Diabetic Peripheral Neuropathy

Transcription

1 Diabetic Peripheral Neuropathy Authors: Juddson Seebrat, Pharm.D. Candidate, Harrison School of Pharmacy, Auburn University; Dominic Beovich, Pharm.D. Candidate, Harrison School of Pharmacy, Auburn University; Joseph Drake, Pharm.D. Candidate, Harrison School of Pharmacy, Auburn University; Wesley T. Lindsey, Pharm.D., Assistant Professor of Pharmacy Practice Drug Information and Learning Resource Center Harrison School of Pharmacy, Auburn University Universal Activity #: H01-P 1.25 contact hours (.125 CEUs) Initial Release Date: Sept. 1, 2015 Expires: March. 1, 2018 Alabama Pharmacy Association FALL 2015: Continuing EDUCATION 1

2 Authors have no relevant financial relationships to disclose. Educational Objectives After the completion of this activity pharmacists will be able to: Discuss causes of neuropathy. List five major categories of diabetic neuropathy. Identify symptoms of diabetic peripheral neuropathy. Describe pharmacologic and non-pharmacologic treatment options for diabetic peripheral neuropathy. Introduction The prevalence of diabetes in the United States has been increasing over the past several decades. While 1.58 million Americans had the condition in 1958, there were million diagnosed cases in Additionally, based on 2010 data, diabetes is the 7 th leading cause of mortality in the United States. 2 Prolonged elevations of blood sugar can lead to many different complications, some of which include nephropathy, retinopathy, cardiovascular disease, and neuropathy. Diabetic neuropathy is defined as the presence of symptoms and/or signs of peripheral nerve dysfunction in people with diabetes after the exclusion of other causes. 3 It is estimated that 60-70% of people with diabetes have some form of neuropathy. 4 ETIOLOGY The exact cause of neuropathy is unknown. 5 Theories abound and range from physical injury to the nerve, nutritional deficiencies, alcoholism, toxins, tumors, vascular disorders, and metabolic conditions. The polyol pathway theory suggests that osmotic pressure on the nerves causes pain. 6 Excess sugar reacts with aldose reductase, an enzyme present in Schwann cells which cover nerves. Sorbitol is formed and draws water into the Schwann cells. This swelling pinches the nerve and causes pain. Advanced glycation end products (AGEs) represent another theory. 7 High intracellular glucose levels leads to a reaction, glycation, in which a protein or a lipid non-enzymatically bonds to a simple sugar. After the AGEs react with their respective receptor for advanced glycation end products, many effects throughout the body are exhibited. Nuclear factor-κb transcription is upregulated, monocytes are activated, endothelial permeability increases, and nitric oxide activity in the endothelium is blocked, causing the production of reactive oxygen species. This one reaction can lead to both microvascular and macrovascular complications. CLASSIFICATION Five major categories of diabetic neuropathy exist: distal symmetric polyneuropathy, acute sensory diabetic neuropathy, autonomic neuropathy, compressive focal neuropathies, and noncompressive focal and multifocal neuropathies. 8 Distal symmetric polyneuropathy, also called peripheral neuropathy, is the most common type of diabetic neuropathy, comprising 75% of all diabetic neuropathies. 8 It affects those nerves that are the furthest from the trunk, such as those in the hands and feet. Early symptoms include tingling and prickling sensations in the toes or feet. Acute sensory diabetic neuropathy is rare. 9 It is often brought on by poor metabolic control (ketoacidosis, for example) or a sudden change in glycemic control. Acute sensory diabetic neuropathy is characterized by an onset of severe sensory symptoms. This neuropathy is reversible. Autonomic neuropathy concerns organs of the body. 9 It can cause numerous side effects, including hypotension, erectile dysfunction, gastroparesis, and resting tachycardia. These issues do not occur often. Another neuropathy caused by diabetes is compressive focal neuropathies, wherein neuropathy is caused by pressure being placed on one nerve. 8 Diabetic focal neuropathies are uncommon. The exact mechanism by which these neuropathies occur is unknown. Examples include Carpal tunnel syndrome, ulnar neuropathy, and peroneal neuropathy. The final category is an amalgamation of the diabetic neuropathies that do not fit in one of the four previous groups. 8 Noncompressive focal neuropathies are caused by mechanisms other than increased pressure on one nerve. Multifocal neuropathies focus not on one nerve, but many. DIAGNOSIS Diagnosis requires careful clinical examination. A general physical exam can isolate certain types of neuropathy. Possible examinations include: muscle strength, reflexes, heart rate, blood pressure, and sensitivity to vibrations, temperature, and touches. Foot exams are an essential tool when diagnosing and checking the progression of neuropathy. 10 Peripheral neuropathy often starts in the foot and can be a sign of things to come. Physicians can check skin color and composition, muscles of the foot and toes, and ability to feel sensations (assessed by a monofilament or a pin). In a good exam, a practitioner would find appropriate blood circulation, strength within the muscles, and responsive nerves. While symptoms are important, some types of neuropathy are asymptomatic. Tests exist to help narrow down specific neuropathies and what they affect. Blood can be drawn and tested for vitamin deficiencies, dysfunction of the liver or kidney, abnormal immune system activity, assorted metabolic disorders, and status of one s diabetes. 10 Cerebrospinal fluid can also be examined to look for abnormal antibodies. Rarely used tests include electromyographies and nerve conduction studies. Electromyographies test how muscle cells react when they are electrically stimulated. Nerve conduction studies determine how well electrical currents travel through a nerve. 2 Alabama pharmacy ASSOCIATION FALL 2015: Continuing EDUCATION

3 Diagnostic Tools: Four tests/questionnaires that can help diagnose and assess neuropathic pain. The Brief Pain Inventory (BPI) is the most commonly used tool. 11 It is a survey that subjectively quantifies the severity of pain and the impact that pain has on day-to-day activities. It uses scales from 0-10 and asks about intensity of pain, how pain has affected one s ability to perform certain actions, location of pain, and how much one s pain has been relieved by any medication they may take. The Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) helps differentiate neuropathic from nociceptive pain. 12 It is comprised of a pain questionnaire and a sensory test. Its questions center around characteristics of neuropathic pain. Its sensory testing involves stroking cotton wool over different areas and gently placing a needle on different areas of skin. The Neuropathic Pain Questionnaire (NPQ) accomplishes a similar task. 13 It asks about pain, but, unlike the LANSS test, does not include any type of physical exam. The questionnaire assesses 10 sensations and 2 emotions by having participants rate the degree of pain on a scale of Three items (increased pain due to touch, pain, and numbness) on the questionnaire have proven to be significant predictors. A shorter form of the NPQ has been developed. The Michigan Neuropathy Screening Instrument (MNSI) is a questionnaire and physical foot examination that has been designed to screen for diabetic neuropathy. 8 Questions focus on specific foot sensations, like temperature sensitivity, pain, and numbness. The physical exam includes an assessment of the color and composition of each foot, assessment of vibration sensation, monofilament testing, and the grading of ankle reflexes. MECHANISM OF NEUROPATHIC PAIN Physiologic pain is a protective mechanism that warns the body and tries to protect one from further injury. 14 Once the stimulus has been removed, physiologic pain tends to subside. It is mediated by nociceptors (receptors on nerve cells) that sense chemical, mechanical, and thermal stimuli. When the threshold for tissue damage is reached by a certain stimulus, signals are sent to the central nervous system and pain is felt. Certain substances, like opioids, serotonin, and norepinephrine, can inhibit the transmission of the pain signal to the central nervous system. Neuropathic pain is caused not by activation of nociceptors, but by damage to nerve itself. 14 It serves no useful purpose and tends to be a chronic condition. When either the central or peripheral nervous system become injured, normal sensations or other stimuli that should not cause pain can elicit highly abnormal responses. Multiple theories explaining the mechanism of neuropathic pain exist. 14 None of them can account for the entirety of neuropathic pain. It is believed that the mechanisms of neuropathic pain are multifactorial and evolve over time. One theory, peripheral sensitization, suggests that after an injury to a nerve, chemicals are released. 14 A partial list includes norepinephrine, bradykinin, cytokines, serotonin, prostaglandins, and neuropeptides. These chemicals sensitize the nociceptors around them. The location and number of ion channels, particularly sodium channels, changes after this sensitization. This change lowers the threshold for depolarization. Essentially, it takes a significantly smaller stimulus to cause pain. Additionally, ectopic (spontaneous) discharges can cause pain with no stimulus whatsoever. Ephatic conduction is another possible mechanism of neuropathic pain. 14 Physiologically, nerve fibers are isolated. Activation of one does nothing to its surrounding neighbors. With persistent injury, electrical connections can form between injured and uninjured nerves in close proximity to one another. Not all theories focus on peripheral sites. The wind up theory focuses on persistently present chemicals after peripheral injury. 14 Tachykinins, like substance P and neurokinin A, and neurotransmitters are released after peripheral injury. Due to prolonged release of these chemicals, and through a chain-reaction, central nociceptor neurons become hyperexcitable, the surface of the neuron that can receive stimuli increases, and the response to stimuli increases in magnitude and duration. SYMPTOMS/ CLINICAL PRESENTATION Diabetic peripheral neuropathy typically presents with a pain or tingling sensation felt in the toes or foot, with symptoms worsening at night. 10 As hyperglycemia persists, so does the nerve damage. The numbness will slowly spread up the legs and can start to be painful. Only acute sensory neuropathy is reversible with glycemic control; peripheral neuropathy is not. The time course of progression is typically slow, taking several months. A list of symptoms of diabetic peripheral neuropathy is found in Table 1. Table 1. Symptoms of Diabetic Peripheral Neuropathy 10 Numbness Insensitivity to pain or temperature Prickling, tingling, or burning sensations Cramps and sharp pain Extreme sensitivity to touch Loss of balance and coordination Muscle weakness and wasting Diarrhea Constipation Problems urinating Sexual dysfunction TREATMENT Because diabetic peripheral neuropathy is a complication of diabetes, the first step in management or treatment is to bring the disease to treatment goal. Since hyperglycemia is the main causative factor, blood glucose must be brought to normal levels to help prevent further neurological damage and progression of neuropathy. Proper control of blood glucose can help to lessen the severity of symptoms, and prevent further problems. 15,16 Unfortunately, there is little clinical evidence to reveal the optimal treatment medication, as there are a number of medications to FALL 2015: Continuing EDUCATION 3

4 choose from, and each patient responds differently to each treatment. 17 There are few head-to-head trials comparing the recommended treatment medications and their effects on quality of life (QOL), but there are many trials showing partial effectiveness in diabetic neuropathy. Treatment must be tailored to each patient, allowing for a trial-and-error approach, while keeping in mind the side effect profiles of each medication. 17 Diabetic peripheral neuropathy is a symptomatic disease that largely presents as pain. As such, pain relief is the goal of treatment. Treatment is typically approached with oral medications ranging from pain relievers to anticonvulsants, but can include other modes of treatment. 16 The American Academy of Neurology (AAN) released guidelines for the treatment of diabetic peripheral neuropathy in These guidelines recommend the use of antidepressants, anticonvulsants, opioids, and other various medications for treatment. Table 2 provides an overview on the AAN treatment recommendations. The AAN denotes their level of recommendations on an alphabetical hierarchy. Level A indicates clear evidence to make a strong recommendation. Level B indicates enough positive evidence has been shown to make a recommendation. Anticonvulsants Anticonvulsants have been used to treat neuropathic pain for many years, and they have many mechanisms by which they work. They are categorized as newer anticonvulsants (pregabalin and gabapentin) and traditional anticonvulsants (sodium valproate, topiramate, oxcarbazepine, lamotrigine, and lacosamide). 19 Of all the recommended agents for diabetic neuropathy, the AAN only recommends pregabalin as the first-line treatment option. The biggest issue with the recommended anticonvulsants is their ability to cause extreme sedation. 20,21 Because they are inhibitory in nature, they will cause somnolence and fatigue. Due to these effects, they do require proper titration based on patient-specific tolerability. Pregabalin is structurally similar to GABA, an inhibitory neurotransmitter, and works by binding calcium channels in the central nervous system and reducing the release of excitatory Level A Level B Table 2. AAN Pharmacological Treatment Recommendations Overview 18 Pregabalin mg/day Gabapentin mg/day Sodium valproate mg/day Venlafaxine mg/day Duloxetine mg/day Amitriptyline mg/day Dextromethorphan 400mg/day Morphine sulfate, up to 120mg/day Tramadol 210mg/day Oxycodone up to 120mg/day Capsaicin 0.075% four times daily Isosorbide dinitrate spray neurotransmitters such as glutamate. This effectively lessens neuronal hyperexcitability leading to its analgesic activity. 22 Of the evidence available, pregabalin has shown up to a 50% decrease in pain associated with diabetic neuropathy. 18 Though the effect is largely dose-dependent; a modest number needed to treat (NNT) of 4 is required for a 50% reduction in pain. Pregabalin is also the only agent that showed improvement in QOL measures such as mental health, decreased sleep interference, and social functioning. To help reduce the side effects of this medication, starting at 150mg daily and titrating to 300mg daily over one week is necessary. 20 AAN also recommends gabapentin and sodium valproate as second-line agents. They do not recommend the use of oxcarbazepine, lamotrigine, or lacosamide. There is also insufficient evidence to support the use of topiramate. 18,19 Gabapentin, much like pregabalin, is also structurally similar to GABA, but does not bind GABA receptors or affect GABA in any way. It is mechanistically similar to pregabalin in that it binds calcium channels and decreases the effects of excitatory neurotransmitters. 21 Gabapentin has shown a modest decrease in overall pain of 11%, but did not show evidence of QOL improvement. 18 As with pregabalin, it is also useful to titrate gabapentin by starting with 300mg daily and increasing the dose by mg daily as tolerated until efficacy is seen. 21 Sodium valproate works differently from pregabalin and gabapentin in that it does act by affecting GABA. 23 Sodium valproate prevents the degradation and uptake of GABA, which lessens neuronal inflammation and nociceptive neurotransmission. 24 Though the evidence regarding the use of sodium valproate in diabetic neuropathy is questionable, it has shown a moderate reduction in pain (approximately 30%) against placebo. 18 Table 3 shows an overview of the anticonvulsant treatment options. Antidepressants There are three classes of antidepressants that are used in diabetic neuropathy: tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), and serotonin/ norepinephrine reuptake inhibitor (SNRI). The TCAs have been a longstanding first-line treatment for diabetic neuropathy, but due to their side effect severity, and with the introduction of pregabalin, they have been downgraded to second-line therapy. 15,17,18 The proposed mechanism by which TCAs effect neuropathic pain is their ability to inhibit the reuptake of norepinephrine and serotonin and also by modulating sodium and N- methyl-daspartate (NMDA) receptors. 15 The TCA of choice in the AAN guidelines is amitriptyline. Amitriptyline has shown a large response in pain reduction close to 60% in some studies. 18 The TCAs are plagued by anticholinergic side effects such as dry mouth, blurred vision, urinary retention, and marked sedation, which may bring limitations to their use. 25 The AAN guidelines go further to say that other TCAs such as desipramine and imipramine do not show conclusive evidence that they are useful, and does not recommend their use. 18 The SNRIs possess a less severe side effect profile, and are typically better tolerated than TCAs. 19 They differ in mechanism 4 Alabama pharmacy ASSOCIATION FALL 2015: Continuing EDUCATION

5 Table 3. Drug Class Overview: Anticonvulsants 20,21,23 Generic Name Brand Name Mechanism of Action Recommend Dosage Pregabalin Lyrica Central calcium channel modulator; inhibits neuroexcitation Gabapentin Neurontin Inhibits the release of excitatory neurotransmitters Sodium valproate Depacon, Depakote Increases GABA activity Table 4. Drug Class Overview: Antidepressants 25,26, mg/day mg/day mg/day Generic Name Brand Name Mechanism of Action Recommend Dosage Amitriptyline Elavil Increases the availability of serotonin and norepinephrine Duloxetine Cymbalta Serotonin/norepinephrine reuptake inhibitor; increases availability of serotonin and norepinephrine Venlafaxine Effexor Serotonin/norepinephrine reuptake inhibitor; increases availability of serotonin and norepinephrine Table 5. Drug Class Overview: Analgesics 30,31, mg/day mg/day Generic Name Brand Name Mechanism of Action Recommend Dosage Morphine MS Contin Binds opiate receptors Up to 120mg/day Oxycodone Oxycontin Binds opiate receptors Up to 120mg/day Tramadol Ultram Binds to opiate receptors and modulates serotonin and norepinephrine uptake from the TCAs in that they selectively inhibit serotonin, or both serotonin and norepinephrine, as with venlafaxine and duloxetine. 26,27 Venlafaxine is a SNRI that has displayed 20% effectiveness in alleviating pain when compared to placebo and a NNT of When gabapentin is added to venlafaxine, the pain relief is modestly increased, and also shows improvement in QOL. Duloxetine is another SNRI that has displayed small reductions in pain in the studies evaluated by the AAN guidelines, but newer research shows that it may provide more benefit than previously thought. Newer studies show upwards of 60% in overall pain relief. They do not, however, show any improvement in QOL. 28,29 Table 4 provides an overview of the antidepressants class. Analgesics Opiate and opiate-like pain relievers should be reserved for use in patients who do not respond to other methods of treatment. Evidence shows that morphine and oxycodone have a small effect over placebo with a 15% and 9% increase in pain relief, respectively. 18 Opiates also possess a high abuse potential, and that may limit their use in some patients. Tramadol is an opiate-like medication that unlike morphine and oxycodone, weakly acts on opiate receptors as well as weakly inhibiting the reuptake of norepinephrine and serotonin. 30 In this respect, tramadol lends opiatelike and TCA-like mechanisms. Tramadol may be more appealing to use since it has lesser abuse potential than morphine and oxycodone, but its ability to lower the seizure threshold must be taken into consideration. 19 Table 5 provides an overview to the analgesics class of pharmacological treatment. Miscellaneous Treatment Other recommended treatments by the AAN guidelines mg/day cover a variety of different pharmacological mechanisms. Dextromethorphan is a NMDA antagonist that is typically used as an antitussive. 33 Due to blocking the excitatory glutamate neurotransmitter, it has shown benefit in diabetic neuropathy by decreasing pain approximately 20% compared to placebo. 18 Another medication that has shown efficacy is isosorbide 210mg/day dinitrate. Some studies indicate that nitric oxide synthesis is impaired in diabetic neuropathy. 15,17 Due to this pathophysiology, isosorbide dinitrate has shown to be useful in alleviating local pain and burning sensations when used in the spray formulation. Capsaicin, an over the counter topical alkaloid found in red pepper, has shown a 40% improvement in pain as compared to placebo. Though not completely understood, it is thought that capsaicin works in diabetic neuropathy by depleting substance P, which is partially responsible for modulating pain, thereby decreasing pain. 34 There is limited evidence showing its effectiveness, and should probably be reserved for localized pain only. 17 Lidocaine has also shown usefulness in diabetic neuropathy, but the AAN guidelines have a conservative recommendation by saying that it may be used for treatment. 18 When used locally with the patch formulation of lidocaine, studies show that it has a modest effect in pain improvement. Lidocaine lessens pain by acting on sodium channels and preventing nerve action potentials FALL 2015: Continuing EDUCATION 5

6 Table 6. Drug Class Overview: Miscellaneous 33,34,35,36 Generic Name Brand Name Mechanism of Action Recommend Dosage Dextromethorphan Creomulsion NMDA antagonist 400mg/day Isosorbide Dinitrate Spray Angitak Vasodilation; increases nitric oxide and causing desensitization. 35 Table 6 provides an overview of the recommended miscellaneous treatments. Non-Pharmacologic Treatments There are many alternatives available to patients who do not wish to use traditional pharmacologic treatment for their diabetic neuropathy. Some of these therapies include percutaneous electrical nerve stimulation, magnetic field treatment, low intensity laser therapy and monochromatic infrared light therapy. These have all shown varying degrees of efficacy in improving outcomes associated with diabetic peripheral neuropathy. Percutaneous Electrical Nerve Stimulation Of the non-pharmacologic treatments for diabetic peripheral neuropathy, percutaneous electrical nerve stimulation has been the most extensively studied. It also has the most promising results in this patient population, as compared to other non-pharmacologic therapies. However, one of the biggest limiting factors hindering more widespread use of this procedure has been its cost, and the lack of understanding of its mechanism of action. 18 It is believed that percutaneous electrical nerve stimulation works by interrupting afferent signaling from nociceptors in the extremities, in this case the feet. 33 The procedure uses very fine acupuncture needles that are inserted into the dermis or muscle tissue. Then, electrical impulses are sent into the local body tissues where the pain is located, causing the afferent nerves to become hyperpolarized and prevent signaling of the painful sensation to the central nervous system. It is also worth noting that this process is very similar to electrical acupuncture, but percutaneous electrical nerve stimulation is guided by the location of pain rather than the theory of energy flow within the body. A recent study in 2013 found that percutaneous nerve stimulation was effective at lowering patients visual analog pain score. 34 The authors reported a 50% response rate, assessed by temperature and vibration sensation, which was comparable to second-line pharmacologic therapy such as duloxetine; however, the study reported that it did not improve conduction velocity of the affected nerves. Also, a three-month follow-up assessment of treatment effects and duration using a visual analog pain scale showed that the benefits of percutaneous electrical nerve stimulation were not sustained, as these scores had returned to baseline scores obtained prior to the study s initiation. A study that was published in 2005 found that percutaneous electrical nerve stimulation was able to reduce the visual analog 1.25mg/day Capsaicin Capzasin-HP Depletes substance P 0.075% cream four times daily Lidocaine Lidoderm Inhibits depolarization; desensitizes neurons One patch daily pain score in the study s experimental group by 25-29% when compared to baseline. 35 The authors also reported an increase in patient reported quality of life as assessed by the Short-Form 36 patient questionnaire. A study that was published in 2000 showed that visual analog pain scale scores were reduced from a mean of 6.2 to 2.5 over a three-week treatment period with percutaneous electrical nerve stimulation. 36 Nonopioid analgesic use by the experimental group was reduced by 49% in this study as well. The patient quality of life was also significantly improved, as assessed by the Short-Form 36 patient questionnaire. Static Magnetic Field Treatment Static magnetic field treatment utilizes magnetic insoles worn in shoes to promote healing of damaged nerves, and improve blood flow in the feet. It is not well understood how this type of therapy works. One theory is that the magnetic fields cause a realignment of molecules in the local area, similar to the mechanism of a MRI, promoting the healing of the damaged nociceptors in the dermis and epidermis. Another theory is that the magnetic fields increase the blood flow, oxygenation, and free radical scavenging of the local tissues through the attractive forces towards the hemoglobin in the blood. There have been two studies in recent years that have shown positive results, both by Weintraub et al. The first study was published in 2003, and concluded that static magnetic field treatment provided a statistically significant reduction in burning, numbness, and tingling sensations in the feet after three months of wearing magnetic insoles, as assessed by visual analog pain scales. 37 The second study published in 2009, did not show any improvement over placebo of neuropathic pain symptoms as assessed by a visual analog pain scale. 38 Low Intensity Laser Therapy The use of lasers in physical therapy and rehabilitation goes back almost to the invention of the first laser. 39 Low intensity laser therapy is primarily used in accelerating wound healing and pain relief. There is still some confusion and uncertainty as to specifically how the procedure works mechanistically. It is believed to work by stimulating the mitochondria of cells in the targeted area to increase the amount of adenosine triphosphate (ATP), reactive oxygen species, intracellular calcium, and nitric oxide released. The increase in these intracellular modulators causes the activation of transcription factors and consequently, the expression of protective, anti-apoptic, anti-oxidant, and proliferative genes. In a study published in 2011, the results of the study showed an improvement in nerve conduction velocity. 40 The study did not assess the patients pain using a visual analog pain scale or other pain assessment tool, however. One of the major limitations to this study was its size and exclusion rate. Of the 107 test subjects 6 Alabama pharmacy ASSOCIATION FALL 2015: Continuing EDUCATION

7 screened, only 17 met the inclusion criteria of the study. In a study published in 2004, the authors concluded that low intensity laser therapy might have some efficacy in reducing pain associated with diabetic neuropathy. 41 Low intensity laser therapy was shown to decrease visual analog pain scale by 16% when compared to placebo, but it was not deemed a statistically significant difference. Monochromatic Infrared Light Therapy Monochromatic infrared light therapy is a procedure where infrared light emitting diodes (LEDs) are placed in contact with the skin of the affected location. 42 This allows for a transfer of both infrared light and heat, which causes a release of nitric oxide and an increase in circulation, and helps to alleviate pain in the feet. This therapy is still controversial due to its questionable duration of effect, and limited and contradicting evidence that supports its use in diabetic peripheral neuropathy. There have been two recent randomized, controlled, doubleblinded studies that assessed the efficacy of monochromatic infrared light therapy. A study published in 2004 found that monochromatic infrared light therapy does have a statistically significant improvement over placebo in monofilament foot exam scores and Michigan neuropathy screening instrument scores after 6 and 12 treatment sessions. 43 A study published in 2008 did not find any difference between monochromatic infrared light therapy and placebo groups in quality of life, monofilament foot exams, or Michigan neuropathy screening instrument scores. 44 have shown efficacy. There are many pharmacological and nonpharmacological treatments that can be chosen, but each patient will need patient-specific treatment, as response to therapy is different for each individual. The AAN guidelines recommend pregabalin as first-line pharmacological treatment, as it has the highest degree of evidence related to its effectiveness. Guidelines then recommend several other pharmacological agents from drug classes (see Table 1) that may also prove very useful in diabetic neuropathy. Of all the non-pharmacological treatments, electrical nerve stimulation has the greatest amount of evidence supporting its use in diabetic neuropathy. The evidence supporting other aforementioned non-pharmacological treatments still has controversy in their use. Though diabetic neuropathy has no cure, there are many ways to help lessen the severity and progression of the disease and to help increase quality of life. FOOT CARE The American Diabetes Association has developed guidelines and specific recommendations for diabetic patients to help prevent further worsening or complications of diabetic peripheral neuropathy. 17 Patients with peripheral neuropathy are at higher risk for later complications, such as amputation, foot ulcers, and disabilities. Patient education on proper steps to keep their feet in good health can help to prevent the development of these complications. The first recommendation by the American Diabetes Association was to have an annual diabetic foot exam, which should include a monofilament foot test. Also, daily personal inspection of his/her feet by the patient should be done. Another method to prevent diabetic foot complications due to increased plantar pressure is to wear well-fitting walking or athletic shoes that provide ample cushion and support. Custom fit diabetic shoes and orthotics are available as well to provide the best fit possible for each individual. CONCLUSION Peripheral neuropathy is one of the most common complications of diabetes. It is a direct consequence of poorly managed diabetic care, but it can be lessened in severity and prevented from worsening. There are a myriad of treatment options available to patients, but first and foremost is treating the source of the neuropathy, not the symptoms. Blood sugar must be kept in control to help attenuate the disease severity and prevent the worsening of the neuropathy. After blood sugar management has been addressed, there are several avenues of treatment that FALL 2015: Continuing EDUCATION 7

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