Treatment options in painful diabetic neuropathy

Diabetic neuropathy is common in patients with diabetes mellitus, and 7.5% of diabetics experience pain from diabetic neuropathy. Complications of diabetes mellitus are more common where control of the disease is not optimal. By improving the control of the disease, both the neuropathy and the pain it can produce may be improved. The pain of diabetic neuropathy can frequently be controlled using analgesics, antidepressants, anticonvulsants, topical capsaicin, and neuromodulation, either alone or in any combination.     

Painful peripheral neuropathy and its nonsurgical treatment

Treatment of neuropathic pain is the primary focus of management for many patients with painful peripheral neuropathy. Antidepressants and anticonvulsants are the two pharmacological classes most widely studied and represent first-line agents in the management of neuropathic pain. The number of pharmacological agents that have demonstrated effectiveness for neuropathic pain continues to expand. In the current review, we summarize data from randomized, controlled pharmacological trials in painful peripheral neuropathies. Although neuropathic pain management remains challenging because the response to therapy varies considerably between patients, and pain relief is rarely complete, a majority of patients can benefit from monotherapy using a well-chosen agent or polypharmacy that combines medications with different mechanisms of action.     

Post-stroke pain case study: clinical characteristics, therapeutic options and long-term follow-up

Central post-stroke pain (CPSP) is a syndrome characterized by sensory disturbances and neuropathic pain. In 40%−60% of CPSP patients, the onset of central pain following a stroke occurs more than 1 month after the stroke, creating a source of diagnostic uncertainty or significant delay in treatment since healthcare providers familiar with CPSP may no longer be caring for the patient when the symptoms occur. In addition to chronic pain, the presence of somatosensory abnormalities is the most important diagnostic corollary of CPSP. Neuropathic or central pain has been estimated to occur in up to 8% of patients after a stroke, and about 18% of stroke patients with a somatosensory disturbance will develop CPSP. Although largely a matter of conjecture, it is generally agreed that damage to spinothalamic sensory pathways plays a significant role in the pathogenesis of CPSP. A comprehensive examination of the patient for sensory deficits is essential before treatment can be initiated. Functional disturbances such as depression, anxiety and sleep disturbances are significant comorbid conditions associated with CPSP; the physician should incorporate an assessment of these potential comorbidities into the examination. Treatment options for CPSP are limited; at present, amitriptyline is the drug of first choice. Other drugs including antidepressants, anticonvulsants, antiarrhythmics, opioids and N -methyl- d -aspartate antagonists may provide relief for some patients who do not respond to amitriptyline. Included in this review is a case study outlining the challenges of managing the patient with CPSP.     

Post-herpetic neuralgia case study: optimizing pain control

Post-herpetic neuralgia (PHN) is a chronic pain syndrome associated with the reactivation of a primary infection with varicella zoster virus (chicken pox), which leads to a chronic infection of the dorsal root ganglia. Under various clinical circumstances, including immunosuppressive diseases or treatments and certain cancers, reactivation of the infection can occur in adults as shingles. Other factors such as psychological distress and stressful life events also appear to play a role in the onset of shingles and the development of PHN. The most common risk factor for shingles and its potential sequela, PHN, is advanced age. For a significant number of patients, the pain following healing of shingles can persist for months to years; this pain is classified as PHN if it persists longer than 3 months. PHN often leads to depression, disrupted sleep, decreased functioning and increased healthcare utilization. Prompt use of antiviral therapy appears to reduce the period of pain following an episode of shingles by about half and may possibly reduce the overall incidence of PHN. Damage to a variety of neurologic pathways as a result of herpes zoster reactivation suggests that intervention with multiple agents having divergent mechanisms of action is an appropriate treatment approach. Current treatment options aimed at relieving the symptoms of PHN include antidepressants, opioids, anticonvulsants and topical analgesics. It is important for the clinician to establish a baseline pain intensity and character as well as quality of life measures against which to judge the effectiveness of any treatment. This review article features a case study of a patient with PHN to illustrate current diagnostic and treatment approaches.     

Oxcarbazepine in painful diabetic neuropathy: results of a dose-ranging study

OBJECTIVES: To evaluate the efficacy and safety of oxcarbazepine in patients with diabetic neuropathy in a multicenter, double-blind, placebo-controlled, dose-ranging 16-week study. METHODS: A total of 347 patients were randomized to oxcarbazepine 600 mg/day (n = 83), 1,200 mg/day (n = 87), 1,800 mg/day (n = 88), or placebo (n = 89). The primary efficacy variable was change in mean visual analog scale (VAS) score from baseline to the last week of the study. RESULTS: No difference between any oxcarbazepine group and the placebo group was noted for the primary efficacy variable. Both the 1,200- and 1,800-mg/day groups showed a trend toward statistical significance (P = 0.101, P = 0.096, respectively). Statistically significant differences were found between the oxcarbazepine 1,200-mg/day (P = 0.038) and 1,800-mg/day (P = 0.005) groups and placebo in the overall mean weekly VAS scores for the entire double-blind treatment phase. CONCLUSIONS: Although the primary efficacy variable did not reach statistical significance, patients taking oxcarbazepine 1,200 and 1,800 mg/day showed improvements in VAS scores compared with placebo. Oxcarbazepine may provide clinically meaningful pain relief in patients with painful diabetic neuropathy.     

Restless legs syndrome in diabetic neuropathy: a frequent manifestation of small fiber neuropathy

As the occurrence of restless legs syndrome (RLS) in diabetes is controversial, the aim of this study was to assess the prevalence of RLS in a cohort of patients with diabetic neuropathy and to analyze the features of the associated neuropathy. We investigated the occurrence of RLS diagnosed in accordance with the criteria of the International Restless Legs Syndrome Study Group in a cohort of patients with polyneuropathy and mononeuropathy multiplex associated with diabetes mellitus (DM), or impaired glucose tolerance (IGT), or impaired fasting glucose (IFG) in a retrospective study. RLS was present in 33/99 patients with neuropathy associated with DM/IGT/IFG (84 with distal polyneuropathy and 15 with multiple mononeuropathy). Comparing patients with or without RLS, small fiber sensory neuropathy was more common in the RLS patients (15/33 vs. 15/66), as were symptoms of burning feet (10/33 vs. 6/66). In several patients, RLS was responsive to neuropathic pain medications. The frequent occurrence of RLS in association with thermal dysesthesias may reflect the involvement of small sensory fibers in the form of hyperexcitable C fibers or A-delta fiber deafferentation. We suggest that RLS may be triggered by abnormal sensory inputs from small fibers, especially involved in neuropathy associated with DM/IGT/IFG. Our data show that RLS is a relevant feature of diabetic neuropathy, as a frequent and potentially treatable manifestation of small fiber involvement in the course of DM and IGT/IFG.     

Phenotyping animal models of diabetic neuropathy: a consensus statement of the diabetic neuropathy study group of the EASD (Neurodiab)

NIDDK, JDRF, and the Diabetic Neuropathy Study Group of EASD sponsored a meeting to explore the current status of animal models of diabetic peripheral neuropathy. The goal of the workshop was to develop a set of consensus criteria for the phenotyping of rodent models of diabetic neuropathy. The discussion was divided into five areas: (1) status of commonly used rodent models of diabetes, (2) nerve structure, (3) electrophysiological assessments of nerve function, (4) behavioral assessments of nerve function, and (5) the role of biomarkers in disease phenotyping. Participants discussed the current understanding of each area, gold standards (if applicable) for assessments of function, improvements of existing techniques, and utility of known and exploratory biomarkers. The research opportunities in each area were outlined, providing a possible roadmap for future studies. The meeting concluded with a discussion on the merits and limitations of a unified approach to phenotyping rodent models of diabetic neuropathy and a consensus formed on the definition of the minimum criteria required for establishing the presence of the disease. A neuropathy phenotype in rodents was defined as the presence of statistically different values between diabetic and control animals in 2 of 3 assessments (nocifensive behavior, nerve conduction velocities, or nerve structure). The participants propose that this framework would allow different research groups to compare and share data, with an emphasis on data targeted toward the therapeutic efficacy of drug interventions.     

Topiramate in painful diabetic polyneuropathy: findings from three double-blind placebo-controlled trials

OBJECTIVES: To evaluate the efficacy and tolerability of topiramate in patients with painful diabetic polyneuropathy. MATERIALS AND METHODS: Patients with moderate to extreme pain (0-4 Categorical Pain Scale score > or = 2) were randomized to placebo or topiramate (100, 200, or 400 mg/day) in three similar double-blind trials. The primary efficacy analysis was pain reduction from final visit to baseline in the 100-mm Visual Analog Scale (VAS) for the intent-to-treat populations. RESULTS: After 18-22 weeks of double-blind treatment, pain reductions were numerically greater with topiramate in two studies but differences between topiramate and placebo in VAS scores or in the secondary efficacy endpoints did not reach statistical significance in any of the three studies. Across all studies, 24% of topiramate-treated patients and 8% of placebo-treated patients discontinued due to adverse events; groups did not differ in the occurrence of serious adverse events. CONCLUSION: These studies did not find topiramate to be significantly more effective than placebo in reducing pain scores in patients with painful diabetic polyneuropathy. Several design features may have precluded the studies from having sufficient sensitivity to differentiate effective and ineffective treatments. The study design and results are instructive for other investigators designing future clinical studies in neuropathic pain.     

Role of A3 adenosine receptor in diabetic neuropathy

Neuropathy is the most common diabetic complication. Although the A1 and A2A adenosine receptors are important pharmacological targets in alleviating diabetic neuropathy, the role of the A3 adenosine receptor remains unknown. Because the A3 adenosine receptor regulates pain induced by chronic constriction injury or chemotherapy, its stimulation might also attenuate diabetic neuropathy. This study examines the effects of systemic treatment with the A3 adenosine receptor agonist 1‐deoxy‐1‐[6‐[[(3‐iodophenyl)methyl]amino]‐9H‐purin‐9‐yl]‐N‐methyl‐β‐d‐ribofuranuronamide (IB‐MECA) on diabetic neuropathy and explores the putative mechanisms underlying its pharmacological effects. We show that IB‐MECA alleviated mechanical hyperalgesia and thermal hypoalgesia in mice 2 weeks but not 4 weeks after streptozocin (STZ) treatment. Furthermore, IB‐MECA prevented the reduction in sciatic motor nerve conduction velocity and sensory nerve conduction velocity in diabetic mice 2 weeks but not 4 weeks after STZ treatment. Similarly, IB‐MECA inhibited the activation of nuclear factor‐κB and decreased the generation of tumor necrosis factor‐α in the spinal cord of mice 2 weeks but not 4 weeks after STZ treatment. These phenomena were associated with reduction of A3 adenosine receptor expression in the spinal cord after long‐term diabetes. Our results suggest that the A3 adenosine receptor plays a critical role in regulating diabetic neuropathy and that reduction in A3 adenosine receptor expression/function might contribute to the progression of diabetic neuropathy. © 2016 Wiley Periodicals, Inc.     

Evidence-based guideline: treatment of painful diabetic neuropathy--report of the American Association of Neuromuscular and Electrodiagnostic Medicine, the American Academy of Neurology, and the American Academy of Physical Medicine & Rehabilitation

The objective of this report was to develop a scientifically sound and clinically relevant evidence‐based guideline for the treatment of painful diabetic neuropathy (PDN). The basic question that was asked was: “What is the efficacy of a given treatment (pharmacological: anticonvulsants, antidepressants, opioids, others; non‐pharmacological: electrical stimulation, magnetic field treatment, low‐intensity laser treatment, Reiki massage, others) to reduce pain and improve physical function and quality of life (QOL) in patients with PDN?” A systematic review of literature from 1960 to August 2008 was performed, and studies were classified according to the American Academy of Neurology classification of evidence scheme for a therapeutic article. Recommendations were linked to the strength of the evidence. The results indicate that pregabalin is established as effective and should be offered for relief of PDN (Level A). Venlafaxine, duloxetine, amitriptyline, gabapentin, valproate, opioids (morphine sulfate, tramadol, and oxycodone controlled‐release), and capsaicin are probably effective and should be considered for treatment of PDN (Level B). Other treatments have less robust evidence, or the evidence is negative. Effective treatments for PDN are available, but many have side effects that limit their usefulness. Few studies have sufficient information on their effects on function and QOL. Muscle Nerve, 2011.     

应用外周神经减压术治疗痛性糖尿病神经病

目的探讨外周神经减压术治疗痛性糖尿病神经病的疗效。方法应用腓总神经、腓深神经及胫后神经三处外周神经减压术治疗28例临床表现为双下肢对称性疼痛的痛性糖尿病神经病患者，并进行回顾性分析。结果36％（10例）患者术后疼痛明显缓解，61％（17例）患者症状缓解，3％（1例）患者症状无变化。结论应用外周神经减压术，可有效帮助痛性糖尿病神经病患者缓解疼痛。     

糖尿病性周围神经病患者的神经电图改变

目的 观察糖尿病性周围神经病（DPN）患者神经电图的改变。方法 对78例DPN患者进行神经电图检查,包括运动神经传叶速发（MCV）、感觉神经传导速度（SCV）和F波检查。结果 共检查78例患者的468条神经,其中MCV减慢166条,MCV减慢合并远端潜伏期延长39条,异常率43．8％;SCV减慢175条,末引出电位75条,SCV减慢兼远端潜伏期延长26条,异常率58．9％．检查102条神经的F波,其中异常66条,异常率为64．7％,12条神经（11．8％）F波时间离散度增加。结论 神经电图是诊断DPN的敏感及特异性的检查,多个参数相结合有助于提高阳性检出率。     

Gabapentin: A new tool in the treatment of neuropathic pain

Human neuropathic pain remains a prevalent and pervasive problem in our society. Pharmacologically there is also no single, uniformly well-tolerated drug that is reliably helpful. Gabapentin has emerged as a useful new tool based on the results of two large multicenter trials in models of human neuropathy. Gabapentin proved to be a significantly better analgesic than placebo, was well tolerated in the elderly population, and had a significant positive impact on several subjective and objective outcome measures. A discussion of the standard treatments and the studies supporting this new tool is the purpose of this review.     

肌电图对糖尿病周围神经病的诊断价值

目的：探讨神经肌电图在糖尿病性周围神经病（DPN ）诊断中的应用价值。方法：选择我院2012年1月～2014年6月收治的200例DPN患者的临床资料,分析肌电诱发电位仪对患者的相关神经进行检测的结果。结果：在200例DPN患者中,神经电图总异常率高达71．5％。且随着病程的延长,其EM G异常率的发生逐渐增加。病程在1年以内的患者EM G异常率为40．8％,而病程在10年以上者异常率达到92．2％。病程在1年以内的患者H反射异常率为46．9％,而病程在10年以上者H反射异常率达到94％。其次是腓总神经运动传导速度（MCV）、腓浅神经感觉传导速度（SCV）异常率,分别是43．1％和58．8％,均超过40％。EM G结果提示：病程＜1年组拇短展肌、肱二头肌、胫前肌、趾总伸肌EM G异常率均为0,病程≥10年组异常率分别为17．6％、9．8％、21．5％、31．4％,同样随病程延长而异常率增加。结论：EM G在诊断DPN中具有较高的准确性,有利于早期发现和进行治疗。     

糖尿病性周围神经病患者受累神经的分布特点

目的 探讨糖尿病件周围神经病(DPN)患者受累神经的分布特点.方法 对900例2型糖尿病并发DPN患者进行感觉及运动神经传导速度检测,对受累神经的分布进行分析.结果 本组感觉神经异常率为89.3%;包括65.2%(587例)的正中神经、38.9%(350例)的尺神经、89.3%(804例)的腓浅神经、60.4%(544例)的腓肠神经及29.6%(64例)的胫后神经异常.运动神经异常率为34.5%;包括32.1%(289例)的正中神经、28.7%(258例)的腓总神经、22.7%(49例)的胫神经异常.感觉神经异常率明显高于运动神经异常率(P<0.01);下肢感觉神经异常率明显高于上肢(P<0.01).结论 DPN患者受累的感觉神经以腓浅神经、正中神经、腓肠神经最普遍,受累的运动神经以正中神经、腓总神经为多见.     

The role of axonal ion conductances in diabetic neuropathy: A review

Diabetic neuropathy is a common complication in diabetes mellitus. Diabetic neuropathy is accompanied by alterations in axonal excitability, which can lead to either “positive” (paresthesia, dysesthesia, pain) and/or “negative” (hypesthesia, anesthesia) symptoms. The mechanisms underlying these alterations in axonal excitability are not well understood. Clinical tests reveal reduced nerve conduction velocity and axonal loss, but fail to explain nerve excitability. Many different factors have been suggested in relation to the pathophysiology of diabetic neuropathy. There are probably as many factors as there are different clinical pictures in diabetic neuropathy. Nevertheless, it seems that hyperglycemic hypoxia is mainly responsible for the electrophysiological changes seen in damaged diabetic nerves. This article summarizes experimental data indicating that a dysfunction of ion conductances, especially voltage-gated ion channels, could contribute to abnormalities in the generation and/or conduction of action potentials in diabetic neuropathy. © 1998 John Wiley & Sons, Inc. Muscle Nerve 21:1246–1255, 1998.     

Neuropathic pain is associated with increased nodal persistent Na+ currents in human diabetic neuropathy

Abstract Peripheral nerve injury alters function and expression of voltage gated Na⁺ channels on the axolemma, leading to ectopic firing and neuropathic pain/paresthesia. Hyperglycemia also affects nodal Na⁺ currents, presumably due to activation of polyol pathway and impaired Na⁺–K⁺ pump. We investigated changes in nodal Na⁺ currents in peripheral sensory axons and their relation with pain in human diabetic neuropathy. Latent addition using computerized threshold tracking was used to estimate nodal persistent Na⁺ currents in radial sensory axons of 81 diabetic patients. Of these, 36 (44%) had chronic neuropathic pain and severe paresthesia. Compared to patients without pain, those with pain had greater nodal Na⁺ currents (p = 0.001), smaller amplitudes of sensory nerve action potentials (SNAP) (p = 0.0003), and lower hemoglobin A1c levels (p = 0.006). Higher axonal Na⁺ conductance was associated with smaller SNAP amplitudes (p = 0.03) and lower hemoglobin A1c levels (p = 0.008). These results suggest that development of neuropathic pain depends on axonal hyperexcitability due to increased nodal Na⁺ currents associated with structural changes, but the currents could also be affected by the state of glycemic control. Our findings support the view that altered Na⁺ channels could be responsible for neuropathic pain/paresthesia in diabetic neuropathy.