Search

No abstract available.

Painful diabetic neuropathy is observed in almost half of patients with diabetes mellitus (DM) and is associated with a decrease in the quality of life, emotional disorders, sleep disorders. The achievement and maintenance of the normal level of glucose in the blood is the basis for the prevention and treatment of DM, but this often does not allow the patient from pain and other clinical manifestations of neuropathy. Drug diabetic neuropathy therapy methods are discussed, the results of randomized placebo controlled studies on the efficiency and side effects of various drugs are analyzed. It is noted that pregabalin and gabapenitin, as antidepressants duloxetin, venlafaxin and amitriptyline, are most effective as anti-epileptic agents. In our country, with painful diabetic neuropathy, the preparations of a-lipoic acid are widely used. Analyzed data on efficacy and complications of the use of transcutaneus electrical nerves stimulation and spinal cord stimulation with pain diabetic neuropathy refractory to drug therapy. It is noted that many patients with pain diabetic neuropathy have combined diseases, detection and effective treatment of which can lead to an improvement in the state of patients and reduce the manifestations of neuropathy.

CONTEXT: Diabetic neuropathy affects 10.5%–32.2% of diabetic population posing clinical burden onto society. AIMS: We aimed to study the efficacy, safety, and tolerability of methylcobalamin, methylcobalamin plus pregabalin, and methylcobalamin plus duloxetine in patients of painful diabetic neuropathy. SETTINGS AND DESIGN: It is a prospective, randomized, open-label, interventional, and parallel-group study done in patients of painful diabetic neuropathy. MATERIALS AND METHODS: A total of 100 patients were recruited and randomized to three study groups A, B, and C on methylcobalamin, methylcobalamin and pregabalin, and methylcobalamin and duloxetine, respectively. Patients were assessed at day 0 and 4, 8, and 12 weeks. The tuning fork test, monofilament test, Thermal Sensitivity testing, and Visual Analog Scale (VAS) were used to analyze vibration, pressure, thermal sensitivity, and pain. STATISTICAL ANALYSIS USED: The results are expressed as mean ± standard deviation. Appropriate statistical methods were used to calculate P value (

Spinal cord stimulation (SCS) has been suggested as a treatment option for patients with painful diabetic neuropathy (PDN). We conducted a systematic review and undertook a meta-analysis on individual patient data from randomised controlled trials (RCTs) to assess the effectiveness of SCS for the management of PDN. Electronic databases were searched from inception to May 2020 for RCTs of SCS for PDN. Searches identified 2 eligible RCTs (total of 93 patients with PDN) and 2 long-term follow-up studies of one of the RCTs. Individual patient data were obtained from the authors of one of these RCTs. Meta-analysis showed significant and clinically meaningful reductions in pain intensity for SCS compared with best medical therapy alone, pooled mean difference (MD) -3.13 (95% confidence interval [CI]: -4.19 to -2.08) on a 10-point scale at the 6-month follow-up. More patients receiving SCS achieved at least a 50% reduction in pain intensity compared with best medical therapy, pooled risk ratio 0.08 (95% CI: 0.02-0.38). Increases were observed for health-related quality of life assessed as EQ-5D utility score (pooled MD 0.16, 95% CI: 0.02-0.30) and visual analogue scale (pooled MD 11.21, 95% CI: 2.26-20.16). Our findings demonstrate that SCS is an effective therapeutic adjunct to best medical therapy in reducing pain intensity and improving health-related quality of life in patients with PDN. Large well-reported RCTs with long-term follow-up are required to confirm these results. ABSTRACT: Spinal cord stimulation (SCS) has been suggested as a treatment option for patients with painful diabetic neuropathy (PDN). We conducted a systematic review and undertook a meta-analysis on individual patient data from randomised controlled trials (RCTs) to assess the effectiveness of SCS for the management of PDN. Electronic databases were searched from inception to May 2020 for RCTs of SCS for PDN. Searches identified 2 eligible RCTs (total of 93 patients with PDN) and 2 long-term follow-up studies of one of the RCTs. Individual patient data were obtained from the authors of one of these RCTs. Meta-analysis showed significant and clinically meaningful reductions in pain intensity for SCS compared with best medical therapy alone, pooled mean difference (MD) -3.13 (95% confidence interval [CI]: -4.19 to -2.08) on a 10-point scale at the 6-month follow-up. More patients receiving SCS achieved at least a 50% reduction in pain intensity compared with best medical therapy, pooled risk ratio 0.08 (95% CI: 0.02-0.38). Increases were observed for health-related quality of life assessed as EQ-5D utility score (pooled MD 0.16, 95% CI: 0.02-0.30) and visual analogue scale (pooled MD 11.21, 95% CI: 2.26-20.16). Our findings demonstrate that SCS is an effective therapeutic adjunct to best medical therapy in reducing pain intensity and improving health-related quality of life in patients with PDN. Large well-reported RCTs with long-term follow-up are required to confirm these results.

The aim of this study was to analyse the differences in cognitive function between women and men with type-2 diabetes mellitus (DMT2) and diabetic peripheral neuropathy (DPN) with and without diabetic neuropathic pain (DNP), and the factors associated with cognitive function in each sex. A cross-sectional study of 149 patients with DMT2 and DPN was performed. Sociodemographic and clinical variables, Test Your Memory (TYM) for cognitive assessment, anxiety and depression (HADS), quality of life (SF-12v2) and sleep characteristics (MOS-sleep) were measured. A high percentage of women presented cognitive impairment (50% vs. 36.1%) and they scored lower on the TYM (mean = 40.77; SD = 6.03 vs. mean = 42.49; SD = 6.05). Women with DNP scored lower on calculation tasks (3.17 vs. 3.52) than men with DNP, while women without DNP scored lower on retrograde memory (2.70 vs. 3.74), executive function (3.83 vs. 4.25) and similarities (2.51 vs. 3.12) than men without DNP. Being older (B = −0.181) and presenting cardiovascular risk factors (B = −5.059) were associated with worse cognitive function in women, while in men this was associated with older age (B = −0.154), a longer duration of diabetes (B = −0.319) and the presence of depression (B = −0.363). Women with and without DNP obtained worse results in cognitive function. However, the presence of pain had a greater impact on the different dimensions in men.

Spinal cord stimulation (SCS) technology has been recently approved by the US Food and Drug Administration (FDA) for painful diabetic neuropathy (PDN). The treatment involves surgical implantation of electrodes and a power source that delivers electrical current to the spinal cord. This treatment decreases the perception of pain in many chronic pain conditions, such as PDN. The number of patients with PDN treated with SCS and the amount of data describing their outcomes is expected to increase given four factors: (1) the large number of patients with this diagnosis, (2) the poor results that have been obtained for pain relief with pharmacotherapy and noninvasive non-pharmacotherapy, (3) the results to date with investigational SCS technology, and (4) the recent FDA approval of systems that deliver this treatment. Whereas traditional SCS replaces pain with paresthesias, a new form of SCS, called high-frequency 10-kHz SCS, first used for pain in 2015, can relieve PDN pain without causing paresthesias, although not all patients experience pain relief by SCS. This article describes (1) an overview of SCS technology, (2) the use of SCS for diseases other than diabetes, (3) the use of SCS for PDN, (4) a comparison of high-frequency 10-kHz and traditional SCS for PDN, (5) other SCS technology for PDN, (6) deployment of SCS systems, (7) barriers to the use of SCS for PDN, (8) risks of SCS technology, (9) current recommendations for using SCS for PDN, and (10) future developments in SCS.

Background and Objective:Both duloxetine (DLX) and transcutaneous electrical nerve stimulation (TENS)are recommended as safe and effective treatments for diabetic peripheral neuropathic pain. However, these methods have not been compared. This study aimed to compare the efficacy of treatment by DLX and TENS in diabetic neuropathy pain relief. Materials and Methods:This survey was performed on 60 eligible diabetic patients randomly divided into two groups of DLX (20, 40, and 60 mg/day for weeks 1, 2, and 3-12, respectively), and TENS (20 min,80 HZ, 50 Amp, 0.2 ms Square pulses 2-3 times sensory threshold). The participants were evaluated according to the numerical rating scale (NRS) after four and twelve weeks of treatment. Moreover, adverse drug reactions were documented during the study period. Results:Baseline demographic data had no significant difference between the two groups (P≥0.05). The average NRS scores were significantly lower in the DLX group in both measurement times. At the end of weeks four (P=0.01) and 12 (P=0.001), the trend of changes was significant from baseline to the third month (P=0.0001). No patient in the TENS group reported any side effects, while 18% did in the DLX group. Conclusion:We found that both DLX and TENS were effective and safe for the management of painful diabetic neuropathy. The DLX seemed to be better, compared to TENS. However, in some conditions, such as drug intolerance or contraindication for medications, TENS could be a proper intervention. Keywords:Duloxetine,Painful diabetic neuropathy,TENS

Background Painful diabetic neuropathy is one of the most common complications of type 2 diabetes mellitus, with approximately 30–50% of people will experience diabetic neuropathy. Chronic hyperglycemia will cause an inflammatory process that will trigger an immune response included leukotrienes. Leukotriene B4 is associated with hemoglobin glycation levels. This study aimed to determine high serum leukotriene B4 levels and other factors as a risk factor for painful diabetic neuropathy in type 2 diabetes mellitus patient. Results Forty-two subjects with 22 cases (median age 56.5 ± 4.9 years) and 20 controls (median age 56.5 ± 5.2 years) group were collected. In bivariate analysis, significant factor for high risk PDN was high leukotriene B4 serum level (OR 5.10; 95% CI 1.34–19.4, p 0.014). Meanwhile, insignificant factors were anti-diabetic drugs (OR 2.139; 0.62–7.37; p = 0.226), and duration of diabetes mellitus (OR 2.282; 0.56–9.25; p = 0.315). Independent risk factor was serum leukotriene B4 levels (OR 5.10; 95% CI 1.336–19.470; p = 0.017). Conclusions In this study, high leukotriene B4 serum levels increase the risk of painful diabetic neuropathy among type 2 diabetes mellitus. The leukotriene B4 may consider as a potential biomarker for early detection in high risk for PDN and early treatment.

Introduction This aim of this study was to delineate current clinical scenarios of painful diabetic peripheral neuropathy (PDN) and associated anxiety and depression among patients in Mainland China, and to report current therapy and clinical practices. Methods A total of 1547 participants were enrolled in the study between 14 June 2018 and 11 November 2019. Recruitment was conducted using a multilevel sampling method. Participants’ demographics, medical histories, glucose parameters, Douleur Neuropathique 4 Questionnaire (DN4) scores, visual analogue scale (VAS) pain scores, Patient Health Questionnaire 9 (PHQ-9) scores, Generalised Anxiety Disorder 7 (GAD-7) scores and therapies were recorded. Results The male-to-female ratio was 1.09:1 (807:740), and the mean age at onset was 61.28 ± 11.23 years. The mean DN4 score (± standard deviation) was 4.91 ± 1.88. The frequencies of DN4 sub-item phenotypes were: numbness, 81%; tingling, 68.71%; pins and needles, 62.90%; burning, 53.59%; hypoaesthesia to touch, 50.16%; electronic shocks, 43.31%; hypoaesthesia to pinprick, 37.94%; brushing, 37.82%; painful cold, 29.61%; and itching, 25.86%. Age, diabetic duration, depression history, PHQ-9 score and GAD-7 score were identified as risk factors for VAS pain score. Peripheral artery disease (PAD) was a protective factor for VAS pain score. For all participants currently diagnosed with PDN and for those previously diagnosed PDN, fasting blood glucose (FBG) was a risk factor for VAS; there was no association between FBG and VAS pain score for PDN diagnosed within 3 months prior to recruitment. Utilisation rate of opium therapies among enrolled participants was 0.71% , contradiction of first-line guideline recommendation for pain relief accounted for 9.43% (33/350) and contradiction of second-line guideline recommendation for opium dosage form was 0.57% (2/350). Conclusion Moderate to severe neuropathic pain in PDN was identified in 73.11% of participants. Age, diabetic duration, depression history, PHQ-9 score, GAD-7 score and FBG were risk factors for VAS pain scores. PAD was protective factor. The majority of pain relief therapies prescribed were in accordance with guidelines. Trial registration ClinicalTrials.gov identifier, NCT03520608, retrospectively registered, 2018-05-11. Supplementary Information The online version contains supplementary material available at 10.1007/s40122-021-00281-w.

Aims/Introduction Painful diabetic peripheral neuropathy (pDPN) is associated with small nerve fiber degeneration and regeneration. This study investigated whether the presence of pDPN might influence nerve regeneration in patients with type 2 diabetes undergoing intensive glycemic control. Materials and Methods This exploratory substudy of an open‐label randomized controlled trial undertook the Douleur Neuropathique en 4 questionnaire and assessment of electrochemical skin conductance, vibration perception threshold and corneal nerve morphology using corneal confocal microscopy in participants with and without pDPN treated with exenatide and pioglitazone or basal–bolus insulin at baseline and 1‐year follow up, and 18 controls at baseline only. Results Participants with type 2 diabetes, with (n = 13) and without (n = 28) pDPN had comparable corneal nerve fiber measures, electrochemical skin conductance and vibration perception threshold at baseline, and pDPN was not associated with the severity of DPN. There was a significant glycated hemoglobin reduction (P, There has been a resurgence of interest in identifying new drug targets or, predictive biomarkers of disease‐modifying therapies in diabetic neuropathy. We show that the presence of painful diabetic neuropathy was associated with greater corneal nerve regeneration and an improvement in painful neuropathic symptoms in patients with type 2 diabetes undergoing intensive glycemic control.

Aims/Introduction This study aimed to evaluate the association between time in range (TIR) obtained from continuous glucose monitoring and the prevalence and degree of painful diabetic neuropathy. Materials and Methods A total of 364 individuals with diabetic peripheral neuropathy were enrolled in this study. Sensor‐based flash glucose monitoring systems were used to monitor the participants’ glucose levels, and the glycemic variability metrics were calculated, including the TIR, glucose coefficient of variation, standard deviation and the mean amplitude of glycemic excursions. The participants were asked to record any form of pain during the 2 weeks of monitoring, and score the pain every day on a numerical rating scale. Based on the numerical rating scale, the patients were divided into the pain‐free group, mild pain group and moderate/severe pain group. Results Overall, 51.92% (189/364) of the participants were diagnosed with painful diabetic neuropathy. Compared with the pain‐free group, the level of TIR decreased significantly in the mild pain and moderate/severe pain groups (P, Time in range is correlated with the degree of painful diabetic neuropathy independently of the glycated hemoglobin level, other glycemic variability metrics and risk factors among diabetes patients. Furthermore, time in range was a valuable clinical evaluation indicator for patients with diabetes.

Background: Neuropathic pain (NP) is a condition that affects the quality of life (QoL) of many patients. It is often difficult to treat effectively due to the complexity of this disorder. This study was aimed to assess clinician's perspectives on NP, particularly for postherpetic neuralgia (PHN), posttraumatic neuralgia (PTN), and painful diabetic neuropathy (PDN). Further, the study aimed to evaluate the safety and efficacy of lidocaine 5% patch with hydrogel technology in PHN. Materials and Methods: These two aspects were assessed through two prospective survey-based questionnaire studies that were conducted from January 2018 to December 2018 with clinicians from relevant specialties across India. Data were collected from clinicians' inputs based on their clinical practice and statistically analyzed. Results: More than half of the clinicians reported prolonged duration of NP in PHN, PTN, and PDN conditions. After applying lidocaine 5% patch with hydrogel technology, around 83.58% of clinicians opined that patients experienced a cooling and soothing effect due to the presence of a hydrogel layer in the patch. A significant reduction in pain score was reported by 76.11% of clinicians and 79.1% of them agreed that there was pain relief during the intermittent patch-free period also. The majority of the doctors (74.6%) reported an absence of any side effects. Conclusion: Study findings revealed that topical application of lidocaine 5% patch with hydrogel technology is safe and effective in PHN.

Painful diabetic neuropathy (pDN) is characterised by both sensory and affective disturbances, suggesting a complex bidirectional relationship of neuropathic pain and mood disorders. Data on pDN indicate that neuropathic pain reduces quality of life, including mood and physical and social functioning. Depression and pain coping strategies such as catastrophising and social support predict pain severity. There is a significant and reciprocal relationship between depressed mood and increased pain. The key features of assessing people with neuropathic pain in relation to psychological aspects of their health are discussed in the context of management in a tertiary pain management centre (The Walton Centre, Liverpool, UK) including cognitive behavioural interventions amongst others to improve the quality of life in patients with pDN. We consider psychological issues as a factor influencing treatment and outcome in patients with pDN.

Brandon M Yanik,1 Jacqueline R Dauch,1 Hsinlin T Cheng1,2 1Department of Neurology, University of Michigan Medical Center, Ann Arbor, Michigan, USA; 2Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USACorrespondence: Hsinlin T ChengMassachusetts General Hospital, Harvard Medical School, WACC 835, 55 Fruit Street, Boston, MA 02114, USATel +1 2 617-724-6213Fax +1 2 617-724-0895Email htcheng@mgh.harvard.eduPurpose: Neurogenic inflammation is a major component of chronic neuropathic pain. Previously, we established the db/db mouse as an animal model of painful diabetic neuropathy (PDN) of type 2 diabetes. In the current study, we investigate the roles of interleukin (IL)-10, an anti-inflammatory cytokine, in the development of neurogenic inflammation and pain behavior in db/db mouse.Materials and Methods: We first studied IL-10 expression in lumbar dorsal root ganglion (LDRG) neurons of db/db mice using immunohistochemistry, immunoblots, and reverse transcription polymerase chain reaction during the period of pain behavior (from 8 to 16 wk of age). To determine if the reduced IL-10 expression mediates the mechanical allodynia in db/db mice, we administered recombinant mouse IL-10 or saline (control) intraperitoneally to control db/+ and db/db mice starting at 8 wk of age. IL-10 treatment was repeated every other day for 2 wk until the mice reached 10 wk of age.Results: During the period of pain behavior, reduction of IL-10 protein and gene expression was detected in LDRG of db/db mice. Treatment with recombinant IL-10, from 8 to 10 wk of age, alleviates pain behaviors in db/db mice without affecting other diabetic parameters. In parallel, IL-10 treatment reduced the upregulation of nerve growth factor (NGF), inducible nitric oxide synthase (iNOS), tumor necrosis factor (TNF)-α, and high-affinity NGF receptor (Trk A) in LDRG, as well as the numbers of iNOS-positive Langerhans cells and CD-68-positive dermal dendritic cells in the hind-foot-pad skin in db/db mice.Conclusion: Our findings suggest that the reduction in neuronal IL-10 increases inflammatory phenomena, ultimately contributing to PDN. These results suggest that the dysregulation of cytokine-mediated inflammation contributes to the development of PDN in db/db mice. Targeting this pathophysiologic mechanism could be an effective approach for treating PDN in type 2 diabetes.Keywords: dorsal root ganglion, painful diabetic neuropathy, cytokine, Langerhans cells, type 2 diabetes

Brandon M Yanik,1 Jacqueline R Dauch,1 Hsinlin T Cheng1,2 1Department of Neurology, University of Michigan Medical Center, Ann Arbor, Michigan, USA; 2Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USACorrespondence: Hsinlin T ChengMassachusetts General Hospital, Harvard Medical School, WACC 835, 55 Fruit Street, Boston, MA 02114, USATel +1 2 617-724-6213Fax +1 2 617-724-0895Email htcheng@mgh.harvard.eduPurpose: Neurogenic inflammation is a major component of chronic neuropathic pain. Previously, we established the db/db mouse as an animal model of painful diabetic neuropathy (PDN) of type 2 diabetes. In the current study, we investigate the roles of interleukin (IL)-10, an anti-inflammatory cytokine, in the development of neurogenic inflammation and pain behavior in db/db mouse.Materials and Methods: We first studied IL-10 expression in lumbar dorsal root ganglion (LDRG) neurons of db/db mice using immunohistochemistry, immunoblots, and reverse transcription polymerase chain reaction during the period of pain behavior (from 8 to 16 wk of age). To determine if the reduced IL-10 expression mediates the mechanical allodynia in db/db mice, we administered recombinant mouse IL-10 or saline (control) intraperitoneally to control db/+ and db/db mice starting at 8 wk of age. IL-10 treatment was repeated every other day for 2 wk until the mice reached 10 wk of age.Results: During the period of pain behavior, reduction of IL-10 protein and gene expression was detected in LDRG of db/db mice. Treatment with recombinant IL-10, from 8 to 10 wk of age, alleviates pain behaviors in db/db mice without affecting other diabetic parameters. In parallel, IL-10 treatment reduced the upregulation of nerve growth factor (NGF), inducible nitric oxide synthase (iNOS), tumor necrosis factor (TNF)-α, and high-affinity NGF receptor (Trk A) in LDRG, as well as the numbers of iNOS-positive Langerhans cells and CD-68-positive dermal dendritic cells in the hind-foot-pad skin in db/db mice.Conclusion: Our findings suggest that the reduction in neuronal IL-10 increases inflammatory phenomena, ultimately contributing to PDN. These results suggest that the dysregulation of cytokine-mediated inflammation contributes to the development of PDN in db/db mice. Targeting this pathophysiologic mechanism could be an effective approach for treating PDN in type 2 diabetes.Keywords: dorsal root ganglion, painful diabetic neuropathy, cytokine, Langerhans cells, type 2 diabetes

Background: There is a lack of data in discrimination of different aspects of quality of life impairment in Egyptian patients with painful diabetic neuropathy (PDN). Objective: To assess the influence of PDN on different aspects of life quality in patients with type 2 diabetes mellitus (T2D). Patients and methods: A cross-sectional study that included 125 patients with T2D (100 with PDN and 25 without) during the period from December 2018 to May 2019. All patients were subjected to history, examination with modified Neuropathy Disability Score (NDS), neuropathy symptom score (NSS), visual analogue pain score (VAS), nerve conduction study for (peroneal, sural and ulnar nerves) bilaterally and Norfolk Quality of Life QuestionnaireDiabetic Neuropathy (Norfolk QOL-DN) and lab. Other neuropathy causes were excluded. Results: PDN patients have longer duration of T2D. Norfolk QOL-DN showed a significant deterioration of the activity of daily life (ADL) and general health status in PDN patients. We found a significant positive correlation between the NSS, VAS, NDS, superficial pain sensation, and the duration of T2D with the effects on ADL and health status in the case group. In addition, there was a significant positive correlation between insulin therapy, HbA1c, electrical sensation, NSS, VAS, NDS and the duration of T2D with axonal neuropathy. The NDS was the only independent predictor of ADL and health status impairment. Axonal neuropathy was independently determined by NDS, electrical sensation and insulin therapy. Conclusion: PDN impaired the activity of daily life and health status of patients with T2D. The NDS independently could predict axonal neuropathy, ADL and health status impairment.

Aim: Previous studies of 10 kHz spinal cord stimulation demonstrated its safety and efficacy for treatment of neuropathic pain of the trunk and/or limbs. This study analyzed data from a subset of subjects with painful diabetic neuropathy enrolled in a prospective, multicenter study of peripheral polyneuropathy with various etiologies. Materials & methods: Of the eight subjects that had permanent devices, seven attended the 12-month follow-up assessment. Results & conclusion: At 12 months, 6/7 subjects were treatment responders (≥50% pain relief) and had pain remission (visual analog scale ≤ 3.0 cm). Worsening of neurologic deficits was not reported in any subject. Instead, 5/7 subjects showed improvements in sensory testing and/or reflexes. These results support further investigation of 10 kHz spinal cord stimulation as a safe and effective treatment for intractable painful diabetic neuropathy.

Introduction Neuropathic pain is a complex phenomenon in patients with diabetes. These patients have many problems, such as psychological problems, high-level pain perception, and pain acceptance. This study aimed to evaluate the effectiveness of acceptance and commitment therapy on pain acceptance and pain perception in patients with painful diabetic neuropathy. Methods This study was performed according to the clinical trial method. The sample size was 50 participants. In this study, participants were divided into interventional and control groups. According to the diagnosis of neurologists, all participants received conventional medications to manage neuropathic pain. The intervention group received acceptance and commitment therapy for eight sessions. The results in the three phases of pre-test, post-test, and follow-up were evaluated. After completing the study, to comply with ethical standards, the control group received psycho-education. The tools used were the McGill Pain Questionnaire (MPQ) and the Chronic Pain Acceptance Questionnaire (CPAQ). Statistical analysis includes mean, standard deviation, and repeated-measures (ANOVA) conducted by SPSS software version 22. Results The results demonstrated that in the post-test and follow-up phases, acceptance and commitment therapy could improve pain acceptance and reduce pain perception in the intervention group compared to the control group (P

Neuropathic pain is a frequent condition caused by a lesion or disease of the central or peripheral somatosensory nervous system. A frequent cause of peripheral neuropathic pain is diabetic neuropathy. Its complex pathophysiology is not yet fully elucidated, which contributes to underassessment and undertreatment. A mechanism-based treatment of painful diabetic neuropathy is challenging but phenotype-based stratification might be a way to develop individualized therapeutic concepts. Our goal is to review current knowledge of the pathophysiology of peripheral neuropathic pain, particularly painful diabetic neuropathy. We discuss state-of-the-art clinical assessment, validity of diagnostic and screening tools, and recommendations for the management of diabetic neuropathic pain including approaches towards personalized pain management. We also propose a research agenda for translational research including patient stratification for clinical trials and improved preclinical models in relation to current knowledge of underlying mechanisms.

Aims Painful diabetic neuropathy (PDN) is a refractory complication of diabetes. The study aimed to investigate the role of α‐lipoic acid (ALA) on the regulation of transient receptor potential vanilloid‐1 (TRPV1) in dorsal root ganglion (DRG) neurons of rats with diabetes. Methods Whole‐cell patch‐clamp recordings were employed to measure neuronal excitability in DiI‐labeled DRG neurons of control and streptozotocin (STZ)‐induced diabetic rats. Western blotting and immunofluorescence assays were used to determine the expression and location of NF‐κBp65 and TRPV1. Results STZ‐induced hindpaw pain hypersensitivity and neuronal excitability in L4‐6 DRG neurons were attenuated by intraperitoneal injection with ALA once a day lasted for one week. TRPV1 expression was enhanced in L4‐6 DRGs of diabetic rats compared with age‐matched control rats, which was also suppressed by ALA treatment. In addition, TRPV1 and p65 colocated in the same DRG neurons. The expression of p65 was upregulated in L4‐6 DRGs of diabetic rats. Inhibition of p65 signaling using recombinant lentiviral vectors designated as LV‐NF‐κBp65 siRNA remarkably suppressed TRPV1 expression. Finally, p65 expression was downregulated by ALA treatment. Conclusion Our findings demonstrated that ALA may alleviate neuropathic pain in diabetes by regulating TRPV1 expression via affecting NF‐κB.

Painful diabetic neuropathy may associate with nerve morphological plasticity in both peripheral and central nervous system. The aim of this study was to determine numerical changes of myelinated fibers in the spinothalamic tract region and oligodendrocytes in the spinal dorsal horn of rats with painful diabetic neuropathy and the effects of metformin on the above changes. Male Sprague–Dawley rats were randomly allocated into the control group (n = 7), the painful diabetic neuropathy group (n = 6) and the painful diabetic neuropathy treated with metformin group (the PDN + M group, n = 7), respectively. Twenty-eight days after medication, numbers of myelinated fibers in the spinothalamic tract and oligodendrocytes in the spinal dorsal horn were estimated by the optical disector (a stereological technique). Compared to the control group, number of myelinated fibers in the spinothalamic tract increased significantly in the painful diabetic neuropathy and PDN + M group, compared to the painful diabetic neuropathy group, number of myelinated fibers decreased in the PDN + M group (P < 0.05). As the oligodendrocyte in the spinal dorsal horn was considered, its number increased significantly in the painful diabetic neuropathy group compared to the control and the PDN + M group (P < 0.05), there was no significant difference between the control and the PDN + M group (P > 0.05). Our results indicate that painful diabetic neuropathy is associated with a serial of morphometric plasticity in the rat spinal cord including the numerical increase of the myelinated fibers in the spinothalamic tract and the oligodendrocytes in the spinal dorsal horn. The analgesic effect of metformin against painful diabetic neuropathy might be related to its adverse effects on the above morphometric plasticity.

Resting State analysis using group ICA. We have provided nifti files of our major findings in the paper. Specifically all spatial components (30) and selected spatial components (8). We used these as inputs to our voxnet based 3DCNN. We can provide preprocessed resting state data on request. These have been labelled based on folder structure into responders(res) and non responders(non) to lidocaine IV treatment of diabetic painful neuropathy patients.&nbsp

Background: Omega-3 polyunsaturated fatty acids (PUFAs) have been proposed to improve chronic neuroinflammatory diseases in peripheral and central nervous systems. For instance, docosahexaenoic acid (DHA) protects nerve cells from noxious stimuli in vitro and in vivo. Recent reports link PUFA supplementation to improving painful diabetic neuropathy (pDN) symptoms, but cellular mechanisms responsible for this therapeutic effect are not well understood. The objective of this study is to identify distinct cellular pathways elicited by dietary omega-3 PUFA supplementation in patients with type 2 diabetes mellitus (T2DM) affected by pDN. Methods: Forty volunteers diagnosed with type 2 diabetes were enrolled in the “En Balance-PLUS” diabetes education study. The volunteers participated in weekly lifestyle/nutrition education and daily supplementation with 1000 mg DHA and 200 mg eicosapentaenoic acid. The Short-Form McGill Pain Questionnaire validated clinical determination of baseline and post-intervention pain complaints. Laboratory and untargeted metabolomics analyses were conducted using blood plasma collected at baseline and after three months of participation in the dietary regimen. The metabolomics data were analyzed using random forest, hierarchical clustering, ingenuity pathway analysis, and metabolic pathway mapping. Results: The data show that metabolites involved in oxidative stress and glutathione production shifted significantly to a more anti-inflammatory state post supplementation. Example of these metabolites include cystathionine (+90%), S-methylmethionine (+9%), glycine cysteine-glutathione disulfide (+157%) cysteinylglycine (+19%), glutamate (−11%), glycine (+11%), and arginine (+13.4%). In addition, the levels of phospholipids associated with improved membrane fluidity such as linoleoyl-docosahexaenoyl-glycerol (18:2/22:6) (+253%) were significantly increased. Ingenuity pathway analysis suggested several key bio functions associated with omega-3 PUFA supplementation such as formation of reactive oxygen species (p = 4.38 × 10−4, z-score = −1.96), peroxidation of lipids (p = 2.24 × 10−5, z-score = −1.944), Ca2+ transport (p = 1.55 × 10−4, z-score = −1.969), excitation of neurons (p = 1.07 ×10−4, z-score = −1.091), and concentration of glutathione (p = 3.06 × 10−4, z-score = 1.974). Conclusion: The reduction of pro-inflammatory and oxidative stress pathways following dietary omega-3 PUFA supplementation is consistent with the promising role of these fatty acids in reducing adverse symptoms associated with neuroinflammatory diseases and painful neuropathy.

Metformin (a widely used antidiabetic drug) has demonstrated efficacy in models of painful diabetic neuropathy (PDN), as well as certain clinical efficacy in relieving/preventing PDN. This study aimed to determine the type of interaction between metformin and duloxetine/oxycodone/eslicarbazepine acetate [ESL]/vitamin B12 in relieving diabetic pain hypersensitivity. Antihyperalgesic efficacy was determined using a Von Frey apparatus in mice with streptozotocin-induced PDN. We examined metformin’s efficacy following oral (acute and prolonged 7-day treatment) and local (spinal and peripheral) application. The examined analgesics were administered in a single oral dose, whereas vitamin B12 was intraperitoneally administered for 7 days. In combination experiments, metformin (prolonged treatment) and analgesics/vitamin B12 were co-administered in fixed-dose fractions of their ED50 values and the type of interaction was determined using isobolographic analysis. Metformin produced dose-dependent antihyperalgesic effects in diabetic mice after oral (acute and prolonged 7-day treatment) and local spinal/peripheral application. Two-drug metformin combinations with analgesics/vitamin B12 also dose- dependently reduced mechanical hyperalgesia. The isobolographic analysis revealed that metformin synergises with analgesics/vitamin B12, with a 6–7 fold dose reduction of both drugs in the examined combinations. In conclusion, metformin reduces hyperalgesia in diabetic animals, most likely by acting at the spinal and pe- ripheral level. Additionally, it synergizes with duloxetine/oxycodone/ESL/vitamin B12 in reducing hyperalgesia. Metformin co-treatment may increase analgesic efficacy and enable the use of lower (and potentially safer) analgesic doses for treating PDN. Combined metformin-vitamin B12 use may provide more effective pain relief and mitigate metformin-induced vitamin B12 deficiency.

Background and purpose Previously it has been shown that patients with painful diabetic neuropathy (PDN) have greater corneal nerve loss compared to patients with painless diabetic neuropathy. This study investigated if the severity of corneal nerve loss was related to the severity of PDN. Methods Participants with diabetic neuropathy (n = 118) and healthy controls (n = 38) underwent clinical and neurological evaluation, quantitative sensory testing, nerve conduction testing and corneal confocal microscopy and were categorized into those with no (n = 43), mild (n = 34) and moderate-to-severe (n = 41) neuropathic pain. Results Corneal nerve fibre density (p = 0.003), corneal nerve fibre length (p < 0.0001) and cold perception threshold (p < 0.0001) were lower and warm perception threshold was higher (p = 0.002) in patients with more severe pain, but there was no significant difference in the neuropathy disability score (p = 0.5), vibration perception threshold (p = 0.5), sural nerve conduction velocity (p = 0.3) and amplitude (p = 0.7), corneal nerve branch density (p = 0.06) and deep breathing heart rate variability (p = 0.08) between patients with differing severity of PDN. The visual analogue scale correlated significantly with corneal nerve fibre density (r = -0.3, p = 0.0002), corneal nerve branch density (r = -0.3, p = 0.001) and corneal nerve fibre length (r = -0.4, p < 0.0001). Receiver operating curve analysis showed that corneal nerve fibre density had an area under the curve of 0.78 with a sensitivity of 0.73 and specificity of 0.72 for the diagnosis of PDN. Conclusions Corneal confocal microscopy reveals increasing corneal nerve fibre loss with increasing severity of neuropathic pain and a good diagnostic outcome for identifying patients with PDN.

Objective: Painful diabetic neuropathy (PDN) is a painful complication of diabetes. This study aimed to explore: (1) strategies used by participants to manage impacts of PDN and (2) their perspectives on whether strategies from pain management programmes (PMPs) had applicability for PDN. Design: Participants were recruited through local National Health Service (NHS) diabetes and PDN clinics, and nationally from a diabetes support charity. One-to-one interviews were conducted. The transcribed data were analysed using inductive thematic analysis. Results: Twenty-three people were interviewed who had PDN symptoms for mean 10 years. Four themes emerged from the data: seeking help and advice, pragmatic approach to management, perspectives on physical activity and perspectives on psychological coping strategies. Conclusion: Some participants were open to the strategies advised by PMP strategies. There were also strong opinions that no exercise or psychological approach could help with diabetes-related pain. It is possible PMPs as currently delivered need to be adapted to maximise engagement from people with PDN. Research is required to understand the healthcare priorities of people with PDN and whether these priorities can be mapped to existing management strategies.

Painful diabetic peripheral neuropathy can be intractable with a major impact, yet the underlying pain mechanisms remain uncertain. A range of neuronal and vascular biomarkers was investigated in painful diabetic peripheral neuropathy (painful-DPN) and painless-DPN and used to differentiate painful-DPN from painless-DPN. Skin biopsies were collected from 61 patients with type 2 diabetes (T2D), and 19 healthy volunteers (HV). All subjects underwent detailed clinical and neurophysiological assessments. Based on the neuropathy composite score of the lower limbs [NIS(LL)] plus seven tests, the T2D subjects were subsequently divided into three groups: painful-DPN (n = 23), painless-DPN (n = 19), and No-DPN (n = 19). All subjects underwent punch skin biopsy, and immunohistochemistry used to quantify total intraepidermal nerve fibers (IENF) with protein gene product 9.5 (PGP9.5), regenerating nerve fibers with growth-associated protein 43 (GAP43), peptidergic nerve fibers with calcitonin gene-related peptide (CGRP), and blood vessels with von Willebrand Factor (vWF). The results showed that IENF density was severely decreased (p < 0.001) in both DPN groups, with no differences for PGP9.5, GAP43, CGRP, or GAP43/PGP9.5 ratios. There was a significant increase in blood vessel (vWF) density in painless-DPN and No-DPN groups compared to the HV group, but this was markedly greater in the painful-DPN group, and significantly higher than in the painless-DPN group (p < 0.0001). The ratio of sub-epidermal nerve fiber (SENF) density of CGRP:vWF showed a significant decrease in painful-DPN vs. painless-DPN (p = 0.014). In patients with T2D with advanced DPN, increased dermal vasculature and its ratio to nociceptors may differentiate painful-DPN from painless-DPN. We hypothesized that hypoxia-induced increase of blood vessels, which secrete algogenic substances including nerve growth factor (NGF), may expose their associated nociceptor fibers to a relative excess of algogens, thus leading to painful-DPN.

Prior research efforts have demonstrated a link between neuroinflammation and the progres-sion of Painful Diabetic Neuropathy (PDN), a chronic cascade of nerve damage that presents as tingling, numbness, hypersensitivity to touch, or intense pain. Current treatments are focused on pain manage-ment, serving to temporarily mask these symptoms without repressing or slowing nerve damage. The chemokine-receptor system has been closely stud-ied for its role in perpetuating neuropathic pain, alt-hough its precise mechanistic involvement remains unclear due to the network’s complexity. Because of its likely role in regulating neuropathic pain, target-ing CCR2 may be the key to effective treatment of PDN.Alternative splicing of CCR2 leads to two dis-tinct isoforms with different C-terminus sequences, CCR2A and CCR2B. The present study was intended to differentiate between these isoforms through spe-cific primer design, selection of optimized pairs, RT-PCR, and amplicon sequencing to verify the PCR products. However, the study has revealed a third, previously unreported isoform, CCR2C, due to evi-dence of alternative splicing and both the absence and insertion of parts of A and B. In the long term, we predict that the relationship between CCR2’s alternatively spliced transcript variants will lead to a distinct pattern of isoform prevalence in individuals suffering from PDN. Discerning the genetic profiles of patients with PDN and healthy individuals will clar-ify the complex mechanism driving CCR2’s intracel-lular interactions and offer more effective therapeu-tic options.

Narges Heidari,1 Firozeh Sajedi,2 Younes Mohammadi,3 Mahtabalsadat Mirjalili,4 Maryam Mehrpooya1 1Department of Clinical Pharmacy, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran; 2Department of Internal Medicine, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran; 3Modeling of Noncommunicable Diseases Research Center, School of Public Health, Hamadan University of Medical Sciences, Hamadan, Iran; 4Department of Clinical Pharmacy, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, IranCorrespondence: Maryam MehrpooyaDepartment of Clinical Pharmacy, School of Pharmacy, Hamadan University of Medical Sciences, Shahid Fahmideh Ave, Hamadan 6517838678, IranTel +98813821868Fax +988138381591Email m_mehrpooya2003@yahoo.comPurpose: Painful diabetic neuropathy (PDN) is a variant of diabetic peripheral neuropathy which is highly prevalent and distressing in diabetic patients. Despite its high burden, the optimal treatment of PDN has remained a clinical challenge. To explain the emergence and maintenance of PDN, increasing attention has been focused on dimensions of inflammation and oxidative toxic stress (OTS). Accordingly, the aim of this study was to investigate the effects of oral N-acetylcysteine (NAC), an agent with known anti-oxidant and anti-inflammatory effects, as an adjunct therapy in patients suffering from PDN.Patients and methods: 113 eligible patients with type 2 diabetes suffering from PDN were randomly assigned to either the pregabalin + placebo or pregabalin + NAC group for 8 weeks (pregabalin at a dose of 150 mg per day, NAC and matched placebo at doses of 600 mg twice a day). Mean pain score was evaluated at baseline, week 1, 2, 4, 6, and 8 of the study based on the mean 24 hr average pain score, using an 11-point numeric rating scale (NRS). As secondary efficacy measures, mean sleep interference score (SIS) resulting from PDN, responder rates, Patient Global Impression of Change (PGIC), Clinical Global Impression of Change (CGIC), and safety were also assessed. Additionally, serum levels of total antioxidant capacity (TAC), total thiol groups (TTG), catalase activity (CAT), glutathione peroxidase (GPx), superoxide dismutase (SOD), nitric oxide (NO), and malondialdehyde (MDA) were assessed at baseline and at the end of the study.Results: Ninety patients completed the eight-week course of the study. The decrease in mean pain scores and mean sleep interference score in pregabalin + NAC group was greater in comparison with pregabalin + placebo group (p value

Numerous investigations implicate pronounced changes in the functioning of T-type Ca2+ channels localized on the somata of primary nociceptor units in the development and maintenance of painful diabetic neuropathy. This review highlights the role of T-type Ca2+ channels of nociceptive afferents in the processing of pain signals under diabetic conditions, as well as suggests a promising therapeutic strategy to treat painful diabetic neuropathy.

Painful diabetic neuropathy (PDN) is a devastating neurological complication of diabetes. Methylglyoxal (MG) is a reactive metabolite whose elevation in the plasma corresponds to PDN in patients and pain-like behavior in rodent models of type 1 and type 2 diabetes. Here, we addressed the MG-related spinal mechanisms of PDN in type 2 diabetes using db/db mice, an established model of type 2 diabetes, and intrathecal injection of MG in conventional C57BL/6J mice. Administration of either a MG scavenger (GERP10) or a vector overexpressing glyoxalase 1, the catabolic enzyme for MG, attenuated heat hypersensitivity in db/db mice. In C57BL/6J mice, intrathecal administration of MG produced signs of both evoked (heat and mechanical hypersensitivity) and affective (conditioned place avoidance) pain. MG-induced Ca(2+) mobilization in lamina II dorsal horn neurons of C57BL/6J mice was exacerbated in db/db, suggestive of MG-evoked central sensitization. Pharmacological and/or genetic inhibition of transient receptor potential ankyrin subtype 1 (TRPA1), adenylyl cyclase type 1 (AC1), protein kinase A (PKA), or exchange protein directly activated by cyclic adenosine monophosphate (Epac) blocked MG-evoked hypersensitivity in C57BL/6J mice. Similarly, intrathecal administration of GERP10, or inhibitors of TRPA1 (HC030031), AC1 (NB001), or Epac (HJC-0197) attenuated hypersensitivity in db/db mice. We conclude that MG and sensitization of a spinal TRPA1-AC1-Epac signaling cascade facilitate PDN in db/db mice. Our results warrant clinical investigation of MG scavengers, glyoxalase inducers, and spinally-directed pharmacological inhibitors of a MG-TRPA1-AC1-Epac pathway for the treatment of PDN in type 2 diabetes.

Background and aims: Approximately 25% of patients with diabetes mellitus type 2 (DMII) develop painful diabetic neuropathy (PDN). PDN is known to affect both mental and physical wellbeing, resulting in anxiety, depression, low quality of life and physical disability. Pharmacological treatment of PDN aims at pain relief and is often ineffective and/or has many side effects. Rehabilitation treatment modalities that are designed to help the patient deal with PDN related complaints, are mostly focussed on either physical (e.g. exercise therapy) or psychological aspects (e.g. cognitive behavioural therapy, CBT). There is emerging evidence that PDN can be approached from a biopsychosocial perspective, in which physical and psychosocial aspects are integrated. From this biopsychosocial approach it is plausible that integrated treatment modalities such as acceptance commitment therapy (ACT) or exposure in vivo (EXP) could be effective in patients with PDN. The objective of this review was to provide an overview of the current evidence on the effects of rehabilitation treatments that combine exercise therapies with psychological therapies in order to improve physical activity (PA) and quality of life (QoL) in patients with PDN.Methods: Systematic review of the current literature. EMBASE, MEDLINE, Medline In-Process citations and e-Pubs ahead-of-print, Pedro, Web of Science, PsycINFO, CENTRAL, PubMed and Google Scholar were searched. All studies on interventions combining exercise therapy with psychological interventions in patients with PDN, aged >18 years, were included. Outcome measures were PA, QoL.Results: The search resulted in 1603 records after removing duplicates. After screening on titles and abstracts, 100 records remained. From these, not one study reported on interventions that combined exercise therapy with psychological interventions. Through a secondary hand search, a total of three reviews were identified that described a total of five studies regarding either physical or psychological interventions in patients with PDN. These studies reported moderate effects of (1) mindfulness meditation on QoL, (2) CBT on pain severity, (3) mindfulness-based stress reduction intervention on function, health-related QoL, pain catastrophizing and depression, (4) aerobic exercise on QoL and (5) Tai Chi on glucose control, balance, neuropathic symptoms, and some dimensions of QoL in patients with PDN. All studies were of a moderate quality, and results should be interpreted with caution.Conclusions: Based on increasing knowledge in the domain of chronic pain, it could be assumed that integrated rehabilitation treatments for patients with PUN are beneficial. There is no literature to support this and more research should be done on integrated biopsychosocial interventions in patients with PDN.

Painful diabetic neuropathy (PDN) is a distressing and disabling condition. There is, surprisingly, relatively little research into the role of psychological variables related to PDN. The aim of this study was to investigate the association between psychological flexibility, daily functioning, and distress in people with PDN. This cross-sectional study included 225 participants who were recruited from hospital services and online. In correlation analyses, acceptance of pain was shown to be negatively correlated with pain intensity (r = −0.21, p

Objective Existing pharmacologic approaches for painful diabetic neuropathy (PDN) are limited in efficacy and have side effects. We examined the feasibility, acceptability, and effects of group acupuncture for PDN. Design and Setting We randomized patients with PDN from a public safety net hospital to 1) usual care, 2) usual care plus 12 weeks of group acupuncture once weekly, or 3) usual care plus 12 weeks of group acupuncture twice weekly. Methods The primary outcome was change in weekly pain intensity (daily 0–10 numerical rating scale [NRS] averaged over seven days) from baseline to week 12. We also assessed health-related quality of life and related symptoms at baseline and weeks 6, 12, and 18. Results We enrolled 40 patients with PDN (baseline pain = 5.3). Among participants randomized to acupuncture, 92% attended at least one treatment (mean treatments = 10.1). We observed no significant differences between once- vs twice-weekly acupuncture and combined those groups for the main analyses. Compared with usual care, participants randomized to acupuncture experienced greater decreases in pain during the 12-week intervention period (between-group differences from baseline = –2.06, 95% confidence interval [CI] = –3.01 to –1.10), but benefits were not maintained after acupuncture ended (baseline to week 18 = –0.61, 95% CI = –1.46 to 0.24). Quality of life improved for acupuncture participants (baseline to week 12 difference = 11.79, 95% CI = 1.92 to 21.66), but group differences were not significant compared with usual care (25.58, 95% CI = –3.90 to 55.06). Conclusions Group acupuncture is feasible and acceptable among linguistically and racially diverse safety net patients. Findings suggest clinically relevant reduction in pain from PDN and quality of life improvements associated with acupuncture, with no differences based on frequency.

Background and aims Approximately 25% of patients with diabetes mellitus type 2 (DMII) develop painful diabetic neuropathy (PDN). PDN is known to affect both mental and physical wellbeing, resulting in anxiety, depression, low quality of life and physical disability. Pharmacological treatment of PDN aims at pain relief and is often ineffective and/or has many side effects. Rehabilitation treatment modalities that are designed to help the patient deal with PDN related complaints, are mostly focussed on either physical (e.g. exercise therapy) or psychological aspects (e.g. cognitive behavioural therapy, CBT). There is emerging evidence that PDN can be approached from a biopsychosocial perspective, in which physical and psychosocial aspects are integrated. From this biopsychosocial approach it is plausible that integrated treatment modalities such as acceptance commitment therapy (ACT) or exposure in vivo (EXP) could be effective in patients with PDN. The objective of this review was to provide an overview of the current evidence on the effects of rehabilitation treatments that combine exercise therapies with psychological therapies in order to improve physical activity (PA) and quality of life (QoL) in patients with PDN. Methods Systematic review of the current literature. EMBASE, MEDLINE, Medline In-Process citations and e-Pubs ahead-of-print, Pedro, Web of Science, PsycINFO, CENTRAL, PubMed and Google Scholar were searched. All studies on interventions combining exercise therapy with psychological interventions in patients with PDN, aged >18 years, were included. Outcome measures were PA, QoL. Results The search resulted in 1603 records after removing duplicates. After screening on titles and abstracts, 100 records remained. From these, not one study reported on interventions that combined exercise therapy with psychological interventions. Through a secondary hand search, a total of three reviews were identified that described a total of five studies regarding either physical or psychological interventions in patients with PDN. These studies reported moderate effects of (1) mindfulness meditation on QoL, (2) CBT on pain severity, (3) mindfulness-based stress reduction intervention on function, health-related QoL, pain catastrophizing and depression, (4) aerobic exercise on QoL and (5) Tai Chi on glucose control, balance, neuropathic symptoms, and some dimensions of QoL in patients with PDN. All studies were of a moderate quality, and results should be interpreted with caution. Conclusions Based on increasing knowledge in the domain of chronic pain, it could be assumed that integrated rehabilitation treatments for patients with PDN are beneficial. There is no literature to support this and more research should be done on integrated biopsychosocial interventions in patients with PDN. Implications This empty review highlights the importance that more research should be done on integrated biopsychosocial interventions in patients with PDN. Currently, our research group is performing a study on the effects of EXP treatment in patients with PDN.

Background Diabetes mellitus is a clinical syndrome characterized by hyperglycemia caused by respective or absolute deficiency of insulin. Painful neuropathy in diabetic population is popular, impacting numerous chronic diabetic patients. Although antidepressants, anticonvulsants, and opioid agonists are useful in alleviating painful neuropathy, they produce a diversity of side effects and are occasionally ineffective. Hence, there is presently a need to pursue safe, non-invasive, and effective therapeutic opportunities. Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive mechanism used in releasing neuropathic pain. TMS pulses—when applied repetitively—can modulate cortical plasticity, consequently causing excitability or inhibition according to the rate of stimulation. Objectives The aim of this study is to evaluate the efficacy of repetitive transcranial magnetic stimulation (rTMS) in improving resistant chronic diabetic neuropathic pain. Subjects and methods Twenty patients were recruited and divided equally into two groups: insulin-dependent (group A) and non-insulin-dependent (group B). A high-frequency (10 Hz) rTMS stimulation protocol was applied to both groups for five consecutive days over lower limbs motor cortex. VAS score and nerve conduction studies were compared before and after rTMS sessions. Results Highly significant improvements in VAS and nerve conduction studies (p > 0.01) were detected for both patient cohorts following the administration of the rTMS protocol. Conclusion According to our study, rTMS significantly reduced painful diabetic neuropathy. rTMS may produce its analgesic effects, inducing motor cortex plasticity and activating descending inhibitory pain control systems.

Objective Diabetes mellitus is associated with a number of complications that can adversely impact patients’ quality of life. A common and often painful complication is painful diabetic neuropathy. The aims of this study were to systematically review and summarize evidence from studies of psychological treatments and psychosocial factors related to painful diabetic neuropathy and assess the methodological quality of these studies. Methods Electronic databases, related reviews, and associated reference lists were searched. Summaries of participants’ data relating to the efficacy of psychological treatments and/or to associations between psychosocial factors and outcomes in painful diabetic neuropathy were extracted from the included studies. The methodological quality of included studies was assessed using two standardized quality assessment tools. Results From 2,921 potentially relevant titles identified, 27 studies were included in this systematic review. The evidence suggests that depression, anxiety, sleep, and quality of life are the most studied variables in relation to pain outcomes in painful diabetic neuropathy and are consistently associated with pain intensity. The magnitude of the associations ranged from small to large. Conclusions Research into psychosocial factors in painful diabetic neuropathy is unexpectedly limited. The available evidence is inconsistent and leaves a number of questions unanswered, particularly with respect to causal associations between variables. The evidence reviewed indicates that depression, anxiety, low quality of life, and poor sleep are associated with pain in painful diabetic neuropathy. The disproportionate lack of research into psychological treatments for painful diabetic neuropathy represents a significant opportunity for future research.

E Morgan Pollard,1 Tim J Lamer,2 Susan M Moeschler,3 Halena M Gazelka,3 W Michael Hooten,3 Markus A Bendel,3 Nafisseh S Warner,3 M Hassan Murad41Division of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, MN 55905, USA; 2Division of Pain Medicine, Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, MN 55905, USA; 3Division of Pain Medicine, Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, MN, USA; 4Preventive, Occupational, and Aerospace Medicine, Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, MN, USAObjective: To synthesize the evidence regarding the effect of spinal cord stimulation (SCS) on opioid and pain medication reduction in patients with intractable spine or limb pain.Methods: A comprehensive literature search was conducted to identify RCTs of patients with chronic back and/or limb pain of greater than one year duration. Only comparative studies were included (ie, conventional SCS vs medical therapy, conventional SCS vs high-frequency SCS) and were required to have a minimum follow-up period of 3 months. Random effect meta-an alysis was used to compare the three interventions. Results were expressed as odds ratio (OR) or weighted mean difference (WMD) with 95% confidence intervals (CI).Results: We identified five trials enrolling 489 patients. Three of the trials reported the results as a number of patients who were able to reduce or eliminate opioid consumption in the SCS vs medical therapy group. The odds of reducing opioid consumption were significantly increased in the SCS group compared to medical therapy (OR 8.60, CI {1.93–38.30}). Two of the trials reported the results as mean medication dose reduction as measured by the Medication Quantification Scale (MQS) in the SCS group vs medical therapy group. MQS score significantly decreased in the SCS group and not in the medical group (WMD –1.97, 95% CI {–3.67, –0.27}). One trial reported a number of patients in high-frequency SCS who were able to reduce opioids vs number of patients in conventional SCS group who were able to reduce opioids. Thirty-four percent of the patients in the high-frequency group and 26% of the patients in the conventional SCS group were able to reduce opioid consumption; however, there was not a significant difference between groups (OR 1.43, 95% CI {0.74, 2.78}). This trial also quantified the opioid reduction in morphine equivalent dosage (MED). In the high-frequency SCS group, average MED decreased by 24.8 mg vs average MED decrease of 7.3 mg in the conventional SCS group. Again, the difference between groups did not reach statistical significance (–17.50, CI {–66.27, 31.27}).Conclusions: In patients with intractable spine/limb pain, SCS was associated with increased odds of reducing pain medication consumption. However, results should be treated with caution as available data were limited, and clinical significance of these findings requires further study.Keywords: spinal cord stimulation, chronic back pain, painful diabetic neuropathy, chronic limb pain, high-frequency spinal stimulations, opioids, pain medications

Diabetic neuropathy (DN) is one of the most common peripheral nervous system disorders. It affects 16% of individuals with type I (young onset) diabetes and 25-26% of individuals with type II (late onset) diabetes [1]. Pain and numbness of the feet and, in advanced cases, weakness in the feet or hands are the usual symptoms. These symptoms are typically more prominent in the lower limbs. The skin in the affected areas is sensitive to touch (hyperesthesia); sometimes touch evokes pain (allodynia). The pain of diabetic neuropathy may develop spontaneously or may be provoked by touch or motion. Pain often interferes with patient’s rest and sleep and has typical characteristics of a neuropathic pain i.e having a sharp and burning quality. Dorsum of the foot and toes are most commonly affected in diabetic neuropathy. On examination, the patients demonstrate decreased sensations (heat, cold, touch, position) in the affected limb. Diabetic neuropathy (DN) is usually bilateral and presents in form of a polyneuropathy.

Purpose The aim of the present study was to further elucidate the role of JAK2/STAT3-CAV-1-NR2B on painful diabetic neuropathy. Methods In vivo, the mechanical withdrawal threshold and thermal withdrawal latency were measured to evaluate neuropathic pain behaviors (n= 8), while western blot (n= 5) and an immunofluorescence double staining experiment (n= 6) were performed to understand the molecular mechanism. In vitro, the individual culture of BV2 mouse microglia cell lines, the co-culture of BV2 mouse microglia cell lines and PC12 rat neuron cell lines, and western blot analysis were performed to understand the molecular mechanism between microglia and neurons. Results The expression of p-JAK2, p-STAT3, t-CAV-1, and p-NR2B was upregulated in the dorsal horn of DNP rats throughout the experiment. Through the immunofluorescence double staining experiment, it was found that p-STAT3 was mainly expressed in activated microglia, and this condition can be stably maintained for approximately 2 weeks after the establishment of the DNP model. The intrathecal injection of JAK2 inhibitor AG490 can relieve the abnormal expression of p-JAK2, p-STAT3, t-CAV-1, and p-NR2B, and relieve pain. The remission of AG490 began on the third day, and it could be stably sustained for 14 days. In vitro high-glucose induced the activation of p-STAT3 in microglia, thereby upregulating the expression of p-CAV-1 and p-NR2B in neurons in the co-culture system. JAK2 inhibitor AG490 can alleviate the abnormal expression of these proteins in the JAK2/STAT3-CAV-1-NR2B signaling pathway in vitro. Conclusions Microglial JAK2/STAT3 signaling probably contributes to neuropathic pain by activating the CAV-1-NR2B pathway.

Painful diabetic neuropathy (PDN) is among the common complications in diabetes mellitus (DM), with its underlying mechanisms largely unknown. Synapsin II is primarily expressed in the spinal dorsal horn, and its upregulation mediates a superfluous release of glutamate and a deficiency of GABAergic interneuron synaptic transmission, which is directly implicated in the facilitation of pain signals in the hyperalgesic nociceptive response. Recently, synapsin II has been revealed to be associated with the modulation of neurite outgrowth, whereas the process of this neuronal structural neuroplasticity following neuronal hyperexcitability still remains unclear. In this study, we found that under conditions of elevated glucose, TNF-α induced the activation of mTOR, mediating the upregulation of synapsin II and neurite outgrowth in dorsal horn neurons. In vivo, we demonstrated that mTOR and synapsin II were upregulated and coexpressed in the spinal dorsal horn neurons in rats with streptozotocin (STZ)-induced diabetes. Furthermore, the intrathecal administration of the mTOR inhibitor rapamycin or synapsin II shRNA significantly diminished the expression of synapsin II, effectively mitigating hyperalgesia in PDN rats. We are the first to discover that in STZ-induced diabetic rats the activation of mTOR mediates the upregulation of synapsin II and neurite outgrowth, both contributing to hyperalgesia. These findings may benefit the clinical therapy of PDN by provision of a novel target.

Painful diabetic neuropathy is a common vexing problem for people with diabetes and a costly problem for society. The pathophysiology is not well understood, and no safe and effective mechanistically-based treatment has been identified. Poor glycemic control is a risk factor for painful diabetic neuropathy. Excessive intraneuronal glucose in people with diabetes can be shunted away from physiological glycolysis into multiple pathological pathways associated with neuropathy and pain. The first three treatments that are traditionally offered consist of risk factor reduction, lifestyle modifications, and pharmacological therapy, which includes only three drugs that are approved for this indication by the United States Food and Drug Administration. All of these traditional treatments are often inadequate for relieving neuropathic pain, and thus, new approaches are needed. Modern devices based on neuromodulation technology, which act directly on the nervous system, have been recently cleared by the United States Food and Drug Administration for painful diabetic neuropathy and offer promise as next-in-line therapy when traditional therapies fail.

Background Painful diabetic neuropathy (PDN) is a common and intractable complication of diabetes mellitus, with little effective treatment. PDN has been associated with spinal neuroinflammation characterized by microglial activation. Recently, the triggering receptor expressed on myeloid cells 2 (TREM2), specifically localized on microglia, has been identified as a vital factor in modulating neuroinflammation and microglial phenotypes in neural diseases. Therefore, we hypothesized that spinal TREM2 might contribute to PDN and neuroinflammation by regulating microglial activity and phenotypes. Methods Type I diabetes mellitus was elicited by a single intraperitoneal administration of streptozotocin (STZ) in mice. The pain behaviors were reflected by paw mechanical withdrawal thresholds (PMWT) and thermal withdrawal latency (PTWL). Results We demonstrated that up-regulation of microglial TREM2 and amplification of both microglial M1 and M2 response was along with the presence of diabetes-related mechanical allodynia and thermal hypersensitivity. Moreover, we found that overexpression of TREM2 in microglia aggravated the symptom of PDN, amplified microglia M1 response, and suppressed microglia M2 polarization in the lumbar spinal cord of diabetic mice. However, inhibition of TREM2 with anti-TREM2 neutralizing antibodies attenuated mechanical allodynia and thermal hyperalgesia in diabetic mice. Besides, we identified Galectin-3 (GLT-3) as the potential ligand of the TREM2 receptor in facilitating the progression of PDN. Conclusions TREM2 could be a critical microglial membrane molecule that modulates microglial phenotypes pain hypersensitivity in PDN. GLT-3 might act as a specific ligand to trigger TREM2 signaling in PDN or other neuropathic pain.

Background: Seven million US adults are living with painful diabetic neuropathy (PDN) with current treatments ineffective for many. Recent RCT results demonstrate high-frequency (10 kHz) spinal cord stimulation (SCS) relieves pain and may improve sensation in patients with refractory symptoms. Methods: Prospective, multicenter RCT assigned 216 patients 1:1 to 10 kHz SCS (Nevro Corp.) plus conventional medical management (CMM) or CMM alone (NCT03228420). Patients had PDN symptoms ≥12 months, lower limb pain ≥5 cm (10 cm visual analog scale), and hemoglobin A1c ≤10%. Outcomes included pain, neurological function, and quality of life over 12 months. Patients could opt to crossover to the alternative treatment at 6 months. Results: Baseline characteristics were similar between groups. At 6 months, 82% of the CMM group crossed over to SCS treatment and none in the 10 kHz SCS group crossed over to CMM. In total, 154 patients underwent SCS implant; 5 (3.2%) were explanted for infection. At 12-month follow-up, there were clear, sustained benefits of 10 kHz SCS in lower limb pain, pain interference with daily living, sleep quality, and activity (Figure). Most patients treated with 10 kHz SCS also showed improvements on neurological examination. Conclusion: The largest RCT to date of SCS management of PDN demonstrates durable pain relief and improved quality of life over 12 months with high-frequency (10 kHz) SCS. Disclosure E. Petersen: Consultant; Self; Abbott, Medtronic, Nevro Corp., Research Support; Self; Neuros Medical, Inc., Nevro Corp., ReNeuron Group plc, Saluda, Stock/Shareholder; Self; SynerFuse. N. Mehta: Research Support; Self; Nevro Corp. P. W. Wu: None. C. Argoff: Consultant; Self; Nevro Corp., Vertex Pharmaceuticals Incorporated, Other Relationship; Self; Amgen Inc., Eli Lilly and Company, Teva Pharmaceutical Industries Ltd., Speaker’s Bureau; Self; AbbVie Inc. C. E. Nasr: Advisory Panel; Self; Nevro Corp. R. Taylor: Consultant; Self; Nevro Corp. Senza-pdn study group: n/a. J. Scowcroft: Research Support; Self; Boston Scientific Corporation, Nevro Corp. E. S. Brooks: Employee; Self; Nevro Corp. J. L. White: Advisory Panel; Self; Eli Lilly and Company, Nevro Corp. K. Amirdelfan: Advisory Panel; Self; Biotronik, Nevro Corp., Consultant; Self; Boston Scientific Corporation. M. Guirguis: Consultant; Self; Avanos medical, Nevro Corp. J. Xu: None. D. G. Patterson: Advisory Panel; Self; Advanced Infusion Systems (AIS), Spark Biomedical, Consultant; Self; Vivex Biologics, Other Relationship; Self; Abbott Laboratories, CornerLoc, Saluda, Vertos Medical Inc., Speaker’s Bureau; Self; AbbVie Inc., Amgen Inc., Lundbeck. V. Galan: None. Funding Nevro Corp.

Painful diabetic neuropathy (DN) is a common, distressing complication of diabetes that is discordant with the degree of peripheral nerve pathology. Very little is known about the cerebral processes involved in pain processing in painful DN. Here we investigated resting-state brain connectivity associated with prolonged pain in DN. Methods: 58 subjects and 36 matched controls were compared with regard to both behavioural measures of pain perception and resting-resting state functional Magnetic Resonance Imaging. The resting-state fMRI brain connectivity was investigated using 20 seed regions located in cardinal pain processing brain regions. Resting-state fMRI analysis was performed using the NITRC Functional Connectivity (CONN) Toolbox and SPM8 (welcome Trust Centre for Neuroimaging London, UK) in Matlab 2014a (the MathWorks, Natick, MA, USA). Functional connectivity matrices between the pre-specified seeds were calculated and the HV versus painful DN phenotype interaction examined. Results: Relative to controls, painful DPN patients displayed increased brain connectivity predominately for the supplementary motor areas (p Conclusion: Our study provides experimental evidence of increased connectivity between frontal midline regions that are implicated in affective pain processing and bilateral sensorimotor regions in painful DPN patients. Disclosure K. Teh: None. I. D. Wilkinson: None. P. Shillo: None. G. P. Sloan: None. S. Tesfaye: Advisory Panel; Self; Angellini, Bayer AG, Eva Pharma, Wörwag Pharma, Speaker’s Bureau; Self; Abbott, AstraZeneca, Grunenthal Group, MSD Corporation, Novo Nordisk, Pfizer Inc. D. Selvarajah: None. Funding Health Education England/University of Sheffield Knowledge Exchange Fund; National Institute for Health Research; EME

The efficacy of monotherapy to reduce pain from diabetic peripheral neuropathy (DPN) is frequently not satisfactory and guidelines do not provide unanimous treatment options. In this context, multiple drug pharmacotherapy may provide benefit.The aim of the present review is to describe the clinical trials addressing the pharmacotherapy of painful DPN. Studies discussing efficacy and tolerability of pharmacological agents that were assessed in monotherapy and in combination treatment are reported and discussed.Several clinical trials have reported benefit of multiple-drug pharmacotherapy. Nevertheless, untoward effects of combination treatment are of concern. Importantly, some trials were restricted to comparison with placebo and other compared only with active comparator(s). Only limited clinical trials assessed selected cohorts of individuals experiencing different stages of painful DPN. Despite current limitations, some evidence of studies implicating a comparison to all active comparators points to safety and effectiveness of the combination of oxycodone with pregabalin and that of pregabalin with the 5% lidocaine plaster but future, clear-cut studies are required to drive evidence-based decisions in the clinical setting.

Painful diabetic neuropathy (PDN) is a common complication of diabetes mellitus that is associated with a significant decline in quality of life. Like other painful neuropathic conditions, PDN is difficult to manage clinically, and a variety of pharmacological and non-pharmacological options are available for this condition. Recommended pharmacotherapies include anticonvulsive agents, antidepressant drugs, and topical capsaicin; and tapentadol, which combines opioid agonism and norepinephrine reuptake inhibition, has also recently been approved for use. Additionally, several neuromodulation therapies have been successfully used for pain relief in PDN, including intrathecal therapy, transcutaneous electrical nerve stimulation (TENS), and spinal cord stimulation (SCS). Recently, 10 kHz SCS has been shown to provide clinically meaningful pain relief for patients refractory to conventional medical management, with a subset of patients demonstrating improvement in neurological function. This literature review is intended to discuss the dosage and prospective data associated with pain management therapies for PDN.