Treatment Of Painful Diabetic Neuropathy Research Articles

Current Pharmacological Treatment of Painful Diabetic Neuropathy: A Narrative Review

Background and Objectives: Distal symmetrical polyneuropathy (DSPN) is one of the most common chronic complications of diabetes mellitus. Although it is usually characterized by progressive sensory loss, some patients may develop chronic pain. Assessment of DSPN is not difficult, but the biggest challenge is making the correct diagnosis and choosing the right treatment. The treatment of DSPN has three primary objectives: glycemic control, pathogenic mechanisms, and pain management. The aim of this brief narrative review is to summarize the current pharmacological treatment of painful DSPN. It also summarizes knowledge on pathogenesis-oriented therapy, which is generally overlooked in many publications and guidelines. Materials and Methods: The present review reports the relevant information available on DSPN treatment. The search was performed on PubMed, Cochrane, Semantic Scholar, Medline, Scopus, and Cochrane Library databases, including among others the terms “distal symmetrical polyneuropathy”, “neuropathic pain treatment”, “diabetic neuropathy”, “diabetes complications”, ”glycaemic control”, “antidepressants”, “opioids”, and “anticonvulsants”. Results: First-line drugs include antidepressants (selective serotonin reuptake inhibitors and tricyclic antidepressants) and pregabalin. Second- and third-line drugs include opioids and topical analgesics. While potentially effective in the treatment of neuropathic pain, opioids are not considered to be the first choice because of adverse reactions and addiction concerns. Conclusions: DSPN is a common complication in patients with diabetes, and severely affects the quality of life of these patients. Although multiple therapies are available, the guidelines and recommendations regarding the treatment of diabetic neuropathy have failed to offer a unitary consensus, which often hinders the therapeutic options in clinical practice.

Diabetic neuropathy.

The global epidemic of prediabetes and diabetes has led to a corresponding epidemic of complications of these disorders. The most prevalent complication is neuropathy, of which distal symmetric polyneuropathy (for the purpose of this Primer, referred to as diabetic neuropathy) is very common. Diabetic neuropathy is a loss of sensory function beginning distally in the lower extremities that is also characterized by pain and substantial morbidity. Over time, at least 50% of individuals with diabetes develop diabetic neuropathy. Glucose control effectively halts the progression of diabetic neuropathy in patients with type 1 diabetes mellitus, but the effects are more modest in those with type 2 diabetes mellitus. These findings have led to new efforts to understand the aetiology of diabetic neuropathy, along with new 2017 recommendations on approaches to prevent and treat this disorder that are specific for each type of diabetes. In parallel, new guidelines for the treatment of painful diabetic neuropathy using distinct classes of drugs, with an emphasis on avoiding opioid use, have been issued. Although our understanding of the complexities of diabetic neuropathy has substantially evolved over the past decade, the distinct mechanisms underlying neuropathy in type 1 and type 2 diabetes remains unknown. Future discoveries on disease pathogenesis will be crucial to successfully address all aspects of diabetic neuropathy, from prevention to treatment.

Psychosocial Factors in Painful Diabetic Neuropathy: A Systematic Review of Treatment Trials and Survey Studies.

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. 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. 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. 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.

Botulinum Toxin Treatment for Painful Diabetic Neuropathy A Review

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.

(212) Gene Expression Profile of Nociceptor Hyper-Excitability in Painful Diabetic Neuropathy

Painful diabetic neuropathy (PDN) is an intractable complication of diabetes that affects 25% of patients. PDN is characterized by neuropathic pain and small-fiber degeneration, accompanied by dorsal root ganglion (DRG) nociceptor hyperexcitability and loss of their axons within the skin. The molecular mechanisms underlying DRG nociceptor hyperexcitability and small-fiber degeneration in PDN are unknown. To delineate the molecular mechanisms behind nociceptor hyperexcitability and small-fiber degeneration, it becomes important to uniquely identify changes in the nociceptor population from within the heterogeneous population of neurons in the DRG. To identify genes that are differentially expressed in PDN, we compared the RNA profile of mice fed a regular-diet (RD) or a high-fat diet (HFD), a commonly used model of PDN. To capture the translational state of these nociceptive neurons, we used transgenic mice expressing tagged ribosomal subunits (RiboTag) in the nociceptor population expressing the sodium channel-Nav1.8. Analysis of the RiboTagged mRNA between HFD and RD mice at 10 weeks revealed 84 upregulated genes and 70 downregulated genes. We identified candidate genes like ApoD, known to increase excitatory signaling through CXCR4/CXCL12. Previously our work demonstrated that CXCR4/CXCR12 signaling is critical for the development of mechanical allodynia and small-fiber degeneration in PDN. Further analysis implicated changes in pathways relating to extracellular matrix organization, gliogenesis and, complex 1 biogenesis. In addition to the translational profiling, we plan to perform single-cell RNA sequencing of the Nav1.8-positive DRG neuron population using Nav1.8-Cre;Ai9 mice fed an RD or an HFD. Single-cell RNA sequencing will give us a better understanding of the transcriptional status of subpopulations within the Nav1.8-positive DRG neurons and generate candidate genes at a higher resolution. This study will provide insight into the genes that are involved in the pathogenesis of neuropathic pain and small-fiber degeneration and yield potential translational targets for disease-modifying treatments for PDN.

Cannabidiol attenuates mechanical allodynia in streptozotocin-induced diabetic rats via serotonergic system activation through 5-HT1A receptors

Most diabetic patients describe moderate to severe pain symptoms whose pharmacological treatment is palliative and poorly effective. Cannabidiol (CBD) has shown promising results in painful conditions. Then, we aimed to investigate the potential antinociceptive effect of CBD over the mechanical allodynia in streptozotocin-induced diabetic (DBT) rats, as well as its involved mechanisms. Wistar adult male diabetic rats were treated acutely or sub-chronically (for 14 days) with CBD (0.1, 0.3 or 3 mg/kg, intraperitoneal; i.p.) and had their mechanical threshold assessed using the electronic Von Frey. Acute treatment with CBD (at doses of 0.3 and 3 mg/kg) exerted a significant anti-allodynic effect, which is not associated with locomotor impairment. The antinociceptive effect of CBD (3 mg/kg) was not altered by the pre-treatment with CB1 or CB2 receptor antagonists (AM251 and AM630; respectively; both at a dose of 1 mg/kg, i.p.) nor by glycine receptor antagonist (strychnine hydrochloride, 10 μg/rat, intrathecal, i.t.). However, this effect was completely prevented by the pre-treatment with the selective 5-HT1A receptor antagonist WAY 100135 (3 μg/rat, i.t.). Sub-chronic treatment with CBD (0.3 or 3 mg/kg) induced a sustained attenuation of the mechanical allodynia in DBT rats. DBT rats presented significantly lower spinal cord levels of serotonin, which was prevented by the daily treatment with CBD (0.3 mg/kg). Taken together, our data suggest that CBD may be effective in the treatment of painful diabetic neuropathy and this effect seems to be potentially mediated by the serotonergic system activation through 5-HT1A receptors.

Methylglyoxal and a spinal TRPA1-AC1-Epac cascade facilitate pain in the db/db mouse model of type 2 diabetes.

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 Ca2+ 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.

Possible involvement of peripheral TRP channels in the hydrogen sulfide-induced hyperalgesia in diabetic rats

BackgroundPeripheral diabetic neuropathy can be painful and its symptoms include hyperalgesia, allodynia and spontaneous pain. Hydrogen sulfide (H2S) is involved in diabetes-induced hyperalgesia and allodynia. However, the molecular target through which H2S induces hyperalgesia in diabetic animals is unclear. The aim of this study was to determine the possible involvement of transient receptor potential (TRP) channels in H2S-induced hyperalgesia in diabetic rats.ResultsStreptozotocin (STZ) injection produced hyperglycemia in rats. Intraplantar injection of NaHS (an exogenous donor of H2S, 3–100 µg/paw) induced hyperalgesia, in a time-dependent manner, in formalin-treated diabetic rats. NaHS-induced hyperalgesia was partially prevented by local intraplantar injection of capsazepine (0.3–3 µg/paw), HC-030031 (100–316 µg/paw) and SKF-96365 (10–30 µg/paw) blockers, at 21 days post-STZ injection. At the doses used, these blockers did not modify formalin-induced nociception. Moreover, capsazepine (0.3–30 µg/paw), HC-030031 (100–1000 µg/paw) and SKF-96365 (10–100 µg/paw) reduced formalin-induced nociception in diabetic rats. Contralateral injection of the highest doses used did not modify formalin-induced flinching behavior. Hyperglycemia, at 21 days, also increased protein expression of cystathionine-β-synthase enzyme (CBS) and TRPC6, but not TRPA1 nor TRPV1, channels in dorsal root ganglia (DRG). Repeated injection of NaHS enhanced CBS and TRPC6 expression, but hydroxylamine (HA) prevented the STZ-induced increase of CBS protein. In addition, daily administration of SKF-96365 diminished TRPC6 protein expression, whereas NaHS partially prevented the decrease of SKF-96365-induced TRPC6 expression. Concordantly, daily intraplantar injection of NaHS enhanced, and HA prevented STZ-induced intraepidermal fiber loss, respectively. CBS was expressed in small- and medium-sized cells of DRG and co-localized with TRPV1, TRPA1 and TRPC6 in IB4-positive neurons.ConclusionsOur data suggest that H2S leads to hyperalgesia in diabetic rats through activation of TRPV1, TRPA1 and TRPC channels and, subsequent intraepidermal fibers loss. CBS enzyme inhibitors or TRP-channel blockers could be useful for treatment of painful diabetic neuropathy.

The Effect of Sodium Channel Blocker, Mexiletine, on Body Weight in Type 2 Diabetes Patients with Visceral Obesity.

Objective:Mexiletine is an anti-arrhythmic agent also used for the treatment of painful diabetic neuropathy. In this study, the effect of mexiletine on body weight was evaluated in type 2 diabetes patients with diabetic neuropathy exhibiting visceral obesity.Methods:Type 2 diabetes patients with neuropathy exhibiting visceral obesity (n = 21) treated by mexiletine (300 mg/day) and a control group of type 2 diabetes patients with the same condition who received vitamin B12 (n = 12) were retrospectively evaluated. Body weight, waist circumference, hemoglobin A1c (HbA1c), blood pressure, liver function, serum lipids, and serum uric acid were assessed before and 6 months after the treatment.Results:Mexiletine significantly decreased body weight and waist circumference. The changes in body weight and waist circumference in 6 months in the mexiletine group were greater than in the control group. In metabolic parameters, there were significant decreases in triglyceride (TG) and serum uric acid. There were positive relationships between the change in body weight and the changes in TG, uric acid, alanine aminotransferase (ALT), and HbA1c.Conclusions:Mexiletine may affect body weight regulation. It ameliorated the metabolic parameters possibly by decreasing visceral fat. Further study should be performed to clarify the mechanism of the effect.

0.075% capsaicin lotion for the treatment of painful diabetic neuropathy: A randomized, double-blind, crossover, placebo-controlled trial

ObjectiveA randomized, double-blinded, crossover, placebo controlled trial was conducted to evaluate the efficacy and safety of 0.075% capsaicin lotion for treating painful diabetic neuropathy (PDN). Patients and methodsPDN subjects were randomized to receive 0.075% capsaicin/placebo for 8 weeks, then crossing over to the other treatment after a 4-weeks washout period. Primary endpoint was the change in visual analog scale score of pain severity. Secondary outcomes were score changes in Neuropathic Pain Scale, short-form McGill Pain Questionnaires, and proportions of patients with pain score reductions of 30% and 50%, and adverse events. ResultsA total of 42 subjects were enrolled, 27 completed at least an 8-week treatment period. Intention-to-treat analysis showed no significant improvement in pain control with capsaicin lotion compared with placebo for all pain measures and proportion of patients who had 30% or 50% pain relief, respectively. Per protocol analysis were consistent. Capsaicin lotion was well tolerated but local skin reactions were common. ConclusionIn patients with PDN, the efficacy of 0.075% capsaicin lotion was similar to placebo but was well tolerated. More work is needed to assess different capsaicin formulations.

Neuropathic pain due to chronic idiopathic axonal neuropathy: fast pain reduction after topical phenytoin cream application

Pain due to chronic idiopathic axonal polyneuropathy (CIAP) is often treated with therapies based on general neuropathic pain guidelines, which are mainly developed with randomized clinical trials having evaluated treatments for painful diabetic neuropathy (PDN) and post-herpetic neuralgia.

Therapeutic alternatives in painful diabetic neuropathy: a meta-analysis of randomized controlled trials.

BackgroundOne of the most frequent problems caused by diabetes is the so called painful diabetic neuropathy. This condition can be treated through numerous types of therapy. The purpose of this study was to analyze, as a meta-analysis, different treatments used to alleviate painful diabetic neuropathy, with the aim of generating results that help making decisions when applying such treatments to tackle this pathology.MethodsA search was conducted in the main databases for Health Sciences, such as PUBMED, Web of Science (WOS), and IME biomedicina (Spanish Medical Reports in Biomedicine), to gather randomized controlled trials about treatments used for painful diabetic neuropathy. The analyzed studies were required to meet the inclusion criteria selected, especially those results related to pain intensity.ResultsNine randomized controlled trials were chosen. The meta-analysis shows significant positive effects for those treatments based on tapentadol [g: −1.333, 95% CI (−1.594; −1.072), P < 0.05], duloxetine [g: −1.622, 95 % CI (−1.650; −1.594), P < 0.05], pregabalin [g: −0.607, 95% CI (−0.980; −0.325), P < 0.05], and clonidine [g: −0.242, 95 % CI (−0.543; −0.058), P < 0.05].ConclusionsThis meta-analysis indicates the effectiveness of the treatments based on duloxetine, gabapentin and pregabalin, as well as other drugs, such as tapentadol and topic clonidine, whose use is better prescribed in more specific situations. The results provided can help increase the knowledge about the treatment of painful diabetic neuropathy and also in the making of clinical practice guidelines for healthcare professionals.

Lack of a Clinically Significant Pharmacokinetic Interaction Between Pregabalin and Thioctic Acid in Healthy Volunteers

PurposePregabalin and thioctic acid are likely to be used concomitantly for the treatment of painful diabetic neuropathy. In this study, the pharmacokinetic interaction between pregabalin and thioctic acid was investigated at steady state. MethodsA randomized, open-label, 6-sequence, 3-period, 3-treatment crossover study was conducted in 42 healthy male volunteers. The volunteers randomly received pregabalin 300 mg BID for 6 times, thioctic acid 600 mg once daily for 3 times, or the combination of pregabalin and thioctic acid. Serial blood samples were collected up to 24 hours after the last dosing in each period. Pharmacokinetic parameters were calculated by using noncompartmental analysis methods. FindingsThe mean concentration–time curves were similar between each drug alone and in combination with the other drug. The 90% CIs of the geometric mean ratios with and without the co-administered drug for Cmax at steady state and AUC during the dosing interval were well within the conventional bioequivalence range of 0.8 to 1.25, except for Cmax at steady state for thioctic acid, which barely exceeded only the lower bound (0.78–1.15). Co-administered pregabalin and thioctic acid was well tolerated. ImplicationsRepeatedly administered pregabalin and thioctic acid do not interact pharmacokinetically. This study suggests that the combination of pregabalin and thioctic acid can safely be administered concomitantly without dose adjustment. ClinicalTrials.gov identifier: NCT01808300.

Surgical peripheral nerve decompression for the treatment of painful diabetic neuropathy of the foot – A level 1 pragmatic randomized controlled trial

AimsTo assess the efficacy of surgical decompression of lower extremity nerves for the treatment of painful diabetic peripheral sensorimotor polyneuropathy (DPN). MethodsPeople with painful diabetic neuropathy were randomized single-blind to a lower extremity decompression surgery (n = 12) or observation (n = 10) for 1 year. ResultsPain was the primary outcome assessed with 2 measures. The McGill pain visual analogue scores over time changed within the groups (p for time < 0.0001), and changed differently over time within the groups (p for group × time = 0.0138). The NeuroQoL pain sensitivity analysis significantly changed from baseline to 12 months comparing intervention to control (p = 0.0079), and the joint effect of group and time on pain scores was statistically significant (p for group × time = 0.0009). At the study end-point of 12 months, intervention group participants had over 3 times the odds of rating their pain as “better” compared to “unchanged” or “worse” in the control group (p = 0.0177). ConclusionsSurgical decompression of lower limb nerves was an effective treatment for decreasing pain in patients with DPN and superimposed nerve compressions.

Inhibitory effect of Ligustrum vulgare leaf extract on the development of neuropathic pain in a streptozotocin-induced rat model of diabetes

BackgroundChronic hyperalgesia and allodynia associated with progressive damage of peripheral neurons are the most prevalent complications of diabetes mellitus. Plants belonging to the family of Oleaceae were traditionally used in folk medicine for the management of diabetes. Hypothesis/PurposeThe aim of this study was to investigate whether an aqueous extract from the leaves of Ligustrum vulgare (common privet) could be useful to target neuropathic pain in a rat streptozotocin (STZ) model of diabetes. MethodsThe chemical composition of the aqueous extract from privet leaf was characterized with the UHPLC-DAD-MS method and the analytical quantification of its constituents was performed with HPLC-DAD. Mechanical hyperalgesia and allodynia were evaluated with the Randall–Selitto and von Frey tests. ResultsOur investigation revealed the presence of secoiridoids: oleacein (23.48 ± 0.87 mg/g), oleocanthal (8.44 ± 0.08 mg/g), oleuropein (1.50 ± 0.01 mg/g), as well as phenylpropanoids: echinacoside (6.46 ± 0.07 mg/g), verbascoside (4.03 ± 0.04 mg/g) and p-coumaroyl glucarates in the dried aqueous extract of privet leaves. Behavioral data indicated that chronic intraperitoneal administration of the extract (50–200 mg/kg) for 21 days resulted in a decrease in diabetes-induced hyperalgesia and allodynia. Blood glucose levels remained unaltered, while body weight and water intake decreased significantly. ConclusionThe aqueous privet leaf extract could serve useful in facilitating treatment of painful diabetic neuropathy. Additionally, the study showed that the antihyperalgesic activity of Ligustrum vulgare leaf extract is not likely related to its antihyperglycemic properties.

Efficacy and safety of pregabalin versus amitriptyline in patients with painful diabetic neuropathy

Background: Painful diabetic neuropathy is a common complication of long standing diabetes mellitus. Amitriptyline is commonly used to treat painful diabetic neuropathy. Pregabalin has been shown to be effective in the treatment of painful diabetic neuropathy with lesser adverse effects. Sustained release (SR) of pregabalin has the advantage of once daily dosing and a better patient compliance. Hence, this study was planned to compare the efficacy and safety of pregabalin-SR with amitriptyline in painful diabetic neuropathy.Methods: It is a prospective, open labelled, randomized controlled study. A total of 80 patients diagnosed with painful diabetic neuropathy based on Diabetic neuropathy symptom score and Michigan neuropathy screening instrument, were randomized into two groups to receive amitriptyline and pregabalin SR. Amitriptyline was started at 25mg OD and pregabalin SR 75mg OD for 6 weeks with optional dose titration. Patients were assessed for pain relief by using visual analogue scale and an overall improvement in their general condition by patient’s global impression of change scale. Adverse drug reactions were recorded on each follow up.Results: All patients had significant improvement in pain relief in both the treatment groups. The median VAS (visual analogue scale) score was slightly higher in pregabalin SR group (25 vs 22) however it was not statistically significant. Intergroup comparison did not show any significant differences between the treatment groups. Good and moderate pain relief were noted in 37(92.5%) and 3(7.5%) patients on amitriptyline and 36 (90%) and 4 (10%) patients on pregabalin SR respectively. The common adverse effects reported in amitriptyline group were drowsiness (27.5%) and dry mouth (17.5%) and in pregabalin-SR group were drowsiness (15%) and dizziness (5%). No serious adverse event was reported in either of the groups.Conclusions: In patients with painful diabetic neuropathy both amitriptyline and pregabalin-SR are equally effective in alleviating pain and improving the patient’s general condition, but pregabalin-SR has the advantage of fewer adverse effects and convenient dosage timing.

Current and Emerging Treatments for Painful Diabetic Neuropathy

Current and Emerging Treatments for Painful Diabetic Neuropathy

Molecular Docking Analysis of Ginger Active Compound on Transient Receptor Potential Cation Channel Subfamily V Member 1 (TRPV1)

Ginger had been reported to ameliorate painful diabetic neuropathy (PDN) in an animal model. Gingerol and shogaol were active compounds of ginger that potentially act on transient receptor potential cation channel subfamily V member 1 (TRPV1), a key receptor in PDN. This study aims to predict the binding of gingerol and shogaol to TRPV1 using an in silico model. The ligands of the docking study were 3 chemical compounds of each gingerol and shogaol, i.e. 6-shogaol, 8-shogaol, 10-shogaol, 6-gingerol, 8 gingerol and 10-gingerol. Capsaicin, a TRPV1 agonist, was used as a native ligand. The TRPV1 structure was taken from Protein Data Bank (ID 3J9J). The docking analysis was performed using Autodock Vina. The result showed that among the ginger active compounds, 6-shogaol had the strongest binding energy (-7.10 kcal/mol) to TRPV1. The 6-shogaol lacked the potential hydrogen bond to Ile265 of TRPV1 protein, which capsacin had. However, it's binding energy towards TRPV1 was not significantly different compared to capsaicin. Therefore, 6-shogaol had potential to be developed as a treatment for PDN.

Tanshinone IIA Improves Painful Diabetic Neuropathy by Suppressing the Expression and Activity of Voltage-Gated Sodium Channel in Rat Dorsal Root Ganglia.

Painful diabetic neuropathy (PDN) is one of the intractable complications of diabetes mellitus, which manifest as exaggerated pain perception. Previous studies showed that Tanshinone IIA (TIIA), one of the major bioactive extracts of Salvia miltiorrhiza Bunge, have obvious analgesic effect on different types of pain process, and the underlying analgesic mechanisms are not fully understood. The present study combined the behavioral, electrophysiological and biochemical methods to elucidate the analgesic mechanism of TIIA, using streptozotocin (STZ)-induced PDN rat models. Intraperitoneal injection (i.p.) of TIIA for 3 weeks in PDN rats significantly improved mechanical allodynia and thermal hyperalgesia. Patch clamp recordings showed that the excitability of dorsal root ganglion (DRG) nociceptive neuron was increased in diabetic state, and TIIA treatment effectively recovered the subnormality, which was achieved by preventing augments of both Tetrodotoxin-sensitive (TTX-resistant) and Tetrodotoxin-sensitive (TTX-S) sodium currents. Further, the protein expressions of voltage-gated sodium channels (VGSCs) α-subunits Nav1.3, Nav1.7 and Nav1.9 increased in DRG of diabetic rats and were normalized by TIIA application. In conclusion, this study provides evidence that the TIIA attenuated PDN by effecting VGSCs activities and expressions, indicating that the TIIA could be a promising agent for PDN treatment.

Pregabalin versus oxcarbazepine in painful diabetic neuropathy in elderly population: Efficacy and safety in terms of pain relief, cognitive function, and overall quality of life

Background and Aims: The treatment of painful diabetic neuropathy (PDN) in elderly patients is challenging considering the adverse effects associated with long term use of drugs. Pregabalin has been recommended as the first line therapy for relief of neuropathic pain in such patients. However, the occurrence of side effects especially cognitive dysfunction and peripheral edema raised concerns during long term therapy in elderly population. Recently, few studies have highlighted the role of oxcarbazepine, a second generation antiepileptic, in PDN. This prospective, randomized, single-blind, parallel-group study was done to compare pregabaline and oxcarbazepine monotherapy in patients of PDN. Materials and Methods: 150 elderly patients of painful diabetic neuropathy, for at least 6 months of duration with an average baseline pain score ≥ 4 on 11 point numeric rating scale (NRS), were divided into two groups to receive either pregabalin 150 mg/day or oxcarbazepine 600 mg/day. Assessment of pain scores, cognitive functions and quality of life were performed at different time intervals during the course of treatment. Results: Patients in both the study groups showed significant reduction in pain scores from the baseline; however no significant differences in pain scores were noted between the two groups during the course of treatment. The incidence of cognitive dysfunction as measured by BCRS score was significantly more in pregabalin group while no significant changes were noted in oxcarbazepine group. The overall quality of life as demonstrated by SF12 scores was significantly better in both the study groups as compared to baseline. Conclusion: Oxcarbazepine can be used as an alternative to pregabalin in elderly patients with PDN considering the similar degree of pain relief and better cognitive profile.