Amy Brian, PharmD, CGP, CPP

This is the second article in a 2-part series discussing currently available treatments for painful diabetic neuropathy (PDN). Neuropathic pain presents in 30% of all diabetes patients, and even in up to another 20% of diabetes patients with good glycemic control. Intensive glycemic control is still the first-line approach for the prevention and treatment of all diabetic neuropathies. 

, April 2006) focused on pharmacologic therapies available to treat the symptoms of PDN. This article will focus on nonpharmacologic approaches to treat the symptoms of PDN as well as some disease-modifying treatments that actually may improve nerve function in these patients. 

Acupuncture is an alternative therapy that originated >3000 years ago in China. It involves the placement of small, fine, nonmedicated needles at various points on the body. Acupuncture commonly is used for pain reduction in many types of diseases or conditions. The results of small studies of PDN patients receiving acupuncture therapy show pain improvement or resolution in the majority of patients. Other beneficial outcomes include overall quality-of-life improvements, such as improved sleep and mobility. 

Polyurethane film dressings have been used with some success and minimal adverse effects. A thin layer of film is applied to the affected areas of the lower extremities to provide a barrier from painful external stimuli. Patients reported significant pain reductions in the affected extremities that were treated with the film, versus those without the film. The use of pain medication was reduced, and other quality-of-life improvements were seen. 

Electrical stimulation encompasses a variety of techniques, including transcutaneous electrical nerve stimulation (TENS) and percutaneous electrical nerve stimulation (PENS). Electrical stimulation involves the use of electrodes, through either a noninvasive or a minimally invasive procedure, to provide a series of electric shocks to an area of the body. Both TENS and PENS have shown significant reduction in pain for patients but require ongoing treatment. In the majority of patients, pain returned within 1 week of treatment cessation. 

The mechanism for analgesia is not well-understood but is thought to be related to stimulation of endogenous opioid-related substances. In the studies that have been conducted, it is virtually impossible to compare the active treatment with placebo, for obvious reasons. Most patients also reported other quality-of-life improvements. 

Other nonpharmacologic approaches can include massage therapy, stretching and relaxation exercises, and short coldwater foot soaks. 

Alpha lipoic acid is an alternative therapy given by infusion that has shown marked reduction in pain associated with PDN. Its mechanism of action is thought to be related to its antioxidant properties. A double-blind study including 328 patients was conducted, using various doses of alpha lipoic acid versus placebo. The 600-mg dose of the medication produced clinically significant relief of pain, burning, and paresthesias, compared with lower doses of the medication or placebo. Although the drug was well-tolerated, one drawback is the requirement of daily outpatient infusions. 

Although some herbal products are on the market, there is no evidence that they provide any relief for PDN. 

Omega-6 fatty acids are required for healthy nerve tissue and myelin production. A component of evening primrose oil is gamma linolenic acid, an omega-6 fatty acid. Evening primrose oil is a traditional herbal medicine used to treat a variety of illnesses. A couple of small studies have evaluated outcomes in nerve conduction in patients taking daily doses of evening primrose oil, versus placebo. Both studies demonstrated improved nerve conduction in patients taking evening primrose oil over placebo. 

Many of the treatments mentioned in this article have been evaluated only in studies with small sample sizes and require further clinical trials to adequately determine their safety and effectiveness. The pain associated with PDN, however, often can be debilitating, and patients often seek any and every treatment option available to them. So, becoming familiar with all the available therapies will help facilitate communication with patients. Strategies must be aimed at optimizing glucose control, relieving symptoms, eliminating secondary complications, and providing proper patient education.

Articles

Painful Diabetic Neuropathy: Alternative Treatments

Neuropathy affects up to 50% of diabetic patients, depending on the duration and extent of their disease. Even in patients with excellent glycemic control, ~20% will still develop painful diabetic neuropathy (PDN). Common symptoms in the extremities may include tingling or burning sensations, loss of sensation, cramping, and hyperalgesia (exaggerated pain response). Patients will often describe the pain as worse at night, and it can be unilateral, but the majority of cases will be bilateral. This article will be the first of a 2-part series to address the current treatments available for PDN. 

Proper glycemic control is first and foremost in the prevention and treatment of neuropathy. Multiple studies, such as the Diabetes Control and Complications Trial and the UK Prospective Diabetes Study Group, have concluded that intensive blood glucose control improves neuropathic symptoms and prevents further damage to the nerves. But, even with proper glucose maintenance, the risk of developing PDN is still present, and those who do develop it need effective treatment. Treatment options are classified into 2 groups: those that deter the course of the disease by improving or enhancing nerve function, and those that alleviate symptoms only, with no associated improvement in nerve function. Both pharmacologic and nonpharmacologic treatments are available. This article will focus on the pharmacologic agents available for symptomatic relief, some of which are listed in the Table. Symptomatic treatment often must consist of careful combinations of therapies. Pharmacologic agents available include analgesics, anticonvulsants, antidepressants, and topical agents. 

OTC and prescription analgesics are available. There are some small studies that compare the effectiveness of OTC and prescription products with placebo for treating neuropathic pain. OTC products include nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and naproxen. Some prescription analgesics which showed improvement in short-term outcomes (reduced pain, improved sleep, improved physical functioning) include controlled-release oxycodone and tramadol. There are no good long-term studies available with narcotics, but sometimes their use in PDN is limited because of adverse effects. Use of any analgesics requires careful consideration of adverse effects, especially related to long-term use. In particular, renal function and gastrointestinal side effects must be considered with chronic NSAID use. Sedation, constipation, risk of falls, and dizziness must be considered with oxycodone or tramadol use. 

Anticonvulsants, such as carbamazepine, gabapentin, and lamotrigine, can be very effective for the relief of pain from PDN. Although their pain-relieving mechanism is not well-understood, all 3 of these anticonvulsants have been proven to be superior to placebo in reducing pain and improving quality of life in patients with PDN. Adverse effects to monitor for include drowsiness, dizziness, light-headedness, and headache. 

Antidepressants, especially tricyclic antidepressants such as amitriptyline, nortriptyline, desipramine, and doxepin, have long been the standards of therapy for treating PDN. Although most studies conclude significant pain reduction in patients on these therapies vs placebo, the primary drawback to their use is intolerable adverse effects. In particular, anticholinergic effects such as drowsiness, dry mouth, constipation, urinary retention, and postural hypotension limit their use in many patients, especially the elderly. Other antidepressants, such as trazodone and venlafaxine, have also been shown in some small studies to reduce the pain associated with neuropathy. Small studies available with certain serotonin-specific reuptake inhibitors, such as paroxetine, fluoxetine, and citalopram, showed only marginal or no improvement in pain reduction vs placebo and should not be considered as first-line therapy. Duloxetine, a serotonin and norepinephrine reuptake inhibitor, was recently approved specifically for PDN. It may be particularly useful as first-line therapy in patients with both PDN and depression. Adverse effects of duloxetine are similar to those of other antidepressants, although usually not as severe as with the tricyclic antidepressants. 

Capsaicin topical cream is believed to exert its pain-reducing effect by depleting substance P, a pain neurotransmitter. Several studies have shown significant pain reduction with the cream vs placebo. Advantages include no systemic side effects, but local irritation at the site of application can occur. 

Although not yet available on the market, isosorbide dinitrate spray has shown promising results in recent studies. In a small group of 22 patients in a 12-week study, isosorbide dinitrate spray was administered once daily at night. The patients treated with active drug had a statistically significant reduction in pain and burning sensation, compared with those patients given placebo spray. Possible mechanism of action may be increased nitric oxide levels. Side effects were minimal, with only 2 patients reporting minor headaches. 

With now over 20 million diabetics in the United States alone, effective treatments for diabetes-related complications are more important than ever. Treatment for PDN includes focused intensive glycemic control and adequate pain control. Whereas this article focused on the currently available pharmacologic therapies for treating the painful symptoms of neuropathy, an upcoming article will focus on disease- modifying treatments and nonpharmacologic symptomatic treatments. 

Painful Diabetic Neuropathy: Treatment Is Available

With the recent development ofsuch drugs as insulin analogues,insulin glargine (Lantus),insulin detemir (Levemir), exenatide(Byetta), and pramlintide acetate (Symlin),this is truly a new era for treating diabetes.The development of another newclass of drugs, the peroxisome proliferator-activated receptor (PPAR) alpha/gamma agonists, confirms that this newera is not about to end anytime soon.This class, if approved, will target not onlyglycemic control, but also one of thecomorbidities that often plagues personswith type 2 diabetes—dyslipidemia. Withmore than 20 million patients with diabetesin the United States alone, newtreatment modalities are a welcomeaddition to the current strategies formanaging this disease.

Two PPAR agonists that are currentlyavailable, rosiglitazone and pioglitazone(glitazones), are PPAR gamma agoniststhat primarily affect glucose levels. PPARgamma is known to be important in theregulation of glucose. The glitazoneslead to insulin sensitization through thebinding to and activation of PPARgamma. Whereas the main effect of theglitazones is glucose lowering, somerecent small studies demonstrate thatpioglitazone also may have a favorableeffect in reducing small, dense low-densitylipoprotein (LDL) particles and raisinghigh-density lipoprotein (HDL) levels.A second PPAR isotype, PPAR alpha,has been recognized as one that regulatesdifferent target genes, most ofwhich are involved in lipid metabolism.PPAR alpha is expressed primarily in theliver and skeletal muscle.

The new class of medications, PPARdual agonists, activates both PPARalpha and PPAR gamma and may leadto a combination effect on insulin sensitizationplus lipid lowering by increasingfatty acid oxidation. Muraglitazar isthe first dual PPAR agonist to be consideredfor approval by the FDA. Earlyresults from a 2-year phase 3 studylook very promising.

The initial trial included 985 patientsrandomized to 1 of 4 different doses ofmuraglitazar (0.5-20 mg) or to pioglitazone15 mg daily. An extension studyincluded 88 type 2 diabetes patients whocontinued on muraglitazar 5 mg daily.These patients achieved an averagehemoglobin A1C level of 6.5% within 4months after beginning the drug andmaintained that level of control throughoutthe 2 years. Lipid results in that groupincluded an average triglyceride reductionof 28.4% and an average HDLincrease of 19.2%. No significant effectson LDL concentrations were seen.

The most common forms of dyslipidemiapresent in patients with type 2 diabetesare elevated triglycerides anddecreased HDL. Although these levelsare just markers, it is well understoodfrom multiple studies that dyslipidemiamust be managed in patients with diabetesin order to reduce the risk of cardiovasculardisease.

On other secondary end points,muraglitazar was associated with significantreductions from baseline in fastingplasma glucose, fasting plasma insulin,apolipoprotein B, free fatty acid, and non-HDL cholesterol levels. Muraglitazartreatment also was associated withincreased insulin sensitivity, as measuredby a decrease in homeostasis modelassessment of insulin resistance.

Adverse effects with muraglitazar aresimilar to those with PPAR gamma agonists.They include weight gain (2-4 kg),peripheral edema (10% incidence), andchronic heart failure exacerbation. Amajor concern is that an increased incidenceof adverse cardiovascular events(myocardial infarction, stroke, transientischemic attack) has been observed, andmore safety studies need to be conductedto analyze the potential cardiovascularrisks of this drug. No cases of hypoglycemiahave been observed. Hepatotoxicity,a concern with the PPARgamma agonists, thus far has not beenobserved.

Many patients with diabetes willrequire lipid-lowering therapy along withtheir medications for blood glucose control.The current drug therapies availablefor the treatment of dyslipidemia include3-hydroxy-3-methylglutaryl coenzyme Areductase inhibitors (statins), fibrates,niacin, bile acid resins, and cholesterolabsorption inhibitors. Although, if approved,the PPAR dual agonists are notlikely to replace current therapies available,they certainly will provide a newtreatment option for the multiple facetsof diabetes management. 

New Drug Class to Target Glucose and Lipids

Patients with diabetes, as well as other people withchronic diseases, commonly experience long-termstress or depression. It often is a direct result of the diseaseitself, because of all the emotional ups and downspatients experience during chronic management. For example,patients with diabetes often worry about lasting complicationsof the disease, how to manage the cost of the disease,and how it will affect their families or their jobs.

As many as 1 in every 3 persons with diabetes suffers fromdepression. The disease itself can be overwhelming andoften leaves a patient wondering, "Why me?" Identifyingthese patients and helping them with tips to manage stressand depression effectively can have a positive impact, notonly on their emotional well-being, but on their long-termclinical outcomes as well.

Sources of stress can be physical or mental. Examples ofphysical stresses include infections, trauma, injuries, or sickness.Mental stresses include relationship difficulties, financialconcerns, and pressure from a stressful job. Physiologically,the body responds to stressors by secreting the counter-regulatoryhormones such as epinephrine, cortisol, and glucagon.These hormones, although helpful in some circumstances,certainly can add to the complications of a diabetic patient.Their effects include increased heart rate, blood pressure,and glucose levels.

Stress and depression also can affect patients' control oftheir diabetes in indirect ways. For example, these patientsmay have a lack of concern for taking care of themselves.They often do not sleep well, or they sleep too much and arenot as attentive to their basic daily needs as they should be.They also often are unconcerned about daily diabetic requirements,such as eating properly, taking the proper medications,or performing regular self-monitoring of blood glucose.

For pharmacists, recognizing the signs and symptoms ofdepression can be the first step in assisting these patients tofind help. Pharmacists can generate conversations that identifypatients' specific issues: Are they losing interest in theirusual activities? Are they experiencing any changes inweight? Are they having trouble sleeping?

Most patients will not seek help or make direct statements,such as "I'm feeling very down and depressed." Yet,paying attention to their usual habits and personalities andnoticing any changes can be the first step. For example, thepharmacist should notice when a patient who has not beenknown to seek medications for insomnia is asking about thebest OTC product to help him or her sleep. The pharmacistalso should take note of a patient recently diagnosed withdiabetes who is asking about alternative therapies to helphim or her feel better or have more energy.

One of the simplest yet most effective interventions is tohelp these patients understand that what they are experiencingis normal and that successful treatments are available.Depression and stress can be treated effectively with psychotherapy(counseling) and/or medication therapy. Most ofthe time, health insurance plans will cover counseling fordiabetes-related depression. For patients without insurance,there may be local health clinics that will offer counselingservices at a reduced fee or on sliding-scale payment options.Local diabetes education centers also traditionally have supportpersonnel to assist with patient counseling. Counselorsoften can teach patients various relaxation techniques.

Patients who lack the basic information or skills needed tomanage their disease will feel more stressed or depressed, simplybecause they feel overwhelmed. Support from family andfriends is important, but sometimes the support of otherpatients experiencing the same illness or problems can bemore therapeutic for a patient. Many communities have wellnesscenters that offer diabetes support groups. For patients tofeel that they are not alone and to be able to express the fearsand difficulties, as well as successes, associated with their diseasecan have a positive impact on their mental and physicalwell-being. Diabetes centers also generally offer group or individualeducation classes.

For patients who are medically cleared by their physician,suggesting a regular exercise regimen can be helpful, notonly for long-term stress management, but also for improvingglycemic and cardiovascular outcomes. Patients shouldbe encouraged to start a physical activity program slowly. 

Dr. Brian is a clinical specialist with Cornerstone Health Care, High

For a list of suggested reading, send a stamped,

self-addressed envelope to: References Department,

Attn. A. Stahl, Pharmacy Times, 241 Forsgate Drive,