Current And Emerging Options For Treating Diabetic Neuropathy

   Neuropathy is a common and debilitating complication of diabetes mellitus. According to data compiled by the National Institute of Diabetes and Digestive and Kidney Disease (NIDDK) and the American Diabetes Association (ADA), roughly 60 to 70 percent of the 18.2 million Americans with diabetes will develop some form of diabetic neuropathy and about 3 million patients with diabetes will experience painful neuropathy.    There are three broad types of neuropathy (sensory, motor and autonomic) associated with diabetes. Sensory neuropathy is the most prevalent of the three and is often simply referred to as diabetic neuropathy. Symptoms usually begin distally at the base of the toes and ascend proximally up the lower leg as the disease progresses. These symptoms can often be described as burning, tingling, stabbing, and a “pins and needles” sensation in a stocking and glove distribution. The paresthesias often result in the loss of pain perception. This loss of protective sensation can lead to the formation of foot ulcerations, infections, even amputations, and cause significant morbidity and mortality.    The pathogenesis of diabetic neuropathy is believed to be multifactorial with hyperglycemia being the primary risk factor.1,2 The exact sequence of physiological events that results in this loss of pain perception is poorly understood and is the focus of current research. Researchers have suggested several theories about the possible etiopathogeny of diabetic neuropathy. These theories include: abnormalities of protein glycation; sorbitol accumulation; polyol pathway flux; protein kinase C activation; advanced glycation endproducts (AGE); receptor for advanced glycation end products (RAGE); a decrease in neuronal nitric oxide synthase (nNOS) protein; and microvascular hypoxia resulting in oxidative stress.2-8    The goals of treating diabetic neuropathy are preventing and possibly reversing the progression of nerve damage, and reducing the symptoms. Currently, there is no available pharmacologic agent in the United States that repairs the underlying nerve damage. Although current medical treatment algorithms stress the importance of delaying the onset of diabetic neuropathy, these algorithms are primarily geared toward alleviating the symptoms. The recent resurgence of interest in the pathogenic mechanisms of diabetic neuropathy has inspired new avenues of investigation for therapeutic intervention with some promising results.    With this in mind, let us take a closer look at current and emerging treatments for diabetic neuropathy.

Emphasizing Glycemic Control

   In general, researchers note that diabetic neuropathy results from chronic nerve damage secondary to hyperglycemia. Rigid glycemic control is of fundamental importance to help delay the onset and slow the progression of neuropathy.9 The diabetes control and complications trial (DCCT) has shown that good glycemic control can decrease the risk of diabetic neuropathy by over 50 percent. It is recommended that people with diabetes ideally maintain their hemoglobin A1c readings at 7.0 or below.    One may combine good glycemic control with the myriad of pharmaceutical agents available for symptom management. These agents include the use of selective serotonin and norepinephrine reuptake inhibitors (SSNRI), anticonvulsants, tricyclic antidepressants (TCAs), antiarrhythmics and topical therapy. Non-narcotic analgesics, such as acetaminophen, tramadol and nonsteroidal antiinflammatories, have been advocated as adjunctive treatments. Opioid analgesics are not very efficacious in the treatment of neuropathic type pain, can lead to addiction and are therefore generally not recommended.

Assessing The Effectiveness Of SSNRI Agents

   Both serotonin and norepinephrine have been characterized to help regulate emotions as well as sensitivity to pain. SSNRIs represent a class of antidepressant agents that help regulate and treat depressive disorders and neuropathic pain by sustaining levels of the two neurotransmitters in a balanced fashion.    Duloxetine is a potent SSNRI indicated for the treatment of major depressive disorders.10 In September of 2004, duloxetine became the first medication approved by the Food and Drug Administration (FDA) for treatment of diabetic neuropathic pain.11 In a double-blinded, placebo controlled study, a 60 mg daily dose of duloxetine was shown to be effective and well tolerated with a rapid onset and sustained effect in reducing pain associated with diabetic neuropathy.11 Side effects were generally mild and may include nausea, drowsiness, constipation and dry mouth. Duloxetine is contraindicated in patients taking MAO inhibitors, thioridazine and in patients with hepatic insufficiency, end-stage renal disease or uncontrolled narrow-angle glaucoma.10    Venlafaxine is another SSNRI that is currently available in the U.S. In a recently published multicenter, double-blinded, randomized, placebo-controlled study, venlafaxine extended-release was shown to be effective and safe in relieving pain associated with diabetic neuropathy.12 Currently, venlafaxine is indicated for the treatment for depressive disorders and is not FDA approved for the treatment of diabetic neuropathy.

A Review Of Anticonvulsants, Tricyclic Antidepressants And Antiarrhythmics

   Several anticonvulsants have been studied for the treatment of diabetic neuropathy. They include carbamazepine, gabapentin and lamotrigine. Clinical trials involving lamotrigine have yielded mixed results. Further studies are required to determine lamotrigine’s effectiveness in treating diabetic neuropathy.    Carbamazepine is an anticonvulsant that is structurally similar to imipramine, a tricyclic antidepressant. It prevents overexcitation of nervous tissue by blocking presynaptic action potentials and the subsequent release of excitatory neurochemical transmitters. Laboratory evaluations of liver function and a complete blood count are recommended both prior to implementation and during the course of carbamazepine therapy because of associated hepatitis and pancytopenia risk.    Gabapentin is a gamma aminobutyric acid (GABA) analog from the Alpha 2 Delta Ligands class. It has minimal drug interactions and a low toxicity rate. Its mechanism of action is unclear. Researchers have found gabapentin efficacious in the treatment of painful diabetic neuropathy although it is currently not officially indicated for this use.13 Side effects may include dizziness, somnolence and ataxia. Gabapentin is now available in generic form and is currently undergoing placebo-controlled studies for the treatment of diabetic neuropathy and other disorders.    Tricyclic antidepressants, such as amitriptyline, nortriptyline, imipramine, doxepin and desipramine, are advocated for the treatment of painful diabetic neuropathy. TCAs have associated anticholinergic side effects such as dry mouth, blurred vision, orthostatic hypotension and heart palpitations. In general, secondary amines, such as nortriptyline and desipramine, exhibit fewer anticholinergic effects and sedation than do the tertiary amines.    Mexiletine, a class IB sodium channel blocker, is a close structural analogue of lidocaine and is often considered an oral local anesthetic. Mexiletine prevents depolarization of small afferent myelinated nerves by blocking sodium channels and has been found to be effective in the relief of chronic nerve pain. Mexiletine is indicated for the treatment of ventricular arrhythmias and has not received FDA approval for the treatment of diabetic neuropathy.

What About Supplements And Antioxidants?

   Although some dietary supplements and antioxidants have been suggested to help improve symptoms of diabetic neuropathy, none of these medications has been widely accepted as being useful. Two of the more popular nutritional supplements advocated for treating painful diabetic neuropathy are acetyl-L-carnitine and alpha lipoic acid. While most dietary supplements are not associated with significant adverse effects, one should warn patients about potential vitamin toxicity.    Acetyl-L-carnitine is a common, naturally occurring chemical that is sold as a dietary supplement. It is derived from lysine and methionine, and is the more bioavailable form of the amino acid L-carnitine. Its molecular structure resembles that of the neurotransmitter acetylcholine and some believe it is also involved in neuronal metabolism.    In a randomized placebo-controlled, intent to treat trial, researchers found that taking 1,000 milligrams of acetyl-L-carnitine three times daily was efficacious in alleviating pain in patients with chronic diabetic neuropathy.14 The data also showed significant improvements in both nerve regeneration and vibratory perception in these patients.    While acetyl-L-carnitine shows promise as an agent to help delay the progression of diabetic neuropathy and reduce its severity, more long-term studies are needed to examine the full effect of acetyl-L-carnitine in treating neuropathic pain.14    Alpha lipoic acid (thioctic acid) is a natural antioxidant that has been suggested to improve both diabetes and symptoms of diabetic neuropathy by stimulating glucose uptake.15-17 As with most dietary supplements, alpha lipoic acid has a highly favorable safety profile with no significant adverse reactions.15-17 The FDA has not yet approved alpha lipoic acid for symptomatic relief of diabetic neuropathy. The efficacy of orally administered alpha lipoic acid will need to be confirmed with long-term multicenter trials.

Can Capsaicin Provide Pain Relief?

   Some clinicians advocate the use of topical creams that contain capsaicin, an extract of the hot capsicum pepper, to help alleviate neuropathic pain.    Capsaicin is postulated to block pain signals by the depletion of substance P but may require numerous daily applications and may not be efficacious in all patients. It has no known systemic side effects but may cause stinging or burning upon application.    Capsaicin has been approved by the FDA for the treatment of neuropathic pain and is available as an over-the-counter medication.

What The Literature Reveals About Monochromatic Near-Infrared Treatment (MIRE)

   A recently published double-blinded, randomized and controlled study showed the monochromatic near-infrared treatment (MIRE) system improves sensation and balance, and reduces pain in patients with diabetic neuropathy.18    This treatment system consists of small flexible pads that one applies to the skin. Each pad contains an array of 60 light emitting diodes (LEDs). These superluminous gallium aluminum arsenide diodes emit 9 milliwatts of near-infrared photo energy per square centimeter at a monochromatic wavelength of 890 nanometers. The 890 nm wavelength was selected for its optimal depth of penetration and high absorption by target tissue. Near-infrared photo energy is postulated to stimulate the release of nitric oxide from hemoglobin and possibly surrounding tissue. The nitric oxide subsequently mediates nerve regeneration and helps increase circulation.    The MIRE system is considered a Class II, non-invasive medical device and has received FDA clearance to help improve circulation and decrease pain. Several other studies have reported up to a 98 percent success rate of symptomatic reversal of diabetic neuropathy after 10 to 12 treatments with this system. However, those studies were neither controlled nor blinded.

What You Should Know About Surgical Decompression

   Surgical decompression has been suggested for the treatment of diabetic peripheral neuropathy.19 Researchers have postulated that decompression of peripheral nerves at a known site of anatomic narrowing can help decrease pain and restore sensory function in diabetic patients.19-20 This is based on the hypothesis that symptoms of diabetic neuropathy may be due partly to entrapment and compression of multiple peripheral nerves.    This procedure is considered controversial and is not indicated for all patients with diabetic neuropathy. However, it may serve as an effective treatment option in the patient population in which nerve entrapment and compression have been clinically diagnosed as contributing factors to symptomatic neuropathy.

A Closer Look At Emerging Treatment Options

   • Pregabalin. Pregabalin is the next generation drug in the same class as gabapentin. Although pregabalin has a similar pharmacologic profile to its developmental predecessor, it has demonstrated greater analgesic activity in rodent models of neuropathic pain. Pregabalin also has anxiolytic and anticonvulsant activity, and has recently been FDA approved (December 2004) for the management of neuropathic pain associated with diabetic peripheral neuropathy and postherpetic neuralgia.    As with gabapentin, the exact mechanism of action of pregabalin is unclear although it has been postulated to reduce excitatory neurotransmitter release by binding to voltage-gated calcium channels.    The efficacy of pregabalin in the treatment of painful diabetic neuropathy has been shown in three randomized, double-blind, multicenter studies totaling 724 patients.21-23 Pregabalin, at fixed dosages of 300 and 600 mg per day and administered three times daily, demonstrated rapid and sustained improvement in pain with less pain-related sleep interference.21-23 Researchers have noted significant improvements in pain and sleep as early as week one and these improvements were maintained in studies up to 12 weeks in duration.21-23    Pregabalin was well tolerated with a low discontinuation rate due to side effects. Common side effects included mild to moderate dizziness, somnolence, peripheral edema, headache and dry mouth.    • Ruboxistaurin mesylate. One of the most promising nerve disease-modifying therapies is ruboxistaurin mesylate, an oral protein kinase C (PKC) beta-inhibitor that is currently in phase III clinical trials for diabetic neuropathy and retinopathy.24,25 PKC beta is an enzyme that has been implicated in the underlying process of microvascular dysfunction including diabetic neuropathy.24,25 Ruboxistaurin’s projected 2006 launch in the U.S. may transform the diabetic neuropathy drug market from a focus on pain control to one of disease modification.    In a phase II investigation, researchers found that when they administered ruboxistaurin early enough in the disease process, it reduced the disease progression of distal symmetrical polyneuropathy.25 Ruboxistaurin was well tolerated and caused no significant adverse events. Side effects noted during the trials were diarrhea, headache, nasopharyngitis and cough.    • Aldose reductase inhibitors. There are a number of research studies on the effects of aldose reductase inhibitors. Researchers have hypothesized that aldose reductase may play a role in initiating the metabolic damage to peripheral nerves during hyperglycemia.26 Aldose reductase is the first enzyme in the pathway that results in high levels of sorbitol in nervous tissue. Rising levels of sorbitol will result in the depletion of Na+K+-ATPase, which helps maintain conduction velocity, and causes a local hyperosmotic effect on the nerves, resulting in swelling and destruction of nervous tissue. Aldose reductase inhibitors slow the production of sorbitol and have been demonstrated in animal models to reverse neuropathy if they are started early and used for a sufficient time.    As a class of pharmaceutical agents, aldose reductase inhibitors have shown some promise in preliminary studies in the treatment of diabetic neuropathy. Some of these agents include epalrestat, zopolrestat, tolrestat, ponalrestat, sorbinil, AS-3201 and lidorestat (formerly IDD 676). Lidorestat is presently in phase two trials to determine its efficacy in reducing sorbitol levels and for the safety of dosage.    In a recently published double blinded study, AS-3201 was found to penetrate the sural nerve and inhibit sorbitol accumulation in patients with mild to moderate diabetic neuropathy. In patients taking 5 mg and 20 mg daily doses of AS-3201, the average nerve sorbitol concentration was reduced by 65 percent and 84 percent respectively. Sensory nerve conduction velocities also improved by > 1 m/s in these patients. Additional studies are needed to confirm the role of AS-3201 in delaying the progression of diabetic neuropathy.    • Topical lidocaine. In an open-label design trial, patients with painful diabetic polyneuropathy showed significant improvements in pain and quality-of-life outcome measures during a three-week treatment period with 5% lidocaine patches.27-29 The maximum treatment was four patches daily for up to 18 hours.28 The therapy was tolerated well with minimal adverse events and no systemic accumulation of lidocaine. However, a randomized controlled trial is necessary to confirm these results.    • Gene therapy. Findings from several research studies suggest that neuropathy is associated with a deficiency or dysfunction of certain neurotrophic factors. These neurotrophic factors are protein peptides that are essential for the survival and proper function of neurons. Researchers have shown that systemic administration of these neurotrophic factors prevents progression of neuropathy in animal models. However, these findings cannot be extrapolated onto human models because adverse effects prevent systemic administration in adequate doses to treat humans. Gene therapy allows for constant replenishment of the peptide factors.    In studies conducted in diabetic mice, researchers noted that gene transfer with nerve growth factor (NGF) reversed nerve dysfunction and restored lost nerve endings to the feet.30 Five weeks after a one-time inoculation, diabetic mice receiving gene therapy had complete reversal of established peripheral neuropathy and restoration of lost nerve endings to their feet. While the results of these preliminary studies are promising, it is evident that further studies are needed to ensure the efficacy and safety of gene therapy.

In Conclusion

   Our knowledge regarding the pathogenesis of diabetic neuropathy has grown significantly during last two decades. Nonetheless, the identification of effective treatment regimens remains challenging and prevention remains the foundation of clinical intervention and the prerequisite of adequate treatment. With advances in technology and ongoing research, we one day hope to elucidate the ideal treatment of this debilitating disease process. Dr. Wu is an Assistant Professor in the Department of Surgery at the William A. Scholl College of Podiatric Medicine at the Rosalind Franklin University School of Medicine in Chicago. She is a Fellow at the Center for Lower Extremity Ambulatory Research (CLEAR) in Chicago.
 

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