Treatment Of Painful Diabetic Neuropathy Research Articles

Astaxanthin has a beneficial influence on pain-related symptoms and opioid-induced hyperalgesia in mice with diabetic neuropathy-evidence from behavioral studies.

The treatment of painful diabetic neuropathy is still a clinical problem. The aim of this study was to determine whether astaxanthin, a substance that inhibits mitogen-activated protein kinases, activates nuclear factor erythroid 2-related factor 2 and influences N-methyl-D-aspartate receptor, affects nociceptive transmission in mice with diabetic neuropathy. The studies were performed on streptozotocin-induced mouse diabetic neuropathic pain model. Single intrathecal and intraperitoneal administrations of astaxanthin at various doses were conducted in both males and females. Additionally, repeated twice-daily treatment with astaxanthin (25mg/kg) and morphine (30mg/kg) were performed. Hypersensitivity was evaluated with von Frey and cold plate tests. This behavioral study provides the first evidence that in a mouse model of diabetic neuropathy, single injections of astaxanthin similarly reduce tactile and thermal hypersensitivity in both male and female mice, regardless of the route of administration. Moreover, repeated administration of astaxanthin slightly delays the development of morphine tolerance and significantly suppresses the occurrence of opioid-induced hyperalgesia, although it does not affect blood glucose levels, body weight, or motor coordination. Surprisingly, astaxanthin administered repeatedly produces a better analgesic effect when administered alone than in combination with morphine, and its potency becomes even more pronounced over time. These behavioral results provide a basis for further evaluation of the potential use of astaxanthin in the clinical treatment of diabetic neuropathy and suggest that the multidirectional action of this substance may have positive effects on relieving neuropathic pain in diabetes.

High-Frequency 10-kHz Spinal Cord Stimulation Provides Long-term (24-Month) Improvements in Diabetes-Related Pain and Quality of Life for Patients with Painful Diabetic Neuropathy.

The SENZA-PDN study evaluated high-frequency 10-kHz spinal cord stimulation (SCS) for the treatment of painful diabetic neuropathy (PDN). Over 24 months, 10-kHz SCS provided sustained pain relief and improved health-related quality of life. This report presents additional outcomes from the SENZA-PDN study, focusing on diabetes-related pain and quality of life outcomes. The SENZA-PDN study randomized 216 participants with refractory PDN to receive either conventional medical management (CMM) or 10-kHz SCS plus CMM (10-kHz SCS + CMM), allowing crossover after six months if pain relief was insufficient. Postimplantation assessments at 24 months were completed by 142 participants with a permanent 10-kHz SCS implant, comprising 84 initial and 58 crossover recipients. Measures included the Brief Pain Inventory for Diabetic Peripheral Neuropathy (BPI-DPN), Diabetes-Related Quality of Life (DQOL), Global Assessment of Functioning (GAF), and treatment satisfaction. Over 24 months, 10-kHz SCS treatment significantly reduced pain severity by 66.9% (P < .001; BPI-DPN) and pain interference with mood and daily activities by 65.8% (P < .001; BPI-DPN). Significant improvements were also observed in overall DQOL score (P < .001) and GAF score (P < .001), and 91.5% of participants reported satisfaction with treatment. High-frequency 10-kHz SCS significantly decreased pain severity and provided additional clinically meaningful improvements in DQOL and overall functioning for patients with PDN. The robust and sustained benefits over 24 months, coupled with high participant satisfaction, highlight that 10-kHz SCS is an efficacious and comprehensive therapy for patients with PDN.

ID: 335676 Double-Blind, RCT Results: Axon Therapy verses Sham for the Treatment of Painful Diabetic Neuropathy

ID: 335676 Double-Blind, RCT Results: Axon Therapy verses Sham for the Treatment of Painful Diabetic Neuropathy

ID: 314772 10 kHz SCS Treatment of Painful Diabetic Neuropathy: Significant Reductions in HbA1c, Weight, and Pain

ID: 314772 10 kHz SCS Treatment of Painful Diabetic Neuropathy: Significant Reductions in HbA1c, Weight, and Pain

ID: 335010 10kHz SCS Treatment of Painful Diabetic Neuropathy: Results Combining Dermatomal Dysesthesias and Limb Sensory Assessments

ID: 335010 10kHz SCS Treatment of Painful Diabetic Neuropathy: Results Combining Dermatomal Dysesthesias and Limb Sensory Assessments

Update on Biomarkers of Chronic Inflammatory Processes Underlying Diabetic Neuropathy.

There is an increasing prevalence of diabetes mellitus (DM), particularly type 2 DM (T2DM), and its associated complications. T2DM is linked to insulin resistance, chronic inflammation, and oxidative stress, which can lead to both macrovascular and microvascular complications, including peripheral diabetic neuropathy (PDN). Inflammatory processes play a key role in the development and progression of T2DM and its complications, with specific markers like C-reactive protein (CRP), interleukins (ILs), and tumor necrosis factor (TNF)-α being associated with increased risk. Other key inflammatory markers such as nuclear factor kappa B (NF-κB) are activated under hyperglycemic and oxidative stress conditions and contribute to the aggravation of PDN by regulating inflammatory gene expression and enhancing endothelial dysfunction. Other important roles in the inflammatory processes are played by Toll-like receptors (TLRs), caveolin 1 (CAV1), and monocyte chemoattractant protein 1 (MCP1). There is a relationship between vitamin D deficiency and PDN, highlighting the critical role of vitamin D in regulating inflammation and immune responses. The involvement of macrophages in PDN is also suspected, emphasizing their role in chronic inflammation and nerve damage in diabetic patients. Vitamin D supplementation has been found to reduce neuropathy severity, decrease inflammatory markers, and improve glycemic control. These findings suggest that addressing vitamin D deficiency could offer therapeutic benefits for PDN. These molecular pathways are critical in understanding the pathogenesis of DM complications and may offer potential biomarkers or therapeutic targets including anti-inflammatory treatments, vitamin D supplementation, macrophage phenotype modulation, and lifestyle modifications, aimed at reducing inflammation and preventing PDN. Ongoing and more extensive clinical trials with the aim of investigating anti-inflammatory agents, TNF-α inhibitors, and antioxidants are needed to advance deeper into the understanding and treatment of painful diabetic neuropathy.

Liquiritin ameliorates painful diabetic neuropathy in SD rats by inhibiting NLRP3-MMP-9-mediated reversal of aquaporin-4 polarity in the glymphatic system.

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.

P86. Treatment of painful diabetic neuropathy: 10 kHz SCS provides durable pain relief and sensory function improvements

P86. Treatment of painful diabetic neuropathy: 10 kHz SCS provides durable pain relief and sensory function improvements

Preclinical Evaluation of Sigma 1 Receptor Antagonists as a Novel Treatment for Painful Diabetic Neuropathy.

The global prevalence of diabetes is steadily rising, with an estimated 537 million adults affected by diabetes in 2021, projected to reach 783 million by 2045. A severe consequence of diabetes is the development of painful diabetic neuropathy (PDN), afflicting approximately one in every three diabetic patients and significantly compromising their quality of life. Current pharmacotherapies for PDN provide inadequate pain relief for many patients, underscoring the need for novel treatments that are both safe and effective. The Sigma 1 Receptor (S1R) is a ligand-operated chaperone protein that resides at the mitochondria-associated membrane of the endoplasmic reticulum. The S1R has been shown to play crucial roles in regulating cellular processes implicated in pain modulation. This study explores the potential of PW507, a novel S1R antagonist, as a therapeutic candidate for PDN. PW507 exhibited promising in vitro and in vivo properties in terms of ADME, toxicity, pharmacokinetics, and safety. In preclinical rat models of Streptozotocin-induced diabetic neuropathy, PW507 demonstrated significant efficacy in alleviating mechanical allodynia and thermal hyperalgesia following both acute and chronic (2-week) administration, without inducing tolerance and visual evidence of toxicity. To the best of our knowledge, this is the first report to evaluate an S1R antagonist in STZ-induced diabetic rats following both acute and 2-week chronic administration, offering compelling preclinical evidence for the potential use of PW507 as a promising therapeutic option for PDN.

A New Application for Cenicriviroc, a Dual CCR2/CCR5 Antagonist, in the Treatment of Painful Diabetic Neuropathy in a Mouse Model.

The ligands of chemokine receptors 2 and 5 (CCR2 and CCR5, respectively) are associated with the pathomechanism of neuropathic pain development, but their role in painful diabetic neuropathy remains unclear. Therefore, the aim of our study was to examine the function of these factors in the hypersensitivity accompanying diabetes. Additionally, we analyzed the analgesic effect of cenicriviroc (CVC), a dual CCR2/CCR5 antagonist, and its influence on the effectiveness of morphine. An increasing number of experimental studies have shown that targeting more than one molecular target is advantageous compared with the coadministration of individual pharmacophores in terms of their analgesic effect. The advantage of using bifunctional compounds is that they gain simultaneous access to two receptors at the same dose, positively affecting their pharmacokinetics and pharmacodynamics and consequently leading to improved analgesia. Experiments were performed on male and female Swiss albino mice with a streptozotocin (STZ, 200 mg/kg, i.p.) model of diabetic neuropathy. We found that the blood glucose level increased, and the mechanical and thermal hypersensitivity developed on the 7th day after STZ administration. In male mice, we observed increased mRNA levels of Ccl2, Ccl5, and Ccl7, while in female mice, we observed additional increases in Ccl8 and Ccl12 levels. We have demonstrated for the first time that a single administration of cenicriviroc relieves pain to a similar extent in male and female mice. Moreover, repeated coadministration of cenicriviroc with morphine delays the development of opioid tolerance, while the best and longest-lasting analgesic effect is achieved by repeated administration of cenicriviroc alone, which reduces pain hypersensitivity in STZ-exposed mice, and unlike morphine, no tolerance to the analgesic effects of CVC is observed until Day 15 of treatment. Based on these results, we suggest that targeting CCR2 and CCR5 with CVC is a potent therapeutic option for novel pain treatments in diabetic neuropathy patients.

A Systematic Guideline by the ASPN Workgroup on the Evidence, Education, and Treatment Algorithm for Painful Diabetic Neuropathy: SWEET.

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. The SWEET Guideline was developed to provide clinicians with the most comprehensive guideline for the safe and appropriate treatment of patients suffering from PDN. 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. 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. The ASPN SWEET Guideline represents the most comprehensive review of the available treatments for PDN and their appropriate and safe utilization.

127 Durable Treatment of Painful Diabetic Neuropathy With 10 kHz Spinal Cord Stimulation

INTRODUCTION: Approximately 25% of people with diabetes experience painful diabetic neuropathy (PDN), but conventional medical management (CMM) is ineffective for many patients. We previously presented partial study results showing that high-frequency (10 kHz) spinal cord stimulation (SCS) provides substantial symptom relief. Here we report full study results through 24-month (24M) follow-up. METHODS: We conducted a multicenter RCT to evaluate 10 kHz SCS in PDN patients. Key study inclusion criteria were: PDN symptoms = 12M refractory to medications, lower limb pain intensity = 5cm (0-10 cm visual analog scale [VAS]), and hemoglobin A1c = 10%. Patients (n = 216) were randomized 1:1 to 10 kHz SCS plus CMM or CMM alone, with optional treatment crossover at 6M. RESULTS: Patients randomized to 10 kHz SCS experienced significantly greater pain relief at 6M than those treated with CMM alone (p &lt; 0.001). For all patients who received 10 kHz SCS, at 24M post-implantation the average pain relief was 80% from pre-implantation (p &lt; 0.001), and the treatment responder rate was 90%. Clinician-assessed sensory function showed significant improvements with 10 kHz SCS. At 6M, 59% of patients treated with 10 kHz SCS had sensory improvement versus 9% of those treated with CMM alone (p &lt; 0.001). At 24M, 10 kHz SCS improved sensory function for 65% of patients. Patients receiving 10 kHz SCS also experienced significant improvements in health-related quality of life (HRQoL, p &lt; 0.001). At 24M, the mean HRQoL improvement was 2.9-4.8 times the minimum clinically important difference for patients with type 2 diabetes. CONCLUSIONS: The results demonstrate that 10 kHz SCS provides significant, durable reductions in pain and improvements in sensory function and HRQoL. Sensory function improvements support the unique disease-modifying potential of 10 kHz SCS.

A review on comparative study of effectiveness of pregabalin and carbamazepine in painful diabetic peripheral neuropathy using mc gill's pain questionnaire

Diabetic neuropathy is a unique degenerative disorder of the peripheral nervous system that preferentially targets sensory axons and autonomic axons. The loss of sensory function that begins distally in the lower extremities is known as Diabetic neuropathy. It is characterized by burning pain, paresthesias and numbness in stocking glove pattern that progress proximally from the feet and hands. Diabetic neuropathy is a highly prevalent condition that substantially affects patients by increasing falls causing pain and reducing quality of life. The major risk factors for diabetic neuropathy is hyperglycemia. In addition to poor glycemic control, more-severe symptoms of diabetic neuropathy are associated with advanced age, hypertension, the duration of diabetes, dyslipidemia, smoking and heavy alcohol intake. Diabetic neuropathy is a major cause for disability of feet and hands globally. Anti-convulsants like pregabalin and carbamazepine are the medications used in the treatment of painful diabetic neuropathy.

IDF23-0077 Does Laser Therapy Have a Role in the Treatment of Painful Diabetic Neuropathy?

IDF23-0077 Does Laser Therapy Have a Role in the Treatment of Painful Diabetic Neuropathy?

Treatment of Painful Diabetic Neuropathy with 10 kHz Spinal Cord Stimulation: Long-Term Improvements in Hemoglobin A1c, Weight, and Sleep Accompany Pain Relief for People with Type 2 Diabetes.

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). 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). 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. 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. ClincalTrials.gov Identifier, NCT03228420.

Where does spinal cord stimulation fit into the international guidelines for refractory painful diabetic neuropathy? a consensus statement

BackgroundAlthough pharmacotherapy with anticonvulsants and/or antidepressants can be effective for many people with painful diabetic neuropathy (PDN), albeit with frequent side-effects, a critical juncture occurs when neuropathic pain no longer responds to standard first- and second-step mono- and dual therapy and becomes refractory. Subsequent to these pharmacotherapeutic approaches, third-line treatment options for PDN may include opioids (short-term), capsaicin 8% patches, and spinal cord stimulation (SCS). AimThis document summarizes consensus recommendations regarding appropriate treatment for refractory peripheral diabetic neuropathy (PDN), based on outcomes from an expert panel convened on December 10, 2022, as part of the Worldwide Initiative for Diabetes Education Virtual Global Summit, “Advances in the Management of Painful Diabetic Neuropathy.” ParticipantsNine attendees, eminent physicians and academics, comprising six diabetes specialists, two pain specialists, and one health services expert. EvidenceFor individuals with refractory PDN, opioids are a high-risk option that do not provide a long-term solution and should not be used. For appropriately selected individuals, SCS is an effective, safe, and durable treatment option. In particular, high-frequency (HF) SCS (10 kHz) shows strong efficacy and improves quality of life. To ensure treatment success, strict screening criteria should be used to prioritize candidates for SCS. Consensus Process:Each participant voiced their opinion after reviewing available data, and a verbal consensus was reached during the meeting. ConclusionGlobally, the use of opioids should rarely be recommended for refractory, severe PDN. Based on increasing clinical evidence, SCS, especially HF-SCS, should be considered as a treatment for PDN that is not responsive to first- or second-line monotherapy/dual therapy.

Spinal cord stimulation in painful diabetic neuropathy: An overview

Up to 25% of people with diabetes develop painful diabetic neuropathy (PDN). The standard of care pharmacotherapies for PDN have limited efficacy with a considerable side effect profile. Spinal cord stimulation (SCS) is a form of electrical neurostimulation that modulates neural function via electrodes implanted into the spinal epidural space. While low frequency SCS has been shown to be potentially effective for treating pain associated with neuropathies, it masks pain perception by inducing paresthesia. Compared to low frequency SCS, high frequency (10 kHz) SCS delivers paresthesia-free therapy. As was shown in a randomized controlled trial, SENZA-PDN (NCT03228420), 10 kHz SCS is safe and effective for the treatment of painful diabetic neuropathy. 10 kHz SCS offered a comprehensive treatment that improved pain levels, sleep, quality of life, and neurological function. These improvements correlated with a high degree of patient satisfaction. 10 kHz SCS provides a safe, durable and effective treatment for PDN with the unique potential to improve neurological function. In patients for whom durable, effective treatments have been limited thus far, the findings of the SENZA-PDN study are encouraging.

Dietary and Nutritional Supplementation for Painful Diabetic Neuropathy: A Narrative Review.

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.

Quantitative assessment of painful diabetic peripheral neuropathy after high-frequency spinal cord stimulation: a pilot study.

Randomized trials have demonstrated efficacy of spinal cord stimulation (SCS) for treatment of painful diabetic neuropathy (PDN). Preliminary data suggested that treatment of PDN with high-frequency SCS resulted in improvements on neurological examination. The purpose of the present study was to explore whether patients with PDN treated with high-frequency SCS would have improvements in lower-extremity peripheral nerve function. Prospective cohort study in an outpatient clinical practice at a tertiary care center. Patients with PDN were treated with high-frequency SCS and followed up for 12 months after SCS implantation with clinical outcomes assessments of pain intensity, neuropathic symptoms, and neurological function. Small-fiber sudomotor function was assessed with the quantitative sudomotor axon reflex test (QSART), and large-fiber function was assessed with nerve conduction studies (NCS). Lower-extremity perfusion was assessed with laser Doppler flowmetry. Nine patients completed 12-month follow-up visits and were observed to have improvements in lower-extremity pain, weakness, and positive sensory symptoms. Neuropathy impairment scores were improved, and 2 patients had recovery of sensory responses on NCS. A reduction in sweat volume on QSART was observed in the proximal leg but not at other sites. No significant differences were noted in lower-extremity perfusion or NCS as compared with baseline. The improvement in pain relief was concordant with improvement in neuropathy symptoms. The findings from this study provide encouraging preliminary data in support of the hypothesis of a positive effect of SCS on peripheral neuropathy, but the findings are based on small numbers and require further evaluation. ClinicalTrials.gov ID NCT03769675.

The Efficacy of Intradermal Injection of Botulinum Toxin Type-A on Painful Diabetic Neuropathy: A Systematic Review.

Diabetes is one of the most common causes of neuropathy. Morbidity and mortality increase in patients suffering from diabetic polyneuropathy and are experienced by approximately 10 to 54% of diabetic patients. Severe pain, loss of sensation, increased risk of ulceration, and even amputation are the complications of diabetic neuropathy. Intradermal injection of botulinum toxin type-A (BTX-A) is a relatively novel method for the treatment of painful diabetic neuropathy. This method is becoming popular considering its acceptable and long-lasting pain control and minimal systemic side effects. This narrative systematic review aimed to evaluate the effectiveness of intradermal BTX-A injection on painful diabetic neuropathy. The queried databases included PubMed, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), ClinicalTrials.gov, Web of Science, Scopus, and Google Scholar. The final search was performed in February 2022, and no time limits were set for the search. All the relevant clinical trials were included. The inclusion criteria and search strategy were set as follows: Type of study: Randomized clinical trial (RCT) or other types of interventional studies; publication date: All published studies until February 22, 2022; sample size: No restrictions; outcomes: Effect on diabetic neuropathy pain; quality: Earning a minimum acceptable score based on critical appraisal; and language: English. The searches and article screening were performed by two independent reviewers to minimize the possibility of bias. In case of disagreement about a study, the comments of an expert (as a third person) were used to resolve the ambiguity. In a review of 4 RCTs and 1 case-control study on the effectiveness of BTX-A in reducing the pain of diabetic neuropathy, 273 patients were evaluated in total. The lowest and highest number of subjects was 18 and 141. The sex distribution included 43.22% men and 56.77% women, all of whom were 47.8 to 74.8 years old. Three studies were conducted in Iran, Taiwan, and Egypt. The results of this review showed significant improvement in pain reduction, e.g., based on the Visual Analog Scale (VAS) and Neuropathic Pain Scale (NPS). A few studies evaluated sleep and psychosocial complications, and their results indicated a statistically significant improvement in the Pittsburgh sleep quality index (PSQI) and the physical subscale of the 36-Item Short Form Survey (SF-36). The results of this systematic review demonstrated that intradermal injection of BTX-A causes significant and long-term (up to 12 weeks) improvement in diabetic neuropathy pain. The improvement in sleep and mental or physical functions was not consistent, and no conclusive result could be reached.