the management of neuropathic pain due to diabetes, limiting severity and relevant symptomology. Diabetes remains a significant sequela of leprosy, as up to 50% of patients in reaction requiring corticosteroids, may develop a biochemical diabetes. As nutritional interventions may modulate both leprosy and diabetes, a specific exploration of these relationships remains relevant. Objectives: (1) To demonstrate the effect of a WFPBD lifestyle intervention, on neuropathic pain variables in leprosy; and (2) To contextualize the significance of diet in the treatment of chronic sequelae in leprosy by evaluating tolerability and side effect profile. Methods: A prospective, randomized, controlled, single-blind, multicentre interventional trial is described. Weekly one-hour dietary counseling sessions promoting a WFPBD emphasizing vegetables, fruits, whole-grains, nuts, and legumes, omitting animal products, and limiting fat intake over a six-month duration will be implemented. Participants will be 70 age and sex-matched individuals experiencing active or treated "cured" leprosy and PNP, randomized to either intervention or control groups. Primary outcome measures include efficacy via visual analog scale, subjective questionnaire and objective quantitative sensory testing, as well as safety, tolerability, and harms of a WFPBD on PNP in leprosy. This study will be initiated after Research Ethics Board (REB) approval at all participating sites, and in advance of study initiation, the trial will be registered at ClinicalTrials.gov. Expected impact: It is hypothesized that WFPBDs will mitigate progression and severity of PNP and potentially reduce the adverse events related to standard corticosteroid treatment of leprosy reactions, thereby reducing disease severity. By examining the effects of WFPBDs on PNP in leprosy, we hope to illuminate data that will lead to the enhanced therapeutic management of this neglected tropical disease.

Novel topical anandamide formulation for alleviating peripheral neuropathic pain.

Peripheral neuropathy (PN) is a condition of peripheral nerve damage leading to severe pain. The first line therapies are associated with adverse psychotropic effects (PSE) and second line therapies are not efficient enough to relieve pain. There is an unmet drug need for relieving pain effectively without PSE in PN. Anandamide, an endocannabinoid activates cannabinoid receptors to relieve the pain due to peripheral neuropathy (PN). Anandamide has a very short biological half-life as they are extensively metabolized by fatty acid amide hydrolase enzyme (FAAH). Regional delivery of safe FAAH inhibitor (FI) with anandamide would be beneficial for PN without PSE. The objective of the study is to identify a safe FI and deliver the anandamide in combination with the FI topically for the management of PN. The FAAH inhibition potential of silymarin constituents was evaluated by molecular docking and in vitro studies. The topical gel formulation was developed to deliver anandamide and FI. The formulation was assessed in chemotherapeutic agent-induced PN rat models to relieve mechanical-allodynia and thermal-hyperalgesia. The molecular docking studies demonstrated that the Prime MM-GBSA free energy of silymarin constituents were in the order of silybin > isosilybin > silychristin > taxifolin > silydianin. In in vitro studies, silybin 20 µM inhibited > 61.8% of FAAH activity and increased the half-life of anandamide. The developed formulation increased permeation of anandamide and silybin across the porcine skin. Furthermore, on the application of anandamide and anandamide-silybin gel to rat paws, there was a significant increase in the pain threshold for allodynic and hyperalgesic stimulus up to 1 h and 4 h, respectively. The topical anandamide with silybin delivery approach could serve to alleviate PN efficiently and thus could minimize unwanted CNS side effects of synthetic or natural cannabinoids in patients.

Clinical Outcomes of Mirogabalin Treatment for Neuropathic Pain Due to Spinal Diseases in Patients Intolerant to Continuous Administration of Pregabalin.

Introduction: We often treat patients with peripheral neuropathic pain due to spine diseases with mirogabalin as an alternative to pregabalin because of adverse events or insufficient efficacy associated with pregabalin treatment. However, there have been few reports on the safety and efficacy of mirogabalin in such cases. This study aimed to evaluate the safety and efficacy of switching from pregabalin to mirogabalin in patients with peripheral neuropathic pain due to spine diseases. Methods: Between January 2019 and July 2021, we treated 106 patients (47 men and 59 women) with peripheral neuropathic pain due to spine diseases. All patients had switched from pregabalin to mirogabalin due to adverse events or lack of efficacy. We evaluated the retention rate, incidence of adverse events, and response rate of mirogabalin during the treatment course. Results: The mean age of the patients was 67.5 years (range, 33-93 years), and the average dose of mirogabalin was 13.8 mg (range, 2.5-30 mg) at the final follow-up. The average duration of mirogabalin treatment was 148.7 days (range, 3-463 days). The retention rate of mirogabalin was 78.3%, the incidence of adverse events after mirogabalin administration was 28.3%, and the response rate of mirogabalin was 66%. Somnolence with pregabalin or mirogabalin administration in the mirogabalin discontinuation group was increased compared with that in the mirogabalin continuation group (pregabalin: 52.2% vs. 19.3%, mirogabalin: 26.1% vs. 7.2%). The patients who responded to mirogabalin had a lower average age, higher retention rate, and longer drug administration period than those who did not respond to it. Conclusions: This study indicated that mirogabalin treatment might be continued in patients with peripheral neuropathic pain due to spinal diseases who could not continue pregabalin treatment.

Sinomenine alleviates diabetic peripheral neuropathic pain through inhibition of the inositol-requiring enzyme 1 alpha-X-box binding protein 1 pathway by downregulating prostaglandin-endoperoxide synthase 2.

INTRODUCTION: We tried to show the effect of sinomenine (SIN) in diabetic peripheral neuropathic pain (DPNP) and the related underlying mechanism. METHODS: Network pharmacological analysis and bioinformatics analysis were carried out for identification of the active ingredients of Sinomenium acutum and the related genes. The DPNP rat model was constructed and primary rat spinal cord microglial cells were isolated for in vitro cell experiments. The therapeutic role of SIN in DPNP was determined in vivo and in vitro through analysis of microglial cell activation and inflammatory response. RESULTS: Therapeutic role of S. acutum in DPNP was mainly achieved by regulating 14 key genes, among which the target gene prostaglandin-endoperoxide synthase 2 (PTGS2) of SIN might be the key gene. An in vivo experiment showed that SIN inactivated the inositol-requiring enzyme 1 alpha-X-box binding protein 1 pathway by downregulating PTGS2, which relieved pain symptoms in DPNP rats. It was confirmed in vivo that SIN inhibited the pathway through PTGS2 to alleviate the activation of spinal cord microglial cells and inflammatory response. CONCLUSION: SIN decreases the expression of PTGS2 to inactivate the inositol-requiring enzyme 1 alpha-X-box binding protein 1 signaling pathway, which inhibits microglial activation, as well as the release of inflammatory factors, thus alleviating DPNP.

Up-regulation of oxytocin receptors on peripheral sensory neurons mediates analgesia in chemotherapy-induced neuropathic pain.

BACKGROUND AND PURPOSE: Chemotherapy-induced neuropathic pain (CINP) currently has limited effective treatment. Although the roles of oxytocin (OXT) and the oxytocin receptor (OXTR) in central analgesia have been well documented, the expression and function of OXTR in the peripheral nervous system remain unclear. Here, we evaluated the peripheral antinociceptive profiles of OXTR in CINP. EXPERIMENTAL APPROACH: Paclitaxel (PTX) was used to establish CINP. Quantitative real-time polymerase chain reaction (qRT-PCR), in situ hybridization, and immunohistochemistry were used to observe OXTR expression in dorsal root ganglia (DRG). The antinociceptive effects of OXT were assessed by hot-plate and von Frey tests. Whole-cell patch clamp was performed to record sodium currents, excitability of DRG neurons, and excitatory synapse transmission. KEY RESULTS: Expression of OXTR in DRG neurons was enhanced significantly after PTX treatment. Activation of OXTR exhibited antinociceptive effects, by decreasing the hyperexcitability of DRG neurons in PTX-treated mice. Additionally, OXTR activation up-regulated the phosphorylation of protein kinase C (pPKC) and, in turn, impaired voltage-gated sodium currents, particularly the voltage-gated sodium channel 1.7 (NaV 1.7) current, that plays an indispensable role in PTX-induced neuropathic pain. OXT suppressed excitatory transmission in the spinal dorsal horn as well as excitatory inputs from primary afferents in PTX-treated mice. CONCLUSION AND IMPLICATIONS: The OXTR in small-sized DRG neurons is up-regulated in CINP and its activation relieved CINP by inhibiting the neural excitability by impairment of NaV 1.7 currents via pPKC. Our results suggest that OXTR on peripheral sensory neurons is a potential therapeutic target to relieve CINP.

Changes in the expression of endocannabinoid system components in an experimental model of chemotherapy-induced peripheral neuropathic pain: Evaluation of sex-related differences.

Chemotherapy-induced neuropathic pain is a serious clinical problem and one of the major side effects in cancer treatment. The endocannabinoid system (ECS) plays a crucial role in regulating pain neurotransmission, and changes in the expression of different components of the ECS have been reported in experimental models of persistent pain. In addition, sex differences have been observed in ECS regulation and function. The aim of our study was to evaluate whether administration of oxaliplatin, a neurotoxic antineoplastic agent, induced changes in the expression of ECS components in peripheral and central stations of the pain pathway, and if those changes exhibited sexual dimorphism. Adult male and female rats were injected with oxaliplatin or saline, and mechanical and cold hypersensitivity and allodynia were evaluated using Von Frey and Choi Tests. The mRNA levels corresponding to cannabinoid receptors (CB1, CB2), cannabinoid-related receptors (GPR55, 5HT1A, TRPV1) and to the main enzymes involved in the synthesis (DAGL, DAGL, NAPE-PLD) and degradation (MGL, FAAH) of endocannabinoids were assessed in lumbar dorsal root ganglia (DRGs) and spinal cord by using real time RT-PCR. In addition, the levels of the main endocannabinoids, 2-arachidonoylglycerol (2-AG) and anandamide (AEA), were evaluated using commercial ELISA kits. Oxaliplatin administration induced the development of mechanical and cold hypersensitivity and allodynia in male and female animals. Oxaliplatin also induced early and robust changes in the expression of several components of the ECS in DRGs. A marked upregulation of CB1, CB2, 5HT1A and TRPV1 was detected in both sexes. Interestingly, while DAGL mRNA levels remained unchanged, DAGL was downregulated in male and upregulated in female rats. Finally, MGL and NAPE-PLD showed increased levels only in male animals, while FAAH resulted upregulated in both sexes. In parallel, reduced 2-AG and AEA levels were detected in DRGs from male or female rats, respectively. In the lumbar spinal cord, only TRPV1 mRNA levels were found to be upregulated in both sexes. Our results reveal previously unreported changes in the expression of cannabinoid receptors, ligands and enzymes occurring mainly in the peripheral nervous system and displaying certain sexual dimorphism. These changes may contribute to the physiopathology of oxaliplatin-induced neuropathic pain in male and female rats. A better understanding of these dynamic changes will facilitate the development of mechanism- and sex-specific approaches to optimize the use of cannabinoid-based medicines for the treatment of chemotherapy-induced pain.

Physiotherapy interventions for pain relief in individuals with peripheral neuropathic pain: A systematic review and meta-analyses of randomized controlled trials.

OBJECTIVE: To evaluate the effectiveness of physiotherapy interventions on peripheral neuropathic pain (pNeP) due to any underlying cause. METHODS: Multiple databases were searched from database inception until Dec 2021. Studies on physiotherapy interventions for pain relief assessed using the visual analogue scale among individuals with pNeP of any underlying cause were included. Methodological quality was assessed using the PEDro scale and the quality of the evidence using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) tool. RESULTS: The searches yielded 1498 articles. Seventeen studies met the inclusion criteria and were included in the review. Meta-analysis revealed a significant benefit for laser therapy compared to sham laser on pNeP (weighted mean difference [WMD] -1.27; 95% CI: -2.29 to -0.25; p = 0.01) in people with carpal tunnel syndrome. The pooled analyses revealed a significant effect of spinal cord stimulation compared to control for failed back syndrome (standardised mean difference [SMD; Hedges'g] -0.73; 95% CI: -1.17 to -0.30; p = 0.001) and diabetic neuropathy (SMD -1.63; 95% CI -2.06--1.21; p < 0.001). The effect of acupuncture on chemotherapy-induced pain (SMD - 2.09; 95% CI: -4.27-0.09; p = 0.06) and electromagnetic stimulation on diabetic neuropathic pain (Hedges' g - 0.77; 95% CI: -1.82-0.27; p = 0.15) were insignificant. CONCLUSION: Evidence supports the use of spinal cord stimulation for the treatment of pNeP secondary to failed back surgery syndrome and diabetic neuropathy. Laser therapy was more effective than sham laser for alleviating pain due to carpal tunnel syndrome. The efficacy of acupuncture and electromagnetic therapy for chemotherapy-induced pain and diabetic neuropathy, respectively remains inconclusive.

Palmitoylethanolamide Mitigates Paclitaxel Toxicity in Primary Dorsal Root Ganglion Neurons.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of several chemotherapeutic agents, such as Paclitaxel. The main symptoms of CIPN are pain and numbness in the hands and feet. Paclitaxel is believed to accumulate in the dorsal root ganglia and free nerve endings. Novel therapeutic agents might help to mitigate or prevent Paclitaxel toxicity on dorsal root ganglion (DRG) neurons. Thus, we used primary DRG neurons as a model to investigate the potential neuroprotective effects of the endocannabinoid-like substance, palmitoylethanolamide (PEA). DRG neurons were isolated from cervical to sacral segments of spinal nerves of Wister rats (6-8 weeks old). After isolation and purification of neuronal cell populations, different concentrations of Paclitaxel (0.01-10 µM) or PEA (0.1-10 µM) or their combination were tested on cell viability by MTT assay at 24 h, 48, and 72 h post-treatment. Furthermore, morphometric analyses of neurite length and soma size for DRG neurons were performed. Adverse Paclitaxel effects on cell viability were apparent at 72 h post-treatment whereas Paclitaxel significantly reduced the neurite length in a concentration-dependent manner nearly at all investigated time points. However, Paclitaxel significantly increased the size of neuronal cell bodies at all time windows. These phenotypic effects were significantly reduced in neurons additionally treated with PEA, indicating the neuroprotective effect of PEA. PEA alone led to a significant increase in neuron viability regardless of PEA concentrations, apparent improvements in neurite outgrowth as well as a significant decrease in soma size of neurons at different investigated time points. Taken together, PEA showed promising protective effects against Paclitaxel-related toxicity on DRG neurons.

Sex-related differences in experimental pain sensitivity in subjects with painful or painless neuropathy after surgical repair of traumatic nerve injuries.

Introduction: Sex-related influences represent a contributor to greater pain sensitivity and have a higher prevalence of many chronic pain conditions, including neuropathic pain (NP), among women. Objectives: The aim was to analyze how differences in ongoing pain, experimental pain intensity, and conditioned pain modulation (CPM) relate to sex in subjects with neuropathy after traumatic nerve injuries. Methods: Endogenous pain modulation was compared between male (n = 77) and female (n = 55) subjects and between subjects with NP (female = 31, male = 39) and pain-free subjects with posttraumatic neuropathy (female = 24, male = 38). Conditioned pain modulation was assessed by pain ratings to pressure stimuli before and after a noxious conditioning stimulus (CS) conducted with one arm submerged in cold water (4°C) for 1 minute. Time of recovery (Time off) of pain intensity from peak VASmaxc after CS was recorded and compared between male and female patients. Results: Greater ongoing pain intensity was found among female patients compared with male patients and more experimental pain after pressure and cold induced pain. Summing all groups together, women had 0.8 times higher odds (20%) of recovering sooner than men after CS (95% CI = 0.65-2.9). No differences in CPM, time off, and psychosocial variables were seen between female and male patients (P < 0.05). Conclusion: Our hypothesis for sex differences in endogenous pain modulation was only supported by a shorter after-sensation time after cold CS in female patients. No sex differences in the magnitude of CPM effect were identified. Increased pain intensity for experimental pain, in both neuropathic pain and neuropathy without pain, was found in female patients.

Sex-related differences in oxaliplatin-induced changes in the expression of transient receptor potential channels and their contribution to cold hypersensitivity.

Transient receptor potential (TRP) channels are involved in the development of oxaliplatin-induced neuropathic pain, a frequent and debilitating side effect of cancer therapy. Here we explored whether oxaliplatin-induced changes in the expression of TRP channels, as well as the development of pain-related behaviours, differed between male and female animals. Adult rats were injected with oxaliplatin or saline and mechanical and cold allodynia were evaluated using Von Frey and Choi Tests. The mRNA levels of TRPV1, TRPM8 and TRPA1 were assessed in lumbar ganglia and spinal cord by using real time RT-PCR. Oxaliplatin administration induced mechanical and cold hypersensitivity and allodynia in both sexes, with more severe responses to cold stimulation detected in females. Oxaliplatin also induced a significant increase in the expression of TRPV1, TRPM8 and TRPA1 in lumbar dorsal root ganglia. Interestingly, while TRPV1 and TRPA1 upregulation showed no sex difference, the increase in TRPM8 mRNA levels was more pronounced in female ganglia, correlating with the increased sensitivity to innocuous cold stimuli observed in females. TRPV1 and TRPM8 were also found to be upregulated in the spinal cord of animals of both sexes. Our results reveal previously undescribed changes in the expression of TRP channels occurring in peripheral ganglia and spinal cord of both male and female oxaliplatin-treated animals, with some of these changes exhibiting sex-related differences that could underlie the development of sex-specific patterns of pain-related behaviours.