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This narrative review examines the therapeutic efficacy of peripheral nerve stimulation (PNS) in the treatment of neuropathic pain (NP), a type of pain arising from lesions or diseases of the somatosensory system with a global prevalence ranging from 6.90% to 10.00%. Traditional pharmacological interventions often fall short for many persons, highlighting the need for alternative treatments such as PNS, which has demonstrated significant promise with minimal side effects. The review summarizes the effectiveness of PNS in various NP conditions, including trigeminal neuralgia and postherpetic neuralgia, and underscores the need for further research to refine treatment approaches. The mechanism of PNS is discussed, involving the activation of non-nociceptive Aβ fibers and modulation of neurotransmitters, and offering pain relief through both peripheral and central pathways. Despite the proven efficacy of PNS, challenges remain, including the need for randomized controlled trials and the optimization of stimulation parameters. The review concludes that PNS is a promising treatment modality for NP, warranting additional high-quality trials to solidify its role in clinical practice. [ABSTRACT FROM AUTHOR]

Background/Objectives: There is increasing evidence linking circulating neurotoxic lipids to the progression of chronic neuroinflammatory diseases in the peripheral and central nervous systems. Strategies to modify lipid profiles, such as docosahexaenoic acid (DHA)-rich supplementation, may aid in managing conditions like painful diabetic neuropathy (pDN). In a previous study, we demonstrated that three months of DHA supplementation significantly altered the metabolomic profile of patients with painful diabetic neuropathy (pDN), resulting in symptom improvement. This study investigates whether DHA-rich supplementation reduces neurotoxic lipid mediators associated with pDN in individuals with type 2 diabetes mellitus (T2DM). Methods: Forty individuals with type 2 diabetes participated in the "En Balance-PLUS" study, attending weekly lifestyle and nutrition education sessions while receiving daily supplementation of 1000 mg DHA and 200 mg EPA. Pain levels were assessed using the Short-Form McGill Pain Questionnaire (SF-MPQ) at baseline and after three months. Blood serum samples collected at these time points underwent untargeted lipidomic analyses, with ELISA used to evaluate biomarkers of necrosis (MLKL), autophagy (ATG5), and lipid chaperone protein (FABP5). Results: Untargeted lipidomic analysis revealed that several neurotoxic-associated lipids significantly decreased after DHA-rich supplementation. Also, circulating levels of MLKL were reduced, while protein levels of ATG5 and FABP5 significantly increased. Conclusions: The reduction of circulating neurotoxic lipids and increase in neuroprotective lipids following DHA-rich supplementation are consistent with the reported roles of omega-3 polyunsaturated fatty acids (PUFAs) in reducing adverse symptoms associated with neuroinflammatory diseases and painful neuropathy. [ABSTRACT FROM AUTHOR]

Background: Identifying distinct mechanisms and biomarkers for painful diabetic peripheral neuropathy (DPN) is required for advancing the treatment of this major global unmet clinical need. We previously provided evidence in calf skin biopsies that disproportion between reduced sensory small nerve fibers and increased blood vessels may distinguish painful from non-painful DPN. We proposed that overexposure of the reduced nerve fibers in DPN to increased hypoxemia-induced vasculature and related algogenic factors, e.g., nerve growth factor (NGF), leads to neuropathic pain. To further investigate this proposed mechanism, we have now studied more proximal thigh skin biopsies, to see if the same disproportion between increased vasculature and decreased nerve fibers generally differentiates painful DPN from painless DPN. Methods: A total of 28 subjects with type 2 diabetes (T2DM) and 13 healthy volunteers (HV) underwent detailed clinical and neurophysiological assessments, based on the neuropathy composite score of the lower limbs [NIS(LL)] plus 7 tests. T2DM subjects were subsequently divided into three groups: painful DPN (n = 15), painless DPN (n = 7), and no DPN (n = 6). All subjects underwent skin punch biopsy from the upper lateral thigh 20 cm below the anterior iliac spine. Results: Skin biopsies showed decreased PGP 9.5-positive intraepidermal nerve fiber (IENF) density in both painful DPN (p < 0.0001) and painless DPN (p = 0.001). Vascular marker von Willebrand Factor (vWF) density was markedly increased in painful DPN vs. other groups, including painless DPN (p = 0.01). There was a resulting significant decrease in the ratio of intraepidermal nerve fiber density to vasculature and PGP9.5 to vWF, in painful DPN vs. painless DPN (p = 0.05). These results were similar in pattern to those observed in these HV and T2DM groups previously in distal calf biopsies; however, the increase in vWF was much higher and nerve fiber density much lower in the calf than thigh for painful DPN. Thigh skin vWF density was significantly correlated with several metabolic (waist/hip ratio, HbA1c), clinical (e.g., pain score), and neurophysiological measures. Conclusion: This study supports our proposal that increased dermal vasculature, and its disproportionate ratio to reduced nociceptors, may help differentiate painful DPN from painless DPN. This disproportion is greater in the distal calf than the proximal thigh skin; hence, neuropathic pain in DPN is length-dependent and first localized to the distal lower limbs, mainly feet. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Painful diabetic neuropathy (PDN) is a leading cause of pain and disability globally with a lack of consensus on the appropriate treatment of those suffering from this condition. Recent advancements in both pharmacotherapy and interventional approaches have broadened the treatment options for PDN. There exists a need for a comprehensive guideline for the safe and effective treatment of patients suffering from PDN. OBJECTIVE: The SWEET Guideline was developed to provide clinicians with the most comprehensive guideline for the safe and appropriate treatment of patients suffering from PDN. METHODS: The American Society of Pain and Neuroscience (ASPN) identified an educational need for a comprehensive clinical guideline to provide evidence-based recommendations for PDN. A multidisciplinary group of international experts developed the SWEET guideline. The world literature in English was searched using Medline, EMBASE, Cochrane CENTRAL, BioMed Central, Web of Science, Google Scholar, PubMed, Current Contents Connect, Meeting Abstracts, and Scopus to identify and compile the evidence for diabetic neuropathy pain treatments (per section as listed in the manuscript) for the treatment of pain. Manuscripts from 2000-present were included in the search process. RESULTS: After a comprehensive review and analysis of the available evidence, the ASPN SWEET guideline was able to rate the literature and provide therapy grades for most available treatments for PDN utilizing the United States Preventive Services Task Force criteria. CONCLUSION: The ASPN SWEET Guideline represents the most comprehensive review of the available treatments for PDN and their appropriate and safe utilization.

Painful diabetic neuropathy (PDN) is nerve damage caused by the accumulation of oxidative stress. Resveratrol, an antioxidant compound found in various plants, including cocoa pod husk, combats this condition. To prove the efficacy of an emulgel from an ethanolic extract of cocoa pod husk in PDN mice. The cocoa husk ethanol extract was formulated into emulgel and evaluated. Dermal sensitization reactions and a dermal acute toxicity test were conducted. In the PDN model, mice were induced using alloxan 225 mg/kg BW i. p. After 14 days, mice were randomized into eight groups: Normal, diabetic, 0.1% capsaicin cream, and cocoa pod husk extract emulgel (CPHEE) (0.25%, 0.5%, 1%, 2%, and 3%). Treatment was given three times a day for 14 days. Latency time and blood glucose levels were observed every week. Plantar skin sections were stained with h and e for histological observation and the transient receptor protein vanilloid (TRPV)-1 for immunohistochemistry. In vivo tests showed that a 2% dose of CPHEE improved hyperalgesia by 92.33% ±1.52%, improved histology, and minimized the expression of TRPV-1 in the skin, same as capsaicin 0.1%. Notably, up to a dose of 2000 mg/kg, CPHEE did not show toxic symptoms in mice or erythema and edema, further confirming its safety for use in PDN. The study confirms that a 2% CPHEE is effective and safe for topical use in PDN, providing a potential solution for patients suffering from this condition.

Abstract This narrative review examines the therapeutic efficacy of peripheral nerve stimulation (PNS) in the treatment of neuropathic pain (NP), a type of pain arising from lesions or diseases of the somatosensory system with a global prevalence ranging from 6.90% to 10.00%. Traditional pharmacological interventions often fall short for many persons, highlighting the need for alternative treatments such as PNS, which has demonstrated significant promise with minimal side effects. The review summarizes the effectiveness of PNS in various NP conditions, including trigeminal neuralgia and postherpetic neuralgia, and underscores the need for further research to refine treatment approaches. The mechanism of PNS is discussed, involving the activation of non-nociceptive Aβ fibers and modulation of neurotransmitters, and offering pain relief through both peripheral and central pathways. Despite the proven efficacy of PNS, challenges remain, including the need for randomized controlled trials and the optimization of stimulation parameters. The review concludes that PNS is a promising treatment modality for NP, warranting additional high-quality trials to solidify its role in clinical practice.

David C Klonoff,1 Brian L Levy,2 Michael J Jaasma,3 Manish Bharara,3 Deborah R Edgar,4 Christian Nasr,5 David L Caraway,3 Erika A Petersen,6 David G Armstrong7 1Diabetes Research Institute, Mills-Peninsula Medical Center, San Mateo, CA, USA; 2New York University Grossman School of Medicine, New York, NY, USA; 3Nevro Corp, Redwood City, CA, USA; 4Commexus Ltd, Dunblane, Scotland, UK; 5Division of Endocrinology, Department of Internal Medicine, The University of Arizona College of Medicine - Phoenix, Phoenix, AZ, USA; 6Department of Neurosurgery, University of Arkansas for Medical Sciences, Little Rock, AR, USA; 7Department of Surgery, Keck School of Medicine of University of Southern California, Los Angeles, CA, USACorrespondence: David C Klonoff, Diabetes Research Institute, Mills-Peninsula Medical Center, 100 South San Mateo Drive, Room 1165, San Mateo, CA, 94401, USA, Tel +1650-218-1142, Email dklonoff@diabetestechnology.orgPurpose: The recent SENZA-PDN study showed that high-frequency (10kHz) spinal cord stimulation (SCS) provided significant, durable pain relief for individuals with painful diabetic neuropathy (PDN), along with secondary benefits, including improved sleep quality and HRQoL. Given that metabolic factors and chronic neuropathic pain are related, we evaluated potential secondary effects of 10kHz SCS on hemoglobin A1c (HbA1c) and weight in SENZA-PDN participants with type 2 diabetes (T2D).Patients and Methods: This analysis included 144 participants with T2D and lower limb pain due to PDN who received 10kHz SCS during the SENZA-PDN study. Changes in HbA1c, weight, pain intensity, and sleep were evaluated over 24 months, with participants stratified according to preimplantation HbA1c (> 7% and > 8%) and body mass index (BMI; ≥ 30 and ≥ 35 kg/m2).Results: At 24 months, participants with preimplantation HbA1c > 7% and > 8% achieved clinically meaningful and statistically significant mean reductions in HbA1c of 0.5% (P = 0.031) and 1.1% (P = 0.004), respectively. Additionally, we observed a significant mean weight loss of 3.1 kg (P = 0.003) across all study participants. In subgroups with BMI ≥ 30 and ≥ 35 kg/m2, weight reductions at 24 months were 4.1 kg (P = 0.001) and 5.4 kg (P = 0.005), respectively. These reductions were accompanied by a mean pain reduction of 79.8% and a mean decrease in pain interference with sleep of 65.2% at 24 months across all cohorts.Conclusion: This is the first study of SCS to demonstrate long-term, significant, and clinically meaningful reductions in HbA1c and weight in study participants with PDN and T2D, particularly among those with elevated preimplantation HbA1c and BMI. Although the mechanism for these improvements has yet to be established, the results suggest possible direct and indirect metabolic benefits with 10kHz SCS in addition to durable pain relief.Trial Registration: ClincalTrials.gov Identifier, NCT03228420.Keywords: diabetic peripheral neuropathy, painful diabetic neuropathy, spinal cord stimulation, neuromodulation, neuropathic pain

Painful diabetic neuropathy (PDN) is nerve damage caused by the accumulation of oxidative stress. Resveratrol, an antioxidant compound found in various plants, including cocoa pod husk, combats this condition. To prove the efficacy of an emulgel from an ethanolic extract of cocoa pod husk in PDN mice. The cocoa husk ethanol extract was formulated into emulgel and evaluated. Dermal sensitization reactions and a dermal acute toxicity test were conducted. In the PDN model, mice were induced using alloxan 225 mg/kg BW i. p. After 14 days, mice were randomized into eight groups: Normal, diabetic, 0.1% capsaicin cream, and cocoa pod husk extract emulgel (CPHEE) (0.25%, 0.5%, 1%, 2%, and 3%). Treatment was given three times a day for 14 days. Latency time and blood glucose levels were observed every week. Plantar skin sections were stained with h and e for histological observation and the transient receptor protein vanilloid (TRPV)-1 for immunohistochemistry. In vivo tests showed that a 2% dose of CPHEE improved hyperalgesia by 92.33% ±1.52%, improved histology, and minimized the expression of TRPV-1 in the skin, same as capsaicin 0.1%. Notably, up to a dose of 2000 mg/kg, CPHEE did not show toxic symptoms in mice or erythema and edema, further confirming its safety for use in PDN. The study confirms that a 2% CPHEE is effective and safe for topical use in PDN, providing a potential solution for patients suffering from this condition. [ABSTRACT FROM AUTHOR]

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

Background: 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. Methods: 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. Results: 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. Conclusion: 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. [ABSTRACT FROM AUTHOR]

Aim: To investigate the efficacy of Palmitoylethanolamide (PEA, 300 mg), Superoxide Dismutase (SOD, 70 UI), Alpha Lipoic Acid (ALA, 300 mg), vitamins B6 (1.5 mg), B1 (1.1 mg), B12 (2.5 mcg), E (7.5 mg), nicotinamide (9 mg), and minerals (Mg 30 mg, Zn 2.5 mg) in one tablet in people with Diabetic Neuropathy (DN). Patients–methods: In the present pilot study, 73 people (age 63.0 ± 9.9 years, 37 women) with type 2 Diabetes Mellitus (DMT2) (duration 17.5 ± 7.3 years) and DN were randomly assigned to receive either the combination of ten elements (2 tablets/24 h) in the active group (n = 36) or the placebo (n = 37) for 6 months. We used the Michigan Neuropathy Screening Instrument Questionnaire and Examination (MNSIQ and MNSIE), measured vibration perception threshold (VPT) with biothesiometer, and Cardiovascular Autonomic Reflex Tests (CARTs). Nerve function was assessed by DPN Check [sural nerve conduction velocity (SNCV) and amplitude (SNAP)]. Sudomotor function was assessed with SUDOSCAN, which measures electrochemical skin conductance in hands and feet (ESCH and ESCF). Pain score (PS) was assessed with Pain DETECT questionnaire. Quality of life was assessed by questionnaire. Results: In the active group, there was a large improvement of pain (PS from 20.9 to 13.9, p < 0.001). There was also a significant improvement of vitamin B12 (B12) levels, MNSIQ, SNCV, VPT, and ESCF (222.1 vs. 576.3 pg/ mL, p < 0.001; 6.1 vs. 5.9, p = 0.017; 28.8 vs. 30.4, p = 0.001; 32.1 vs. 26.7, p = 0.001; and 72.2 vs. 74.8, p < 0.001 respectively). In the placebo group, neither pain (21.6 vs. 21.7, p = 0.870) or any other aforementioned parameters changed significantly, and MNSIE worsened (2.9 vs. 3.4, p < 0.001). As a result, changes from baseline to follow-up in pain, B12 levels, VPT, and MNSIQ differed significantly between the two groups (p < 0.001, 0.025, 0.009, and <0.001, respectively). CARTs, SNAP, ESCH did not significantly change in either of the two groups. Conclusions: The combination of the ten elements in one tablet for 6 months at a daily dose of two tablets in people with DN significantly improves pain, vibration perception threshold, and B12 levels. [ABSTRACT FROM AUTHOR]

In this paper we investigated lipid and metabolite changes in diabetic neuropathy, using untargeted lipidomics and metabolomics analyses of the spinal cords from streptozotocin-treated diabetic rats.170 metabolites and 45 lipids were dysregulated in the painful diabetic neuropathy (PDN) phase. Pathway enrichment analysis revealed perturbations in starch and sucrose, tryptophan, pyrimidine, cysteine and methionine, thiamine, tyrosine, and nucleotides. The disturbance of tyrosine, tryptophan, methionine, triacylglycerol, and phosphatidylethanolamine metabolism indicated that pathological mechanisms in the PDN involved energy metabolism, oxidative stress, and neural reparative regeneration. These revelations offered potential biomarkers for PDN and enriched the comprehension of the complex molecular mechanisms characterizing PDN, establishing a solid foundation for subsequent inquiries into neural convalescence and recovery after PDN. [ABSTRACT FROM AUTHOR]

Introduction: 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. Methods: This was a phase II, randomized, double-blind, placebo and reference controlled, dose-finding, multicenter, international, prospective study. Male and female diabetic patients aged 18–75 years and affected by PDN were eligible for enrolment. Patients were randomized (1:1:1:1:2 ratio) to trazodone and gabapentin (Trazo/Gaba) 2.5/25 mg t.i.d. for 8 weeks, Trazo/Gaba 5/50 mg t.i.d. for 8 weeks, Trazo/Gaba 10/100 mg t.i.d. for 8 weeks, 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 8 weeks 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. Results: A total of 240 patients were included in the modified intention-to-treat (m-ITT) population: 39 in Trazo/Gaba 2.5/25 mg, 38 in Trazo/Gaba 5/50 mg, 37 in Trazo/Gaba 10/100 mg, 83 in PLB, and 43 in Gaba. After 8 weeks 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 2.5/25 mg group, − 2.24 ± 1.96 in Trazo/Gaba 5/50 mg group, − 2.46 ± 2.12 in Trazo/Gaba 10/100 mg 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 8 weeks of treatment: Trazo/Gaba 2.5/25 mg (95% confidence interval (CI) − 1.2739, 0.2026; p = 0.1539); Trazo/Gaba 5/50 mg (95% CI − 0.9401, 0.5390; p = 0.5931); Trazo/Gaba 10/100 mg (95% CI − 1.0342, 0.4582; p = 0.4471). However, patients receiving the lowest dose of Trazo/Gaba 2.5/25 mg showed a statistically significant difference to PLB after 6 weeks 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. Conclusions: 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 8 weeks of treatment. While the primary endpoint was not reached, patients treated with Trazo/Gaba 2.5/25 mg t.i.d. showed statistically significant improvement of pain and other scores after 6 weeks 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. Clinical Trial Registration: NCT03749642. [ABSTRACT FROM AUTHOR]

Abstract Background Painful diabetic neuropathy (PDN) is closely linked to inflammation, which has been demonstrated to be associated with pyroptosis. Emerging evidence has implicated TANK-binding kinase 1 (TBK1) in various inflammatory diseases. However, it remains unknown whether activated TBK1 causes hyperalgesia via pyroptosis. Methods PDN mice model of type 1 or type 2 diabetic was induced by C57BL/6J or BKS-DB mice with Lepr gene mutation. For type 2 diabetes PDN model, TBK1-siRNA, Caspase-1 inhibitor Ac-YVAD-cmk or TBK1 inhibitor amlexanox (AMX) were delivered by intrathecal injection or intragastric administration. The pain threshold and plantar skin blood perfusion were evaluated through animal experiments. The assessments of spinal cord, dorsal root ganglion, sciatic nerve, plantar skin and serum included western blotting, immunofluorescence, ELISA, and transmission electron microscopy. Results In the PDN mouse model, we found that TBK1 was significantly activated in the spinal dorsal horn (SDH) and mainly located in microglia, and intrathecal injection of chemically modified TBK1-siRNA could improve hyperalgesia. Herein, we described the mechanism that TBK1 could activate the noncanonical nuclear factor κB (NF-κB) pathway, mediate the activation of NLRP3 inflammasome, trigger microglia pyroptosis, and ultimately induce PDN, which could be reversed following TBK1-siRNA injection. We also found that systemic administration of AMX, a TBK1 inhibitor, could effectively improve peripheral nerve injury. These results revealed the key role of TBK1 in PDN and that TBK1 inhibitor AMX could be a potential strategy for treating PDN. Conclusions Our findings revealed a novel causal role of TBK1 in pathogenesis of PDN, which raises the possibility of applying amlexanox to selectively target TBK1 as a potential therapeutic strategy for PDN.

Abstract Introduction 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. Methods This was a phase II, randomized, double-blind, placebo and reference controlled, dose-finding, multicenter, international, prospective study. Male and female diabetic patients aged 18–75 years and affected by PDN were eligible for enrolment. Patients were randomized (1:1:1:1:2 ratio) to trazodone and gabapentin (Trazo/Gaba) 2.5/25 mg t.i.d. for 8 weeks, Trazo/Gaba 5/50 mg t.i.d. for 8 weeks, Trazo/Gaba 10/100 mg t.i.d. for 8 weeks, 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 8 weeks 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) 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 8 weeks of treatment: Trazo/Gaba 2.5/25 mg (95% confidence interval (CI) − 1.2739, 0.2026; p = 0.1539); Trazo/Gaba 5/50 mg (95% CI − 0.9401, 0.5390; p = 0.5931); Trazo/Gaba 10/100 mg (95% CI − 1.0342, 0.4582; p = 0.4471). However, patients receiving the lowest dose of Trazo/Gaba 2.5/25 mg showed a statistically significant difference to PLB after 6 weeks 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. Conclusions 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 8 weeks of treatment. While the primary endpoint was not reached, patients treated with Trazo/Gaba 2.5/25 mg t.i.d. showed statistically significant improvement of pain and other scores after 6 weeks 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. Clinical Trial Registration NCT03749642.

Background: Painful diabetic neuropathy (PDN) is closely linked to inflammation, which has been demonstrated to be associated with pyroptosis. Emerging evidence has implicated TANK-binding kinase 1 (TBK1) in various inflammatory diseases. However, it remains unknown whether activated TBK1 causes hyperalgesia via pyroptosis. Methods: PDN mice model of type 1 or type 2 diabetic was induced by C57BL/6J or BKS-DB mice with Lepr gene mutation. For type 2 diabetes PDN model, TBK1-siRNA, Caspase-1 inhibitor Ac-YVAD-cmk or TBK1 inhibitor amlexanox (AMX) were delivered by intrathecal injection or intragastric administration. The pain threshold and plantar skin blood perfusion were evaluated through animal experiments. The assessments of spinal cord, dorsal root ganglion, sciatic nerve, plantar skin and serum included western blotting, immunofluorescence, ELISA, and transmission electron microscopy. Results: In the PDN mouse model, we found that TBK1 was significantly activated in the spinal dorsal horn (SDH) and mainly located in microglia, and intrathecal injection of chemically modified TBK1-siRNA could improve hyperalgesia. Herein, we described the mechanism that TBK1 could activate the noncanonical nuclear factor κB (NF-κB) pathway, mediate the activation of NLRP3 inflammasome, trigger microglia pyroptosis, and ultimately induce PDN, which could be reversed following TBK1-siRNA injection. We also found that systemic administration of AMX, a TBK1 inhibitor, could effectively improve peripheral nerve injury. These results revealed the key role of TBK1 in PDN and that TBK1 inhibitor AMX could be a potential strategy for treating PDN. Conclusions: Our findings revealed a novel causal role of TBK1 in pathogenesis of PDN, which raises the possibility of applying amlexanox to selectively target TBK1 as a potential therapeutic strategy for PDN. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the effect of nerve decompression on pain in patients with lower extremity painful diabetic peripheral neuropathy (DPN). Background: Currently, no treatment provides lasting relief for patients with DPN. The benefits of nerve decompression remain inconclusive. Methods: This double-blinded, observation and same-patient sham surgery--controlled randomized trial enrolled patients aged 18 to 80 years with lower extremity painful DPN who failed 1 year of medical treatment. Patients were randomized to nerve decompression or observation group (2:1). Decompression-group patients were further randomized and blinded to nerve decompression in either the right or left leg and sham surgery in the opposite leg. Pain (11-point Likert score) was compared between decompression and observation groups and between decompressed versus sham legs at 12 and 56 months. Results: Of 2987 screened patients, 78 were randomized. At 12 months, compared with controls (n=37), both the right-decompression group (n= 22) and left-decompression group (n= 18) reported lower pain (mean difference for both: -4.46; 95% CI: -6.34 to -2.58 and -6.48 to -2.45, respectively; P < 0.0001). Decompressed and sham legs equally improved. At 56 months, compared with controls (n=m 14), pain was lower in both the right-decompression group (n=20; mean difference: -7.65; 95% CI: -9.87 to -5.44; P < 0.0001) and left-decompression group (n=16; mean difference: -7.26; 95% CI: -9.60 to -4.91; P < 0.0001). The mean pain score was lower in decompressed versus sham legs (mean difference: 1.57 95% CI: 0.46 to 2.67; P=0.0002). Conclusions: Although nerve decompression was associated with reduced pain, the benefit of surgical decompression needs further investigation as a placebo effect may be responsible for part or all of these effects. [ABSTRACT FROM AUTHOR]

Background: Painful diabetic neuropathy (PDN) is a common chronic neurological complication of diabetes mellitus. Medications are often used to relieve pain, but with significant side effects. Acupuncture is now a component of pragmatic and integrative treatment for PDN. An increasing number of relevant randomized controlled trials have been published in recent years, but a comprehensive meta-analysis has not yet been performed. The aim of this paper is to verify the effectiveness and safety of acupuncture for PDN by metaanalysis and trial sequential analysis (TSA). Methods: All participants in this study should have had a PDN diagnosis and the trial group was treated with acupuncture. Eight databases, including EMbase, PubMed, Web of science, Cochrane Library, China Biology Medicine disc (CBM), China National Knowledge Infrastructure (CNKI), Wanfang and Chongqing VIP (CQVIP) were retrieved from inception to 5 April 2023. Meta-analysis was conducted utilizing RevMan 5.3 and Stata 15.0. TSA was performed to assess the adequacy of sample size for the outcomes. Results: A total of 36 studies, comprising 2,739 PDN patients, were included. Among them, 1,393 patients were assigned to the trial group and 1,346 patients were treated in the control group. Outcomes covers the primary indicator Total effective rate (RR = 1.42, 95%CI [1.34, 1.52], p < 0.00001), with 21 studies reported, Pain intensity (SMD = -1.27, 95%CI [-1.58, -0.95], p < 0.00001), with 23 studies reported, and other outcomes, including motor nerve conduction velocity (MCV; MD = 3.58, 95%CI [2.77, 4.38], p < 0.00001), sensory nerve conduction velocity (SCV; MD = 3.62, 95%CI [2.75, 4.49], p < 0.00001), Depression score (SMD = -1.02, 95%CI [1.58, 0.46]), Toronto clinical scoring system (TCSS; MD = -2.41, 95%CI [-3.37, -1.45], p < 0.00001), Quality of life (SMD = 1.06, 95%CI [0.66, 1.46]), traditional Chinese medicine (TCM) syndrome score (MD = -4.99, 95%CI [-6.79, -3.18], p < 0.00001), suggesting that acupuncture have an ameliorating effect on PDN in various respect. Egger's test revealed publication bias for four outcomes. TSA showed that as for Total effective rate, Pain Intensity, MCV and SCV, the number of included studies was sufficient to support the conclusions. Conclusion: Acupuncture demonstrates significant effectiveness in improving PDN outcomes, including Total effective rate, Pain intensity, MCV, SCV, Depression score, TCSS, Quality of life, TCM syndrome score. But the Adverse events rate is no different in trail group and control group. The publication bias presented in Total effective rate, Pain intensity, MCV and SCV can be remedied by Trim and filling method. [ABSTRACT FROM AUTHOR]

Painful diabetic neuropathy (PDN) is one of the most common and intractable complications of diabetes. Painful diabetic neuropathy is characterized by neuropathic pain accompanied by dorsal root ganglion (DRG) nociceptor hyperexcitability, axonal degeneration, and changes in cutaneous innervation. However, the complete molecular profile underlying the hyperexcitable cellular phenotype of DRG nociceptors in PDN has not been elucidated. This gap in our knowledge is a critical barrier to developing effective, mechanism-based, and disease-modifying therapeutic approaches that are urgently needed to relieve the symptoms of PDN. Using single-cell RNA sequencing of DRGs, we demonstrated an increased expression of the Mas-related G protein-coupled receptor d (Mrgprd) in a subpopulation of DRG neurons in the well-established high-fat diet (HFD) mouse model of PDN. Importantly, limiting Mrgprd signaling reversed mechanical allodynia in the HFD mouse model of PDN. Furthermore, in vivo calcium imaging allowed us to demonstrate that activation of Mrgprd-positive cutaneous afferents that persist in diabetic mice skin resulted in an increased intracellular calcium influx into DRG nociceptors that we assess in vivo as a readout of nociceptors hyperexcitability. Taken together, our data highlight a key role of Mrgprd-mediated DRG neuron excitability in the generation and maintenance of neuropathic pain in a mouse model of PDN. Hence, we propose Mrgprd as a promising and accessible target for developing effective therapeutics currently unavailable for treating neuropathic pain in PDN. [ABSTRACT FROM AUTHOR]

BackgroundIdentifying distinct mechanisms and biomarkers for painful diabetic peripheral neuropathy (DPN) is required for advancing the treatment of this major global unmet clinical need. We previously provided evidence in calf skin biopsies that disproportion between reduced sensory small nerve fibers and increased blood vessels may distinguish painful from non-painful DPN. We proposed that overexposure of the reduced nerve fibers in DPN to increased hypoxemia-induced vasculature and related algogenic factors, e.g., nerve growth factor (NGF), leads to neuropathic pain. To further investigate this proposed mechanism, we have now studied more proximal thigh skin biopsies, to see if the same disproportion between increased vasculature and decreased nerve fibers generally differentiates painful DPN from painless DPN.MethodsA total of 28 subjects with type 2 diabetes (T2DM) and 13 healthy volunteers (HV) underwent detailed clinical and neurophysiological assessments, based on the neuropathy composite score of the lower limbs [NIS(LL)] plus 7 tests. T2DM subjects were subsequently divided into three groups: painful DPN (n = 15), painless DPN (n = 7), and no DPN (n = 6). All subjects underwent skin punch biopsy from the upper lateral thigh 20 cm below the anterior iliac spine.ResultsSkin biopsies showed decreased PGP 9.5-positive intraepidermal nerve fiber (IENF) density in both painful DPN (p

Abstract Objectives Painful diabetic neuropathy (PDN) is highly prevalent and annoyingly in patients with diabetes. The aim of this study was to investigate the effects of oral N-acetylcysteine (NAC) compared to pregabalin in PDN. Methods One hundred two eligible patients with type 2 diabetes and PDN were randomly recievied pregabalin (150 mg/day) or N-Acetylcysteine (NAC) (600 mg/ twice a day) for 8 weeks. Mean pain score, Sleep interference score (SIS), Patient Global Impression of Change (PGIC), Clinical Global Impression of Change (CGIC), and also, serum levels of total antioxidant capacity (TAC), total thiol groups (TTG), catalase activity (CAT), nitric oxide (NO), and malondialdehyde (MDA) were assessed at baseline and at the end of the study. Results NAC was well tolerated in all patients. The decrease in mean pain scores and increase in SIS was similar between two groups. More improvement in PGIC and CGIC from the baseline was reported in NAC group. NAC, significantly, decreased serum levels of MDA, and NO, but increased TAC, TTG, and CAT. Pregabalin, significantly, decreased serum levels of MDA, and NO and increased TAC. Discussion NAC is efficacious in alleviate symptoms of PDN which is probably related to its antioxidant effects. Trial registration The research protocol received approval from the Ethics Committee of Hamadan University of Medical Sciences (IR.UMSHA.REC.1397.137). The trial registry URL and number in Iranian Registry of Clinical Trials (IRCT): https://www.irct.ir/trial/33313 , IRCT20180814040795N2 (Registration date: 2019-01-21, Retrospectively registered)

Dawood Sayed,1 Timothy Ray Deer,2 Jonathan M Hagedorn,3 Asim Sayed,4 Ryan S D’Souza,3 Christopher M Lam,1 Nasir Khatri,5 Zohra Hussaini,1 Scott G Pritzlaff,6 Newaj Mohammad Abdullah,7 Vinicius Tieppo Francio,1 Steven Michael Falowski,8 Yussr M Ibrahim,9 Mark N Malinowski,10 Ryan R Budwany,2 Natalie Holmes Strand,11 Kamil M Sochacki,12 Anuj Shah,13 Tyler M Dunn,11 Morad Nasseri,14 David W Lee,15 Leonardo Kapural,16 Marshall David Bedder,17,18 Erika A Petersen,19 Kasra Amirdelfan,20 Michael E Schatman,21,22 Jay Samuel Grider23 1Department of Anesthesiology and Pain Medicine, The University of Kansas Medical Center, Kansas City, KS, USA; 2Pain Services, Spine and Nerve Center of the Virginias, Charleston, WV, USA; 3Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, MN, USA; 4Podiatry/Surgery, Susan B. Allen Memorial Hospital, El Dorado, KS, USA; 5Interventional Pain Medicine, Novant Spine Specialists, Charlotte, NC, USA; 6Department of Anesthesiology and Pain Medicine, University of California, Davis, Sacramento, CA, USA; 7Department of Anesthesiology, University of Utah, Salt Lake City, UT, USA; 8Neurosurgery, Neurosurgical Associates of Lancaster, Lancaster, PA, USA; 9Pain Medicine, Northern Light Eastern Maine Medical Center, Bangor, ME, USA; 10OhioHealth Neurological Physicians, OhioHealth, Columbus, OH, USA; 11Anesthesiology and Pain Medicine, Mayo Clinic, Phoenix, AZ, USA; 12Department of Anesthesiology and Perioperative Medicine, Rutgers Robert Wood Johnson, New Brunswick, NJ, USA; 13Department of Physical Medicine and Rehabilitation, Detroit Medical Center, Detroit, MI, USA; 14Interventional Pain Medicine / Neurology, Boomerang Healthcare, Walnut Creek, CA, USA; 15Pain Management Specialist, Fullerton Orthopedic, Fullerton, CA, USA; 16Carolinas Pain Institute, Winston Salem, NC, USA; 17Chief of Pain Medicine Service, Augusta VAMC, Augusta, GA, USA; 18Associate Professor and Director, Addiction Medicine Fellowship Program, Department Psychiatry and Health Behavior, Medical College of Georgia at Augusta University, Augusta, GA, USA; 19Department of Neurosurgery, University of Arkansas for Medical Sciences, Little Rock, AR, USA; 20Director of Clinical Research, Boomerang Healthcare, Walnut Creek, CA, USA; 21Department of Anesthesiology, Perioperative Care & Pain Medicine, NYU Grossman School of Medicine, New York, NY, USA; 22Department of Population Health – Division of Medical Ethics, NYU Grossman School of Medicine, New York, NY, USA; 23Anesthesiology, Division of Pain Medicine, University of Kentucky College of Medicine, Lexington, KY, USACorrespondence: Dawood Sayed, Anesthesiology and Pain Medicine, the University of Kansas Medical Center, Kansas City, KS, USA, Tel +1 785-550-5800, Email dsayed@kumc.eduIntroduction: Painful diabetic neuropathy (PDN) is a leading cause of pain and disability globally with a lack of consensus on the appropriate treatment of those suffering from this condition. Recent advancements in both pharmacotherapy and interventional approaches have broadened the treatment options for PDN. There exists a need for a comprehensive guideline for the safe and effective treatment of patients suffering from PDN.Objective: The SWEET Guideline was developed to provide clinicians with the most comprehensive guideline for the safe and appropriate treatment of patients suffering from PDN.Methods: The American Society of Pain and Neuroscience (ASPN) identified an educational need for a comprehensive clinical guideline to provide evidence-based recommendations for PDN. A multidisciplinary group of international experts developed the SWEET guideline. The world literature in English was searched using Medline, EMBASE, Cochrane CENTRAL, BioMed Central, Web of Science, Google Scholar, PubMed, Current Contents Connect, Meeting Abstracts, and Scopus to identify and compile the evidence for diabetic neuropathy pain treatments (per section as listed in the manuscript) for the treatment of pain. Manuscripts from 2000-present were included in the search process.Results: After a comprehensive review and analysis of the available evidence, the ASPN SWEET guideline was able to rate the literature and provide therapy grades for most available treatments for PDN utilizing the United States Preventive Services Task Force criteria.Conclusion: The ASPN SWEET Guideline represents the most comprehensive review of the available treatments for PDN and their appropriate and safe utilization.Keywords: diabetes, painful diabetic neuropathy, neuropathy, spinal cord stimulation, chronic pain, diabetic neuropathy

Introduction: Painful diabetic neuropathy (PDN) is a common complication of diabetes. Previous studies have implicated that mitochondrial dysfunction plays a role in the development of PDN, but its pathogenesis and mechanism have not been fully investigated. Methods: In this study, we used high‐fat diet/low‐dose streptozotocin‐induced rats as a model of type 2 diabetes mellitus. Behavioral testing, whole‐cell patch‐clamp recordings of dorsal root ganglion (DRG) neurons, and complex sensory nerve conduction velocity studies were used to assess peripheral neuropathy. Mitochondrial membrane potential (MMP), ATP, tissue reactive oxygen species, and transmission electron microscopy were used to evaluate the function and morphology of mitochondria in DRG. Real‐time PCR, western blot, and immunofluorescence were performed to investigate the mechanism. Results: We found that damaged mitochondria were accumulated and mitophagy was inhibited in PDN rats. The expression of sirtuin 3 (SIRT3), which is an NAD+‐dependent deacetylase in mitochondria, was inhibited. Overexpression of SIRT3 in DRG neurons by intrathecally administered LV‐SIRT3 lentivirus ameliorated neurological and mitochondrial dysfunctions. This was evidenced by the reversal of allodynia and nociceptor hyperexcitability, as well as the restoration of MMP and ATP levels. Overexpression of SIRT3 restored the inhibited mitophagy by activating the FoxO3a‐PINK1‐Parkin signaling pathway. The effects of SIRT3 overexpression, including the reversal of allodynia and nociceptor hyperexcitability, the improvement of impaired mitochondria and mitophagy, and the restoration of PINK1 and Parkin expression, were counteracted when FoxO3a siRNA was intrathecally injected. Conclusion: These results showed that SIRT3 overexpression ameliorates PDN via activation of FoxO3a‐PINK1‐Parkin‐mediated mitophagy, suggesting that SIRT3 may become an encouraging therapeutic strategy for PDN. [ABSTRACT FROM AUTHOR]

Background: Diabetes mellitus (DM) is associated with structural grey matter alterations in the brain, including changes in the somatosensory and pain processing regions seen in association with diabetic peripheral neuropathy. In this case‐controlled biobank study, we aimed to ascertain differences in grey and white matter anatomy in people with DM compared with non‐diabetic controls (NDC). Methods: This study utilises the UK Biobank prospective, population‐based, multicentre study of UK residents. Participants with diabetes and age/gender‐matched controls without diabetes were selected in a three‐to‐one ratio. We excluded people with underlying neurological/neurodegenerative disease. Whole brain, cortical, and subcortical volumes (188 regions) were compared between participants with diabetes against NDC corrected for age, sex, and intracranial volume using univariate regression models, with adjustment for multiple comparisons. Diffusion tensor imaging analysis of fractional anisotropy (FA) was performed along the length of 50 white matter tracts. Results: We included 2404 eligible participants who underwent brain magnetic resonance imaging (NDC, n = 1803 and DM, n = 601). Participants with DM had a mean (±standard deviation) diagnostic duration of 18 ± 11 years, with adequate glycaemic control (HbA1C 52 ± 13 mmol/mol), low prevalence of microvascular complications (diabetic retinopathy prevalence, 5.8%), comparable cognitive function to controls but greater self‐reported pain. Univariate volumetric analyses revealed significant reductions in grey matter volume (whole brain, total, and subcortical grey matter), with mean percentage differences ranging from 2.2% to 7% in people with DM relative to NDC (all p < 0.0002). The subcortical (bilateral cerebellar cortex, brainstem, thalamus, central corpus callosum, putamen, and pallidum) and cortical regions linked to sensorimotor (bilateral superior frontal, middle frontal, precentral, and postcentral gyri) and visual functions (bilateral middle and superior occipital gyri), all had lower grey matter volumes in people with DM relative to NDC. People with DM had significantly reduced FA along the length of the thalamocortical radiations, thalamostriatal projections, and commissural fibres of the corpus callosum (all; p < 0·001). Interpretation: This analysis suggests that anatomic differences in brain regions are present in a cohort with adequately controlled glycaemia without prevalent microvascular disease when compared with volunteers without diabetes. We hypothesise that these differences may predate overt end‐organ damage and complications such as diabetic neuropathy and retinopathy. Central nervous system alterations/neuroplasticity may occur early in the natural history of microvascular complications; therefore, brain imaging should be considered in future mechanistic and interventional studies of DM. [ABSTRACT FROM AUTHOR]

This preregistered (CRD42021223379) systematic review and meta-analysis aimed to characterize the placebo and nocebo responses in placebo-controlled randomized clinical trials (RCTs) on painful diabetic neuropathy (PDN), updating the previous literature by a decade. Four databases were searched for PDN trials published in the past 20 years, testing oral medications, adopting a parallel-group design. Magnitude of placebo or nocebo responses, Cochrane risk of bias, heterogeneity, and moderators were evaluated. Searches identified 21 studies (2425 placebo-treated patients). The overall mean pooled placebo response was −1.54 change in the pain intensity from baseline [95% confidence interval (CI): −1.52, −1.56, I² = 72], with a moderate effect size (Cohen d = 0.72). The pooled placebo 50% response rate was 25% [95% CI: 22, 29, I² = 50%]. The overall percentage of patients with adverse events (AEs) in the placebo arms was 53.3% [95% CI: 50.9, 55.7], with 5.1% [95% CI: 4.2, 6] of patients dropping out due to AEs. The year of study initiation was the only significant moderator of placebo response (regression coefficient = −0.06, [95% CI: −0.10, −0.02, P = 0.007]). More recent RCTs tended to be longer, bigger, and to include older patients (N = 21, rs = 0.455, P = 0.038, rs = 0.600, P = 0.004, rs = 0.472, P = 0.031, respectively). Our findings confirm the magnitude of placebo and nocebo responses, identify the year of study initiation as the only significant moderator of placebo response, draw attention to contextual factors such as confidence in PDN treatments, patients' previous negative experiences, intervention duration, and information provided to patients before enrollment. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: While the risk factors for diabetic peripheral neuropathy (DPN) are now well recognised, the risk factors for painful DPN remain unknown. We performed analysis of the EURODIAB Prospective Complications Study data to elucidate the incidence and risk factors of painful DPN. Methods: The EURODIAB Prospective Complications Study recruited 3250 participants with type 1 diabetes who were followed up for 7.3±0.6 (mean ± SD) years. To evaluate DPN, a standardised protocol was used, including clinical assessment, quantitative sensory testing and autonomic function tests. Painful DPN (defined as painful neuropathic symptoms in the legs in participants with confirmed DPN) was assessed at baseline and follow-up. Results: At baseline, 234 (25.2%) out of 927 participants with DPN had painful DPN. At follow-up, incident DPN developed in 276 (23.5%) of 1172 participants. Of these, 41 (14.9%) had incident painful DPN. Most of the participants who developed incident painful DPN were female (73% vs 48% painless DPN p=0.003) and this remained significant after adjustment for duration of diabetes and HbA1c (OR 2.69 [95% CI 1.41, 6.23], p=0.004). The proportion of participants with macro- or microalbuminuria was lower in those with painful DPN compared with painless DPN (15% vs 34%, p=0.02), and this association remained after adjusting for HbA1c, diabetes duration and sex (p=0.03). Conclusions/interpretation: In this first prospective study to investigate the risk factors for painful DPN, we definitively demonstrate that female sex is a risk factor for painful DPN. Additionally, there is less evidence of diabetic nephropathy in incident painful, compared with painless, DPN. Thus, painful DPN is not driven by cardiometabolic factors traditionally associated with microvascular disease. Sex differences may therefore play an important role in the pathophysiology of neuropathic pain in diabetes. Future studies need to look at psychosocial, genetic and other factors in the development of painful DPN. [ABSTRACT FROM AUTHOR]

Painful diabetic neuropathy (PDN) is a serious and very common complication of diabetes mellitus (DM). It negatively affects the quality of life, increases morbidity and poses a financial burden on the health care system. Currently, treatment of PDN focuses on glycaemic control, while pathogenesis-oriented therapy has not yielded satisfactory results. The need to improve therapy remains. There is accumulating evidence on the potential benefit of nutritional interventions. This narrative review aims to examine the potential benefit of dietary and nutritional supplementation for PDN management. According to the preliminary research, supplementation with vitamin E, B-complex, omega-3 fatty acids, CoQ10 or N-acetylcysteine seems to be associated with promising results in improving PDN symptoms. [ABSTRACT FROM AUTHOR]

Adam R Burkey,1 Jeffrey Chen,2 Charles E Argoff,3 Deborah R Edgar,4 Erika A Petersen5 1Anesis Spine and Pain Care, Renton, WA, USA; 2UCSD Department of Anesthesiology Center for Pain, University of California San Diego Medical Center, La Jolla, CA, USA; 3Department of Neurology, Albany Medical Center, Albany, NY, USA; 4Commexus Ltd, Dunblane, Perthshire, UK; 5Department of Neurosurgery, University of Arkansas for Medical Sciences, Little Rock, AR, USACorrespondence: Erika A Petersen, Department of Neurosurgery, University of Arkansas for Medical Sciences, 4301 W Markham St, Slot 507, Little Rock, AR, 72205, USA, Tel +1-501-686-5270, Email eapetersen@uams.eduIntroduction: Painful peripheral neuropathy (PPN) is a debilitating condition with varied etiologies. Spinal cord stimulation (SCS) is increasingly used when conservative treatments fail to provide adequate pain relief. Few published reviews have examined SCS outcomes in all forms of PPN.Methods: We conducted a systematic review of SCS in PPN. The PubMed database was searched up to February 7th, 2022, for peer-reviewed studies of SCS that enrolled PPN patients with pain symptoms in their lower limbs and/or lower extremities. We assessed the quality of randomized controlled trial (RCT) evidence using the Cochrane risk of bias tool. Data were tabulated and presented narratively.Results: Twenty eligible studies documented SCS treatment in PPN patients, including 10 kHz SCS, traditional low-frequency SCS (t-SCS), dorsal root ganglion stimulation (DRGS), and burst SCS. In total, 451 patients received a permanent implant (10 kHz SCS, n=267; t-SCS, n=147; DRGS, n=25; burst SCS, n=12). Approximately 88% of implanted patients had painful diabetic neuropathy (PDN). Overall, we found clinically meaningful pain relief (≥ 30%) with all SCS modalities. Among the studies, RCTs supported the use of 10 kHz SCS and t-SCS to treat PDN, with 10 kHz SCS providing a higher reduction in pain (76%) than t-SCS (38– 55%). Pain relief with 10 kHz SCS and DRGS in other PPN etiologies ranged from 42– 81%. In addition, 66– 71% of PDN patients and 38% of nondiabetic PPN patients experienced neurological improvement with 10 kHz SCS.Conclusion: Our review found clinically meaningful pain relief in PPN patients after SCS treatment. RCT evidence supported the use of 10 kHz SCS and t-SCS in the diabetic neuropathy subpopulation, with more robust pain relief evident with 10 kHz SCS. Outcomes in other PPN etiologies were also promising for 10 kHz SCS. In addition, a majority of PDN patients experienced neurological improvement with 10 kHz SCS, as did a notable subset of nondiabetic PPN patients.Keywords: painful diabetic neuropathy, peripheral neuropathy, spinal cord stimulation, 10 kHz SCS, diabetes, neuropathic pain, systematic review

Background Plai or Zingiber cassumunar Roxb. was registered into the Thai Traditional Medicine list since 2011. However, there is limited evidence regarding Plai as a treatment in painful diabetic neuropathy (PDN). Therefore, this study aimed to evaluate the efficacy of topical Zingiber cassumunar. Methods A RCT was conducted in patients with PDN during February to March 2019. All participants received oral gabapentin 300 mg before bed as a standard regimen. The intervention group (n=16) received Plai balm 15%w/w 0.5 gram to apply on their feet three times a day and the control group (n=15) received placebo balm to similarly apply. Pain score at baseline, 2 nd and 4 th weeks were assessed and compared. Patients’ quality of life, and adverse events, were collected. Mean pain scores before and after treatment in each group and between groups were also analyzed. Results At the end of week two and week four, the Plai group showed statistically significant lesser mean pain scores than the placebo group by -1.47 (95%CI: -1.96 to -1.30, p-value < 0.001), and by -1.51 (95%CI: -1.92 to -0.13, p-value = 0.027), respectively. Moreover, the Plai group had more cases number/ percentages with at least 50% pain score reduction than the placebo group [12/16 (75%) vs 3/15 (20%), p-value = 0.004]. However, there was no statistically significant difference in quality of life between the two groups (overall p-value = 0.366). Adverse event was not found in any groups. Conclusions Zingiber cassumunar balm (Plai) was efficacious for pain reduction in painful diabetic neuropathy. Registration Registered with the Thai Clinical Trials Registry; TCTR20200221001.

Background Plai or Zingiber cassumunar Roxb. was registered into the Thai Traditional Medicine list since 2011. However, there is limited evidence regarding Plai as a treatment in painful diabetic neuropathy (PDN). Therefore, this study aimed to evaluate the efficacy of topical Zingiber cassumunar. Methods A RCT was conducted in patients with PDN during February to March 2019. All participants received oral gabapentin 300 mg before bed as a standard regimen. The intervention group (n=16) received Plai balm 15%w/w 0.5 gram to apply on their feet three times a day and the control group (n=15) received placebo balm to similarly apply. Pain score at baseline, 2nd and 4th weeks were assessed and compared. Patients’ quality of life, and adverse events, were collected. Mean pain scores before and after treatment in each group and between groups were also analyzed. Results At the end of week two and week four, the Plai group showed statistically significant lesser mean pain scores than the placebo group by -1.47 (95%CI: -1.96 to -1.30, p-value < 0.001), and by -1.51 (95%CI: -1.92 to -0.13, p-value = 0.027), respectively. Moreover, the Plai group had more cases number/ percentages with at least 50% pain score reduction than the placebo group [12/16 (75%) vs 3/15 (20%), p-value = 0.004]. However, there was no statistically significant difference in quality of life between the two groups (overall p-value = 0.366). Adverse event was not found in any groups. Conclusions Zingiber cassumunar balm (Plai) was efficacious for pain reduction in painful diabetic neuropathy. Registration Registered with the Thai Clinical Trials Registry; TCTR20200221001.

Objective: To assess the effect of a single-dose, oral vitamin D supplementation (soft gel capsule of 200,000 IU) in subjects with painful diabetic neuropathy (PDN) in Pakistan. Design: Randomized control trial. Materials and Methods: This randomized control trial was conducted at the Baqai Institute of Diabetology and Endocrinology (BIDE), Pakistan from November 2021 to August 2022. Subjects with diabetes without any signs of vitamin D deficiency were included. Baseline details were obtained by a predesigned questionnaire. Douleur neuropathy 4 (DN4) score was used for diagnosing PDN. Biochemical tests include serum 25-hydroxyvitamin D (OH)D and HbA1c for screening at baseline and at 3 months follow-up were analyzed. Subjects were categorized into two: a control group and an intervention group. The intervention group was given a single soft gel vitamin D capsule (200,000 IU) after screening by expert paramedical staff. Based on baseline serum vitamin D levels, the intervention group was further categorized into insufficient vs. deficient groups, and the control group was categorized into insufficient vs. sufficient. Results: Of 159 participants, 19.5% vs. 44.7% subjects were with insufficient vs. deficient vitamin D levels in the intervention group, and 10.7% vs. 25.1% were with insufficient vs. sufficient vitamin D levels in the control group, respectively. Though the findings are insignificant, DN4 score at follow-up in intervention groups and control groups was reduced compared to the baseline DN4 score. Furthermore, we observed a reduction in post-HbA1c levels in both the intervention groups (insufficient vs. deficient) and the control-sufficient group. Conclusion: Treatment with vitamin D supplementation in people with PDN helps to improve vitamin D levels, DN4 score, and HbA1c levels, though doseresponse is yet to be compared. [ABSTRACT FROM AUTHOR]

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

Purpose of Review: Almost half of people diagnosed with diabetes mellitus will develop painful diabetic neuropathy (PDN), a condition greatly impacting quality of life with complicated pathology. While there are different FDA approved forms of treatment, many of the existing options are difficult to manage with comorbities and are associated with unwanted side effects. Here, we summarize the current and novel treatments for PDN. Recent Findings: Current research is exploring alternative pain management treatments from the first line options of pregabalin, gabapentin, duloxetine, and amitriptyline which often have side effects. The use of FDA approved capsaicin and spinal cord stimulators (SCS) has been incredibly beneficial in addressing this. In addition, new treatments looking at different targets, such as NMDA receptor and the endocannabinoid system, show promising results. Summary: There are several treatment options that have been shown to be successful in helping treat PDN, but often require adjunct treatment or alterations due to side effects. While there is ample research for standard medications, treatments such as palmitoylethanolamide and endocannabinoid targets have extremely limited clinical trials. We also found that many studies did not evaluate additional variables other than pain relief, such as functional changes nor were there consistent measurement methods. Future research should continue trials comparing treatment efficacies along with more quality of life measures. [ABSTRACT FROM AUTHOR]

Objective: To assess the effect of a single-dose, oral vitamin D supplementation (soft gel capsule of 200,000 IU) in subjects with painful diabetic neuropathy (PDN) in Pakistan. Design: Randomized control trial. Materials and Methods: This randomized control trial was conducted at the Baqai Institute of Diabetology and Endocrinology (BIDE), Pakistan from November 2021 to August 2022. Subjects with diabetes without any signs of vitamin D deficiency were included. Baseline details were obtained by a predesigned questionnaire. Douleur neuropathy 4 (DN4) score was used for diagnosing PDN. Biochemical tests include serum 25-hydroxyvitamin D (OH)D and HbA1c for screening at baseline and at 3 months follow-up were analyzed. Subjects were categorized into two: a control group and an intervention group. The intervention group was given a single soft gel vitamin D capsule (200,000 IU) after screening by expert paramedical staff. Based on baseline serum vitamin D levels, the intervention group was further categorized into insufficient vs. deficient groups, and the control group was categorized into insufficient vs. sufficient. Results: Of 159 participants, 19.5% vs. 44.7% subjects were with insufficient vs. deficient vitamin D levels in the intervention group, and 10.7% vs. 25.1% were with insufficient vs. sufficient vitamin D levels in the control group, respectively. Though the findings are insignificant, DN4 score at follow-up in intervention groups and control groups was reduced compared to the baseline DN4 score. Furthermore, we observed a reduction in post-HbA1c levels in both the intervention groups (insufficient vs. deficient) and the control-sufficient group. Conclusion: Treatment with vitamin D supplementation in people with PDN helps to improve vitamin D levels, DN4 score, and HbA1c levels, though dose-response is yet to be compared.

Die Diabetische Polyneuropathie (DPN) geht mit deutlich erhöhten Gesundheitskosten und somit einer wirtschaftlichen Belastung für die Gesellschaft und das Gesundheitssystem einher (Happich et al. 2008; Khdour 2020; Shillo et al. 2019). Eine hohe Anzahl an Krankenhausaufenthalten, Pflegebedürftigkeit, Arbeitsunfähigkeit sowie Folgekosten der DPN (bspw. Amputationen) und eine insgesamt stärkere Inanspruchnahme von Gesundheitsressourcen sind für die höheren medizinischen Kosten verantwortlich (Sadosky et al. 2015; Schroeter/Hartung 2005; Ziegler 2020) und verdeutlichen die Belastung der an DPN erkrankten Patient:innen. Tendenziell steigen die Kosten dabei mit zunehmender Krankheitslast an (Happich et al. 2008).

The neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) is involved in numerous physiological functions and plays a key role in pain modulation including neuropathic pain. Diabetic neuropathy is a common complication of diabetes mellitus often accompanied by chronic neuropathic pain. Animal models of diabetes offer relevant tools for studying the pathophysiological mechanisms and pharmacological sensitivity of diabetic neuropathic pain and for identifying new therapeutic targets. In this review, we report data from preclinical work published over the last 15 years on the analgesic activity of drugs acting on the serotonergic system, such as serotonin and noradrenaline reuptake inhibitor (SNRI) antidepressants, and on the involvement of certain serotonin receptors-in particular 5-HT1A, 5-HT2A/2c and 5-HT6 receptors-in rodent models of painful diabetic neuropathy. [ABSTRACT FROM AUTHOR]

Objective: This study aims to evaluate the efficacy and safety of spinal cord stimulation (SCS) compared to conventional medical management (CMM) for patients diagnosed with chronic pain. Furthermore, the study seeks to compare the utilization of analgesics, as well as the long-term outcomes in terms of quality of life and functional capacity. Data sources: We systematically searched Cochrane Library, Web of Science, PubMed, and EMBASE for randomized controlled trials from inception up to February 2022. Review methods: Inclusion and exclusion criteria were set according to the PICOS criteria. We searched for studies in which SCS was compared with CMM alone for chronic pain. Two reviewers independently identified eligible studies and extracted data. Risk of bias assessments were performed according to Cochrane review criteria and Interventional Pain Management Techniques–quality Appraisal of Reliability and Risk of Bias Assessment (IPM-QRB) criteria. Results: The present meta-analysis comprised eight studies and included a total of 893 patients. Our findings demonstrate that spinal cord stimulation (SCS) in combination with conventional medical management (CMM) is associated with a significant reduction in visual analogue scale (VAS) pain intensity (P = 0.0005) and decreased scores on the McGill Pain Questionnaire (MPQ) (P < 0.0001). Moreover, SCS plus CMM was found to improve patients' quality of life, as evidenced by improvements in SF-36 scores (P < 0.00001), EQ-5D utility index (P = 0.008), and Oswestry Disability Index (ODI) (P < 0.00001). Based on the results of four high-quality randomized controlled trials (RCTs), the level of evidence supporting the efficacy of SCS for the treatment of painful neuropathy is graded as level I to II. In contrast, there is currently only low-level evidence to support the use of high-frequency stimulation and other chronic pain conditions, which can be attributed to a lack of sufficient randomized controlled trials. Limitations: The principal limitation of our study is the significant heterogeneity observed among the cohorts investigated. The primary source of this heterogeneity is the fact that spinal cord stimulation is indicated for the treatment of multiple chronic pain conditions. Moreover, variations in the stimulation parameters, differences among manufacturers, and the specific surgical implantation settings contribute to the increased heterogeneity observed in our analyses. To address this issue, we conducted a subgroup analysis based on specific situations and performed evidence synthesis to mitigate the potential impact of heterogeneity. These approaches allow for a more precise interpretation of the results and a more accurate evaluation of the quality of the included studies. Conclusions: SCS is an effective treatment to relieve the pain level of chronic pain, decrease analgesic usage, and increase long-term quality of life and functional capacity. [ABSTRACT FROM AUTHOR]

Objectives: To compare pregabalin with duloxetine in terms of mean reduction in pain score, in the management of patients with painful diabetic neuropathy. Study Design: Randomized Controlled Trial. Setting: Department of Medicine, FMU & Affiliated Hospitals, Faisalabad. Period: 1st March, 2020 to 3rd March 2021. Material & Methods: A total of 180 patients with known diabetics of at least 5 years duration, 18 to 75 years of age were included. Patients with ischemic pain or other types of pain not related to diabetes such as arthritic pain or phantom pain secondary to amputations, CRF & CLD were excluded. Group A received 150mg of Pregabalin at night before sleeping and was increased to 150mg twice daily after 02 week if VAS pain score reduction was found to be less than 50% from baseline. Group B received 60mg Duloxetine at bed time and it was increased to 120mg after 04 weeks if the VAS pain score was less than 50% after 04 weeks. The patients were again assessed after another 04 weeks to assess VAS Pain Score reduction. The primary outcome is pain as assessed by the Visual Analogue Score (VAS) at the end of 04 weeks from start of medications. Results: Age range in this study was from18 to75 years with mean age of 40.87±13.67 years. The mean age of patients in pregabalin group was 38.80 ± 13.01 years and in duloxetine group was 41.07 ± 13.85 years. Majority of the patients 34 (56.67%) were between 20 to 40 years of age. Mean reduction in pain in pregabalin group was 1.63 ± 1.07 while in duloxetine group was 3.23 ± 1.38 (p-value =0.0001). Conclusion: This study concluded that duloxetine had significantly greater pain reduction than pregabalin in the management of patients with painful diabetic neuropathy. [ABSTRACT FROM AUTHOR]

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

One of the most common chronic complications arising from diabetes is diabetic peripheral neuropathy. Depending on research statistics, approximately half of the people who have diabetes will suffer from diabetic peripheral neuropathy over time, which manifests as abnormal sensations in the distal extremities, and about 25%–50% of these patients have symptoms of neuralgia, called painful diabetic neuropathy. These patients often exhibit adverse emotional conditions, like anxiety or depression, which can reduce their quality of life. The pathogenesis of diabetic peripheral neuropathy is complex, and although persistent hyperglycemia plays a central role in the development of diabetic peripheral neuropathy, strict glycemic control does not eliminate the risk of diabetic peripheral neuropathy. This suggests the need to understand the role of the central nervous system in the development of diabetic peripheral neuropathy to modulate treatment regimens accordingly. Magnetic resonance imaging not only allows for the noninvasive detection of structural and functional alterations in the central nervous system, but also provides insight into the processing of abnormal information such as pain by the central nervous system, and most importantly, contributes to the development of more effective pain relief protocols. Therefore, this article will focus on the mechanisms and related imaging evidence of central alterations in diabetic peripheral neuropathy, especially in painful diabetic neuropathy.

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 metaanalysis 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. [ABSTRACT FROM AUTHOR]

Background : Plai or Zingiber cassumunar Roxb. was registered into the Thai Traditional Medicine list since 2011. However, there is limited evidence regarding Plai as a treatment in painful diabetic neuropathy (PDN). Therefore, this study aimed to evaluate the efficacy of topical Zingiber cassumunar. Methods : A RCT was conducted in patients with PDN during February to March 2019. All participants received oral gabapentin 300 mg before bed as a standard regimen. The intervention group (n=16) received Plai balm 15%w/w 0.5 gram to apply on their feet three times a day and the control group (n=15) received placebo balm to similarly apply. Pain score at baseline, 2 nd and 4 th weeks were assessed and compared. Patients’ quality of life, and adverse events, were collected. Mean pain scores before and after treatment in each group and between groups were also analyzed. Results : At the end of week two and week four, the Plai group showed statistically significant lesser mean pain scores than the placebo group by -1.47 (95%CI: -1.96 to -1.30, p-value < 0.001), and by -1.51 (95%CI: -1.92 to -0.13, p-value = 0.027), respectively. Moreover, the Plai group had more cases number/ percentages with at least 50% pain score reduction than the placebo group [12/16 (75%) vs 3/15 (20%), p-value = 0.004]. However, there was no statistically significant difference in quality of life between the two groups (overall p-value = 0.366). Adverse event was not found in any groups. Conclusions : Zingiber cassumunar balm (Plai) was efficacious for pain reduction in painful diabetic neuropathy. Registration : Registered with the Thai Clinical Trials Registry; TCTR20200221001.

The common chronic complication from diabetes mellitus (DM) is painful diabetic neuropathy. The available symptomatic treatment with standard therapy is not sufficient for pain reduction. Previous studies showed that vitamin D deficiency was common in type 2 diabetes. Some studies report the benefit of vitamin D supplementation. We report a case of a type 2 diabetic 54-year-old obese female with painful diabetic neuropathy. The combination of lifestyle modifications and 2000 IU vitamin D supplementation improved neuropathy eight weeks of therapy symptoms. The literature search found a valid article that supports the use of combined exercise and vitamin D supplementation. Further research with a larger sample and better design is warranted.