Case Studies In Painful Diabetic Neuropathy

   Approximately 800,000 new cases of diabetes mellitus are diagnosed each year. The disease affects over 18 million people, approximately 6 percent of the population of the United States.1 Type 2 diabetes, which is typically not diagnosed in patients under age 45, is overwhelmingly the most prevalent of all types of diabetes as it affects nearly 17 million Americans.1 Symptoms of Type 2 diabetes are often not detected until they are severe or until patients seek treatment for related complications.2 Diabetes complications can result in blindness, end-stage renal disease, stroke, heart disease and neuropathy.2

   Diabetic peripheral neuropathy (DPN) is the most common and debilitating complication of diabetes mellitus. It affects up to 62 percent of Americans with diabetes and is one of the most commonly encountered neuropathic pain syndromes in clinical practice.3 According to both the American Diabetes Association and the National Institute of Diabetes and Digestive and Kidney Disease (NIDDK), about 60 to 70 percent of the 18.2 million Americans with diabetes will develop some form of diabetic neuropathy and about 3 million people with diabetes will experience painful neuropathy.

   Diabetic neuropathy has three broad types of manifestations: sensory, motor and autonomic. The most prevalent form is somatic or sensorimotor neuropathy, which is often simply referred to as diabetic neuropathy. Symptoms often exhibit a distal symmetric pattern, beginning distally at the base of the toes and ascending proximally up the lower leg as the disease progresses. These symptoms are often described as burning, tingling, stabbing and a pins-and-needles sensation in a stocking and glove distribution. Patients may also display muscle weakness, incoordination and ataxia. 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.

   Despite being the focus of current research, the sequence of physiological events that result in this debilitating condition is poorly understood. The pathogenesis of DPN is believed to be multifactorial with hyperglycemia being the primary risk factor.4,5 Suggested theories that postulate the etiopathogeny of diabetic neuropathy include abnormalities of protein glycation, sorbitol accumulation, polyol pathway flux, protein kinase C activation, advanced glycation endproducts (AGE), receptor for advanced glycation endproducts (RAGE), a decrease in neuronal nitric oxide synthase (nNOS) protein, and microvascular hypoxia, resulting in oxidative stress.5-11

   Diabetic peripheral neuropathy is a significant public health issue that is often associated with negative physical, psychological and social sequelae.12,13 Pain perception and interpretation is further complicated by cognitive, cultural and environmental interaction on the quality of patient life.14 The association between neuropathic pain and decreased quality of life (QoL) in people with DPN is well documented.15,16

   In one study, patients with painful DPN reported greater sleep interference in comparison with the general U.S. population, and significant impairment in both physical and mental functioning compared to diabetic people without neuropathy.17 Researchers have shown that painful diabetic neuropathy (>or=4 on 0-10 scales) not only interferes with activities of daily living (ADLs) but substantially affects patients’ moods and their enjoyment of life.17,18 Patients reported moderate ADL interference despite 91 percent of them using prescription medications for painful DPN.18 Moreover, 43 percent of the patients in this study reported concurrent use of prescription medication for anxiety, depression or sleep disturbance while disruption in employment was reported by 35 percent of the patients.18

Understanding The Current Pharmacologic Armamentarium For DPN

   Currently, there are no pharmacologic agents available in the United States to repair the underlying nerve damage of diabetic peripheral neuropathy. While current medical treatment algorithms stress the importance of delaying the onset of diabetic neuropathy, treatment is primarily geared toward alleviating the symptoms. Clinicians have traditionally utilized a variety of agents from diverse pharmacologic
classes, the so-called adjuvant analgesics, to help treat painful DPN.19

   Pharmacologic options are, however, largely limited to drugs approved for other conditions. These drugs include tricyclic antidepressants, antiarrhythmics, antiepileptics, first- and second-generation anticonvulsants, topical agents, N-methyl-d-aspartate receptor antagonists, and opiate analgesics. Unfortunately, few patients obtain complete symptomatic relief from these medications.19-21

   Based on current understandings of the pathophysiology of painful DPN, researchers and industry have focused on the development of drugs that interrupt distinct activities involved in the perpetuation of pain.22 Some potential agents such as N-methyl-D-aspartate and AMPA/kainate antagonists are currently in phase 2 and phase 3 clinical trials.22 However, several newer and available agents show promise to help alleviate chronic pain. Accordingly, let us take a closer look at case studies involving the use of current, emerging diabetic neuropathy treatments.

Case Study: When A Sedentary Senior Notices Burning And Tingling In The Feet And Hands

   The patient is a slightly overweight, sedentary 68-year-old male with a 15-year history of impaired glucose tolerance. He quit smoking 16 years ago and denies the use of alcohol. The patient retired from a sales job three years ago. Other medical problems include hypertension and hypercholesterolemia, which are treated with an angiotensin-converting enzyme inhibitor and a statin respectively. The patient has no known drug allergies. His glucose intolerance was discovered with routine laboratory testing. He was referred for diabetes education, learned home glucose monitoring, and followed a diet and exercise program suggested by the diabetes educator.

   Approximately four months ago, this patient noticed a burning and tingling in his hands and feet. The patient also felt that his sense of balance was diminished but thought it was merely a sign of aging and was reluctant to see a doctor. He denied fever, chills, nausea, vomiting, chest pain or shortness of breath. The patient also had no cough, vertigo or orthostatic hypotension.

   His physical examination was unremarkable except for some hyperesthesia of both hands and feet as well as decreased vibratory sensation. The patient had no open lesions on either foot and had intact protective sensation for both feet. Reflexes were normal and pedal pulses were palpable. We noted a slight ataxia. The patient had no clinical signs of depression.

   Laboratory studies revealed normal chemistries except for a fasting blood glucose of 136 mg/dl. His HbA1c was 7.6% (normal is 4.0 to 6.0%), up from 7.1% six months earlier. A complete blood count, lipid panel, liver screening and a renal profile were all normal as was a prostate-specific antigen (PSA) test. We also noted the patient’s serum levels of B12, T3, T4 thyroid stimulating hormone (TSH) were within normal limits.

   The patient was sent for diabetic education, where he was taught that rigid glycemic control is fundamentally important to help slow the progression of DPN.1 The patient was also instructed that maintaining his hemoglobin A1c readings at 7.0 or below is ideal. We also started the patient on duloxetine (Cymbalta, Eli Lilly) 60 mg once daily. The patient reported that his burning and tingling sensation started going away after taking the medication for only two days. He has been taking duloxetine for almost four months now and reports no side effects from taking the medications. The patient states the medication helped reduce the uncomfortable sensations down to about 10 percent of the original presenting pain. He is very happy that his wife urged him to seek medical attention for what he thought was normal signs of aging. The patient also better understands the importance of maintaining proper blood glucose levels.

Diagnostic Discussion Points

   Diabetic peripheral neuropathy is purely a clinical diagnosis but one would arrive at this diagnosis only after a careful clinical exam that excludes non-diabetic causes. Other forms of neuropathy, including chronic inflammatory demyelinating polyneuropathy (CIDP), B12 deficiency, hypothyroidism and uremia, occur more frequently in people with diabetes and clinicians should rule these out.2

   Further, all patients with diabetes should be screened annually for DPN. Accordingly, clinicians should examine sharp/dull sensation, temperature, vibration perception (using a 128-Hz tuning fork), 10-g monofilament pressure sensation at the distal halluces, and ankle reflexes.2 Combinations of more than one test have greater than 87 percent sensitivity in detecting DPN and longitudinal studies have shown that a simple clinical examination is a good predictor of future foot ulcer risk.23

What The Research Reveals About Duloxetine

   Duloxetine hydrochloride is a balanced and potent selective serotonin and norepinephrine reuptake inhibitor (SNRI) for the treatment of major depressive disorder, pain associated with diabetic peripheral neuropathy, and female stress urinary incontinence.24,25 Although it is not currently approved for all indications in all countries, duloxetine is one of two drugs currently approved by the Food and Drug Administration (FDA) for the management of neuropathic pain secondary to diabetes.25,26

   Selective serotonin and norepinephrine reuptake inhibitors represent a class of antidepressant agents that help regulate and treat depressive emotions and neuropathic pain by sustaining balanced levels of the two neurotransmitters serotonin and norepinephrine. Serotonin and norepinephrine are implicated in modulating descending inhibitory pain pathways in the central nervous system, and are known to help regulate emotions as well as sensitivity to pain.27 Clinical evidence suggests that dual acting agents may better modulate pain than those agents that increase serotonin or noradrenaline alone.28

   Duloxetine is safe and generally well tolerated with few reported serious side effects.25 The adverse effects of duloxetine are similar to those of traditional SNRIs. Nausea is common and has been cited as the primary reason for discontinuation of duloxetine in clinical trials.24 Researchers have noted mild increases in blood pressure so clinicians should exercise caution when considering this drug for patients with hypertension. Patients with a creatinine clearance of less than 30 mL/min and patients with hepatic impairment should avoid duloxetine.24 As with other SNRIs, duloxetine is contraindicated in patients taking nonselective, irreversible monoamine oxidase inhibitors, CYP 1A2 inhibitors or thioridazine, and in patients with hepatic insufficiency, end-stage renal disease or uncontrolled narrow angle glaucoma.25

   Absorption of duloxetine begins about two hours after oral administration and reaches maximum plasma concentration in about six hours.24 With a half life of about 12 hours, duloxetine is eliminated primarily in the urine after extensive hepatic metabolism by multiple oxidative pathways, methylation and conjugation.25

   In September 2004, duloxetine became the first medication approved by the FDA for the treatment of DPN.29 In a double-blinded, placebo-controlled study, researchers showed that a 60 mg daily dose of duloxetine was effective and well tolerated. Furthermore, they noted a rapid onset and sustained effect in reducing pain associated with diabetic neuropathy.29 The maximum dose approved for marketing is 120 mg per day (administered 60 mg twice daily) but the recommended dosage of duloxetine is 40 to 80 mg daily, depending on the indication, and preferably split into two doses per day.24,25

   A 12-week, multicenter, double-blind study found duloxetine to be safe and efficacious in the management of diabetic peripheral neuropathic pain. In this study, researchers randomized 457 patients with symptomatic diabetic neuropathy into one of four treatment arms to receive duloxetine 20 mg QD, 60 mg QD, 60 mg BID or a placebo.30 Duloxetine at 60 and 120 mg per day doses demonstrated statistically significant improvement in comparison to the placebo on the average pain score. This improvement was noted one week after randomization and continued through the 12-week trial.30 Duloxetine was noted to be safe and well tolerated with less than 20 percent discontinuation due to adverse events.30

   Similarly, in a multicenter, double-blind, randomized, placebo-controlled trial that enrolled 348 patients with DPN, patients were randomized to either receive duloxetine 60 mg once daily, duloxetine 60 mg twice daily or a placebo for 12 weeks.31 Both duloxetine-treated groups improved significantly more on the 24-hour average pain score in comparison to patients in the placebo group.31 However, discontinuations due to adverse events were more frequent with the duloxetine 60 mg BID group (12.1 percent) versus the placebo-treated group (2.6 percent).31 Duloxetine showed no adverse effects on the diabetic control and researchers noted that both duloxetine 60 mg QD and duloxetine 60 mg BID were safely administered and well tolerated.31

Case Study: When A Patient On Multiple Medications Seeks An Alternate Remedy

   A 56-year-old male patient was diagnosed with Type 2 diabetes at the age of 30 and has been insulin-dependent for the last five years. The medical history of the sedentary accountant includes congestive heart failure, hypertension, peripheral arterial disease of bilateral lower extremity, DPN, diabetic foot ulcers, Charcot foot deformity, a partial fifth ray amputation, and a kidney transplant from a non-matched donor.

   The patient takes 18 different medications including two different immunosuppressive medications and prednisone because of his kidney transplant. He is also taking an angiotensin-converting enzyme inhibitor for hypertension. The patient has no known drug allergies and denies the use of alcohol and tobacco.

   The patient stated his foot has been asleep for the past 10 years. However, within the past three months, he has felt persistent pain to both feet and has had to take Tylenol #3 to help alleviate the pain. The patient denied fever, chills, nausea, vomiting, chest pain, shortness of breath or changes to his medication. He also denies any other new symptoms. The patient also denied resting tachycardia, orthostatic lightheadedness, early satiety, early morning nausea, changes in bowel habits or postprandial sweating.

   The patient’s glycemic control had never been optimal despite medications and a multiple-dose insulin program. His hemoglobin A1C levels have typically been in the 8 to 9 percent range.

   The physical exam findings remain unchanged from his last visit. The exam revealed a moderately overweight (BMI 30 kg/m2) man with a blood pressure of 131/85 mmHg with no orthostatic change and a resting pulse of 72 with no change with Valsalva maneuver. A lower extremity exam showed decreased position sense as well as absent sensation to 10 g monofilament testing. Laboratory testing revealed an A1c of 8.2% (normal <6.5%); an albumin-to-creatinine ratio of 28 µg/mg (normal <30 µg/mg); normal serum creatinine, a complete blood count, total protein, normal sedimentation rate and thyroid stimulating hormone.

   We recommended pregabalin (Lyrica, Pfizer) as a possible agent for treating his neuropathy because of the drug’s lack of serious toxicity and drug interactions. However, the patient was reluctant to take yet another oral medication. He was hoping for topical alternatives so we utilized a 5% lidocaine patch (Lidoderm, Endo Pharmaceuticals). After using the 5% lidocaine patch twice daily for five weeks, the patient states the patch alleviates 80 percent of his pain and discomfort. He is happy that he does not have to take another pill.

A Closer Look At Pregabalin

   Initially developed in 1992, pregabalin is the next generation drug in the same class as gabapentin (Neurotin, Pfizer). Although pregabalin has a similar pharmacologic profile to that of its developmental predecessor, it has demonstrated greater analgesic activity in rodent models of neuropathic pain. Pregabalin is FDA-approved for the management of DPN and postherpetic neuralgia, a complication of shingles. Pregabalin, a schedule V drug, is the first FDA-approved pharmacologic agent for both of these neuropathic pain states.32

   Although pregabalin has a similar pharmacological profile to that of its developmental predecessor, it also demonstrates analgesic, anxiolytic as well as anticonvulsant activity. As with gabapentin, the exact mechanism of action of pregabalin is unclear although researchers have postulated that it binds with high affinity to the alpha 2-delta subunit protein of voltage-gated calcium channels to subsequently reduce the release of excitatory neurotransmitters.33

   Peak plasma levels occur approximately one hour after oral administration. Food does not significantly affect the extent of absorption and the oral bioavailability of pregabalin is about 90 percent.34 Pregabalin has a linear pharmacokinetic profile. It is completely absorbed and is not protein-bound. Pregabalin exhibits a plasma half-life of about six hours, which is not dose-dependent.34 Hepatic metabolism is negligible and most of the oral dose (95 percent) is eliminated unchanged through the kidneys.33,34 However, clinicians must adjust doses in patients with renal insufficiency and, as with gabapentin, one should not discontinue pregabalin rapidly.33

   Researchers have shown the efficacy of pregabalin in treating painful diabetic neuropathy in three randomized, double-blind, multicenter studies with a total of 724 patients.35-37 They found that administering pregabalin at total fixed dosages of 300 and 600 mg per day (with patients taking the medication three times a day) demonstrated rapid and sustained improvement in pain with less pain-related sleep interference.35-37 Study authors noted significant improvements in pain and sleep as early as week one and these improvements were maintained in studies of up to 12 weeks in duration.35,37 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.

   Researchers have consistently demonstrated the efficacy, tolerability and safety of pregabalin in the treatment of DPN in several randomized, double-blind, multi-center, placebo-controlled studies.38-40

   A recently published six-week, randomized, double-blind, multicenter study found pregabalin to be efficacious and safe in the treatment of painful diabetic neuropathy.39 This study involved 264 patients with painful diabetic neuropathy who received pregabalin (150 mg or 600 mg per day by mouth) or placebo. The researchers noted that pregabalin at a dose of 600 mg per day significantly decreased the mean pain score and pain intensity, and significantly reduced sleep interference.39 They found that pregabalin at a dose of 150 mg per day was no different from placebo. The most common side effects were dizziness and somnolence.39,40 According to one study, withdrawal due to adverse events was more frequent with pregabalin than with the placebo.40

   Rosenstock, et. al., evaluated the effectiveness of pregabalin 300 mg/day in alleviating pain associated with DPN in 146 patients in an eight-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial.36 In comparison to the placebo, pregabalin produced significant improvements in pain reduction, reduced sleep interference and reduced mood disturbance.36 The authors concluded that pregabalin was safe and effective in decreasing pain associated with DPN with improved mood, less sleep disturbance and an improved quality of life.

   Pregabalin appears to be a safe and well-tolerated new treatment for neuropathic pain. Furthermore, pregabalin has proven efficacy in adjunctive therapy of refractory partial seizures and in the treatment of acute pain, generalized anxiety disorder and social phobia.34

Is The Topical Lidocaine Patch A Viable Alternative?

   The topical lidocaine patch is FDA approved for the treatment of postherpetic neuralgia but may serve an alternative treatment for DPN.

   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.41-43 The maximum application in this study was four patches daily for up to 18 hours.41 The therapy was well tolerated with minimal adverse events and no systemic accumulation of lidocaine.43

   In a similar prospective open-label, flexible dosing study, 20 patients with a diagnosis of idiopathic distal sensory polyneuropathy received a 5% lidocaine patch for a maximum of four patches daily for 18 hours.44 Over a three-week treatment period, all patients showed significant improvements in pain and quality of life outcome measures. A subgroup of patients maintained these improvements for an additional five weeks. Use of the patch also permitted tapering of concomitant analgesics in 25 percent of the patients in the study.44

   The 5% lidocaine patch appears to be well tolerated and potentially effective in the management of painful neuropathy.44 Future randomized controlled trials will be necessary to confirm these results.

Final Notes

   Our knowledge regarding the pathogenesis of diabetic neuropathy has grown significantly during last two decades. Nonetheless, identifying effective treatment regimens remains challenging. Prevention remains the foundation of clinical intervention and the prerequisite of adequate treatment. With advances in technology and ongoing research, we hope to one day elucidate the ideal treatment of this debilitating disease process.

   Neuropathic pain is not a single entity but manifests as several different clinical syndromes and is associated with increased morbidity. The magnitude of the problem and its economic impact make it extremely important to understand the natural history of neuropathic pain and identify more successful preventive and therapeutic options. Further advances in the understanding of pain mechanisms at multiple levels should facilitate the emergence of better treatment modalities with less prominent side effects.19

Dr. Wu is the American Podiatric Medical Association/American Diabetes Association Senior Fellow at the Center for Lower Extremity Ambulatory Research (CLEAR) at the William M. Scholl College of Podiatric Medicine at Rosalind Franklin University of Medicine and Science in Chicago.

Editor’s Note: For related articles, see “Current And Emerging Treatment Options For Diabetic Neuropathy” in the March 2005 issue, “How To Diagnose Diabetic Peripheral Neuropathy” in the March 2006 issue, and “Expert Insights On Painful Diabetic Neuropathy” in the March 2003 issue.

Also be sure to check out the archives at www.podiatrytoday.com.

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