Numerous studies have shown a relationship between hyperglycemia and the development and severity of DN. The Diabetes Control and Complication Trial (DCCT) research group reported that clinical and electrophysiological evidence of neuropathy was reduced by 50% in those treated intensively with insulin (19). In the UK Prospective Diabetes Study (UKPDS), control of blood glucose was associated with improvement in vibration perception (80,81). The Steno trial, using multifactorial intervention reported a reduction in the odds ratio to 0.32 for the development of autonomic neuropathy (82). Furthermore, the EURODIAB, a prospective study that included 3,250 patients across Europe, has shown that the incidence of neuropathy is also associated with potentially modifiable cardiovascular risk factors, including a raised triglyceride level, body-mass index, smoking, and hypertension (83). Treatment of neuropathy should, therefore, include measures to reduce macrovascular risk factors, including hyperglycemia, blood pressure and lipid control and lifestyle modifications including exercise and weight reduction, smoking cessation, a diet rich in omega-3 fatty acids and avoidance of excess alcohol consumption (82). C-peptide replacement in animal models of type 1 DM has shown improvement of nerve function (84). Moreover, it is known to have stimulatory effects on endothelial nitric oxide synthase, thereby enhancing endoneurial blood flow (85). Previous studies in humans have shown significant improvement in sensory nerve conduction velocities, vibration perception and autonomic nerve function (86,87). In a recent exploratory, multicenter, randomized, placebo-controlled study including 139 patients, 6 weeks of treatment demonstrated improvement in sensory nerve conduction velocities, vibration perception and neurologic impairment scores (88).

A number of studies have shown that hyperglycemia causes oxidative stress in tissues that are susceptible to complications of diabetes, including peripheral nerves. Figure 1 presents our current understanding of the mechanisms and potential therapeutic pathways for oxidative-stress-induced nerve damage. Studies show that hyperglycemia induces an increased presence of markers of oxidative stress, such as superoxide and peroxynitrite ions, and that antioxidant defense moieties are reduced in patients with diabetic peripheral neuropathy (89). Therapies known to reduce oxidative stress are therefore recommended. Therapies that are under investigation include aldose reductase inhibitors (ARIs), α-lipoic acid, γ-linolenic acid, benfotiamine, and protein kinase C (PKC) inhibitors.

Advance glycation end-products (AGE) are the result of non-enzymatic addition of glucose or other saccharides to proteins, lipids, and nucleotides. In diabetes, excess glucose accelerates AGE generation that leads to intra- and extracellular protein cross-linking and protein aggregation. Activation of RAGE (AGE receptors) alters intracellular signaling and gene expression, releases pro-inflammatory molecules and results in an increased production of reactive oxygen species (ROS) that contribute to diabetic microvascular complications. Aminoguanidine, an inhibitor of AGE formation, showed good results in animal studies but trials in humans have been discontinued because of toxicity (90). Benfotiamine is a transketolase activator that reduces tissue AGEs. Several independent pilot studies have demonstrated its effectiveness in diabetic polyneuropathy. The BEDIP 3-week study demonstrated subjective improvements in neuropathy scores in the group that received 200 mg daily of benfotiamine tablets, with a pronounced decrease in reported pain levels (91). In a 12-week study, the use of benfotiamine plus vitamin B6/B12 significantly improved nerve conduction velocity in the peroneal nerve along with appreciable improvements in vibratory perception. An alternate combination of benfotiamine (100 mg) and pyridoxine (100 mg) has been shown to improve diabetic polyneuropathy in a small number of diabetic patients (92). The use of benfotiamine in combination with other antioxidant therapies such as α-Lipoic acid (see below) will soon be commercially available.

ARIs reduce the flux of glucose through the polyol pathway, inhibiting tissue accumulation of sorbitol and fructose. In a 12-month study of zenarestat a dose dependent improvement in nerve fiber density was shown (93) In a one year trial of fidarestat in Japanese diabetics, improvement of symptoms was shown (94) and a 3 year study of epalrestat showed improved nerve function (NCV) as well as vibration perception (95). Newer ARIs are currently being explored, and some positive results have emerged (96), but it is becoming clear that these may be insufficient per se and combinations of treatments may be needed (17).

Gamma-Linolenic acid can cause significant improvement in clinical and electrophysiological tests for neuropathy (97).

Alpha-Lipoic acid or thioctic acid has been used for its antioxidant properties and for its thiol-replenishing redox-modulating properties. A number of studies show its favorable influence on microcirculation and reversal of symptoms of neuropathy (98-101). A meta-analysis including 1,258 patients from four randomized clinical trials concluded that 600 mg of i.v., α-Lipoic acid daily significantly reduced symptoms of neuropathy and improved neuropathic deficits (102). The recently published SYDNEY 2 trial showed significant improvement in neuropathic symptoms and neurologic deficits in 181 diabetic patients with 3 different doses of α-Lipoic acid compared to placebo over a 5-week period (103). The result of the NATHAN study, which examined the long-term effects on electrophysiology and clinical assessments, presented at the 2007 ADA meeting, showed that 4-year treatment with α-lipoic acid in mild to moderate DSP is well tolerated and improves some neuropathic deficits and symptoms, but not nerve conduction (104).

Protein kinase C (PKC) activation is a critical step in the pathway to diabetic microvascular complications. It is activated by both hyperglycemia and disordered fatty-acid metabolism resulting in increased production of vasoconstrictive, angiogenic, and chemotactic cytokines including transforming growth factor β (TGF-β), vascular endothelial growth factor (VEGF), endothelin (ET-1), and intercellular adhesion molecules (ICAMs). A multinational, randomized, phase-2, double blind, placebo-controlled trial with ruboxistaurin (a PKC-β inhibitor) failed to achieve the primary endpoints although significant changes were observed in a number of domains (105). Nevertheless, in a subgroup of patients with less severe DN (sural nerve action potential greater than 0.5 μV) at baseline and clinically significant symptoms, a statistically significant improvement in symptoms and vibratory detection thresholds was observed in the ruboxistaurin-treated groups as compared with placebo (106). A smaller, single center study recently published showed improvement in symptom scores, endothelium dependent skin blood flow measurements and quality of life scores in the ruboxistaurin treated group (24). These studies and the NATHAN studies have pointed out the change in natural history of DN with the advent of therapeutic lifestyle change, statins and ACE inhibitors, which have slowed the progression of DN and drastically changed the requirements for placebo-controlled studies.

There is increasing evidence that there is a deficiency of nerve growth factor (NGF) in diabetes, as well as the dependent neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP) and that this contributes to the clinical perturbations in small-fiber function (107). Clinical trials with NGF have not been successful but are subject to certain caveats with regard to design and NGF still holds promise for sensory and autonomic neuropathies (108). The pathogenesis of DN includes loss of vasa nervorum, so it is likely that appropriate application of VEGF would reverse the dysfunction. Introduction of VEGF gene into muscle of DM animal models improved nerve function (109). There are ongoing VEGF gene studies with transfection of the gene into the muscle in humans. INGAP peptide comprises the core active sequence of Islet Neogenesis Associated Protein (INGAP), a pancreatic cytokine that can induce new islet formation and restore euglycemia in diabetic rodents. Maysinger et al showed significant improvement in thermal hypoalgesia in diabetic mice after 2-week treatment with INGAP peptide (110).

Several different autoantibodies in human sera have been reported that can react with epitopes in neuronal cells and have been associated with DN. We have reported a 12% incidence of a predominantly motor form of neuropathy in patients with diabetes associated with monosialoganglioside antibodies (anti GM1 antibodies) (46). Perhaps the clearest link between autoimmunity and neuropathy has been the demonstration of an 11-fold increase likelihood of CIDP, multiple motor polyneuropathy, vasculitis and monoclonal gammopathies in diabetes (44). New data, however, support a predictive role of the presence of antineuronal antibodies on the later development of neuropathy, which may not be innocent bystanders but neurotoxins(111,112). There may be selected cases, particularly those with autonomic neuropathy, evidence of antineuronal autoimmunity and CIDP that may benefit from intravenous immunoglobulin or large dose steroids (42).

Small unmyelinated C-fiber damage gives rise to burning or lancinating pain often accompanied by hyperalgesia and dysesthesia. Peripheral sympathetic fibers are C fibers, too, and spontaneous firing or activation exacerbates the pain, which can be blocked with systemic administration of the a2-adrenergic agonist Clonidine. It can be applied topically, but the dose titration may be more difficult (113). These nerve fibers are peptidergic carrying substance P as the neurotransmitter. Depletion of substance P with local application of capsaicin abolishes transmission of painful stimuli to higher centers (114). Capsaicin is extracted from chili peppers, and a simple cheap mixture is to add one to three tea-spoons of cayenne pepper to a jar of cold cream and apply to the area of pain. Prolonged application of capsaicin depletes stores of substance P, and possibly other neurotransmitters, from sensory nerve endings. This reduces or abolishes the transmission of painful stimuli from the peripheral nerve fibers to the higher centers (114). Care must be taken to avoid eyes and genitals, and gloves must be worn. Because of capsaicin's volatility it is safer to cover affected areas with plastic wrap. There is initial exacerbation of symptoms followed by relief in 2 to 3 weeks. Targeting higher levels of pain transmission also helps with C-fiber pain (115-117).

Pain from Aδ fibers is deep-seated, dull and aching. It responds to nerve blocks, Tramadol or dextromethorphan, antidepressants and tricyclic agents. Insulin infusion at a rate of 0.8–1.0 units/h without lowering blood glucose helps in resolution of pain in about 48 hrs (118). N-methyl-D-aspartate (NMDA) receptor antagonists like dextromethorphan exert an analgesic effect in hyperalgesia and allodynia (119) whereas centrally acting opioids such as Tramadol achieve symptomatic relief (120). Nerve Blocking agent lidocaine given by slow infusion has been shown to provide relief of intractable pain for 3 to 21 days. This form of therapy may be of most use in self-limited forms of neuropathy. If successful, therapy can be continued with oral mexiletine. These compounds target the pain caused by hyperexcitability of superficial, free nerve endings (121).

These drugs inhibit reuptake of norepinephrine and/or serotonin. Anticholinergic effects, orthostatic hypotension and sexual side effects limit their use. They remain first-line agents in many centers, but consideration of their safety and tolerability is important in avoiding adverse effects, a common result of treatment of neuropathic pain. Dosages must be titrated on the basis of positive responses, treatment adherence, and adverse events (122). Among the norepinephrine reuptake inhibitors, desipramine, amitriptyline and nortriptyline have been shown to be of benefit. In patients with intolerance to amitriptyline, switching to nortriptyline may lessen some of the anticholinergic effects. Selective serotonin-reuptake inhibitors that have been used for neuropathic pain are paroxetine, fluoxetine, sertraline, and citalopram (123). Paroxetine appears to be associated with more pain relief. Fluoxetine failed a placebo controlled trial (124). Recent interest has focused on antidepressants with dual selective inhibition of serotonin and norepinephrine, such as duloxetine and venlafaxine. Duloxetine has recently been approved for neuropathic pain in the USA. It is a selective, balanced and potent serotonin and norepinephrine reuptake inhibitor (SNRI) in the brain and spinal cord, and its use leads to increased neuronal activity in efferent inhibitory pathways. In a 12-week multicenter, double-blind clinical trial of 457 patients, Goldstein et al showed a 50% reduction in 24-h Average Pain Score (primary endpoint) in 49 to 52% of patients treated with 60 mg and 120 mg of duloxetine vs. 26% of patients in the placebo group (p<0.05) (115). A second study by Raskin et al conducted in 449 patients for 6 months, similarly demonstrated maintenance of pain relief through 28 weeks (125). Nonetheless a number of side effects were reported, including dizziness, somnolence, dry mouth, nausea, constipation and reduced appetite. Physicians must be alert to suicidal ideation, exacerbation of autonomic symptoms, as well as aggravation of depression, and should stop the drug immediately if required (115). Venlafaxine in doses of 150 and 225 mg daily significantly improved pain scores, although side effects included somnolence, nausea and myalgias, and 7 of 244 treated patients developed significant electrocardiographic abnormalities (126).

Anticonvulsants have stood the test of time in treatment of DN. Principal mechanisms of action include sodium-channel blockade, potentiation of g-amino butyric (GABA) activity, calcium-channel blockade, antagonism of glutamate at N-methyl-D-aspartate receptors or α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (28).

Diphenylhydantoin has long been used in the treatment of painful neuropathies. Double-blind crossover studies do not demonstrate a therapeutic benefit of phenytoin compared with placebo in DN (127). Also, side effects mitigate its use in people with diabetes. Its ability to suppress insulin secretion has resulted in precipitation of hyperosmolar diabetic coma.

Several double-blind placebo-controlled studies have demonstrated carbamazepine to be effective in the management of pain in DN. At a dose of 200 mg twice daily is useful for patients with shooting or electric, shock-like pain but is rapidly discontinued due to adverse events.

Gabapentin is an effective anticonvulsant whose mechanism is not well understood, yet holds additional use as an analgesic agent in painful neuropathy (128). In a placebo-controlled trial gabapentin-treated patients had significantly lower mean daily pain scores and improvement of all secondary efficacy parameters (129). Gabapentin has the additional benefit of improving sleep, which is often compromised in patients with chronic pain (122). In the long term, it is known to produce weight gain, (130) which may complicate diabetes management, and it has not been successful in all trials.

Pregabalin produced significant improvements in pain scores within 1 week of treatment, which persisted for 6-12 weeks in four randomized controlled trials including 146-724 patients with diabetic neuropathy (116,131-133). Adverse events included dose related somnolence, ataxia and confusion, peripheral edema and constipation. A recent Canadian study evaluated cost-effectiveness of pregabalin vs gabapentin for the treatment of painful DN concluding that pregabalin was more cost effective when compared with gabapentin (134).

In trials with topiramate, a fructose analog, 50% of patients on topiramate versus 34% on placebo responded to treatment, defined as >30% reduction in pain score (P <0.004). Topiramate also reduced pain intensity versus placebo (P <0.003) as well as sleep disruption scores (P <0.02). This drug also lowers blood pressure, has a favorable impact on lipids, decreases insulin resistance and causes growth of intraepidermal nerve fibers and improves quality of life (135,136).

Lamotrigine (200 to 400 mg daily) is an anticonvulsant with dual-action inhibition of neuronal hyperexcitability. Two randomized, placebo-controlled studies including 720 patients showed that the drug was inconsistently effective for the treatment of pain when compared with placebo, although it was generally safe and well tolerated (117).

Another approach is the use of combination treatments. Gilron et al showed that the use morphine and gabapentin together, in an outpatient study, is superior to either alone, although the combination was associated with an increased frequency of side effects (137).

As mentioned previously, pain symptoms in neuropathy significantly impact QOL (78) (138). Neuropathic pain therapy is challenging and selection of pain medication and dosages must be individualized, with attention to potential side effects and drug interactions. An algorithm for the Management of Symptomatic Diabetic Neuropathy is described in figure 8.

Large-fiber neuropathy is manifested by reduced vibration perception and position sense, weakness and muscle wasting and depressed deep-tendon reflexes. Diabetic patients with large-fiber neuropathies are uncoordinated and ataxic, and are 17-times more likely to fall than their non-neuropathic counterparts (139). It is important, therefore, to improve strength and balance in patients with large-fiber neuropathy. Patients can benefit from high-intensity strength training by increasing muscle strength, improving coordination and balance, and thus reducing falls and fracture risks (140). Low-impact activities such as Pilates, yoga, and Tai Chi—which emphasize muscular strength and coordination, and challenge the vestibular system—may also be particularly helpful. In addition, options to prevent and correct foot deformities are available, for example orthotics, surgery and reconstruction.

Basic management of small fiber neuropathies by the patient should be encouraged. These are as follows: foot protection and ulcer prevention by wearing padded socks; regular foot inspection using a mirror to examine the soles of the feet daily; selection of proper footwear; scrutiny of shoes for the presence of foreign objects; avoidance of sun-heated surfaces, hot bathwater or sleeping with feet in front of fireplaces or heaters. Nails should be cut transversely and preferably by a podiatrist. Patient education should reinforce these strategies and, additionally, discourage soaking feet in water. Providing patients with a monofilament for self-testing reduces ulcers. Education will also promote foot care by encouraging emollient creams to help skin retain moisture and prevent cracking and infection. Transcutaneous nerve stimulation (electrotherapy) occasionally may be helpful and certainly represents one of the more benign therapies for painful neuropathy (141). Care should be taken to move the electrodes around to identify sensitive areas and obtain maximal relief.

Surgical Decompression for Diabetic Sensorimotor Polyneuropathy:

“The utility of surgical decompression for symptomatic diabetic neuropathy received a grade IV rating; i.e., based on evidence from uncontrolled studies, case reports, or expert opinion. It was assigned a U grading, which is defined as "data inadequate or conflicting given current knowledge, treatment is unproven." (142). “We believe the findings of the American Academy of Neurology’s evidence-based review should be strong evidence that the procedures should not be considered care but, rather, subjected to further research until proven beneficial. Only well-controlled, randomized, double-masked, sham-procedure, controlled clinical trials will allow us to know whether these surgeries are safe and effective for this indication—the same standard that any drug for DPN would have to meet.” (142)