Painful Diabetic Peripheral Neuropathy Patients Research Articles

Conventional, high frequency and differential targeted multiplexed spinal cord stimulation in experimental painful diabetic peripheral neuropathy: Pain behavior and role of the central inflammatory balance.

Spinal cord stimulation (SCS) is a last resort treatment for pain relief in painful diabetic peripheral neuropathy (PDPN) patients. However, the effectivity of SCS in PDPN is limited. New SCS paradigms such as high frequency (HF) and differential target multiplexed (DTM) might improve responder rates and efficacy of SCS-induced analgesia in PDPN patients, and are suggested to modulate the inflammatory balance and glial response in the spinal dorsal horn. The aim of this study was to research the effects of Con-, HF- and DTM-SCS on pain behavior and the spinal inflammatory balance in an animal model of PDPN. Streptozotocin-induced PDPN animals were stimulated for 48 hours with either Con-SCS (50Hz), HF-SCS (1200Hz) or DTM-SCS (combination of Con- and HF-SCS). Mechanical hypersensitivity was assessed using Von Frey (VF) test and the motivational aspects of pain were assessed using the mechanical conflict avoidance system (MCAS). The inflammatory balance and glial response were analyzed in the dorsal spinal cord based on RNA expression of pro- and anti-inflammatory cytokines (Tnf-α, Il-1ß, Il-4, Il-10), a microglia marker (Itgam), an astrocyte marker (Gfap), a T-cell marker (Cd3d), microglia proliferation markers (Irf8, Adgre1) and P2X4, p13-MAPK, BDNF signaling markers (P2x4, Mapk14, Bdnf). The results show that Con-, HF-, and DTM-SCS significantly decreased hypersensitivity after 48 hours of stimulation compared to Sham-SCS in PDPN animals, but at the same time did not affect escape latency in the MCAS. At the molecular level, Con-SCS resulted in a significant increase in spinal pro-inflammatory cytokine Tnf-α after 48 hours compared to DTM-SCS and Sham-SCS. In summary, Con-SCS showed a shift of the inflammatory balance towards a pro-inflammatory state whilst HF- and DTM-SCS shifted the balance towards an anti-inflammatory state. These findings suggest that the underlying mechanism of Con-SCS induced pain relief in PDPN differs from that induced by HF- and DTM-SCS.

Vitamin D status and its association with inflammatory markers among Kurdish type 2 diabetic patients with painful diabetic peripheral neuropathy

Several clinical studies have shown an association between vitamin D deficiency and painful diabetic peripheral neuropathy (DPN). However, it is still unclear whether vitamin D status and inflammatory markers correlate in patients with painful DPN. In this context, we aimed to investigate the associations between serum vitamin D levels and inflammatory status in Kurdish type 2 diabetes patients (T2DM) with painful DPN and without painful DPN. A clinical case-control study was conducted on 86 Kurdish patients with T2DM. The patients were divided into two groups: the case group consisted of 45 patients with painful DPN and the control group consisted of 41 age- and sex-matched diabetics without DPN. In T2DM patients with and without painful DPN, the prevalence of severe vitamin D deficiency was observed in 46.67% and 21.95% of the patients, respectively (p = 0.0283). The mean serum 25(OH)-vitamin D level in patients with painful DPN (mean = 12.00, SD = 5.78) was significantly lower than in patients without DPN (mean = 16.36, SD = 7.86; p = 0.0041). Regression analysis revealed that vitamin D deficiency (p = 0.0120) and higher glycated hemoglobin (HbA1c) (p = 0.00003) were identified as predictive risk factors for painful DPN. However, there was no significant association between inflammatory status and vitamin D levels. The duration of sun exposure was the only controlling factor for vitamin D in painful DPN patients. In the Kurdish population, lower vitamin D and high HbA1c levels were predictive factors for painful DPN.

Efficacy of Pregabalin and Duloxetine in Patients with Painful Diabetic Peripheral Neuropathy (PDPN): A Multi-Centre Phase IV Clinical Trial-BLOSSOM.

Our trial (ClinicalTrials.gov Identifier: NCT04246619) evaluates the efficacy of two generic medications, pregabalin and duloxetine, for treating pain in PDPN patients. The patients were randomised either into the pregabalin (99) or the duloxetine (102) arm. Pain was evaluated using the DN-4 questionnaire, and visual analogue scales (VASs, 0-100 mm) were used to measure the average pain intensity (API), worst pain intensity (WPI) in the last 24 h and current pain intensity (CPI). The proportion of patients with a clinically significant improvement in the API at Week 12 was 88.3% [CI 81.7%, 94.8%] in the pregabalin arm and 86.9% [CI 76.7%, 97.1%] in the duloxetine arm. After 12 weeks, the CPI, API, and WPI decreased by -35.3 [-40.5, -30.0], -37.0 [-41.4, -32.6], and -41.6 [-46.6, -36.5] in the pregabalin arm, and by -35.0 [-39.2, -30.7], -36.9 [-41.5, -32.3], and -40.0 [-44.8, -35.2] in the duloxetine arm (all in mm, all p < 0.001). Our results demonstrate that pregabalin and duloxetine are effective medications for treating pain in PDPN in more than 86% of all randomised patients.

ID: 200950 Differential Targeted Multiplexed, High-Frequency and Conventional Spinal Cord Stimulation Reduce Streptozotocin induced Mechanical Hypersensitivity

Treatment of painful diabetic peripheral neuropathy (PDPN) patients remains a major challenge, as most pharmacological options still are unsuccessful. For these patients, spinal cord stimulation (SCS) can be a last resort treatment option. Although SCS often provides effective pain relief, a substantial number of PDPN patients do not respond to the treatment. Novel stimulation paradigms such as Differential Targeted Multiplexed (DTM) SCS are suggested to further improve the efficacy of SCS on pain relief and increase responder rates. DTM-SCS is a combination of more than one electrical field delivered with signals at different stimulation parameters (1). The aim of this study was to investigate the effects of DTM-SCS on pain relief in an animal model for PDPN and compare this to Sham-SCS, conventional (Con-) SCS and High frequency (HF-) SCS.

Keratinocyte Biomarkers Distinguish Painful Diabetic Peripheral Neuropathy Patients and Correlate With Topical Lidocaine Responsiveness.

This study investigated quantifiable measures of cutaneous innervation and algesic keratinocyte biomarkers to determine correlations with clinical measures of patient pain perception, with the intent to better discriminate between diabetic patients with painful diabetic peripheral neuropathy (PDPN) compared to patients with low-pain diabetic peripheral neuropathy (lpDPN) or healthy control subjects. A secondary objective was to determine if topical treatment with a 5% lidocaine patch resulted in correlative changes among the quantifiable biomarkers and clinical measures of pain perception, indicative of potential PDPN pain relief. This open-label proof-of-principle clinical research study consisted of a pre-treatment skin biopsy, a 4-week topical 5% lidocaine patch treatment regimen for all patients and controls, and a post-treatment skin biopsy. Clinical measures of pain and functional interference were used to monitor patient symptoms and response for correlation with quantitative skin biopsy biomarkers of innervation (PGP9.5 and CGRP), and epidermal keratinocyte biomarkers (Nav1.6, Nav1.7, CGRP). Importantly, comparable significant losses of epidermal neural innervation (intraepidermal nerve fibers; IENF) and dermal innervation were observed among PDPN and lpDPN patients compared with control subjects, indicating that innervation loss alone may not be the driver of pain in diabetic neuropathy. In pre-treatment biopsies, keratinocyte Nav1.6, Nav1.7, and CGRP immunolabeling were all significantly increased among PDPN patients compared with control subjects. Importantly, no keratinocyte biomarkers were significantly increased among the lpDPN group compared with control. In post-treatment biopsies, the keratinocyte Nav1.6, Nav1.7, and CGRP immunolabeling intensities were no longer different between control, lpDPN, or PDPN cohorts, indicating that lidocaine treatment modified the PDPN-related keratinocyte increases. Analysis of the PDPN responder population demonstrated that increased pretreatment keratinocyte biomarker immunolabeling for Nav1.6, Nav1.7, and CGRP correlated with positive outcomes to topical lidocaine treatment. Epidermal keratinocytes modulate the signaling of IENF, and several analgesic and algesic signaling systems have been identified. These results further implicate epidermal signaling mechanisms as modulators of neuropathic pain conditions, highlight a novel potential mode of action for topical treatments, and demonstrate the utility of comprehensive skin biopsy evaluation to identify novel biomarkers in clinical pain studies.

Capsaicin 8% Patch for Alternative Therapy of Painful Diabetic Peripheral Neuropathy

Abstract&#x0D; Diabetes is one of the most common health problems due to its high incidence and complications. One of the complications associated with diabetes is painful diabetic peripheral neuropathy (PDPN). The capsaicin 8% patch is a localized pain treatment that provides effective pain relief from a single application in patients with peripheral neuropathic pain. The aim of this review is to discuss the effect of capsaicin patch 8% in patients with painful diabetic peripheral neuropathy. The search strategy was conducted in PubMed and modified for other databases. The search was limited to English-language reports. The keywords used were "capsaicin”, "capsaicin patch", "painful diabetic peripheral neuropathy", and "pain management". The inclusion criteria used were randomized controlled trials (RCTs), clinical trials or another interventional analysis with full text in English with publications less than the last 10 years. The exclusion criteria used were a review, systematic review, or meta-analysis, studies that were not conducted in humans and non-full text in English with publications over the last 10 years. Results: There are 2 full-text that meet inclusion criteria. From articles related to studies that have been conducted, the use of capsaicin 8% patch can reduce pain, improve nerve function and quality of life in PDPN patients. The use of capsaicin 8% patch has the advantage to pain relief for patients with painful diabetic peripheral neuropathy. &#x0D; Keywords: Alternative therapy, Capsaicin 8% Patch, Diabetes complications, Pain Relief, Painful Diabetic Peripheral Neuropathy, topical drugs

Retrospective Case Series on the Treatment of Painful Diabetic Peripheral Neuropathy With Dorsal Root Ganglion Stimulation

The dorsal root ganglion (DRG) has been identified as an important neural structure in the development and maintenance of chronic pain. We present a retrospective case series of patients with refractory painful diabetic peripheral neuropathy (PDPN) that underwent electrical stimulation of the DRG and report on changes in their overall perceived pain and complication rates. Ten diabetic males (mean age 65.2 [SD 8.8] years) with painful symptoms of the lower limbs were enrolled and trialed with up to four quadripolar percutaneous DRG stimulation leads between L2 and L5 spinal levels. Patients received a fully implantable neurostimulation system (Abbott Laboratories, Sunnyvale, CA, USA) immediately or after a successful trial period (>50% reduction in pain). Overall perceived pain was measured by visual analogue scale (VAS) at baseline, one-week postimplantation and one-, three-, six-, and twelve-month follow-up (n = 5). Ten patients were included in this retrospective study. Seven of these subjects received permanent stimulator implants after successful externalized or intraoperative trials. Two of those patients subsequently required explantation, due to failure to capture primary pain area (n = 1) and personal reasons (n = 1). For the five subjects that proceeded to clinical follow-ups, baseline VAS was reduced by an average of 63.90% (SD 21.39; p < 0.001) postimplantation. For four patients with available 12-month follow-up data, mean relative reduction in overall perceived pain averaged 64.16% (SD 35.8; p< 0.001). Early findings from this small retrospective case series, suggest DRG is a safe and effective neuromodulation modality to improve painful symptoms in PDPN patients. Future prospective trials are required to further investigate the use of DRG stimulation for this clinical indication.

(400) Increased keratinocyte Nav subunit expression among painful diabetic peripheral neuropathy patients predicts Lidoderm patch responsiveness

(400) Increased keratinocyte Nav subunit expression among painful diabetic peripheral neuropathy patients predicts Lidoderm patch responsiveness

Evaluating the Measurement Properties of the Self-Assessment of Treatment Version II, Follow-Up Version, in Patients with Painful Diabetic Peripheral Neuropathy.

Background. The Self-Assessment of Treatment version II (SAT II) measures treatment-related improvements in pain and impacts and impressions of treatment in neuropathic pain patients. The measure has baseline and follow-up versions. This study assesses the measurement properties of the SAT II. Methods. Data from 369 painful diabetic peripheral neuropathy (PDPN) patients from a phase III trial assessing capsaicin 8% patch (Qutenza®) efficacy and safety were used in these analyses. Reliability, convergent validity, known-groups validity, and responsiveness (using the Brief Pain Inventory-Diabetic Neuropathy [BPI-DN] and Patient Global Impression of Change [PGIC]) analyses were conducted, and minimally important differences (MID) were estimated. Results. Exploratory factor analysis supported a one-factor solution for the six impact items. The SAT II has good internal consistency (Cronbach's alpha: 0.96) and test-retest reliability (intraclass correlation coefficients: 0.62–0.88). Assessment of convergent validity showed moderate to strong correlations with change in other study endpoints. Scores varied significantly by level of pain intensity and sleep interference (p < 0.05) defined by the BPI-DN. Responsiveness was shown based on the PGIC. MID estimates ranged from 1.2 to 2.4 (pain improvement) and 1.0 to 2.0 (impact scores). Conclusions. The SAT II is a reliable and valid measure for assessing treatment improvement in PDPN patients.

A Trial-Based Economic Evaluation Comparing Spinal Cord Stimulation With Best Medical Treatment in Painful Diabetic Peripheral Neuropathy.

Painful diabetic peripheral neuropathy is a common complication of diabetes mellitus and the humanistic and economic burden is high. This article presents the cost-effectiveness of SCS in patients suffering from painful diabetic peripheral neuropathy from a societal and health care perspective with a time horizon of 12months.

Investigating the role of neuropathic pain relief in decreasing gait variability in diabetes mellitus patients with neuropathic pain: a randomized, double-blind crossover trial.

BackgroundSubjects with diabetes mellitus (DM) develop gait dysfunction contributing to falls, reluctance to perform activities and injuries. Neuropathic pain (NeP) related to diabetic peripheral neuropathy (DPN) is associated with increased gait variability that may contribute to gait dysfunction. We used a portable device (GaitMeter™) and related gait and balance measures to measure gait parameters in painful DPN (PDPN) subjects prior to and during analgesia. Our hypothesis was that PDPN subjects would have decreased gait step variability when receiving pharmacological relief of NeP.MethodsDPN subjects with at least moderate NeP were assessed in a randomized, double-blind crossover study of pregabalin versus placebo. The outcome measure was variability in step length and step velocity. Testing for Timed Get-Up-and-Go Test, Tinetti Mobility Scales, Sway Testing, a Physiological Profile Approach, and fall-related surveys were also performed. DPN severity was quantified using the Utah Early Neuropathy Score.ResultsPDPN subjects developed increased, rather than decreased, step length and step velocity variability during pregabalin treatment. There were no significant differences between cohorts for other physiological gait and balance testing. Non-significant NeP relief occurred in the pregabalin phase of study as compared with placebo. There was a negative relationship for step length with pain severity.ConclusionAnalgesia did not decrease gait variability in PDPN patients, and in fact, increased gait variability was seen during pregabalin treatment. Other important relationships of gait dysfunction with PDPN should be sought.Electronic supplementary materialThe online version of this article (doi:10.1186/1743-0003-11-125) contains supplementary material, which is available to authorized users.

Identification of subpopulations of painful diabetic peripheral neuropathy patients who have a favorable cost profile with pregabalin treatment

Identification of subpopulations of painful diabetic peripheral neuropathy patients who have a favorable cost profile with pregabalin treatment

Economic evaluation of duloxetine as a first-line treatment for painful diabetic peripheral neuropathy in Mexico

Objective:To perform an economic evaluation of duloxetine, pregabalin, and both branded and generic gabapentin for managing pain in patients with painful diabetic peripheral neuropathy (PDPN) in Mexico.Research design and methods:The analysis was conducted using a 3-month decision model, which compares duloxetine 60 mg once daily (DUL), pregabalin 150 mg twice daily (PGB), and gabapentin 600 mg three-times daily (GBP) for PDPN patients with moderate-to-severe pain. A systematic review was performed and placebo-adjusted risk ratios for achieving good pain relief (GPR), adverse events (AE), and withdrawal owing to intolerable AE were calculated. Direct medical costs included drug acquisition and additional visits due to lack of efficacy (poor pain relief) or intolerable AE. Unit costs were taken from local sources. Adherence rates were used to estimate the expected drug costs. All costs are expressed in 2010 Mexican Pesos (MXN). Utility values drawn from published literature were applied to health states. The proportion of patients with GPR and quality-adjusted life years (QALY) were assessed.Results:Branded-GBP was dominated by all the other options. PGB was more costly and less effective than DUL. Compared with branded-GBP and PGB, DUL led to savings of 1.01 and 1.74 million MXN (per 1000 patients). The incremental cost per QALY gained with DUL used instead of generic-GBP was $102 433 MXN. This amount is slightly lower than the estimated gross domestic product per capita in Mexico for 2010. During a second-order Monte Carlo simulation, DUL had the highest probability of being cost-effective (61%), followed by generic-GBP (25%) and PGB (14%).Limitations:Study limitations include a short timeframe and using data from different dosage schemes for GBP and PGB.Conclusions:This study suggests that DUL provides overall savings and better health outcomes compared with branded-GBP and PGB. Administering DUL rather than generic-GBP is a cost-effective intervention to manage PDPN in Mexico.

Association between Pain Severity and Health Care Resource Use, Health Status, Productivity and Related Costs in Painful Diabetic Peripheral Neuropathy Patients

Research has shown that painful diabetic peripheral neuropathy (pDPN) is associated with worse health outcomes. However, among pDPN patients, few studies have examined the relationship between the severity of pain and health outcomes. The current project included pDPN patients (N=1506) from the 2006, 2007, and 2008 waves of the National Health and Wellness Survey. Health status (Short Form [SF]-12), work productivity (Work Productivity and Activity Impairment questionnaire), and health care resource use in the past 6 months were compared among pDPN patients with mild, moderate, and severe pain, adjusting for demographics and clinical characteristics. More than half (51.2%) of the patients reported their pain as severe, 45.2% reported moderate pain, and 3.7% reported mild pain. Those with severe pain reported significantly lower levels of health status, higher levels of work and activity impairment, and higher levels of resource use relative to the other groups. Annual per-patient costs for those with severe pain were $12,856, $3927, and $16,783 for direct, indirect, and total costs, respectively. Both direct and total costs were significantly higher in this group relative to both mild and moderate pain patients. These results suggest that pain severity contributes substantially to the health outcomes of pDPN patients and that greater resources should be allocated to the management of patients with severe pain.