Neuropathic Pain Symptoms Research Articles

The Evolving Landscape of Small Fiber Neuropathy.

Small fiber neuropathy (SFN) belongs to a heterogeneous group of disorders in which thinly myelinated Aδ and unmyelinated C-fibers are primarily affected, leading to neuropathic pain and autonomic symptoms. SFN can be associated with systemic conditions such as diabetes, autoimmune diseases, exposure to drugs and toxins, and infection, with the list of associated diseases continuing to expand. Variants in the SCN9A, SCN10A, and SCN11A genes encoding Nav 1.7, Nav 1.8, and Nav 1.9 sodium channel subunits, as well as in the TRPA1 gene, have been found in SFN patients, expanding the spectrum of underlying conditions and enhancing our understanding of pathophysiological mechanisms. There is also growing interest in immune-mediated forms that could help identify potentially treatable subgroups. According to international criteria, diagnosis is established through clinical examination, the assessment of intraepidermal nerve fiber density, and/or quantitative sensory testing. Autonomic functional tests allow for a better characterization of dysautonomia in SFN, which can be subclinical. Other tests can support the diagnosis. Currently, the management of SFN prioritizes treating the underlying condition, if identified, within a multidisciplinary approach that combines symptomatic pain therapy, lifestyle changes, and biopsychological interventions. Emerging insights from the molecular characterization of SFN channelopathies hold promise for improving diagnosis, potentially leading to the discovery of new drugs and refining trial designs in the future. This article reviews the clinical presentation, diagnostic workup, and advancing knowledge of associated conditions and interventional management of SFN.

Clinical characteristics of patients with chronic post-traumatic pain: data from a prospective study

Chronic post-traumatic pain (CPTP) is diagnosed when pain persists for ≥3 months after injury. This is a serious condition that significantly limits patients' quality of life and ability to work and is one of the predictors of the development of post-traumatic osteoarthritis.Objective. To investigate the clinical features of CPTP after knee injury.Material and methods. The study group comprised 103 patients (mean age 39.4±12.5 years, 51.5% women). All patients had a knee injury with diagnosed involvement of the anterior cruciate ligament and/or meniscus and suffered from pain ≥1 month after the injury ≥4 points on the numerical rating scale (NRS, 0–10). Patients were assessed after 3 and 6 months. Pain intensity during movement, at rest and at night and functional impairment were assessed using NRS. KOOS, EQ-5D, PainDETECT, CSI, Pain Catastrophizing, HADS, FIRST and FACIT questionnaires.Results and discussion. After 3 months, the number of patients with CPTP was 33 (32.0%). After 6 months, these patients had significantly more severe symptoms than patients with knee injuries without CPTP (control group, n=70). In the CPTP and control groups, the median pain during movement was 5.0 [4.0; 6.0] and 1.0 [0.0; 1.0] respectively, p12 was found in 24.2 and 2.9% of cases, p <0.001 ; pain at rest – 2.0 [2.0; 3.0] and 0.0 [0.0; 1.0], p <0.001 <0.001;; pain at night – 2.0 [1.0; 3.0] and 0.0 [0.0; 0.0], p <0.001; KOOS score – 4.0 [1.0; 5.5] and 2.0 [1.0; 3.5], p <0.001; quality of life according to EQ-5D – 0.65 [0.52; 0.73] and 0.89 [0.69; 1.0], p <0.001; according to EQ-5D scale – 64.0 [50.0; 70.0] and 80.0 [70.0; 90.0], p <0.001 ; a PainDETECT score of >12 was found in 24.2 and 2.9% of cases, p< 0.0037; according to HADS, depression ≥11 – in 21.2 and 2.9%, p< 0.001, according to HADS, anxiety ≥11 – in 24.2 and 4.3%, p=0.0038; CSI ≥40 – in 9.0 and 0%, p=0.03; pain catastrophizing ≥30 – in 12.1 and 0%, p=0.005; FIRST ≥5 – in 6.1 and 0%, p=0.358; FACIT <30 – in 15.2 and 2.9%, p=0.004. After 6 months, statistically significant differences were found between the CPTP group and the control group in all sections of KOOS questionnaire (p <0.001 for all parameters).Conclusion. Three months after knee injury, 32.0% of patients developed CPTP. All had moderate/severe pain with impaired function and reduced quality of life, one in five patients had symptoms of neuropathic pain, signs of depression and anxiety. Patients with CPTP showed significant changes in all sections of KOOS questionnaire.

METHA-NeP: effectiveness and safety of methadone for neuropathic pain: a controlled randomized trial.

In this randomized, double-blind, parallel placebo-controlled clinical trial, we evaluated the efficacy of methadone as an add-on therapy for people with chronic neuropathic pain (NP). Eighty-six patients were randomly assigned to receive methadone or placebo for 8 weeks. The primary outcome was the proportion of participants achieving at least 30% pain relief from baseline using a 100-mm pain Visual Analogue Scale. Secondary outcomes included global impression of change, NP symptoms, sleep quality, quality of life, pain interference in daily activities, and mood. A larger number of responders were found in the methadone (68%), compared to the placebo (33%) arm; risk difference 33.6%; 95% confidence interval 13.0%-54.3%; P = 0.003; number needed to treat = 3.0. Methadone reduced pain intensity ( P < 0.001), burning ( P = 0.023), pressing ( P = 0.005), and paroxysmal dimensions ( P = 0.006) of NP. Methadone also improved sleep ( P < 0.001) and increased the patient's global impression of improvement ( P = 0.002). Methadone did not significantly impact quality of life, pain interference, or mood. Treatment-emergent adverse events occurred in all methadone- and in 73% of placebo-treated patients ( P < 0.001). No serious adverse events or deaths occurred. Discontinuation due to adverse events was reported in 2 participants in the methadone and none in the placebo arm. Methadone use as an add-on to an optimized treatment for NP with first- and/or second-line drugs provided superior analgesia, improved sleep, and enhanced global impression of change, without being associated with significant serious adverse effects that would raise safety concerns.

Olokizumab effect on chronic pain in rheumatoid arthritis: Results of the PROLOGUE observational study.

Evaluate the efficacy and safety ® (olokizumab) in patients with rheumatoid arthritis (RA) in real-world clinical practice, with a targeted assessment of patient report outcomes (PRO) and central sensitization. An open-label observational non-interventional study was conducted, enrolling 183 patients with moderate and severe RA activity. All patients received OKZ 64 mg SC as injections every 4 weeks (Q4W) with methotrexate. The patients' follow-up period was 24 weeks or less. RA activity (DAS28-CRP), pain severity (NRS), patient global assessment (PGA, NRS), functional impairment (NRS), fatigue (FACIT-F), central sensitization (central sensitization inventory, CSI), and symptoms of neuropathic pain (PainDETECT) were evaluated. The study cohort was comprised of 144 patients. And 39 patients were lost to follow-up, refused OKZ treatment, or were not dosed with OKZ for administrative reasons. In 6 months, DAS28-CRP decreased to 3.3 ± 0.9 (p < .001) and statistically significant reductions in pain intensity, PGA, functional impairment, and fatigue were achieved. Pain intensity decreased as early as 2 days after the first OKZ administration (p < .05). The number of patients with CSI >40 in 24 weeks decreased from 71.0% to 21.0% (p < .001), with PainDETECT >18 - from 21.5% to 13.2%. NSAIDs use decreased from 70.8% to 33.8% (р < .001), steroids - from 54.2% to 32.6%. AEs were reported in 14.2% patients, serious events were observed in three patients. OKZ is effective in reducing RA activity and controlling chronic pain related to dysfunction of the nociceptive system.

Discovery of E0199: A novel compound targeting both peripheral NaV and KV7 channels to alleviate neuropathic pain

This research study focuses on addressing the limitations of current neuropathic pain (NP) treatments by developing a novel dual-target modulator, E0199, targeting both NaV1.7, NaV1.8, and NaV1.9 and KV7 channels, a crucial regulator in controlling NP symptoms. The objective of the study was to synthesize a compound capable of modulating these channels to alleviate NP. Through an experimental design involving both in vitro and in vivo methods, E0199 was tested for its efficacy on ion channels and its therapeutic potential in a chronic constriction injury (CCI) mouse model. The results demonstrated that E0199 significantly inhibited NaV1.7, NaV1.8, and NaV1.9 channels with a particularly low half maximal inhibitory concentration (IC50) for NaV1.9 by promoting sodium channel inactivation, and also effectively increased KV7.2/7.3, KV7.2, and KV7.5 channels, excluding KV7.1 by promoting potassium channel activation. This dual action significantly reduced the excitability of dorsal root ganglion neurons and alleviated pain hypersensitivity in mice at low doses, indicating a potent analgesic effect without affecting heart and skeletal muscle ion channels critically. The safety of E0199 was supported by neurobehavioral evaluations. Conclusively, E0199 represents a ground-breaking approach in NP treatment, showcasing the potential of dual-target small-molecule compounds in providing a more effective and safe therapeutic option for NP. This study introduces a promising direction for the future development of NP therapeutics.

Agomelatine-loaded nanostructured lipid carriers alleviate neuropathic pain in rats by Nrf2/HO-1 signalling pathway.

Neuropathic pain arises from impairments or malfunctions within the nervous system, resulting in atypical transmission and interpretation of pain signals. In the present study, we examined the neuroprotective effects of agomelatine (AGM) and agomelatine-loaded nanostructured lipid carriers (AGM-NLCs) in neuropathic animal models induced by chronic constriction injury (CCI) of the sciatic nerve. Male Sprague Dawley rats were divided into seven experimental groups to compare the effects of AGM and AGM-NLCs, which were administered at 20 mg/kg for 14 consecutive days after CCI. Our finding demonstrated that CCI triggered the onset of analgesia in these animals, corroborated by mechanical allodynia and thermal hyperalgesia. Furthermore, CCI induced an elevation in inflammatory mediators such as interleukin (IL)-1β and inducible nitric oxide synthase (iNOS), and downregulated heme oxygenase-1 (HO-1) and nuclear factor E2-related factor (Nrf2). Treatment with AGM and AGM-NLCs reversed inflammatory cascades and elevated antioxidant enzyme levels, leading to a reduction in paw withdrawal latency and threshold in rats. To further investigate the effect of AGM and AGM-NLCs, all-trans retinoic acid (ATRA) was administered, which antagonizes Nrf2. ATRA substantially downregulated Nrf2 expression and exacerbated thermal hyperalgesia, whereas Nrf2 and HO-1 expressions were significantly upregulated after AGM-NLCs administration. Overall, the results demonstrated that AGM-NLCs offer promising antinociceptive and anti-inflammatory properties in alleviating neuropathic pain symptoms, which can be attributed to improved drug delivery and therapeutic outcomes compared with AGM alone.

Neuropathic pain in spondyloarthritis: Decoding its prevalence, risk factors, and impact on disease activity

ObjectivesThis study aimed to evaluate the prevalence and characteristics of neuropathic pain in patients with various subtypes of spondyloarthritis (SpA), including axial SpA (axSpA), psoriatic arthritis (PsA), and undifferentiated peripheral SpA (p-SpA). Additionally, the study sought to identify potential risk factors associated with the presence or severity of neuropathic pain and to investigate its impact on clinical disease activity assessment. MethodsWe conducted a cross-sectional study at two tertiary rheumatology centers, enrolling patients diagnosed with SpA. Data on demographic and clinical characteristics, comorbidities, and current therapies were collected. Neuropathic pain was assessed using the PainDETECT Questionnaire (PD-Q) and the Neuropathic Pain Symptom Inventory (NPSI). Statistical analyses included descriptive statistics, t-tests, and Pearson's correlations to evaluate the relationships between neuropathic pain scores and clinical disease activity indices. ResultsThe study included 177 patients. Of these, 22.2% had a PD-Q score ≥19, showing a high likelihood of neuropathic pain, while 64.9% scored ≤12, suggesting the absence of significant neuropathic components. The mean PD-Q score was 11.5 ± 10.1. Subgroup analyses showed that females had significantly higher scores for paroxysmal and evoked pain (p < 0.05), and obese patients had significantly higher scores across all NPSI subscores (p < 0.05). Moderate positive correlations were found between neuropathic pain scores and clinical disease activity indices, such as DAPSA (r = 0.46, p < 0.0001) and ASDAS-CRP (r = 0.42, p < 0.01). ConclusionsNeuropathic pain is prevalent among patients with SpA and is significantly associated with disease activity assessments and management. This study highlights the importance of integrating neuropathic pain evaluation into the clinical assessment of SpA to tailor treatment approaches effectively and improve patient outcomes.

High-frequency terahertz stimulation alleviates neuropathic pain by inhibiting the pyramidal neuron activity in the anterior cingulate cortex of mice.

Neuropathic pain (NP) is caused by a lesion or disease of the somatosensory system and is characterized by abnormal hypersensitivity to stimuli and nociceptive responses to non-noxious stimuli, affecting approximately 7-10% of the general population. However, current first-line drugs like non-steroidal anti-inflammatory agents and opioids have limitations, including dose-limiting side effects, dependence, and tolerability issues. Therefore, developing new interventions for the management of NP is urgent. In this study, we discovered that the high-frequency terahertz stimulation (HFTS) at approximately 36 THz effectively alleviates NP symptoms in mice with spared nerve injury. Computational simulation suggests that the frequency resonates with the carbonyl group in the filter region of Kv1.2 channels, facilitating the translocation of potassium ions. In vivo and in vitro results demonstrate that HFTS reduces the excitability of pyramidal neurons in the anterior cingulate cortex likely through enhancing the voltage-gated K+ and also the leak K+ conductance. This research presents a novel optical intervention strategy with terahertz waves for the treatment of NP and holds promising applications in other nervous system diseases.

Melatonin Induces Analgesic Effects through MT2 Receptor-Mediated Neuroimmune Modulation in the Mice Anterior Cingulate Cortex.

Neuropathic pain (NP) represents a considerable clinical challenge, profoundly impacting patients' quality of life. Presently, pharmacotherapy serves as a primary approach for NP alleviation, yet its efficacy often remains suboptimal. Melatonin (MLT), a biologically active compound secreted by the pineal gland, has long been associated with promoting and maintaining sleep. Although recent studies suggest analgesic effects of MLT, the underlying mechanism remains largely unknown, particularly its impact on the cortex. In this study, we induced an NP model in mice through spared nerve injury (SNI) and observed a considerable, dose-dependent alleviation in NP symptoms following intraperitoneal or anterior cingulate cortex (ACC) administration of MLT. Our findings further indicated that the NP management of MLT is selectively mediated by MLT-related receptor 2 (MT2R), rather than MT1R, on neurons and microglia within the ACC. Transcriptome sequencing, complemented by bioinformatics analysis, implicated MLT in the modulation of Gα(i) and immune-inflammatory signals. Specifically, MLT inhibited the excitability level of pyramidal cells in the ACC by activating the Gα(i) signaling pathway. Simultaneously, MLT attenuated M1 polarization and promoted M2 polarization of microglia, thereby mitigating the inflammatory response and type II interferon response within the ACC. These findings unveil a hitherto unrecognized molecular mechanism: an MLT-mediated neuroimmune modulation pathway in the ACC mediated by MT2R. This elucidation sheds light on the regulatory character of MLT in chronic nociceptive pain conditions, offering a prospective therapeutic strategy for NP management.

Beyond pain: Using Unsupervised Machine Learning to Identify Phenotypic Clusters of Small Fiber Neuropathy.

Small fiber neuropathy (SFN) is characterized by dysfunction and loss of peripheral unmyelinated and thinly myelinated nerve fibers, resulting in a phenotype that includes varying combinations of somatosensory and dysautonomia symptoms, which can be profoundly disabling and lead to decreased quality of life. Treatment aimed mainly at pain reduction, which may not target the underlying pathophysiology, is frequently ineffective. Another impediment to the effective management of SFN may be the significant between-patient heterogeneity. Accordingly, we launched this study to gain insights into the symptomatic variability of SFN and determine if SFN patients can be sub-grouped based on clinical characteristics. To characterize the phenotype and investigate how patients with SFN differ from those with large fiber involvement, 105 patients with skin-biopsy proven SFN and 45 with mixed fiber neuropathy (MFN) were recruited. Using unsupervised machine learning, SFN patients were clustered based upon symptom concurrence and severity. Demographics, clinical data, symptoms, and skin biopsy- and laboratory findings were compared between the groups. MFN- as compared to SFN patients, were more likely to be male, older, had a lower intraepidermal nerve fiber density at the ankle and more frequent abnormal immunofixation. Beyond these differences, symptom prevalence and intensities were similar in the two cohorts. SFN patients comprised three distinct phenotypic clusters, which differed significantly in symptom severity, co-occurrence, localization, and skin biopsy findings. Only one subgroup, constituting about 20% of the patient population, was characterized by intense neuropathic pain, which was always associated with several other SFN symptoms of similarly high intensities. A pauci-symptomatic cluster comprised patients who experienced few SFN symptoms, generally of low to moderate intensity. The largest cluster was characterized by intense fatigue, myalgias and subjective weakness, but lower intensities of burning pain and paresthesia. This data-driven study introduces a new approach to subgrouping patients with SFN. Considering both neuropathic pain and pernicious symptoms beyond pain, we identified three clusters, which may be related to distinct pathophysiological mechanisms. Although additional validation will be required, our findings represent a step towards stratified treatment approaches and, ultimately, personalized treatment.

Knowledge levels of oncology nurses regarding evidence-based practices in the assessment and management of chemotherapy-induced peripheral neuropathy

ObjectiveThe study aimed to determine the level of oncology nurses' knowledge of evidence-based practice for assessing and managing chemotherapy-induced peripheral neuropathy (CIPN). MethodsThis study employed a descriptive and cross-sectional research design. It was carried out with oncology nurses who were working at a university hospital in the Western Region of Turkey and who were members of the Oncology Nursing Association. The sample of the study consisted of 96 nurses who met the inclusion criteria. ResultsThe study sample comprised 94.8% female oncology nurses, 57.3% of whom held an undergraduate degree, and over half (58.5%) of whom were employed as clinical nurses. A majority of nurses (76.0%) indicated that they had not received any training in peripheral neuropathy. 35.4% of the nurses assessed patients receiving neurotoxic chemotherapy for peripheral neuropathy at each visit/each chemotherapy cycle. A total of 43.8% of nurses indicated that they frequently assessed patients for peripheral neuropathy at the conclusion of the treatment protocol. The oncology nurses assessed the patient-reported symptoms of motor neuropathy (58.3%), sensory neuropathy (56.3%), autonomic neuropathy (51.0%), neuropathic pain (55.2%), and co-occurring symptoms (52.1%) on a frequent basis. The nurses reported that they assessed muscle strength (56.3%), gait and balance (58.3%), and quality of life (52.1%) “frequently”. In contrast, they assessed deep tendon reflex (41.7%), neurological tests (36.5%), and social activities (46.8%) “rarely”. ConclusionsThe study findings indicated that oncology nurses require further education and training in evidence-based practices for the assessment and management of CIPN.

A Three-way Attack on the Gastrointestinal System- COVID-19, Ehler-Danlos Syndrome, and Anorexia Nervosa Leading to Severe Gastroparesis in a Young Female

A 28-year-old female with a past medical history of Major Depressive Disorder, Generalized Anxiety Disorder, Anorexia Nervosa, Chronic Pain Syndrome, and Gastro-esophageal Reflux presented to our clinic for establishing care in November 2022 with severe gastric dysmotility ever since contracting COVID-19 virus in December 2021. The patient’s symptoms were refractory to Erythromycin and metoclopramide therapy. A GI motility study in February 2022 showed delayed gastric emptying based on which the patient was diagnosed with Post COVID Gastroparesis. Based on an extensive clinical review of the patient’s past medical and surgical history, the patient was found to have cumulative symptoms of GERD, joint instability, abdominal hernia and chronic neuropathic pain, raising the suspicion of Ehler-Danlos syndrome- Hypermobility type. Given the failure of treatment with prokinetic agents and over 60 pounds of weight loss the patient underwent Percutaneous Endoscopic Gastrostomy-Jejunostomy in August 2022, the patient was started on Organic Tube Feeding Formula. To this date, the patient is using the PEG-J for feeding and remains nil per oral. Multiple trials of reintroducing oral feeding have been attempted but the patient still is unable to tolerate oral feeds completely and continues to complain of early satiety, nausea, and vomiting on reintroducing feeds.

“I don’t know the correct way to describe it”: neuropathic pain experiences among athletes with spinal cord injury

BackgroundChronic pain among athletes is often misinterpreted as tissue damage resulting from sport. While researchers have started to examine neuropathic pain among athletes with spinal cord injury (SCI), there is...

Analysis of the efficacy and safety of pulsed radiofrequency for the treatment of thoracic postherpetic neuralgia in elderly patients with different pain phenotypes

Objective: To analyze the efficacy and safety of pulsed radiofrequency (PRF) for the treatment of thoracic postherpetic neuralgia (PHN) in elderly patients with different pain phenotypes. Methods: A total of 201 elderly thoracic PHN patients, including 110 males and 91 females aged (72.2±6.9) years who received high-voltage, long-duration PRF at the dorsal root ganglion at Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine from January 2020 to December 2022, were retrospectively included. The neuropathic pain symptom inventory (NPSI) was used to evaluate the five different pain phenotypes, which included superficial spontaneous pain, deep spontaneous pain, paroxysmal pain, evoked pain, and paresthesia/dysesthesia, and to analyze the distribution of the five pain phenotypes. The numerical rating scale (NRS) and NPSI scores of all patients were compared before treatment and three months after treatment to evaluate the efficacy and safety of PRF for different pain phenotypes and pain phenotype combinations. Results: All patients had two or more pain phenotypes, and 50.2% (101/201) of the patients had five pain phenotypes at the same time. Compared with those before treatment, three months after treatment, the NPSI scores for superficial spontaneous pain, deep spontaneous pain, paroxysmal pain, evoked pain and paresthesia/dysesthesia decreased (all P<0.05), and the scores decreased by［M（Q1，Q3）］3.0 (2.0, 4.0), 1.5 (0.5, 2.5), 3.0 (2.5, 4.0), 2.3 (1.0, 4.0), and 1.0 (0.5, 2.0) points, respectively, the differences were statistically significant (P<0.001). The decrease in the NPSI score in patients with paroxysmal pain was greater than that in patients with the other 4 pain phenotypes (all P<0.05). After treatment, the NRS score decreased by 4.0 (3.0, 5.0), 4.0 (3.0, 5.0), 4.0 (3.0, 5.0) and 5.0 (4.0, 6.0) points in patients with 2, 3, 4 and 5 pain phenotypes, respectively, and the difference was statistically significant (P<0.001). The decrease in the NRS score was greater in patients with a combination of 5 pain phenotypes than that in patients with a combination of 3 and 4 pain phenotypes (all P<0.05). No complications, such as pneumothorax, haematoma or infection, occurred in any of the patients during treatment. Conclusion: PRF has different therapeutic effects on PHN patients with different pain phenotypes, it has the best effect on paroxysmal pain, and the treatment is safe.

The Electrophysiological Evaluation of Small Fiber Neuropathy in Symptomatic Patients with Vitamin B12 Deficiency before and after Treatment

ABSTRACT Background: Small fiber neuropathy (SFN) leads to sensory and autonomic dysfunction by affecting small-diameter myelinated A-delta and unmyelinated C fibers, with vitamin B12 deficiency identified as one of its causes. Objectives: To achieve early diagnosis of SFN in patients with vitamin B12 deficiency and to illustrate the impact of vitamin B12 replacement therapy using noninvasive electrophysiological tests. Materials and Methods: Patients aged 18 to 65 with vitamin B12 deficiency experiencing neuropathic pain or autonomic symptoms were included. A control group consisted of asymptomatic, healthy volunteers with normal B12 levels. Neurological examinations, cutaneous silent period (CSP), sympathetic skin response (SSR), and cardiovascular autonomic tests (R-R interval variability during the Valsalva maneuver [RRIV-VM] and standing [RRIV-S]) were performed at admission and six months later. Patients received 1000 mcg cyanocobalamin intramuscularly daily for one week, weekly for one month, and monthly for three months. Results: The final analyses included 25 patients and 25 controls. At admission, patients had significantly longer CSP and SSR latencies compared to controls (P = 0.047, P &lt; 0.001) and shortened CSP durations (P = 0.043). The SSR amplitude was lower in patients but not significantly (P = 0.823). Post-treatment, CSP latency, CSP duration, and SSR latency significantly improved (P &lt; 0.001, P = 0.002, P &lt; 0.001). Positive symptoms and autonomic symptoms improved significantly after treatment (P = 0.039, P = 0.016). The number of patients with neuropathic pain significantly decreased (P = 0.008). Conclusion: CSP latency, CSP duration, and SSR latency are effective, non-invasive, and cost-effective screening tests for diagnosing SFN in individuals with B12 deficiency. These tests are also valuable for monitoring the progression of SFN following vitamin B12 replacement therapy. The study supports the use of these noninvasive electrophysiological tests to enhance early diagnosis and treatment efficacy in SFN associated with vitamin B12 deficiency.

Analgesic Effect of Auricular Vagus Nerve Stimulation on Oxaliplatin-induced Peripheral Neuropathic Pain in a Rodent Model.

Cancer chemotherapy often triggers peripheral neuropathy in patients, leading to neuropathic pain in the extremities. While previous research has explored various nerve stimulation to alleviate chemotherapy-induced peripheral neuropathy (CIPN), evidence on the effectiveness of noninvasive auricular vagus nerve stimulation (aVNS) remains uncertain. This study aimed to investigate the efficacy of non-invasive aVNS in relieving CIPN pain. To induce CIPN in experimental animals, oxaliplatin was intraperitoneally administered to rats (6 mg/kg). Mechanical and cold allodynia, the representative symptoms of neuropathic pain, were evaluated using the von Frey test and acetone test, respectively. The CIPN animals were randomly assigned to groups and treated with aVNS (5 V, square wave) at different frequencies (2, 20, or 100 Hz) for 20 minutes. Results revealed that 20 Hz aVNS exhibited the most pronounced analgesic effect, while 2 or 100 Hz aVNS exhibited weak effects. Immunohistochemistry analysis demonstrated increased c-Fos expression in the locus coeruleus (LC) in the brain of CIPN rats treated with aVNS compared to sham treatment. To elucidate the analgesic mechanisms involving the adrenergic descending pathway, α1-, α2-, or β-adrenergic receptor antagonists were administered to the spinal cord before 20 Hz aVNS. Only the β-adrenergic receptor antagonist, propranolol, blocked the analgesic effect of aVNS. These findings suggest that 20 Hz aVNS may effectively alleviate CIPN pain through β-adrenergic receptor activation.

Efficacy and Safety of Trazodone and Gabapentin Fixed-Dose Combination in Patients Affected by Painful Diabetic Neuropathy: Randomized, Controlled, Dose-Finding Study.

Up to 50% of diabetic patients with neuropathy suffer from chronic pain, namely painful diabetic neuropathy (PDN), an unmet medical need with significant impact on quality of life. Gabapentin is widely used for PDN, albeit with frequent dose-limiting effects. Trazodone, an antidepressant with multi-modal action, has shown promising results when given at low doses as an add-on to gabapentin. Upon previous clinical trials and experimental evidence, a fixed-dose combination (FDC) of both compounds, at low doses, was developed for neuropathic pain. This was a phase II, randomized, double-blind, placebo and reference controlled, dose-finding, multicenter, international, prospective study. Male and female diabetic patients aged 18-75years and affected by PDN were eligible for enrolment. Patients were randomized (1:1:1:1:2 ratio) to trazodone and gabapentin (Trazo/Gaba) 2.5/25mg t.i.d. for 8weeks, Trazo/Gaba 5/50mg t.i.d. for 8weeks, Trazo/Gaba 10/100mg t.i.d. for 8weeks, gabapentin (Gaba), or placebo (PLB). The aim of the study was to collect preliminary information on the effect of the 3 different FDCs of Trazo/Gaba on pain intensity based on the 11-point numeric rating score (NRS) after 8weeks of treatment. The secondary objectives were the evaluation of the percentage of responders, neuropathic pain symptoms, anxiety, sleep, quality of life, safety, and tolerability. The primary efficacy endpoint was evaluated with last observation carried out forward (LOCF), using an analysis of covariance (ANCOVA), including treatment and centers as factors and baseline as covariate and applying linear contrast test, excluding the active treatment. Only if the linear contrast test was significant (p < 0.05), the step-down Dunnett test would be used to determine the minimum effective dose significantly different from PLB. If linearity was not verified, an adjusted ANCOVA model and comparisons with Dunnett test were performed. Before the application of the ANCOVA model, the non-significance of interaction treatment per baseline was verified. A total of 240 patients were included in the modified intention-to-treat (m-ITT) population: 39 in Trazo/Gaba 2.5/25mg, 38 in Trazo/Gaba 5/50mg, 37 in Trazo/Gaba 10/100mg, 83 in PLB, and 43 in Gaba. After 8weeks of treatment, changes of the average daily pain score based on the 11-point NRS from baseline were - 2.52 ± 2.31 in Trazo/Gaba 2.5/25mg group, - 2.24 ± 1.96 in Trazo/Gaba 5/50mg group, - 2.46 ± 2.12 in Trazo/Gaba 10/100mg group, - 1.92 ± 2.21 in Gaba group, and - 2.02 ± 1.95 in the PLB group. The linear contrast test did not result in significant differences (p > 0.05) among treatment groups. Consequently, the minimum effective dose against PLB was not determined. The multiple comparison with Dunnett adjustment did not show any statistically significant differences vs. PLB after 8weeks of treatment: Trazo/Gaba 2.5/25mg (95% confidence interval (CI) - 1.2739, 0.2026; p = 0.1539); Trazo/Gaba 5/50mg (95% CI - 0.9401, 0.5390; p = 0.5931); Trazo/Gaba 10/100mg (95% CI - 1.0342, 0.4582; p = 0.4471). However, patients receiving the lowest dose of Trazo/Gaba 2.5/25mg showed a statistically significant difference to PLB after 6weeks of treatment (95% CI - 1.6648, - 0.2126; p = 0.0116). Positive results were also found for responder patients, other items related to the pain, anxiety, depression, sleep, and quality of life, consistently in favor to the lowest Trazo/Gaba FDC. Two serious adverse events (SAEs) occurred but were judged unrelated to the study treatment. Treatment-emergent adverse events (TEAEs) were mainly mild-to-moderate in intensity and involved primarily nervous system, gastrointestinal disorders, and investigations. The primary end point of the study was the change from baseline of the average daily pain score based on the 11-point NRS after 8weeks of treatment. While the primary endpoint was not reached, patients treated with Trazo/Gaba 2.5/25mg t.i.d. showed statistically significant improvement of pain and other scores after 6weeks and reported consistent better results in comparison to PLB on primary and secondary endpoints for the overall study duration. According to these results, the lowest dose of Trazo/Gaba FDC may be the best candidate for further clinical development to confirm the potential benefits of the FDC drug for this condition. NCT03749642.

Is there a relationship between somatosensory impairment and the perception of pain in stroke survivors? An exploratory study.

Pain and somatosensory impairments are commonly reported following stroke. This study investigated the relationship between somatosensory impairments (touch detection, touch discrimination and proprioceptive discrimination) and the reported presence and perception of any bodily pain in stroke survivors. Stroke survivors with somatosensory impairment ( N = 45) completed the Weinstein Enhanced Sensory Test (WEST), Tactile Discrimination Test, and Wrist Position Sense Test for quantification of somatosensation in both hands and the McGill Pain Questionnaire, visual analog scale and the Neuropathic Pain Symptom Inventory (NPSI) for reporting presence and perception of pain. No relationship was observed between somatosensory impairment (affected contralesional hand) of touch detection, discriminative touch or proprioceptive discrimination with the presence or perception of pain. However, a weak to moderate negative relationship between touch detection in the affected hand (WEST) and perception of pain intensity (NPSI) was found, suggesting that stroke survivors with milder somatosensory impairment of touch detection, rather than severe loss, are likely to experience higher pain intensity [rho = -0.35; 95% confidence interval (CI), -0.60 to -0.03; P = 0.03]. Further, a moderate, negative relationship was found specifically with evoked pain (NPSI) and touch detection in the affected hand (rho = -0.43; 95% CI, -0.72 to -0.02; P = 0.03). In summary, our findings indicate a weak to moderate, albeit still uncertain, association, which prevents making a definitive conclusion. Nevertheless, our findings contribute to our understanding of the complexities surrounding the experience of pain in survivors of stroke and provide direction for future studies.

Neuropathic pain after major limb amputation: a cross-sectional study

Background &amp; Objective: Residual limb pain (RLP) and phantom pain can arise following amputation and may require additional treatment or surgery. This study aimed to determine the prevalence of neuropathic RLP following limb amputation and identify prognostic factors for the development of neuropathic RLP. Methods: A cross-sectional study was performed of patients who underwent upper or lower extremity amputation between 1990 and 2021 with a minimum of twelve months follow-up. The primary outcome was the prevalence of neuropathic RLP, defined as a 0-10 NRS pain score in the residual limb of ≥4, in combination with a score ≥4 on the short form DN4 questionnaire (s-DN4), validated for discriminating between nociceptive and neuropathic pain. The secondary outcome was quality of life for amputees with and without (neuropathic) RLP. A multivariable linear regression model was used to identify prognostic factors for neuropathic RLP development. Results: A total of 121 patients were included: 87 with lower extremity amputations, 29 with upper extremity amputations, and 5 with both. Neuropathic RLP was experienced by 21.5%, while 10.7% reported non-neuropathic RLP. Smoking status and Complex Regional Pain Syndrome as indication for limb amputation were associated with more severe neuropathic pain symptoms. Patients experiencing neuropathic RLP reported a significantly lower quality of life compared to patients without neuropathic RLP. Conclusions: This study demonstrates that neuropathic RLP is common after limb amputation and impacts daily functioning. The absence of numerous manageable prognostic factors associated with neuropathic pain development emphasizes the importance of the consideration of prophylactic interventions at the time of amputation.

6-Methoxyflavone antagonizes chronic constriction injury and diabetes associated neuropathic nociception expression

Neuropathy is a disturbance of function or a pathological change in nerves causing poor health and quality of life. A proportion of chronic pain patients in the community suffer persistent neuropathic pain symptoms because current drug therapies may be suboptimal so there is a need for new therapeutic modalities. This study investigated the neuroprotective flavonoid, 6-methoxyflavone (6MF), as a potential therapeutic agent and gabapentin as the standard comparator, against neuropathic models. Thus, neuropathic-like states were induced in Sprague-Dawley rats using sciatic nerve chronic constriction injury (CCI) mononeuropathy and systemic administration of streptozotocin (STZ) to induce polyneuropathy. Subsequent behaviors reflecting allodynia, hyperalgesia, and vulvodynia were assessed and any possible motoric side-effects were evaluated including locomotor activity, as well as rotarod discoordination and gait disruption. 6MF (25–75 mg/kg) antagonized neuropathic-like nociceptive behaviors including static- (pressure) and dynamic- (light brushing) hindpaw allodynia plus heat/cold and pressure hyperalgesia in the CCI and STZ models. 6MF also reduced static and dynamic components of vulvodynia in the STZ induced polyneuropathy model. Additionally, 6MF reversed CCI and STZ suppression of locomotor activity and rotarod discoordination, suggesting a beneficial activity on motor side effects, in contrast to gabapentin. Hence, 6MF possesses anti-neuropathic-like activity not only against different nociceptive modalities but also impairment of motoric side effects.