The Diabetic Neuropathies

Practical and Rational Therapy

J. Robinson Singleton, M.D.; A. Gordon Smith, M.D.

Disclosures

Semin Neurol. 2012;32(3):196-203. 

In This Article

Treatment Based on Recognized Steps in Diabetic Pathophysiology

The pathophysiology of DSP is complex and several important mechanistic pathways have been identified. Neuropathy likely results as a combination of direct axonal injury due to metabolic consequences of hyperglycemia, insulin resistance, and toxic adiposity in addition to endothelial injury and microvascular dysfunction leading to nerve ischemia. Diabetes causes functional deficits in nitric-oxide-mediated microvascular reactivity as well as a structural microangiopathy that share pathologic features with microvascular injury to the retina. Additional relevant metabolic pathways include oxidative and nitrosative stress,[30,31] accumulation of advanced glycation end products,[32] direct toxic effects of free fatty acids and proinflammatory adipokines.[33] These pathways produce microischemia of nutrient nerve arterioles, dysregulate axonal mitochondrial function, inhibit axonal transport of proteins necessary for distal axonal function, and elicit an autoimmune response.[32]

Pathogenic elucidation spawned a plethora of animal models and medications designed to block specific putative pathogenic pathways. Despite several promising therapies in cell culture and animal models of diabetic neuropathy, no rational treatment has clearly proven effective at reversing or slowing progression. Multiple trials of small vessel vasodilatory agents showed no clinical response,[34] nor did a large trial of nerve growth factor (NGF).[35] Trials of aldose reductase inhibitors (ARI), which control entry of excess glucose into the polyol pathway and reduce glucose mediated oxidative stress and microvascular disease in animals, have generally shown no efficacy in humans.[36,37]

Three related potential medications for DSP combine neuropathic pain relief with possible direct effect on neuropathic injury. Alpha lipoic acid, acetyl-L carnitine, and benfotiamine each act to reduce oxidative stress, which has been identified as a key component of neuropathy pathogenesis. In diabetes, excess lipids and glucose both produce oxidative free radicals that directly damage axonal mitochondria and divert nitric oxide from its normal vasodilatory role, resulting in impaired vasoregulation and ischemia of nutritive arterioles.[38] Alpha lipoic acid (ALA) is an orally bioavailable antioxidant. The Symptomatic Diabetic Neuropathy (SYDNEY) Study randomized diabetic neuropathy subjects to double-blinded treatment with either placebo or up to 1800 mg of oral ALA. Over the 5-week treatment course, subjects treated with any of the ALA doses reported a significantly greater reduction in neuropathic pain than did the placebo-treated controls.[39] Most clinical measures of neuropathy severity did not significantly improve; previous studies had reported modest improvement in neuropathy measures following IV ALA injection.[40] Alpha lipoic acid is regulated as a drug in many European nations, but is available in the United States as a dietary supplement. ALA may be started at a dose of 300 mg by mouth daily and titrated as high as 600 mg twice daily. ALA may lower blood glucose and thiamine stores, and has unpredictable effects on thyroid function.

Diabetes is associated with reduced serum levels and cellular concentrations of acetyl-L carnitine (ALC), another antioxidant that has been shown to inhibit lipid peroxidation and increase nitric oxide synthase and nitric oxide in experimental models. Two parallel randomized, blinded controlled trials used measures including the Visual Analog Pain Scale (VAS), and morphometric analysis of sural nerves to assess neuropathy severity at baseline and after 52 weeks of treatment; 1257 diabetic neuropathy subjects received either placebo or one of two ALC doses.[41] ALC significantly improved sural morphology and VAS. These also improved significantly with the larger ALC dose. ALC is available as a nutritional supplement, often in combination with ALA, and a target dose of 500 mg daily is best supported.

Benfotiamine or S-benzoylthiamine O-monophosphate is a vitamin B1 derivative with antioxidant properties. A phase III study randomized 165 diabetic neuropathy subjects to either placebo or benfotamine.[42] Subjects receiving active drug showed significant improvement in the neuropathy-specific Total Symptom Score and its pain subscore over the 6-week trial, with greater benefit in the 600 mg dose group. Taken together, trials of these medications strongly implicate oxidative stress as a contributor to neuropathy pathogenesis.

Delivery of a putative therapeutic agent to the target organ (dorsal root ganglia or nerve) without limiting off-target side effects has proven challenging. This issue was particularly problematic in the phase III NGF trial, in which even a low dose of NGF was complicated by symptomatic hyperalgesia.[43] One solution to this problem is use of delivery vectors derived from the herpes simplex virus, which has trophism for dorsal root ganglia neurons. A recent phase I study of a replication deficient HSV vector expressing the gene for preproenkephalin in patients with cancer-related pain demonstrated an apparent dose-related treatment effect.[44] Other studies have used plasmids (naked DNA) containing growth factor genes to deliver therapy to nerve via intramuscular injection. A small trial of a plasmid containing the gene for vascular endothelial growth factor suggested benefit, and other trials using this delivery system are underway.[45]

Numerous physical, surgical, or energy therapies are purported to improve neuropathy by increasing vascular or microvascular blood flow. These include "triple decompressive surgery" to release the peroneal nerve at the fibular head and foot dorsum, and the tibial nerve at anatomic tunnels in the foot,[46] fixed or pulsed magnetic field therapy,[47,48] near infrared phototherapy,[49] and various nonpenetrating laser therapies. In all cases, either rigorous blinded and randomized trials have not been performed, or as in the case of magnetic field therapy, these studies have not demonstrated improvement in nerve function.[50]

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