April 2016

Emerging treatments for diabetic neuropathy

4diabetes-iStock17835840Strict glycemic control is the most reliable treatment for diabetic peripheral neuropathy, but expanding knowledge of central and peripheral nervous system processes may help identify therapeutic methods that can effectively target the underlying mechanisms of pathogenesis.

By Sarnarendra Miranpuri, DPM, MD; Kush Patel; Gurwattan Miranpuri, PhD; Abhishek Chopra; and Ravinderjit Singh

The dramatic rise in the incidence of diabetes worldwide can be attributed to human behavior and lifestyle changes over the last century. In 1864, Marchel de Calvi described diabetic peripheral neuropathy (DPN) as a consequence rather than a cause of diabetes.1 Neuropathy is a common complication of type 1 and type 2 diabetes, with a prevalence of nearly 8% in newly diagnosed patients with diabetes and more than 50% in patients with long-standing disease.2 Several risks factors are associated with DPN, including hyperglycemia, older age, tobacco use, hypertension, obesity, alcohol consumption, and taller height.1,2 The landmark Diabetes Control and Complication Trial demonstrated that proper glycemic control can reduce the development and progression of neuropathy significantly, by 64%.3

The presentation of diabetic neuropathy characteristically involves a burning or tingling sensation, hyperesthesia, sensory loss in the feet or hands, or combinations of these factors.1 Patients may also experience cold or numb sensations. Sensorimotor and autonomic neuropathies are the most common diabetic neuropathies. Sensorimotor neuropathy presents with pain, paresthesia, and sensory loss, while autonomic neuropathy can contribute to myocardial infarction, malignant arrhythmia, and sudden death.

As therapeutic approaches to diabetic neuropathy have evolved, researchers’ understanding of the mechanisms underlying its pathogenesis has expanded.

Distal sensory diabetic polyneuropathy affects up to 50% of patients.2 The symptoms frequently affect patients’ ability to perform daily activities. Up to half of these patients, however, may be asymptomatic, and an incidental finding of a painless foot ulceration can confirm the diagnosis.2

Pathophysiologically, DPN involves metabolic and vascular dysfunction. Hyperglycemia, paramount to the pathogenesis of DPN, plays a central role in the cascade of nerve damage, which is described below:1

1) Increased intracellular glucose and nerve and vascular tissue increases sorbitol and fructose and decreases myo-inositol. It also reduces nicotinamide adenine dinucleotide phosphate, which leads to impairment of the primary vasodilatory system. The impaired vascular supply to the nerves ultimately plays a role in DPN.

2) Advanced glycation end products (hemoglobin, plasma albumin, lipoproteins, fibrin, and collagen) cause tissue damage.

3) Oxidative stress is the main pathological process that induces nerve damage by a direct toxic effect or by inhibition of nitric oxide production, thereby leading to nerve ischemia.

4) Intracellular glucose activates protein kinase C, decreases nerve growth factor, and decreases gamma-linolenic acid (subsequently reducing prostacyclin, a vasodilator), which is necessary for ensuring blood flow.

Currently, strict glycemic control is the most tangible treatment for DPN. Expanding knowledge of central and peripheral nervous system processes may help identify therapeutic methods that effectively target the underlying mechanisms of pathogenesis. An improved therapeutic approach may include using protective and regenerative factors to enhance the action to insulin-regulated genes in the endothelial cells to promote antioxidant and anti-inflammatory factors.4

A large number of neuroanatomical, neurophysiologic, and neurochemical mechanisms are thought to contribute to the development and maintenance of DPN.1 Pathogenetic-oriented treatment overlooks the role of glycemic control and cardiovascular risk factors. Combination treatments involving pathogenetic and symptomatic drugs, however, are the most effective treatments for DPN.5

Long-standing therapies

Restoration of function and improved pain control are the treatment goals for DPN. Prior to initiation of medicinal therapy, clinicians can help manage risks of DPN with optimal glycemic control, improved lipid levels, blood pressure regulation, smoking cessation, and reduction of alcohol consumption.2 There are several established modalities used in clinical practice for the treatment of DPN and improving patient quality of life.

First-line therapy with tricyclic antidepressants (TCAs, including amitriptyline, nortriptyline, imipramine, and desipramine)6-12 in appropriately selected patients has been used widely without approved labeling from the US Food and Drug Administration (FDA). TCAs are thought to relieve pain by blocking neuronal reuptake of norepinephrine and serotonin, thereby inhibiting neurotransmitters in nociceptive pathways.7 In particular, TCAs are used for deep pain (“pins and needles,” “electric,” or numb, achy pain).

A recent Cochrane review assessed five studies on the use of TCAs in the treatment of DPN and revealed overall effectiveness with a number needed to treat (NNT) of 1.3.12 Of the TCAs, amitriptyline has the most published data in support of its use as a treatment for DPN; therefore, it should be recommended as the initial therapy in young patients. Desipramine is recommended for elderly patients and patients who are at risk for anticholinergic adverse effects.7 These adverse effects often lead clinicians or their patients, particularly older adults, to discontinue use despite the overall effectiveness and affordability of this group of medications.

diabetes-table1

Although used to treat anxiety disorders, serotonin and norepinephrine reuptake inhibitors (SNRIs, including duloxetine, venlafaxine, and milnacipran)2,12 are better tolerated and have fewer drug interactions than the TCAs typically used for DPN. A 2007 Cochrane review revealed an NNT of 3.1 for venlafaxine and 6 for duloxetine.13,14 The selective serotonin reuptake inhibitors paroxetine and citalopram can also be used to treat DPN, but have a limited role.12

Anticonvulsants (eg, gabapentin, pregabalin)14 can be used for DPN if there is inadequate response to TCAs. Gabapentin and pregabalin bind to the alpha-2-delta subunit of the calcium sensitive channels, modulating release of neurotransmitter. The FDA first approved gabapentin in 1994 for use in adult patients with partial epilepsy. In 1998, animal and human studies showed gabapentin has a possible analgesic action.5 However, up-titrating the dosing to the level necessary for achieving a therapeutic effect is commonly needed.5 Pregabalin, conversely, has a narrow therapeutic dosing range, which ensures a predictable response and enables an easy dosing process. Pregabalin is also FDA approved for treatment of DPN pain.

Another anticonvulsant, carbamazepine, has been used in treating neuropathy since the 1960s. It requires laboratory monitoring (renal function, liver function, reticulocyte count, platelet count).15 Topiramate and lamictal are other anticonvulsants that lack evidence for their use in treating DPN.

Opiate (eg, methadone, levorphanol, morphine, oxycontin)1,12 monotherapy, although controversial, is used to treat DPN in patients who fail other therapies. Nine studies showed a consistent benefit with this group of medications, with an approximately 20% to 30% reduction in pain.16 Despite the concern of dependency with chronic opiate therapy, study guidelines do suggest a benefit to patients with DPN.17 Tramadol, a synthetic opiate-like centrally acting narcotic analgesic, acts at mu-opioid receptors and inhibits reuptake of norepinephrine and serotonin. With a lower abuse potential than true opiates, the NNT with tramadol is 3.8.18

Topical therapies (capsaicin cream and lidocaine 5% patches)19,20 have been used to treat neuropathic conditions. Capsaicin, an extract from chili pepper, stimulates depletion of substance P, the most common neurotransmitter in the pain transmission pathway. This cream has been specifically targeted for patients with superficial pain (eg, burning, allodynia, tingling). Most patients experience an initial burning sensation that may persist for several weeks. Lidoderm patches block neuronal sodium channels and have shown limited effectiveness in recent trials. The prime benefit of topical therapy is that it can be used in conjunction with systemic treatment.

Other therapies include N-methyl-D-aspartate (NMDA) antagonists, aldose reductase inhibitors, neurotropic factors, vascular endothelial growth factor, gamma linolenic acid, protein kinase C beta inhibitors, immune therapy, and hyperbaric oxygen therapy.1,12,21,22 L-carnitine and alpha-lipoic acid are alternative therapeutic agents that are available over the counter, but more long-term data are required to demonstrate their efficacy. Despite limited clinical data, these alternative options are still being used in patients with DPN.

plantar-table2

Emerging therapies

Gene therapy and growth factor treatment have also been studied as viable treatments for DPN.26 Creation of excess matrix metalloproteinase (MMP)-9 and MMP-2 causes deterioration in the extracellular matrix of blood vessels, which in turn can cause sensory or neuropathic difficulties for patients with diabetes.4 Using minocycline and aspirin as nonselective cyclooxygenase inhibitors can be a novel method of decreasing diabetic neuropathy and restoring motor and sensory nerve conduction velocity.25

Resveratrol, a natural phenol, may play a significant role in treating the diabetic foot.26 It may reinstitute insulin sensitivity, cytokine formation, tissue reconstruction, microcirculation, and peripheral nerve function.

Ghrelin, a small peptide, has been shown to have a relevant effect in multiple tissue systems when used to treat DPN due to its anti-inflammatory and regenerative abilities within neural tissues.27

ABT-594, a neuronal nicotinic acetylcholine receptor ligand, is extremely potent in animal models with neuropathic and nociceptive pain. In a placebo-controlled, double-blinded, seven-week study, individuals with painful diabetic neuropathy were randomized into four groups.28 They received twice-daily treatment of either placebo or ABT-594. The experimental treatment was associated with improved pain scores in 50% of patients, but there were adverse effects, including headache, vomiting, dizziness, nausea, and abnormal dreams. Users of nicotine were less sensitive to these adverse effects.

Oxidative and nitrosative stress are key factors to consider when creating potential therapies for DPN.29,30 Coenzyme Q10 acts as a free radical scavenger and an antioxidant to decrease oxidative stress within the peripheral and central nervous system.

Puerarin, one of several known isoflavones, has been found to alleviate the mechanical and thermal nociceptive response triggered by diabetes without interfering with the normal nociceptive process. Furthermore, it reduces levels of nuclear factor-κB and other proinflammatory cytokines, such as interleukin (IL)-6, IL-1β, and tumor necrosis factor (TNF)-α.31

Lipoic acid has therapeutic value as a nutritional supplement for DPN. Because of lipoic acid’s lack of bioavailability due to its accelerated metabolism and instability, pharmacophores in conjunction with lipoic acid hybrids are being tested.32

Animal models

The streptozotocin diabetic rat has, to date, been the most commonly used model of DPN.33 A systematic review of possible natural drugs to combat chronic neuropathic pain include: carotenoids (10%), phenols (10%), alkaloids (14%), terpenes (17%), flavonoids (28%), and others (21%).34 One quarter of these studies looked at streptozotocin-induced diabetic neuropathy.

Baclofen, a gamma aminobutyric acid B (GABAB) receptor agonist, is a novel treatment for DPN that has been tested in animal models.35 The attenuation of DPN can be accomplished by down-regulating the expression of N-methyl-D-aspartate receptor subunit 2B (NR2B) and phosphorylated (p)-cyclic AMP response element-binding protein (CREB) through the activation of the GABAB receptor.

Combination therapies—which include neutral endopeptidase inhibitors, aldose reductase inhibitors, lipoic acid supplementation, and insulin therapy with antioxidants—have been shown to prevent the loss of nerve conduction velocity in a diabetic rat model.36 These therapies decrease levels of neuropeptide Y, tyrosine hydroxylase, somatostatin, IL-1β, and MMP-2 in streptozotocin-induced diabetic bone marrow supernatant.

Treating diabetic rats with a combination of enalapril, alpha lipoic acid, and menhaden oil ameliorated diabetes-induced steatosis, and elevated serum lipid levels and improved motor and sensory nerve conduction and corneal sensitivity of epineurial arterioles of the sciatic nerves.37 These findings suggest the combination therapy’s potential for treatment of vascular and neural complications caused by type 2 diabetes.

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Gene and stem cell therapy

Gene therapy has been a high-yield research focus in the past few years with identification of various well-tolerated and effective gene therapy options for painful diabetic neuropathy. Various emerging gene therapy approaches for DPN35,38-51 are shown in Table 1.

Clinical and basic science studies are beginning to highlight that stem cell therapies may be a suitable option in the near future for regenerative medical therapy. Indeed, stem cell therapy is continually being investigated worldwide in hopes of developing safer and more efficacious treatment options for diabetic neuropathy. Emerging stem cell therapies for DPN are shown in Table 2.52-61

Stem cell therapy is continually being investigated worldwide in hopes of developing safer and more efficacious treatment options for diabetic neuropathy.

Future perspectives

As therapeutic approaches to DPN have evolved, researchers’ understanding of the mechanisms underlying DPN pathogenesis has expanded (Table 3).38-44,62-68 In addition, recent clinical trials are evaluating the efficacy of multiple proteins involved in the treatment of DPN, such as erythropoietin analogs, angiotensin II receptor type 2 antagonists, and sodium channel blockers.69

This knowledge will be instrumental for the development of gene and cell therapies that will provide a foundation for the treatment of future generations.

Sarnarendra Miranpuri, DPM, MD, is a podiatric surgeon with Aurora Health Care in Oshkosh, WI. Kush Patel is an undergraduate research scholar; Gurwattan Miranpuri, PhD, is a senior scientist; Abhishek Chopra is an undergraduate research scholar; and Ravinderjit Singh is an undergraduate research scholar, all in the Department of Neurological Surgery at the University of Wisconsin School of Medicine and Public Health in Madison.

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