Treatment Of Painful Diabetic Neuropathy Research Articles

Effect of single-dose oral vitamin D (200,000 IU) for the treatment of painful diabetic neuropathy

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

Long-term efficacy of high-frequency (10 kHz) spinal cord stimulation for the treatment of painful diabetic neuropathy: 24-Month results of a randomized controlled trial

AimsTo evaluate the long-term efficacy of high-frequency (10 kHz) spinal cord stimulation (SCS) for treating refractory painful diabetic neuropathy (PDN). MethodsThe SENZA-PDN study was a prospective, multicenter, randomized controlled trial that compared conventional medical management (CMM) alone with 10 kHz SCS plus CMM (10 kHz SCS+CMM) in 216 patients with refractory PDN. After 6 months, participants with insufficient pain relief could cross over to the other treatment. In total, 142 patients with a 10 kHz SCS system were followed for 24 months, including 84 initial 10 kHz SCS+CMM recipients and 58 crossovers from CMM alone. Assessments included pain intensity, health-related quality of life (HRQoL), sleep, and neurological function. Investigators assessed neurological function via sensory, reflex, and motor tests. They identified a clinically meaningful improvement relative to the baseline assessment if there was a significant persistent improvement in neurological function that impacted the participant’s well-being and was attributable to a neurological finding. ResultsAt 24 months, 10 kHz SCS reduced pain by a mean of 79.9% compared to baseline, with 90.1% of participants experiencing ≥50% pain relief. Participants had significantly improved HRQoL and sleep, and 65.7% demonstrated clinically meaningful neurological improvement. Five (3.2%) SCS systems were explanted due to infection. ConclusionsOver 24 months, 10 kHz SCS provided durable pain relief and significant improvements in HRQoL and sleep. Furthermore, the majority of participants demonstrated neurological improvement. These long-term data support 10 kHz SCS as a safe and highly effective therapy for PDN.Trial Registration: ClincalTrials.gov Identifier, NCT03228420.

A Brief Review on the Novel Therapies for Painful Diabetic Neuropathy.

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

Spinal Cord Stimulation Alleviates Pain Hypersensitivity by Attenuating Neuroinflammation in a Model of Painful Diabetic Neuropathy.

Painful diabetic neuropathy (PDN) is an intractable chronic pain condition affecting a growing number of adults in China. Spinal cord stimulation (SCS) has been employed in the treatment of PDN for several decades. However, the efficacy and underlying mechanisms of SCS are still inconclusive. In this study, we adopted an implantable pulse generator to deliver electrical stimulation (50 Hz, 200 us pulse width, 12 hours/day in 5 weeks) via a quadripolar electrode in the lumbar epidural space to treat pain hypersensitivity in the rat model of PDN. Electronic von Frey and Hargreaves tests were used to measure the responses to mechanical and heat stimuli, respectively. Quantitative PCR, western blotting, and enzyme-linked immunosorbent assay (ELISA) were adopted to explore the changes in neuroinflammation after SCS. SCS alleviated mechanical allodynia and heat hyperalgesia over a period of 3 weeks in diabetic rats. SCS completely suppressed neuropathy-induced Tlr4 and NFκB p65 elevation, resulting in the reduction of pain-promoting Il1β, Il6, and Tnfα proteins in the spinal cord dorsal horn. SCS may alleviate diabetic neuropathy-induced pain hypersensitivity via attenuating neuroinflammation in the spinal cord dorsal horn.

Abstract #1399039: Treatment of Painful Diabetic Neuropathy: 10 kHz SCS Provides Durable Pain Relief and Sensory Improvements

Of the 37 million Americans who have diabetes, up to 25% experience painful diabetic neuropathy (PDN). While conventional medical management (CMM), which includes pharmacotherapies, can be ineffective for many patients, high-frequency (10 kHz) spinal cord stimulation (SCS) has been shown to provide substantial symptom relief for PDN. Here we report durability of outcomes to 24 months (24M) months for 10 kHz SCS treatment of PDN. We conducted a prospective, multicenter, randomized, controlled trial (RCT) to evaluate 10 kHz SCS in PDN patients. Key inclusion criteria were: PDN symptoms ≥12M refractory to medications, lower limb pain intensity ≥5cm (0-10cm 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 group crossover at 6M. Patients randomized to 10 kHz SCS experienced average pain relief of 76% at 6M, while patients receiving CMM alone experienced average pain increase of 2%. After 6M, 93% of eligible CMM patients crossed over to 10 kHz SCS, while no 10 kHz SCS patients crossed over to CMM. At 24M, patients receiving 10 kHz SCS experienced durable pain relief, with average pain relief of 80%. Reductions in pain-associated sleep disturbance and pain interference with mood and daily activities were consistent with pain relief. At 6M, 10 kHz SCS provided substantial reductions vs. CMM. At 24M, patients receiving 10 kHz SCS experienced a 65% decrease in pain-associated sleep disturbance and a 67% decrease in pain interference with mood and daily activities. Clinician-assessed sensory function improvements in the feet and legs were observed with 10 kHz SCS. At 6M, improvements were observed in 59% of patients receiving 10 kHz SCS vs. only 9% of patients receiving CMM alone. Sensory improvements were durable as 65% of patients receiving 10 kHz SCS had improvements at 24M. In total, 154 patients received an SCS implant. There were eight (5.2%) study-related infections (n=3 resolved; n=5 (3.2%) explanted), which is within the range reported across all SCS patient populations (2.5-10%). The results of this RCT demonstrate that 10 kHz SCS provides durable reductions in pain and pain-associated effects on health-related quality of life with acceptable safety, now observed through 24-month follow-up. The durable sensory function improvements highlight the disease-modifying potential of 10 kHz SCS.

Treatment of Painful Diabetic Neuropathy Using Frequency Rhythmic Electro Magnetic Neural Stimulation (FREMS); Effectiveness in Daily Practice.

Painful diabetic peripheral neuropathy (PDPN) is common and difficult to treat with limited treatment options. We assessed the efficacy of frequency rhythmic electromagnetic neural stimulation (FREMS) in patients with PDPN. An uncontrolled prospective survey of patients with PDPN and pain despite at least two lines of pharmacotherapy. The primary outcome, 50% reduction in pain scores at 1 and/or 3 months post FREMS. FREMS was applied to both legs below the knees using 4 sets of electrodes per leg; the treatment consisted of 10 sessions of 35 min applications given over 14 days. FREMS was repeated every 4 months and patients were followed up for 12 months. Pain was assessed using the neuropathic pain symptom inventory (NPSI) and quality of life (QOL) by the EQ-5D. Out of 336 subjects, 248 patients met the inclusion criteria (56% men), average age and diabetes duration were 65 and 12.6 years respectively. FREMS was associated with a median decrease NPSI of 31% at M1 (range -100;+93%), and a median decrease of -37.5% at M3 (range -100;+250%). The 50% reduction in pain was reached in 80/248 (32.3%) and 87/248 (35.1%) after M1 and M3 respectively. The change in NPSI was accompanied by a decrease in self reported use of opiates of >50%. FREMS treatment was associated with a significant reduction in pain severity over a three months period in patients who did not have adequate response to pharmacotherapy. Randomised (sham)-controlled trials examining the role of FREMS as a treatment for PDPN in non-responders to pharmacotherapy are needed.

10 kHz SCS Provides Durable Pain Relief and Neurological Improvements for Patients with Painful Diabetic Neuropathy: 24-Month RCT Results (PL4.004)

10 kHz SCS Provides Durable Pain Relief and Neurological Improvements for Patients with Painful Diabetic Neuropathy: 24-Month RCT Results (PL4.004)

A Study on the Effects of Pregabalin and Amitriptyline in Treatment of Patients with Painful Diabetic Neuropathy

Objective: To compare the effect of Amitriptyline and Pregabalin in treatment of painful diabetic neuropathy. Material and Methods: The design of this study was Randomized Controlled Trial study design. This study was conducted in the Department of Medicine in, Holy Family Hospital, Rawalpindi and the duration of this study was Six months after the approval of synopsis i.e from 1st November 2019 to 1st May 2020. Approval from ethical committee of the hospital was taken. Written informed consent was taken from patients. Consent form is attached with this. Patients were randomly allocated into two groups by lottery method. The dose of Pregabalin was used as 50mg thrice daily for a period of six weeks and label as group-A and group B received amitriptyline as 25mg once daily before bedtime for a period of six weeks as prescribed by a senior consultant who was blind to object of the study. At the start and end of treatment pain was marked by patients on Visual Analogue Scale (VAS) and numerical score. It was noted on the Performa. Results: Total 100 patients were included according to the inclusion criteria of the study. The dose of Pregabalin was given in patients in group-A and group-B received amitriptyline. Mean age (years) in the study was 55.87+6.43 whereas there were 55 (55.0) male and 45 (45.0) female patients who were included in the study according to the inclusion criteria. In our study, frequency and percentage of effect (pain relief) among Pregabalin and Amitriptyline in treatment of painful diabetic neuropathy was 27 (54.0) and 11 (22.0) respectively which was statistically significant (p-value 0.001). Practical Implication: In this study Pregabalin is more responsible for pain relief than Amitriptyline in treatment of painful diabetic neuropathy. Further studies at multiple studies must be conduct in future for determining the efficacy of amitriptyline and Pregabalin in diabetic neuropathy in order to formulate guidelines for management of diabetic peripheral neuropathy. Conclusion: The study concluded that Pregabalin is more responsible for pain relief than Amitriptyline in treatment of painful diabetic neuropathy. Further studies at multiple studies must be conduct in future for determining the efficacy of Pregabalin and amitriptyline in diabetic neuropathy in order to formulate guidelines for management of diabetic peripheral neuropathy. Keywords: Amitriptyline, Pregabalin, Neuropathy, Pain Relief, Diabetic Sensorimotor Polyneuropathy, Prevalence.

Indirect Comparison of 10 kHz Spinal Cord Stimulation (SCS) versus Traditional Low-Frequency SCS for the Treatment of Painful Diabetic Neuropathy: A Systematic Review of Randomized Controlled Trials.

Spinal cord stimulation (SCS) is increasingly used to treat painful diabetic neuropathy (PDN). At the time of a recent meta-analysis in this field, data were only available from randomized controlled trials (RCTs) of traditional low-frequency SCS (LF-SCS). However, outcomes from high-frequency 10 kHz SCS treatment are now available. Our study aimed to systematically review the contemporary evidence for SCS in patients with lower limb pain due to PDN and include an indirect comparison of the high- and low-frequency modalities. We searched the PubMed/CENTRAL databases up to 18 August 2022, for peer-reviewed RCTs of SCS that enrolled PDN patients with lower limb pain symptoms. The quality of the evidence was assessed with the Cochrane Risk of Bias tool. Using SCS treatment arm data from the RCTs, we indirectly compared the absolute treatment effect of 10 kHz SCS and LF-SCS. Results are presented in tables and forest plots. This systematic review was reported according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) 2020 guidelines. Three RCTs met our eligibility criteria, including the recent 10 kHz SCS RCT (N = 216, 90 implanted) and 2 others that examined LF-SCS (N = 36, 17 implanted; N = 60, 37 implanted). Our analysis of 6-month data found clinically meaningful pain relief with each SCS modality. However, significantly greater pain reduction was identified for 10 kHz SCS over LF-SCS: average pain reduction in the 10 kHz SCS cohort was 73.7% compared with 47.5% in the pooled LF-SCS group (p < 0.0001). In the permanent implant subset, the 50% pain reduction responder rate was 83.3% in the 10 kHz SCS cohort versus 63.0% in the pooled LF-SCS group (p = 0.0072). The overall risk of bias of each included RCT was deemed high, mainly due to the absence of patient blinding. Our analysis indicates that paresthesia-free 10 kHz SCS can provide superior pain relief and responder rate over LF-SCS for managing PDN patients refractory to conventional medical management.

Painful Diabetic Neuropathy as a Cause for Refractory Ear Pain in Type 2 Diabetic Patients.

To assess painful diabetic neuropathy (PDN) as a cause for refractory ear pain in type 2 diabetics. An observational prospective case series study. Otolaryngology departments of tertiary referral hospitals from November 2019 to January 2021. Sixty-eight patients with type 2 diabetes with refractory ear pain of more than 1-month duration not responding to the routine analgesics. Diagnostic intervention. The primary outcome measure was the prevalence of painful diabetic neuropathy among different causes of ear pain in the study sample of type II diabetics with refractory ear pain with an assessment of the response of these cases to routine neuropathic pain treatment with pregabalin. Fifteen out of 68 (22.1%) were diagnosed as having painful diabetic neuropathy based on the "Douleur Neuropathique en 4 Questions" (DN4) questionnaire with its mean value being 6.47±1.19. There was a highly significant improvement of the 10 items of painful diabetic neuropathy scales after 1 month of treatment ( p < 0.001 for all). There was a significant positive correlation between the Hemoglobin A1c level and duration of diabetes at one hand and intensity of pain derived from the painful diabetic neuropathy scale at the other hand ( p = 0.0002, and p = 0.032 respectively). Painful diabetic neuropathy showed a potential correlation with refractory ear pain in type II diabetic patients with significant improvement after painful diabetic neuropathy treatment. Further studies are needed to confirm these findings.

Evidence-Based Treatment of Painful Diabetic Neuropathy: a Systematic Review

Evidence-Based Treatment of Painful Diabetic Neuropathy: a Systematic Review

The Treatment of Painful Diabetic Neuropathy.

Painful diabetic peripheral neuropathy (painful-DPN) is a highly prevalent and disabling condition, affecting up to one-third of patients with diabetes. This condition can have a profound impact resulting in a poor quality of life, disruption of employment, impaired sleep, and poor mental health with an excess of depression and anxiety. The management of painful-DPN poses a great challenge. Unfortunately, currently there are no Food and Drug Administration (USA) approved disease-modifying treatments for diabetic peripheral neuropathy (DPN) as trials of putative pathogenetic treatments have failed at phase 3 clinical trial stage. Therefore, the focus of managing painful- DPN other than improving glycaemic control and cardiovascular risk factor modification is treating symptoms. The recommended treatments based on expert international consensus for painful- DPN have remained essentially unchanged for the last decade. Both the serotonin re-uptake inhibitor (SNRI) duloxetine and α2δ ligand pregabalin have the most robust evidence for treating painful-DPN. The weak opioids (e.g. tapentadol and tramadol, both of which have an SNRI effect), tricyclic antidepressants such as amitriptyline and α2δ ligand gabapentin are also widely recommended and prescribed agents. Opioids (except tramadol and tapentadol), should be prescribed with caution in view of the lack of definitive data surrounding efficacy, concerns surrounding addiction and adverse events. Recently, emerging therapies have gained local licenses, including the α2δ ligand mirogabalin (Japan) and the high dose 8% capsaicin patch (FDA and Europe). The management of refractory painful-DPN is difficult; specialist pain services may offer off-label therapies (e.g. botulinum toxin, intravenous lidocaine and spinal cord stimulation), although there is limited clinical trial evidence supporting their use. Additionally, despite combination therapy being commonly used clinically, there is little evidence supporting this practise. There is a need for further clinical trials to assess novel therapeutic agents, optimal combination therapy and existing agents to determine which are the most effective for the treatment of painful-DPN. This article reviews the evidence for the treatment of painful-DPN, including emerging treatment strategies such as novel compounds and stratification of patients according to individual characteristics (e.g. pain phenotype, neuroimaging and genotype) to improve treatment responses.

84-OR: Responders to Neuropathic Pain Treatment Have Greater Target Engagement of Opioid Receptor Systems: A Resting State Functional Magnetic Resonance Imaging Study in Painful Diabetic Neuropathy

Painful diabetic neuropathy (DN) is a common and distressing complication. New approaches are required to identify novel targets that will serve as a catalyst for future drug discovery programmes. We have demonstrated that responders to neuropathic pain treatment have greater functional connectivity between the insula cortex and the corticolimbic system compared to non-responders. Activity within these networks is mediated by endogenous opioid receptor systems and may hold clues to possible future treatment targets. Methods: 43 painful-DN subjects [responders (VAS&amp;lt;4; n=29) and non-responders (VAS≥4; n=14) ] underwent detailed clinical and neurophysiological assessment, and RS-fMRI. Data analysis was performed using the NITRC Functional ConnectivityToolbox and SPM8 in MatLab. RS-fMRI data was masked and binarised using an opioid receptor atlas to restrict the analysis to the voxels with high receptor density. Subject-specific spatial maps of responders and non-responders were compared. Results: Compared to painful-DN non-responders, responders had greater functional connectivity between the corticolimbic system with the opioid receptor networks [F (2) (41) =43.53;intensity=128.7; R-amygdala beta=0.48; p-FDR&amp;lt;0.0001; R-putamen beta=0.3; p-FDR&amp;lt;0.0001; dorsal lateral prefrontal cortex beta=0.25; p-FDR=0.0002 and the posterior parietal cortex networks beta0.25; p-FDR=0.0002]. Conclusion: Painful DN treatment responders have better target engagement of opioid receptors systems compared to non-responders. This indicates that a functioning/intact descending pain inhibition network is crucial for a better pain response. Interventions targeted at this network could provide better pain relief in non-responders to neuropathic pain treatment. Disclosure K.Teh: None. G.P.Sloan: None. I.D.Wilkinson: None. S.Tesfaye: Advisory Panel; Astellas Pharma Inc., Bayer AG, Grünenthal Group, Nevro Corp., Wörwag Pharma GmbH &amp; Co. KG, Speaker's Bureau; Eva Pharma, Pfizer Inc., Viatris Inc. D.Selvarajah: None. Funding National Institute of Health Research EME grant; European Foundation for the Study of Diabetes

Neuromodulation Interventions for the Treatment of Painful Diabetic Neuropathy: a Systematic Review.

Painful diabetic neuropathy (PDN) is a prevalent and debilitating condition, characterized by severe burning, tingling, and lancinating pain usually located in the distal lower extremities. In addition to manifesting with severe pain, PDN may also be associated with poor quality of life and sleep, mood disorders, burns, falls, and social withdrawal. The authors appraised the current body of literature for evidence on neuromodulation interventions for PDN. In patients with refractory PDN unresponsive to conventional medical management (glucose optimization and oral analgesic medications), there is level I evidence supporting the use of 10-kHz and tonic dorsal column spinal cord stimulation (SCS). Included studies reported significant associations between 10-kHz and tonic dorsal column SCS and superior analgesic outcomes, physical functioning, and patient satisfaction. Current level of evidence remains limited for other modalities of neuromodulation for PDN including burst SCS (level II-3), dorsal root ganglion SCS (level III), and peripheral nerve stimulation (level II-3). Some studies reported improvements in neurological physical examination, sensory testing, and/or reflex testing in patients undergoing 10-kHz SCS for treatment of PDN. In summary, the purpose of this review is to equip provider with important updates on the use of neuromodulation interventions for the treatment of PDN that is refractory to conventional medical therapy, with current level I evidence supporting use of 10-kHz and tonic SCS for PDN.

Painful Diabetic Neuropathy Is Associated with Compromised Microglial IGF-1 Signaling Which Can Be Rescued by Green Tea Polyphenol EGCG in Mice.

Background Painful diabetic neuropathy (PDN) is a frequent and troublesome complication of diabetes, with little effective treatment. PDN is characterized by specific spinal microglia-mediated neuroinflammation. Insulin-like growth factor 1 (IGF-1) primarily derives from microglia in the brain and serves a vital role in averting the microglial transition into the proinflammatory M1 phenotype. Given that epigallocatechin-3-gallate (EGCG) is a potent anti-inflammatory agent that can regulate IGF-1 signaling, we speculated that EGCG administration might reduce spinal microglia-related neuroinflammation and combat the development of PDN through IGF-1/IGF1R signaling. Methods Type 1 diabetes mellitus (T1DM) was established by a single intraperitoneal (i.p.) injection of streptozotocin (STZ) in mice. The protein expression level of IGF-1, its receptor IGF1R, interleukin 1β (IL-1β), tumor necrosis factor-α (TNF-α), and inducible nitric oxide synthase (iNOS) was determined by Western blot or immunofluorescence. Results The spinal IGF-1 expression markedly decreased along with the presence of pain-like behaviors, the spinal genesis of neuroinflammation (increased IL-1β, TNF-α, and Iba-1+ microglia), and the intensified M1 microglia polarization (increased iNOS+Iba-1+ microglia) in diabetic mice. IGF-1 could colocalize with neurons, astrocytes, and microglia, but only microglial IGF-1 was repressed in T1DM mice. Furthermore, we found that i.t. administration of mouse recombinant IGF-1 (rIGF-1) as well as i.t. or i.p. treatment with EGCG alleviated the diabetes-induced pain-like behaviors, reduced neuroinflammation (suppressed IL-1β, TNF-α, and Iba-1+ microglia), prevented the M1 microglia polarization (less iNOS+Iba-1+ microglia), and restored the microglial IGF-1 expression. Conclusions Our data highlighted the importance of maintaining spinal IGF-1 signaling in treating microglia-related neuroinflammation in PDN. This study also provides novel insights into the neuroprotective mechanisms of EGCG against neuropathic pain and neuroinflammation through IGF-1 signaling, indicating that this agent may be a promising treatment for PDN in the clinical setting.

A pharmacoeconomic evaluation of the pharmacotherapeutic options for painful diabetic neuropathy

ABSTRACT Introduction Painful diabetic neuropathy (PDN) is a high incidence and severe complication of diabetes mellitus, significantly compromising patients’ quality of life and causing tremendous economic burden. Considering drug costs becomes part of treatment decisions, with the growing choice of monotherapy or combination treatment strategies for PDN treatment. Areas covered This systematic review aims to identify the cost-effectiveness of pharmacotherapies in PDN, summarize key findings, and assess the quality of studies to inform healthcare resource allocation decisions and future research. Economic evaluations were identified by searching PubMed, Web of Science, Scopus and health technology assessment (HTA) databases, as well as screening reference lists of previously identified studies. Relevant data was extracted, and the CHEERS checklist was used to assess the quality of the studies. Expert opinion Collectively, the findings indicate that more pharmacoeconomics research is urgently needed to directly compare high-quality research for PDN combination medication/sequential treatment, and which is performed from a societal perspective. Simultaneously, to strengthen the reliability of the analysis, metrics such as adherence, incidence of adverse drug reactions, and pain levels utility value should be examined to verify the robustness of the basic results.

An Insight into Potential Pharmacotherapeutic Agents for Painful Diabetic Neuropathy.

Diabetes is the 4th most common disease affecting the world's population. It is accompanied by many complications that deteriorate the quality of life. Painful diabetic neuropathy (PDN) is one of the debilitating consequences of diabetes that effects one-third of diabetic patients. Unfortunately, there is no internationally recommended drug that directly hinders the pathological mechanisms that result in painful diabetic neuropathy. Clinical studies have shown that anticonvulsant and antidepressant therapies have proven fruitful in management of pain associated with PDN. Currently, the FDA approved medications for painful diabetic neuropathies include duloxetine, pregabalin, tapentadol extended release, and capsaicin (for foot PDN only). The FDA has also approved the use of spinal cord stimulation system for the treatment of diabetic neuropathy pain. The drugs recommended by other regulatory bodies include gabapentin, amitriptyline, dextromethorphan, tramadol, venlafaxine, sodium valproate, and 5 % lidocaine patch. These drugs are only partially effective and have adverse effects associated with their use. Treating painful symptoms in diabetic patient can be frustrating not only for the patients but also for health care workers, so additional clinical trials for novel and conventional treatments are required to devise more effective treatment for PDN with minimal side effects. This review gives an insight on the pathways involved in the pathogenesis of PDN and the potential pharmacotherapeutic agents. This will be followed by an overview on the FDA-approved drugs for PDN and commercially available topical analgesic and their effects on painful diabetic neuropathies.

The Treatment of Painful Diabetic Neuropathy

The Treatment of Painful Diabetic Neuropathy

Upregulation of TLR9 may contribute to activation of microglia and painful diabetic neuropathy via the p38 MAPK pathway in rats.

Painful diabetic neuropathy is a common chronic complication of diabetes, and the underlying mechanism remains largely elusive. A rat model of painful diabetic neuropathy was established via streptozotocin (STZ) injection and assessed as increased heat and mechanical hypersensitivity. An upregulation of TLR9 was observed in the spinal cords of rats injected with STZ and rat microglia (primary microglia and immortalized microglia HAPI) treated with high glucose. To investigate the role of TLR9 in high glucose-induced microglia activation, short hairpin RNAs targeting TLR9 were used in vitro to knock down TLR9 in HAPI cells. TLR9 interference suppressed the high glucose-induced expression and secretion of inflammatory cytokines (TNF-α, IL-1β, and IL-6), IBA-1 expression and the chemotaxis of HAPI microglia. Similar results were obtained when HAPI microglia were incubated with a p38 inhibitor (SB203580). P38 and ERK were downstream of TLR9 because TLR9 ablation markedly inhibited the phosphorylation of p38 and ERK. TLR9 was also knocked down in vivo via the injection of shTLR9 lentiviral vector into the rat spinal cord. Relief of STZ-induced heat and mechanical hypersensitivity was observed in rats with TLR9 interference, and TLR9 knockdown prevented STZ-induced inflammatory cytokine secretion and microglial and MAPK signaling activation. Our study revealed the participation of TLR9 in microglial activation and diabetes-induced hyperalgesia likely via the MAPK pathway. The targeting of TLR9 may be an effective strategy for the treatment of painful diabetic neuropathy.

Polyneuropathy Quality Measurement Set: Quality Improvement in Neurology.

Peripheral neuropathy affects ∼5% of the population and diabetes is the most common cause.1 Diabetic neuropathy often leads to pain, but clinicians do not always address neuropathic pain with their patients.1,2 Given the effect of painful diabetic neuropathy (PDN) on patients' quality of life, appropriate treatment of this prevalent condition is essential.1 To increase the delivery of effective management for patients with PDN, the American Academy of Neurology Institute (AANI) published a guideline on the treatment of PDN in 2011, and recently updated this guideline.1