This study aims to evaluate the efficacy and safety of Crisugabalin in patients with diabetic peripheral neuropathic pain (DPNP), with a focus on its rapid onset of action.

All the analyses in this study were based on data from a phase 2/3 adaptive randomized clinical trial that enrolled 596 patients. Participants were categorized into four treatment groups according to the intervention received: Crisugabalin 40 mg/day, Crisugabalin 80 mg/day, placebo, and Pregabalin 300 mg/day. The primary endpoint was the change in the average daily pain score (ADPS) over a 13-week treatment period. Secondary endpoints included changes in the Numeric Rating Scale (NRS) and the daily sleep interference score (DSIS) during the first two weeks of treatment.

Both Crisugabalin treatment groups (40 mg/day and 80 mg/day) demonstrated statistically significant reductions in ADPS compared to the placebo group starting from week 1 and continuing through week 13 (P < 0.05). Significant differences in pain relief for the Pregabalin group were observed only from week 6. Improvements in NRS and DSIS scores were also noted in both Crisugabalin groups, with statistically significant enhancements evident as early as day 2 of administration. Safety assessments indicated that Crisugabalin was well-tolerated, with a low incidence of serious adverse events and no significant increase in dropout rates among participants.

The findings suggest that Crisugabalin offers effective pain relief with an acceptable safety profile, highlighting its rapid onset in patients with DPNP.

Clinical trial registration number derived from our parent project, we have retained the original registration identifier: NCT04647773.

Neuromodulation therapies (including non-invasive and invasive neuromodulation) are being used to treat painful diabetic neuropathy (PDN).

A systematic search of the PubMed, Embase, Cochrane Library, Web of Science, and Scopus databases was conducted, from their inception until 1 October 2024, to identify randomized controlled trials (RCTs) on neuromodulation therapies for PDN. Data were collected on pain intensity of various adjunctive therapies for PDN, including transcutaneous electrical nerve stimulation (TENS), percutaneous electrical nerve stimulation, repetitive transcranial magnetic stimulation, pulsed electromagnetic field therapy, spinal cord stimulation (SCS), transcranial direct current stimulation, frequency rhythmic electrical modulation system, mesodiencephalic modulation, and sham.

The data from an aggregate of 12 separate studies, comprising a total sample size of 922 participants, was subject to analysis. All seven neuromodulation therapies exhibited better outcomes in pain intensity compared to the Sham intervention, with TENS achieving the highest ranking, followed by SCS. At the final follow-up time point, statistically significant reductions in pain intensity (vs. Sham) was only observed for SCS.

The results of this network meta-analysis should facilitate the development of clinical guidance and enhance the decision-making process for both patients and healthcare professionals, thereby identifying the most appropriate PDN treatment options.

PROSPERO: CRD42024597208.

This study aims to adapt and validate the Foot Health Status Questionnaire, developed by Bennett et al., in Portuguese patients with diabetic foot.

A cross-sectional study was conducted with 143 patients with diabetic foot. A principal component analysis with oblique rotation and a confirmatory factor analysis using structural equation modeling were performed.

The Portuguese version of the FHSQ (FHSQ-PT) in patients with diabetic foot remains equal to the original version, although with all factors correlated with each other. All scales presented high internal consistency values (pain: ω = 0.884; function: ω = 0.890; general foot health: ω = 0.910; and footwear: ω = 0.702), except for the footwear scale, although with a minimum acceptable coefficient. The FHSQ-PT scales showed good convergent validity and good discriminant validity. The FHSQ-PT scales were also able to discriminate between male and female patients as well as between patients with an active diabetic foot ulcer from those who did not.

The results of the validated FHSQ-PT for Portuguese patients with diabetic foot showed good psychometric properties, being a useful, objective, and small instrument that may be used in clinical practice by health professionals without consuming too much time.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common and debilitating adverse effect of neurotoxic chemotherapy characterized by symptoms such as numbness, tingling, and weakness. Effective monitoring and detection of CIPN are crucial for avoiding progression to irreversible symptoms. Due to the inconvenience of clinic-based objective assessment, CIPN detection relies primarily on patients' reporting of subjective symptoms, and patient-reported outcomes are used to facilitate CIPN detection. Our previous study found evidence that objective functional assessments completed within a smartphone app may differentiate patients with and those without CIPN after treatment.

This prospective, longitudinal observational cohort study aimed to determine the feasibility and accuracy of app-based remote monitoring of CIPN in patients with cancer undergoing neurotoxic chemotherapeutic treatment and to conduct exploratory comparisons of app-based functional CIPN monitoring versus patient-reported outcome-only monitoring.

The NeuroDetect app (Medable Inc) includes subjective EORTC (European Organization for Research and Treatment of Cancer) Quality of Life Questionnaire (QLQ)-20-item scale (CIPN20) and 6 objective functional assessments that use smartphone sensors to mimic neurological examinations, such as walking, standing, and manual dexterity tests. The functional assessment data were collected from patients with cancer undergoing neurotoxic chemotherapy, and a neurological examination was conducted at the end of treatment to diagnose CIPN in the feet (CIPN-f) or CIPN in the hands (CIPN-h). Various classification models including NeuroDetect features only (NeuroDetect Model) CIPN20-only (CIPN20 Model) or a combination of both (Combined Model) were trained and evaluated for accuracy in predicting CIPN probability.

Of the 45 patients who completed functional assessments and neurological examinations, 24 had CIPN-f, and 29 had CIPN-h. The NeuroDetect Model could discriminate between patients with and those without CIPN-f (area under the curve=83.8%, comparison with no information rate P=.02) but not CIPN-h (area under the curve=67.9%, P=.18). The rolling rotation features from the eyes-closed phase of the Romberg Stance assessment showed the greatest contribution to CIPN-f (40% of total variable importance) and the Finger Tapping assessment showed the greatest contribution to CIPN-h (85% of total variable importance). The NeuroDetect Model had numerically, and at some time points statistically, superior performance to the CIPN20 Model in both CIPN-f and CIPN-h, particularly before and early in treatment. The Combined Model numerically, though not statistically, outperformed either assessment strategy individually, indicating that the combination of functional and patient-reported assessment within a smartphone may be optimal to CIPN detection.

Our findings demonstrate the feasibility of integrating subjective and objective CIPN assessment into a smartphone app for remote, longitudinal CIPN monitoring. Studies of larger patient cohorts are needed to refine the app-based CIPN detection models and determine whether their use in practice improves CIPN detection.

We report the efficacy and safety of E-52862-a selective, sigma-1 receptor antagonist-from phase 2, randomized, proof-of-concept studies in patients with moderate-to-severe, neuropathic, chronic postsurgical pain (CPSP) and painful diabetic neuropathy (PDN).

Adult patients (CPSP [N = 116]; PDN [N = 163]) were randomized at a 1:1 ratio to 4 weeks of treatment with E-52862 (CPSP [n = 55]; PDN [n = 85]) or placebo (CPSP [n = 61]; PDN [n = 78]) orally once daily. Pain intensity scores were measured using a numerical pain rating scale from 0 (no pain) to 10 (worst pain imaginable). The primary analysis population comprised patients who received study drug with ≥1 baseline and on-treatment observation (full analysis set).

In CPSP, mean baseline average pain was 6.2 for E-52862 vs. 6.5 for placebo. Week 4 mean change from baseline (CFB) for average pain was -1.6 for E-52862 vs. -0.9 for placebo (least squares mean difference [LSMD]: -0.9; p = 0.029). In PDN, mean baseline average pain was 5.3 for E-52862 vs. 5.4 for placebo. Week 4 mean CFB for average pain was -2.2 for E-52862 vs. -2.1 for placebo (LSMD: -0.1; p = 0.766). Treatment-emergent adverse events (TEAEs) were reported in 90.9% of E-52862-treated patients vs. 76.7% of placebo-treated patients in CPSP and 34.1% vs. 26.9% in PDN. Serious TEAEs occurred in CPSP only: E-52862: 5.5%; placebo: 6.7%.

E-52862 demonstrated superior relief of CPSP vs. placebo after 4 weeks. Reductions in pain intensity were seen in PDN with E-52862; high placebo response rates may have prevented differentiation between treatments. E-52862 had acceptable tolerability in both populations.

These proof-of-concept studies validate the mode of action of E-52862, a selective sigma-1 receptor antagonist. In CPSP, E-52862 resulted in clinically meaningful pain relief. In PDN, reductions in pain intensity were seen with E-52862; high placebo response rates may have prevented differentiation between E-52862 and placebo. These findings are clinically relevant given that neuropathic pain is highly incapacitating, lacking effective treatments and representing a significant unmet medical need, and support further development of sigma-1 receptor antagonists for peripheral neuropathic pain.

Peripheral Neuropathy (PN) can significantly impair quality of life, but often remains undiagnosed due to limited clinic time, lack of specialist expertise and lack of patient awareness. There are several validated questionnaires for diagnosing PN, but the time taken to administer them in busy primary care clinics limits their utilization. A new, simpler questionnaire was developed following an advisory board meeting in Southeast Asia and was further refined and translated to Portuguese and Spanish following a second advisory board meeting in Latin America. We consider current hurdles and propose a quick and reliable questionnaire that can be widely adopted to enable earlier diagnosis and improved management of PN in resource-limited settings in Latin America.

Diabetes mellitus is a chronic metabolic disease characterized by abnormally elevated blood glucose levels. Type II diabetes accounts for approximately 90% of all cases. Several drugs are available for hyperglycemia treatment. However, the current therapies for managing high blood glucose do not prevent or reverse the disease progression, which may result in complications and adverse effects, including diabetic neuropathy, retinopathy, and nephropathy. Hence, developing safer and more effective methods for lowering blood glucose levels is imperative. Transient receptor potential vanilloid-1 (TRPV1) is a significant member of the transient receptor potential family. It is present in numerous body tissues and organs and performs vital physiological functions.

This review aimed to develop new targeted TRPV1 hypoglycemic drugs by systematically summarizing the mechanism of action of the TRPV1-based signaling pathway in preventing and treating diabetes and its complications.

Literature searches were performed in the PubMed, Web of Science, Google Scholar, Medline, and Scopus databases for 10 years from 2013 to 2023. The search terms included "diabetes," "TRPV1," "diabetic complications," and "capsaicin."

TRPV1 is an essential potential target for treating diabetes mellitus and its complications. It reduces hepatic glucose production and food intake and promotes thermogenesis, metabolism, and insulin secretion. Activation of TRPV1 ameliorates diabetic nephropathy, retinopathy, myocardial infarction, vascular endothelial dysfunction, gastroparesis, and bladder dysfunction. Suppression of TRPV1 improves diabetes-related osteoporosis. However, the therapeutic effects of activating or suppressing TRPV1 may vary when treating diabetic neuropathy and periodontitis.

This review demonstrates that TRPV1 is a potential therapeutic target for diabetes and its complications. Additionally, it provides a theoretical basis for developing new hypoglycemic drugs that target TRPV1.

Despite advancements in diabetes treatment, the management of Painful Diabetic Neuropathy (PDN) remains challenging. Our previous research indicated a significant correlation between the expression and distribution of Aquaporin-4 (AQP4) in the spinal glymphatic system and PDN. However, the potential role and mechanism of liquiritin in PDN treatment remain uncertain.

This study established a rat model of PDN using a combination of low-dose Streptozotocin (STZ) and a high-fat, high-sugar diet. Rats were treated with liquiritin and MCC950 (an NLRP3 inhibitor). We monitored fasting blood glucose, body weight, and mechanical allodynia periodically. The glymphatic system's clearance function was evaluated using Magnetic Resonance Imaging (MRI), and changes in proteins including NLRP3, MMP-9, and AQP4 were detected through immunofluorescence and Western blot techniques.

The rats with painful diabetic neuropathy (PDN) demonstrated several physiological changes, including heightened mechanical allodynia, compromised clearance function within the spinal glymphatic system, altered distribution of AQP4, increased count of activated astrocytes, elevated expression levels of NLRP3 and MMP-9, and decreased expression of AQP4. However, following treatment with liquiritin and MCC950, these rats exhibited notable improvements.

Liquiritin may promote the restoration of AQP4 polarity by inhibiting NLRP3 and MMP-9, thereby enhancing the clearance functions of the spinal cord glymphatic system in PDN rats, alleviating the progression of PDN.

Bibliometric analysis is a rigorous method to analyze significant quantities of bibliometric data to assess their impact on a particular field. This study used bibliometric analysis to investigate the academic research on diabetes detection and classification from 2000 to 2023. The PRISMA 2020 framework was followed to identify, filter, and select relevant papers. This study used the Web of Science database to determine relevant publications concerning diabetes detection and classification using the keywords "diabetes detection", "diabetes classification", and "diabetes detection and classification". A total of 863 publications were selected for analysis. The research applied two bibliometric techniques: performance analysis and science mapping. Various bibliometric parameters, including publication analysis, trend analysis, citation analysis, and networking analysis, were used to assess the performance of these articles. The analysis findings showed that India, China, and the United States are the top three countries with the highest number of publications and citations on diabetes detection and classification. The most frequently used keywords are machine learning, diabetic retinopathy, and deep learning. Additionally, the study identified "classification", "diagnosis", and "validation" as the prevailing topics for diabetes identification. This research contributes valuable insights into the academic landscape of diabetes detection and classification.

There is no approved effective drug for diabetic peripheral neuropathic pain (DPNP) in China. Gabapentinoids including mirogabalin have shown promise, although data in Chinese patients are scarce.

This phase 3, multicenter, randomized, double-blind, placebo-controlled trial investigated the efficacy and safety of mirogabalin for treating DPNP in China. Mirogabalin was administered at 5 mg twice daily for the first week and uptitrated to 15 mg twice daily for a total duration of 14 weeks. The primary efficacy endpoint was the change from baseline in weekly average daily pain score (ADPS) at week 14; secondary endpoints included the ADPS responder rate, Short-Form McGill Pain Questionnaire visual analogue scale score, patient global impression of change (PGIC), average daily sleep interference score (ADSIS), EuroQol 5-dimensions 5-levels (EQ-5D-5L), and incidence of treatment-emergent adverse events (TEAEs).

Of 393 patients (mirogabalin, n = 196; placebo n = 197), the mean age was 58.2 years (mirogabalin, 58.7 years; placebo, 57.7 years) and 54.2% were male (mirogabalin, 56.1%; placebo, 52.3%). Mirogabalin elicited a greater change from baseline in the weekly ADPS vs. placebo at week 14: least-squares mean difference (95% confidence interval) vs. placebo - 0.39 (- 0.74, - 0.04), p = 0.0301. PGIC, ADSIS, and EQ-5D-5L data reflected significantly better improvements for patients receiving mirogabalin vs. placebo. The incidence of TEAEs was 75.0% and 75.1% in the mirogabalin and placebo groups, respectively. Most TEAEs were mild or moderate, and the incidence of TEAEs leading to treatment discontinuation was 2.6% in the mirogabalin group and 1.5% in the placebo group.

Although the effect size of mirogabalin was reduced due to the placebo effect, mirogabalin is a safe and effective treatment option for Chinese patients with DPNP.

ClinicalTrials.gov identifier, NCT04094662.

To explore the clinical utility of ultrasound in evaluating and grading neuromuscular diseases in the lower extremities of patients with diabetes mellitus.

A total of 126 inpatients from the Department of Diabetes at Zhangzhou Affiliated Hospital of Fujian Medical University, China, were recruited from June 2020 to December 2022. The cohort included 69 patients with type 2 diabetes mellitus (T2DM) and diabetic peripheral neuropathy (DPN group) and 57 patients with T2DM but without DPN (non-DPN group). Additionally, 80 healthy controls were included. High-frequency ultrasound was used to scan the common peroneal, sural, and tibial nerves, measuring their transverse (D1) and anteroposterior (D2) diameters, and calculating the cross-sectional area (CSA). Changes in the internal echo of the extensor digitorum brevis (EDB) muscle, including maximum thickness and CSA, were also recorded. The DPN group was further subdivided based on disease duration to assess ultrasonic changes over time and the statistical significance of these variations.

Ultrasonic changes such as uneven internal echo reduction, ill-defined epineurial boundaries, and obscured cribriform structures were most prevalent in the DPN group. Significant differences in ultrasound parameters (D1, D2, CSA) were observed among the groups (all P<0.05), with the most pronounced changes in the DPN group. In patients with a disease duration of over 15 years, a significant increase in CSA of lower extremity nerves and a decrease in CSA of the EDB were noted compared to those in the 5-10 years subgroup (19.89±0.98 vs 19.00±0.94; 5.25±0.74 vs 5.93±0.94; all P<0.05).

High-frequency ultrasound provides a valuable imaging basis for diagnosing and monitoring DPN, demonstrating significant changes in nerve and muscle parameters among diabetic patients.

Thermal threshold testing (TTT) is a simple non-invasive approach for diagnosing diabetic neuropathy earlier. Conventionally the TTT is done in all four limbs and at least 6 trials are done to obtain the mean threshold, which is time consuming.

We propose to assess the validity and reliability of reduced number of trials of TTT in the lower limbs.

After obtaining ethics approval from the Institute Ethics Committee, 100 patients with type 2 Diabetes Mellitus of both gender between the ages of 35 to 65 years attending medicine OPD were recruited. Neuropathy assessment was done using Temperature threshold testing. At least 6 trials were performed for each site and the mean threshold obtained. The mean of 5 trials, 4 trials and 3 trials were noted for the comparison.

On comparing hot tests of 3 trials with 6 trials had a sensitivity and specificity of 88.7% and 96.6 %. In cold threshold testing, 4 trials and 3 trials showed similar results of sensitivity of 77.8%, specificity of 98.8%. The measures of agreement between the hot trials 6 vs 5 had Kappa value of 0.953, 6vs 4 showed a Kappa value of 0.862 and 6 vs 3 showed Kappa value of 0.819.

Hot threshold tests of lower limb are more sensitive than cold thresholds. The 4 trial test is a reliable test and can be performed over 6 trial tests. When time is a factor, three trials are sufficient to diagnose small fibre neuropathy.

Peripheral neuropathy (PN) is one of the most common diseases of the peripheral nervous system. Symptoms range from mild sensory signs to severe neuropathic pain. Untreated PN is progressive and can lead to complications and impair quality of life (QoL). However, PN prevalence is underestimated in the general population and affected individuals often remain undiagnosed. This study aimed to contribute to the global generation of prevalence data and determine sociodemographic and disease-related characteristics of PN sufferers.

This cross-sectional study collected information on PN prevalence and associated factors in the adult population (40-65 years) of the Mexico City area. Participants were recruited in public places and screened for PN using the Michigan Neuropathy Screening Instrument (MNSI). Subjects with PN answered the Neuropathy Total Symptom Score-6 (NTSS-6), the Short Form-36 Health Survey (SF-36), and the QoL Pharmacoeconomic Questionnaire. Statistical analysis included descriptive methods and calculation of PN prevalence with 95% confidence intervals.

Of 3066 participants, 448 had PN based on the MNSI physical examination. The overall PN prevalence was 14.6%, with the highest (18.9%) seen in subjects aged 61-65 years. PN was undiagnosed in 82.6%, and 62.9% had never heard of PN. Although half of all subjects had only mild PN symptoms, QoL was impacted in 91.8%.

The results confirm that PN prevalence in the general population is high. Despite the disease burden, most affected persons are undiagnosed and unaware of the disease. Almost all felt their QoL was impacted. The data highlight the need to raise awareness and identify undiagnosed individuals to prevent complications.

Peripheral neuropathy characterized by rapidly increasing numbers of patients is commonly diagnosed via analyzing electromyography signals obtained from stimulation-recording devices. However, existing commercial electrodes have difficulty in implementing conformal contact with skin and gentle detachment, dramatically impairing stimulation/recording performances. Here, this work develops on-skin patches with polyaspartic acid-modified dopamine/ethyl-based ionic liquid hydrogel (PDEH) as stimulation/recording devices to capture electromyography signals for the diagnosis of peripheral neuropathy. Triggered by a one-step electric field treatment, the hydrogel achieves rapid and wide-range regulation of adhesion and substantially strengthened mechanical performances. Moreover, hydrogel patches assembled with a silver-liquid metal (SLM) layer exhibit superior charge injection and low contact impedance, capable of capturing high-fidelity electromyography. This work further verifies the feasibility of hydrogel devices for accurate diagnoses of peripheral neuropathy in sensory, motor, and mixed nerves. For various body parts, such as fingers, the elderly's loose skin, hairy skin, and children's fragile skin, this work regulates the adhesion of PDEH-SLM devices to establish intimate device/skin interfaces or ensure benign removal. Noticeably, hydrogel patches achieve precise diagnoses of nerve injuries in these clinical cases while providing extra advantages of more effective stimulation/recording performances. These patches offer a promising alternative for the diagnosis and rehabilitation of neuropathy in future.

Small fiber neuropathy (SFN) is a well-defined chronic painful condition causing severe individual and societal burden. While mood disorders have been described, cognitive and behavioral profiles of SFN patients has not been investigated.

Thirty-four painful SFN patients underwent comprehensive cognitive, behavioral, psychological, quality of life (QoL), and personality assessment using validated questionnaires. As control samples, we enrolled 36 patients with painful peripheral neuropathy (PPN) of mixed etiology and 30 healthy controls (HC). Clinical measures of neuropathic pain, duration, frequency, and intensity of pain at the time of assessment were recorded. Between-group and correlation analyses were performed and corrected for multiple comparisons.

No differences in clinical measures were found between SFN and PPN, and all groups had similar cognitive profiles. SFN patients showed higher levels of anxiety and alexithymia (p < .005) compared to PPN and HC, considering also pain intensity. Maladaptive coping strategies characterized both patient groups, but only SFN revealed higher levels of acceptance of pain (p < .05). Pain intensity and neuropathic symptoms were associated with mood, low QoL and catastrophism (p < .001), particularly, the higher the perceived pain intensity, the higher the use of maladaptive coping strategies (p < .001). The personality assessment revealed significant feelings of worthlessness and somatization traits both in SFN and PPN (p < .002 vs HC).

our results suggest that SFN patients had a normal-like cognitive profile, while their behavioral profile is characterized by mood disorders, alexithymia, maladaptive coping strategies, and poor QoL, as other chronic pain conditions, possibly related to pain intensity. Personality assessment suggests that somatization and feelings of worthlessness, which may worsen the neuropsychological profile, deserve clinical attention when considering patients' therapeutic approaches. At the same time, the high level of acceptance of pain is promising for therapeutic approaches based on psychological support.

Dysfunction of small nerve fibers remains a major public health concern. Subjects suspected of having small nerve fiber damage need to undergo reliable tests to confirm the diagnosis. Sudomotor function test is a reliable noninvasive exploration for detecting peripheral neuropathies. Nevertheless, the normal reference values derived from the sudomotor function test are not known in the African population. The objective of this study was therefore to describe the normal values of Electrochemical Skin Conductance (ESC) measured by the sudomotor function test in healthy African subjects.

Between December 1st, 2021 and May 31st, 2022, ESC was measured in 475 healthy subjects (median age: 42 [31-53] years, 46% men) using a sudomotor function test, in the hands and feet. Investigators proposed the examination and received participants' consent; demographic, anthropometric, biological, and clinical data were obtained before the test. Data on 475 healthy study participants who underwent sudomotor function testing was collected and analyzed. The sociodemographic (age, sex), anthropometric (weight, height, waist circumference, body mass index), diastolic blood pressure, systolic blood pressure, heart rate, and electrochemical skin conductances of the hands and feet were assessed.

ESC values were statistically higher in men compared to women (right hand ESC: 70 [60-78] versus 63 [53-72], left hand ESC: 72 [61-80] versus 68 [57-75], right foot ESC: 77 [82-99] versus 72 [64-79], ESC left foot: 76 [68-82] versus 72 [62-78] respectively). ESC values were significantly inversely correlated with age (right hand ESC: r=-0.12, P=0.006; left hand ESC: r=-0.11, P=0.01; right foot ESC: r=-0.37, P<0.0001; ESC left foot: r=-0.38, P<0.0001). ESC values measured in feet were significantly inversely correlated with body mass index (right foot r=-0.22, P<0.0001; left foot r=-0.21, P<0.0001).

This study reports normal reference values for ESCs according to age and gender in the healthy African population. Progressive decrease in ESC with aging is confirmed by our data. The value of ESC seems lower in the African population than in other reported ethnicities. This finding needs to be further explored in additional studies.

Diagnosing diabetic neuropathy is a challenge at times as it is asymptomatic. Diagnosing diabetic neuropathy involves the use of quantitative sensory testing, nerve conduction study, and autonomic testing. Tempearture threshold testing (TTT) can aid in diagnosing small fiber neuropathy at early stages. This study aimed to assess the small fiber neuropathy using TTT in diabetes mellitus (DM) and correlate with age, duration of diabetes, and lipid profile.

The study was commenced after obtaining ethics approval from the institute ethics committee. The study participants included 100 patients with type 2 DM of both genders between the ages of 40 and 65 years. The glycemic status and lipid profile were noted along with physical examination. Neuropathy assessment was done using Michigan Neuropathy Screening Instrument (MNSI) and TTT.

The prevalence of small fiber neuropathy based on TTT was 63%. The lipid profile was similar in both the groups. The MNSI B scale had significantly higher scores in the neuropathy group. In the neuropathy group, the thresholds for hot were significantly greater in all four limbs and cold were significantly lower. Age and years of DM were positively correlated with the neuropathy. Hot threshold in the lower limb had shown a strong positive correlation.

The age and duration of diabetes are independent risk factors for diabetic peripheral neuropathy. Small fiber neuropathy is a prequel to the motor neuropathy. Hot threshold testing in the lower limb is more sensitive than cold threshold testing for diagnosing small fiber neuropathy.

Neuropathic pain is a disabling condition caused by various diseases and can profoundly impact the quality of life. Unfortunately, current treatments often do not produce complete amelioration and can be associated with potential side effects. Recently, herbal drugs have garnered more attention as an alternative or a complementary treatment. In this article, we summarized the results of randomized clinical trials to evaluate the effects of various phytomedicines on neuropathic pain. In addition, we discussed their main bioactive components and potential mechanisms of action to provide a better view of the application of herbal drugs for treating neuropathic pain.

Diabetic neuropathy (DN) is a common and debilitating complication of diabetes mellitus that affects the peripheral nerves and causes pain, numbness, and impaired function. The pathogenesis of DN involves multiple molecular mechanisms, such as oxidative stress, inflammation, and pathways of advanced glycation end products, polyol, hexosamine, and protein kinase C. Phytochemicals are natural compounds derived from plants that have various biological activities and therapeutic potential. Flavonoids, terpenes, alkaloids, stilbenes, and tannins are some of the phytochemicals that have been identified as having protective potential for diabetic neuropathy. These compounds can modulate various cellular pathways involved in the development and progression of neuropathy, including reducing oxidative stress and inflammation and promoting nerve growth and repair. In this review, the current evidence on the effects of phytochemicals on DN by focusing on five major classes, flavonoids, terpenes, alkaloids, stilbenes, and tannins, are summarized. This compilation also discusses the possible molecular targets of numerous pathways of DN that these phytochemicals modulate. These phytochemicals may offer a promising alternative or complementary approach to conventional drugs for DN management by modulating multiple pathological pathways and restoring nerve function.

Chronic neuropathic pain (NP) is an increasingly prevalent disease and leading cause of disability which is challenging to treat. Several distinct classes of drugs are currently used for the treatment of chronic NP, but each drug targets only narrow components of the underlying pathophysiological mechanisms, bears limited efficacy, and comes with dose-limiting side effects. Multimodal therapies have been increasingly proposed as potential therapeutic approaches to target the multiple mechanisms underlying nociceptive transmission and modulation. However, while preclinical studies with combination therapies showed promise to improve efficacy over monotherapy, clinical trial data on their efficacy in specific populations are lacking and increased risk for adverse effects should be carefully considered. Drug-drug co-crystallization has emerged as an innovative pharmacological approach which can combine two or more different active pharmaceutical ingredients in a single crystal, optimizing pharmacokinetic and physicochemical characteristics of the native molecules, thus potentially capitalizing on the synergistic efficacy between classes of drugs while simplifying adherence and minimizing the risk of side effects by reducing the doses. In this work, we review the current pharmacological options for the treatment of chronic NP, focusing on combination therapies and their ongoing developing programs and highlighting the potential of co-crystals as novel approaches to chronic NP management.

Painful Diabetic Peripheral Neuropathy (PDN) is common, affecting around a quarter of patients with both type 1 and type 2 diabetes, and can lead to significant curtailment of functionality and quality of life. Patients may present with unremitting burning, aching or "electric-shock" type pains in their feet, legs and later, in the hands. Conventional management approaches must focus not only on pain relief, but also on concurrent sleep problems, mood disorders and functionality. The mainstay of treatment is pharmacotherapy. Most current international guidelines recommend a choice of four drugs: amitriptyline, duloxetine, pregabalin or gabapentin, as initial treatment for PDN. Recent evidence from the OPTION-DM trial demonstrated that these drugs and their combinations have equivalent efficacy. Moreover, combination treatment provided significant pain relief to patients with inadequate response to the maximum tolerated dose of monotherapy. PDN refractory to pharmacotherapy can be treated with capsaicin 8% or high frequency spinal cord stimulation.

Painful Diabetic Peripheral Neuropathy (PDPN) is a common complication of diabetes, it severely affects the quality of life of patients. Acupuncture has been shown to be effective in the treatment of PDPN. To evaluate the efficacy and safety of acupuncture for pain relief in patients diagnosed with diabetic peripheral neuropathy, we conducted a systematic review and meta-analysis.

We thoroughly searched specific databases, which included PUBMED, EMBASE, Web of Science, the Cochrane Library, the Chinese Biomedical Literature Database, the Chinese National Knowledge Infrastructure, China Science and Technology Journal Database and the Wanfang Data. All randomized controlled trials of acupuncture therapy for PDPN with pain change scales were included. Included studies were assessed for methodological quality according to the risk of bias from the Cochrane handbook. Meta-analyses were carried out to analyze the outcomes, subgroup analyses, sensitivity analyses, and funnel plot analyses were undertaken.

This systematic review evaluated a total of 25 trials of acupuncture therapy in combination with conventional treatment, involving a total of 1,561 patients with PDPN. According to the results, among 16 trials using VAS scores with a total of 1,552 patients, 2 acupoint injection trials (MD -2.38, 95% CI: -2.76 to -2.01, p < 0.00001), 12 acupuncture trials (MD -1. 31, 95% CI: -1.60 to -1.02, p < 0.00001) and 2 moxibustion trials showed that acupuncture therapy combined with conventional treatment improved pain better than conventional treatment (MD -2.50, 95% CI: -2.76 to -2.24, p < 0.00001). In the subgroup analysis of the acupuncture group, the results of the 5 trials in which the location of acupuncture was only in the limbs (MD -1.27, 95% CI: -1.54 to -1.01, p < 0.00001) and the 7 trials both in limbs and torso (MD -1.38, 95% CI: -1.81 to -0.95, p < 0.00001) also demonstrated that acupuncture was effective in pain improvement.

This meta-analysis analyzed the possible efficacy of acupuncture in combination with conventional treatment for pain in diabetic peripheral neuropathy, particularly when acupoints are located in the limbs. However, there are limitations to this meta-analysis and future clinical studies are needed to confirm these findings.

https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023449447, identifier (CRD42023449447).

We aimed to assess DPNCheck's reliability for repeated sural nerve conduction (NC) parameters. This post hoc analysis used data from the randomized controlled ACUDPN trial assessing NC of the N. Suralis every eight weeks over a 6-month period in 62 patients receiving acupuncture against diabetic peripheral neuropathy (DPN) symptoms. The reliability of DPNCheck for nerve conduction velocity and amplitude was assessed using intraclass correlation coefficients (ICC) and was calculated using data from single time points and repeated measures design. The results of the NC measurements were correlated with the Total Neuropathy Score clinical (TNSc). Overall, for both nerve velocity and amplitude, the reliability at each measurement time point can be described as moderate to good and the reliability using repeated measures design can be described as moderate. Nerve velocity and amplitude showed weak correlation with TNSc. DPNCheck's reliability results question its suitability for monitoring DPN's progression. Given the limitation of our analysis, a long-term, pre-specified, fully crossed study should be carried out among patients with DPN to fully determine the suitability of the device for DPN progression monitoring. This was the first analysis assessing the reliability of the DPNCheck for DPN progression monitoring using data from multiple collection time points.

Diabetic neuropathies are the most frequent complications of diabetes, contributing to high morbidity, excess mortality, reduced quality of life, and increased healthcare costs. Prediabetes is characterised by glucose levels within an intermediate range above normoglycaemia yet below the diagnostic threshold for diabetes. In 2021, 10.6% and 6.2% of adults worldwide were estimated to have impaired glucose tolerance and impaired fasting glucose, respectively, the majority of whom are unaware of having prediabetes. Evidence has accumulated suggesting that prediabetes is a predictor of cardiovascular disease (CVD) and increased mortality. The past 2 decades have witnessed an extensive debate, particularly among diabetologists and neurologists, as to whether prediabetes is associated with peripheral neuropathy. In this review, we elaborate on the current evidence, particularly from population-based studies supporting an increased risk of distal sensorimotor polyneuropathy (DSPN) and cardiovascular autonomic neuropathy (CAN) in people with prediabetes. Moreover, we discuss whether lifestyle interventions showing efficacy in preventing or delaying the transition from prediabetes to diabetes in persons with prediabetes may also exert favourable effects on the development and progression of DSPN and CAN. This review should help in raising the awareness of and translating the current knowledge on neuropathies in people with prediabetes into clinical practice and public health. The current recommendation that adults who are overweight or obese should be screened for prediabetes and referred to or offered preventive interventions should ultimately culminate in preventing not only CVD but also prediabetic neuropathy.

The nociceptive flexion reflex (NFR) is a polysynaptic and multisegmental spinal reflex that develops in response to a noxious stimulus and is characterized by the withdrawal of the affected body part. The NFR possesses two excitatory components: early RII and late RIII. Late RIII is derived from high-threshold cutaneous afferent A-delta fibers, which are prone to injury early in the course of diabetes mellitus (DM) and may lead to neuropathic pain. We investigated NFR in patients with DM with different types of polyneuropathies to analyze the role of NFR in small fiber neuropathy (SFN).

We included 37 patients with DM and 20 healthy participants of similar age and sex. We performed the Composite Autonomic Neuropathy Scale-31, modified Toronto Neuropathy Scale, and routine nerve conduction studies. We grouped the patients into large fiber neuropathy (LFN), SFN, and no overt neurological symptom/sign groups. In all participants, NFR was recorded on anterior tibial (AT) and biceps femoris (BF) muscles after train stimuli on the sole of the foot, and NFR-RIII findings were compared.

We identified 11 patients with LFN, 15 with SFN, and 11 with no overt neurological symptoms or signs. The RIII response on the AT was absent in 22 (60%) patients with DM and 8 (40%) healthy participants. The RIII response on the BF was absent in 31 (73.8%) patients and 7 (35%) healthy participants (P = .001). In DM, the latency of RIII was prolonged, and the magnitude was reduced. Abnormal findings were seen in all subgroups; however, they were more prominent in patients with LFN compared to other groups.

The NFR-RIII was abnormal in patients with DM even before the emergence of the neuropathic symptoms. The pattern of involvement before neuropathic symptoms was possibly related to an earlier loss of A-delta fibers.

Diabetic neuropathy is a neuro-degenerative disorder that encompasses numerous factors that impact peripheral nerves in the context of diabetes mellitus (DM). Diabetic peripheral neuropathy (DPN) is very prevalent and impacts 50% of diabetic patients. DPN is a length-dependent peripheral nerve lesion that primarily causes distal sensory loss, discomfort, and foot ulceration that may lead to amputation. The pathophysiology is yet to be fully understood, but current literature on the pathophysiology of DPN revolves around understanding various signaling cascades involving the polyol, hexosamine, protein-kinase C, AGE, oxidative stress, and poly (ADP ribose) polymerase pathways. The results of research have suggested that hyperglycemia target Schwann cells and in severe cases, demyelination resulting in central and peripheral sensitization is evident in diabetic patients. Various diagnostic approaches are available, but detection at an early stage remains a challenge. Traditional analgesics and opioids that can be used "as required" have not been the mainstay of treatment thus far. Instead, anticonvulsants and antidepressants that must be taken routinely over time have been the most common treatments. For now, prolonging life and preserving the quality of life are the ultimate goals of diabetes treatment. Furthermore, the rising prevalence of DPN has substantial consequences for occupational therapy because such therapy is necessary for supporting wellness, warding off other chronic-diseases, and avoiding the development of a disability; this is accomplished by engaging in fulfilling activities like yoga, meditation, and physical exercise. Therefore, occupational therapy, along with palliative therapy, may prove to be crucial in halting the onset of neuropathic-symptoms and in lessening those symptoms once they have occurred.

The aim of this research was to compare pain medication use trends among adults with and without type 2 diabetes in the US. This cross-sectional study used data of adults with and without (type 2) diabetes from the National Health and Nutrition Examination Survey waves 2005-2018. Use of pain medication including opioids, prescription nonsteroidal anti-inflammatory drugs, gabapentinoids, serotonin norepinephrine reuptake inhibitors, skeletal muscle relaxants, and headache treatment agents was compared by diabetes status and within select social determinants of health and clinical factors. Adults with type 2 diabetes were twice as likely to be prescribed pain medications compared to those without a diabetes diagnosis (16.2% vs 8.6%). Females and those with a history of smoking or arthritis were more likely to be on pain medications. Opioid use was the most prevalent regardless of diabetes status, and use was twice as high among those with diabetes (10.8% vs 5.5%). Patients with type 2 diabetes in the US are twice as likely to be prescribed pain medications overall as well as opioids compared with those without diabetes. Clinical guideline recommendations are necessary to find pharmacologic and nonpharmacologic nociceptive pain management specific for patients with diabetes.

Background and objectives: Worldwide, approximately 500 million people suffer from diabetes and at least 50% of these people develop neuropathy. Currently, therapeutic strategies for reducing diabetic neuropathy (DN)-associated pain are limited and have several side effects. The purpose of the study was to evaluate the antihyperalgesic action of different sildenafil (phosphodiesterase-5 inhibitor) and metformin (antihyperglycemic agent) combinations in alloxan-induced DN. Methods: The study included 100 diabetic mice and 20 non-diabetic mice that were subjected to hot and cold stimulus tests. Furthermore, we determined the influence of this combination on TNF-α, IL-6 and nitrites levels in brain and liver tissues. Results: In both the hot-plate and tail withdrawal test, all sildenafil-metformin combinations administered in our study showed a significant increase in pain reaction latencies when compared to the diabetic control group. Furthermore, all combinations decreased blood glucose levels due to the hypoglycemic effect of metformin. Additionally, changes in nitrite levels and pro-inflammatory cytokines (TNF-α and IL-6) were observed after 14 days of treatment with different sildenafil-metformin combinations. Conclusions: The combination of these two substances increased the pain reaction latency of diabetic animals in a dose-dependent manner. Moreover, all sildenafil-metformin combinations significantly reduced the concentration of nitrites in the brain and liver, which are final products formed under the action of iNOS.

Painful diabetic peripheral neuropathy (PDPN) is present in nearly a quarter of people with diabetes. It is estimated to affect over 100 million people worldwide. PDPN is associated with impaired daily functioning, depression, sleep disturbance, financial instability, and a decreased quality of life. Despite its high prevalence and significant health burden, it remains an underdiagnosed and undertreated condition. PDPN is a complex pain phenomenon with the experience of pain associated with and exacerbated by poor sleep and low mood. A holistic approach to patient-centred care alongside the pharmacological therapy is required to maximise benefit. A key treatment challenge is managing patient expectation, as a good outcome from treatment is defined as a reduction in pain of 30-50%, with a complete pain-free outcome being rare. The future for the treatment of PDPN holds promise, despite a 20-year void in the licensing of new analgesic agents for neuropathic pain. There are over 50 new molecular entities reaching clinical development and several demonstrating benefit in early-stage clinical trials. We review the current approaches to its diagnosis, the tools, and questionnaires available to clinicians, international guidance on PDPN management, and existing pharmacological and non-pharmacological treatment options. We synthesise evidence and the guidance from the American Association of Clinical Endocrinology, American Academy of Neurology, American Diabetes Association, Diabetes Canada, German Diabetes Association, and the International Diabetes Federation into a practical guide to the treatment of PDPN and highlight the need for future research into mechanistic-based treatments in order to prioritise the development of personalised medicine.

Diabetes sensory polyneuropathy (DSPN) is a significant complication of diabetes affecting up to 50% of patients in their lifetime and approximately 20% of patients suffer from painful diabetes neuropathic pain. DSPN - both painless and painful - leads to considerable morbidity including reduction of quality of life, increased lower limb amputations and is associated with worsening mortality. Significant progress has been made in the understanding of pathogenesis of DSPN and the last decade has seen newer techniques aimed at its earlier diagnosis. The management of painful DSPN remains a challenge despite advances made in the unravelling the pathogenesis of pain and its transmission. This article discusses the heterogenous clinical presentation of DSPN and the need to exclude key differential diagnoses. Furthermore, it reviews in detail the current diagnostic techniques involving both large and small neural fibres, their limitations and advantages and current place in the diagnosis of DSPN. Finally, the management of DSPN including newer pharmacotherapies are also discussed.

Painful diabetic peripheral neuropathy (PDPN) is one of the major complications of diabetes. Currently, centrally acting drugs and topical analgesics are used for treating PDPN. These drugs have adverse effects; some are ineffective, and treatment with opioids is associated with use dependence and addiction. Recent research indicates that transient receptor potential vanilloid 1 (TRPV1) expressed in the peripheral sensory nerve terminals is an emerging target to treat pain associated with PDPN. Block of TRPV1 ion channel with specific antagonists, although effective as an analgesic, induced hyperthermia in clinical trials. However, TRPV1 agonists are useful to treat pain by virtue of their ability to cause Ca 2+ influx and subsequently leading to nerve terminal desensitization. Here, we report the effectiveness of an ultrapotent TRPV1 agonist, resiniferatoxin (RTX) nanoparticle, in a topical formulation (RTX-cream; RESINIZIN) that alleviates pain associated with DPN in animal models of diabetes. Resiniferatoxin causes nerve terminal depolarization block in the short term, which prevents pain during application and leading to nerve terminal desensitization/depletion in the long term resulting in long-lasting pain relief. Application of RTX cream to the hind limbs suppresses thermal hyperalgesia in streptozotocin-induced diabetic rats and mini pigs without any adverse effects as compared with capsaicin at therapeutic doses, which induces intense pain during application. Resiniferatoxin cream also decreases the expression of TRPV1 in the peripheral nerve endings and suppresses TRPV1-mediated calcitonin gene-related peptide release in the skin samples of diabetic rats and mini pigs. Our preclinical data confirm that RTX topical formulation is an effective treatment option for PDPN.

Diabetic neuropathy is the most common microvascular complication of diabetes mellitus and a major risk factor for diabetes-related lower-extremity complications. Diffuse neuropathy is the most frequently encountered pattern of neurological dysfunction and presents clinically as distal symmetrical sensorimotor polyneuropathy. Due to the increasing public health significance of diabetes mellitus and its complications, screening for diabetic peripheral neuropathy is essential. Consequently, a review of the principles that guide screening practices, especially in resource-limited clinical settings, is urgently needed.

Numerous evidence-based assessments are used to detect diabetic peripheral neuropathy. In accordance with current guideline recommendations from the American Diabetes Association, International Diabetes Federation, International Working Group on the Diabetic Foot, and National Institute for Health and Care Excellence, a screening algorithm for diabetic peripheral neuropathy based on multiphasic clinical assessment, stratification according to risk of developing diabetic foot syndrome, individualized treatment, and scheduled follow-up is suggested for use in resource-limited settings.

Screening for diabetic peripheral neuropathy in resource-limited settings requires a practical and comprehensive approach in order to promptly identify affected individuals. The principles of screening for diabetic peripheral neuropathy are: multiphasic approach, risk stratification, individualized treatment, and scheduled follow-up. Regular screening for diabetes-related foot disease using simple clinical assessments may improve patient outcomes.

To investigate the AMPK pathway-mediated effect of alpha-lipoic acid (ALA) on the dorsal root ganglia (DRGs) of rats with diabetic peripheral neuropathy (DPN) and to attempt to elucidate the underlying mechanism.

Sprague-Dawley rats (n = 15) were randomly divided into three groups. The control group was fed a standard diet, and the other groups were fed a high-carbohydrate/high-fat diet. Diabetes was established by a single streptozotocin (STZ) (30 mg/kg) injection, and control rats were injected with an equal volume of citrate buffer. ALA (60 mg/kg/day) was administered for 12 weeks. The nerve conduction velocity (NCV) of the sciatic nerve was measured. Glutathione (GSH) and malondialdehyde (MDA) concentrations in serum were measured with the thiobarbituric acid method and biochemistry. Pathological changes in the rat DRGs were observed. AMPK, phospho-AMPK (p-AMPK), nuclear factor erythroid-2-related factor 2 (Nrf2), phospho-nuclear factor erythroid-2-related factor 2 (p-Nrf2), heme oxygenase 1 (HO-1), quinone oxidoreductase 1 (NQO1), Forkhead box O3 (FoxO3a), phospho-Forkhead box O3 (p-FoxO3a), and Bcl-2 interacting mediator of cell death (Bim) expression levels were assessed by immunohistochemistry and western blotting.

ALA improved the motor NCV (MNCV) and sensory NCV (SNCV) of rats with DPN and reduced their mechanical pain threshold. ALA increased serum GSH concentrations and decreased serum MDA concentrations. Additionally, AMPK was activated by ALA. Nrf2, p-Nrf2, HO-1, and NQO1 expression was upregulated, while FoxO3a, p-FoxO3a, and Bim expression was downregulated. ALA reduced oxidative stress and apoptosis in DRG.

ALA alleviates DPN and improves peripheral nerve function. ALA reduces oxidative stress by activating Nrf2 through AMPK and inhibits FoxO3a and Bim thereby reducing neuronal apoptosis.

Functional magnetic resonance imaging (fMRI) has been shown successfully to assess and stratify patients with painful diabetic peripheral neuropathy (pDPN). This supports the idea of using neuroimaging as a mechanism-based technique to individualise therapy for patients with painful DPN. The aim of this study was to use deep learning to predict treatment response in patients with pDPN using resting state functional imaging (rs-fMRI). We divided 43 painful pDPN patients into responders and non-responders to lidocaine treatment (responders n = 29 and non-responders n = 14). We used rs-fMRI to extract functional connectivity features, using group independent component analysis (gICA), and performed automated treatment response deep learning classification with three-dimensional convolutional neural networks (3D-CNN). Using gICA we achieved an area under the receiver operating characteristic curve (AUC) of 96.60% and F1-Score of 95% in a ten-fold cross validation (CV) experiment using our described 3D-CNN algorithm. To our knowledge, this is the first study utilising deep learning methods to classify treatment response in pDPN.

Objective: The objective of this systematic review and meta-analysis is to assess the effectiveness and security of Chinese herbal medicine (CHM) in the therapy of painful diabetic neuropathy (PDN). Methods: We searched databases for randomized controlled trials (RCTs) of CHM in the treatment of PDN. Outcome indicators included nerve conduction velocity, clinical efficiency, pain score, TCM syndrome score, and adverse events. Stata 16.0 was used to carry out the Meta-analysis. Results: A total of 21 RCTs with 1,737 participants were included. This meta-analysis found that using CHM as adjuvant treatment or as monotherapy for PDN can improve SCV of median nerve [mean difference (MD) = 3.56, 95% Confidence interval (CI) (2.19, 4.92) ], MCV of median nerve [ MD = 3.82, 95% CI (2.51, 5.12) ], SCV of common peroneal nerve [ MD = 4.16, 95% CI (1.62, 6.70) ], MCV of common peroneal nerve [ MD = 4.37, 95% CI (1.82, 6.93) ], SCV of gastrocnemius nerve [ MD = 4.95, 95% CI (3.52, 6.37) ], SCV of tibial nerve [ MD = 3.17, 95% CI (-2.64, 8.99) ], MCV of tibial nerve [MD = 6.30, 95%CI (5.00, 7.60)] and clinical effective rate [ odds ratio (OR) = 4.00, 95% CI (2.89, 5.52) ] and reduce pain score [standardized mean difference (SMD) = -2.23, 95% CI (-3.04, -1.41) ], TCM syndrome score [ MD = -4.70, 95% CI (-6.61, -2.80) ]. In addition, compared to the control group, adverse events of Chinese medicine intervention occurred less. Conclusion: CHM as adjuvant therapy or single treatment has a good curative effect and is safe for patients with PDN, which is worthy of clinical promotion and use, however; higher quality clinical studies are still needed to prove. Systematic Review Registration: https://www.crd.york.ac.uk/, identifier CRD42022327967.

Background: Neuropathy is a prevalent and debilitating complication of poorly managed diabetes, contributing towards poor quality of life, amputation risk, and increased mortality. The available therapies for diabetic neuropathic pain (DPN) have limitations in terms of efficacy, tolerability and patient compliance. Dysfunction in the peripheral and central monoaminergic system has been evidenced in various types of neuropathic and acute pain. The objective of the present study was to investigate 1-methyl 1, 2, 3, 4-tetrahydroisoquinoline (1MeTIQ), an endogenous amine found in human brain with a known neuroprotective profile, in a model of streptozotocin (STZ) induced neuropathic pain. Methods: Diabetic neuropathy in male BALB/c mice was induced by intraperitoneal injection of a single dose of STZ (200 mg/kg). Upon development of DPN after 4 weeks, mice were investigated for mechanical allodynia (von Frey filament pressure test) and thermal hyperalgesia (tail immersion test). Ondansetron (1.0 mg/kg i.p.), naloxone (3.0 mg/kg i.p.) and yohimbine (2.0 mg/kg i.p.) were used to elucidate the possible mechanism involved. Postmortem frontal cortical, striatal and hippocampal tissues were dissected and evaluated for changes in levels of dopamine, noradrenaline and serotonin using High-Performance Liquid Chromatography (HPLC) with UV detection. Results: Acute administration of 1MeTIQ (15-45 mg/kg i.p.) reversed streptozotocin-induced diabetic neuropathic static mechanical allodynia (von Frey filament pressure test) and thermal hyperalgesia (tail immersion test), these outcomes being comparable to standard gabapentin. Furthermore, HPLC analysis revealed that STZ-diabetic mice expressed lower concentrations of serotonin in all three brain regions examined, while dopamine was diminished in the striatum and 1MeTIQ reversed all these neurotransmitter modifications. These findings suggest that the antihyperalgesic/antiallodynic activity of 1MeTIQ may be mediated in part via supraspinal opioidergic and monoaminergic modulation since they were naloxone, yohimbine and ondansetron reversible. Conclusion: It was also concluded that acute treatment with 1MeTIQ ameliorated STZ-induced mechanical allodynia and thermal hyperalgesia and restored brain regionally altered serotonin and dopamine concentrations which signify a potential for 1MeTIQ in the management of DPN.

In this study we aimed to investigate the functional connectivity of brain regions involved in sensory processing in diabetes with and without painful and painless diabetic peripheral neuropathy (DPN) and the association with peripheral nerve function and pain intensity.

In this cross-sectional study we used resting-state functional MRI (fMRI) to investigate functional brain connectivity of 19 individuals with type 1 diabetes and painful DPN, 19 with type 1 diabetes and painless DPN, 18 with type 1 diabetes without DPN, and 20 healthy control subjects. Seed-based connectivity analyses were performed for thalamus, postcentral gyrus, and insula, and the connectivity z scores were correlated with peripheral nerve function measurements and pain scores.

Overall, compared with those with painful DPN and healthy control subjects, subjects with type 1 diabetes without DPN showed hyperconnectivity between thalamus and motor areas and between postcentral gyrus and motor areas (all P ≤ 0.029). Poorer peripheral nerve functions and higher pain scores were associated with lower connectivity of the thalamus and postcentral gyrus (all P ≤ 0.043). No connectivity differences were found in insula (all P ≥ 0.071).

Higher functional connectivity of thalamus and postcentral gyrus appeared only in diabetes without neuropathic complications. Thalamic/postcentral gyral connectivity measures demonstrated an association with peripheral nerve functions. Based on thalamic connectivity, it was possible to group the phenotypes of type 1 diabetes with painful/painless DPN and type 1 diabetes without DPN. The results of the current study support that fMRI can be used for phenotyping, and with validation, it may contribute to early detection and prevention of neuropathic complications.

These are the guidelines for diagnosis and treatment of diabetic neuropathy and diabetic foot.The position statement summarizes characteristic clinical symptoms and techniques for diagnostic assessment of diabetic neuropathy, including the complex situation of the diabetic foot syndrome. Recommendations for the therapeutic management of diabetic neuropathy, especially for the control of pain in sensorimotor neuropathy, are provided. The needs to prevent and treat diabetic foot syndrome are summarized.

Painful diabetic peripheral neuropathy (DPN) is often refractory to conventional medications. Triple-nerve decompression was proposed for painful DPN due to the frequent involvement of multiple nerve entrapments in diabetes. However, the role of decompressive surgery remains controversial. This trial aims to assess the efficacy of triple-nerve decompression for patients with painful DPN suggestive of nerve entrapment using a randomized controlled trial (RCT) design.

This trial is a single-center RCT and will be conducted in Shanghai Ninth People's Hospital. Enrolled subjects (n = 74) with painful DPN due to nerve compression, which can be detected by nerve conduction studies, will be randomly allocated at a 1:1 ratio into surgical and non-surgical groups. The primary outcome will be measured by 50% responder rates, which is defined as the proportion of subjects with at least 50% reduction of the mean weekly visual analog score (VAS) of pain from baseline after 6 months of treatment. Mean weekly VAS will be additionally evaluated 1 week (W1), 1 month (M1), and 3 months (M3) after treatment to monitor the changes in pain intensity. The secondary outcomes include two-point discrimination (TPD), Toronto clinical scoring system (TCSS), electrophysiological indexes, hospital anxiety and depression scale (HADS), and the medical outcome study short-form 36-item questionnaire (SF-36). A quantitative analgesic questionnaire (QAQ) will be used as a secondary outcome to quantify the analgesic medication weekly. TPD and TCSS will be conducted at W1, M1, M3, and M6 after treatment. Electrophysiological tests, HADS, and SF-36 will be performed at M3 and M6.

Ethics approval has been obtained from the Ethics Committee of Shanghai Ninth People's Hospital (SH9H-2-21-T323-2). It was registered on the Chinese Clinical Trial Registry website (http://www.chictr.org.cn) on 16 August 2021 with the number ChiCTR2100050049. Written informed consent will be obtained from all participants. The results of this trial will be disseminated via peer-reviewed journals, mass media, and presentations at national and international academic conferences.